DRUGS OF TODAY Vol. 31, No. 7, 1995, pp. 463-498
LOSARTAN POTASSIUM (COZAAR™): A NONPEPTIDE
ANTAGONIST OF ANGIOTENSIN II
R.D. Smith, C.S. Sweet, A. Goldberg and P.B.M.W.M. Timmermans
DuPont Merck Research Laboratories, Experimental Station, P.O. Box 80400, Wilmington, Delaware
19880-0400, and Merck & Co., Inc., 10 Century Parkway, Blue Bell, Pennsylvania 19422, USA
CONTENTS
Introduction .............................................................................................
Discovery of Losartan ...........................................................................
Chemical strategy ................................................................................
Biological strategy................................................................................
Preclinical Pharmacology ........................................................................
Blockade of the physiological effects of angiotensin II ..........................
Active metabolite (EXP-3174) ..............................................................
Selectivity for the AT1 receptor subtype ..............................................
Antihypertensive and antihypertrophic activity in experimental
models of hypertension ...................................................................
Angiotensin II as a growth factor acting via the AT1 receptor subtype ..
Activity in models of cardiovascular disease ......................................
AT1 receptor antagonism in experimental models of heart failure...........
Commentary . ......................................................................................
Clinical Experience with Losartan and Other AT1 -Selective Antagonists
Clinical trials in normal subjects ...........................................................
Clinical trials in salt-depleted volunteers ..............................................
Uricosuric effect ................................................................................
Antihypertensive effects .......................................................................
Antihypertensive effects of EXP-3174..................................................
Antiproteinuric effects in nondiabetic hypertensives ............................
Concomitant administration with hydrochlorothiazide ...........................
Safety and tolerability ...........................................................................
Clinical trials in patients with heart failure .............................................
Conclusions .............................................................................................
References .............................................................................................
Introduction
The discovery of losartan represents the culmination of an extensive search for an agent that
would specifically block the pathological effects of
angiotensin II (Ang II) at its receptor (1 -3). The rationale for this search was based on the role of Ang II in
463
465
465
466
467
467
468
469
470
471
471
474
475
475
475
478
479
479
480
480
480
480
481
482
484
the control of arterial blood pressure, the pathological role of Ang II in cardiovascular disease, and the
therapeutic effectiveness of nonselective inhibitors
of the renin-angiotensin system (RAS). Losartan is
the first orally active, nonpeptide, long-acting and
specific inhibitor of the RAS and represents: 1) a
MEDICAMENTOS DE ACTUALIDAD
464
Fig. 1. The angiotensin system. (Reproduced with permission from Timmermans et al. Angiotensin II receptors
and angiotensin II receptor antagonists. Pharmacol Rev
1993, 45(2):205-251.)
potentially important new therapeutic agent, 2) a
powerful experimental tool for exploring the biological and pathological effects of Ang II, and 3) a prototype molecule for continued drug discovery. Losartan has already broadly stimulated interest in Ang II
research and has been instrumental in the definition
of Ang II receptor heterogeneity, the cloning of multiple Ang II receptors and subtypes, and in generating
significant new insights into the biology of Ang II and
how it interacts with its specific receptors. Presently,
there are over 2000 publications describing the preclinical and early clinical experience with losartan
(for reviews, see 4, 5).
Angiotensin II is the primary mediator of the RAS
and is involved in blood pressure control at the cellular, tissue and organ integration levels (5-7). Angiotensin II is an octapeptide that acts both as a circulating hormone and as a locally released and active
"paracrine" agent (Fig. 1). Historically, the focus of
RAS research and clinical discussion has been
"renin" because methods were available to measure
plasma renin activity (PRA) and it was not possible
to routinely measure Ang II levels. The renin-sodium
profile has even been identified as a risk factor for
myocardial infarction in patients with hypertension
(8). it is Ang II, however, that is the risk factor for and
mediator of the cardiovascular pathology.
Our current understanding of the pathological
role of Ang II has evolved over a long period of time
beginning with the clinical postulate by Bright, in
1836, that there was an association between renal
disease and hypertension (Table I). The Goldblatt
experiments (9) and the identification of the pressor
hormone angiotensin were critical elements in the
development of our current understanding. The synthesis of the pure peptide Ang II led to the investigation of the acute effects of angiotensin (vasoconstriction, aldosterone release) and the synthesis of
peptide analogs of Ang II with varying degrees of
agonist (Ang ll-like effects) and antagonist effects
(18-20). One such peptide Ang II antagonist, saralasin, was evaluated in hypertensive patients and was
shown to significantly lower blood pressure in
patients with high PRA (21). This was the first important evidence that blocking Ang II resulted in antihypertensive effects in patients with essential hypertension. The peptide nature of saralasin meant that
it was short-acting and had to be administered by
constant infusion. Furthermore, as a close analog of
Ang II, it retained significant partial agonist activity
(22). It was evident early in clinical trials that saralasin significantly increased blood pressure in a significant proportion of low-renin patients (22), and was
thus not suitable for general medical use.
Our current understanding of the importance of
the RAS in hypertension has also evolved from
experience with other inhibitors such as -adrenoceptor antagonists, which have been shown to
Table I: Discovery of angiotensin II.
"Highlight"
Reference
• Postulated association between renal
disease and hypertension, 1836
10
• Demonstrated pressor substance in
renal extracts, 1898
11
• Renal artery constriction produced
hypertension in dogs, 1934
9
• Independently showed that renin acted
on plasma substrate to produce pressor
hormone,1940
12,13
• "Hypertension" peptide isolated, 1956
14
• Angiotensin II formed by action of converting enzyme, 1956
15
• Independently synthesized the octapeptide "Ang II", 1957
Ang II = angiotensin II.
16,17
DRUGS OF TODAY VOL. 31,NO.7, 1995
inhibit renin release and are widely used antihypertensive agents (23). Since these agents have other
pharmacological actions, the importance of this
property of -biockers has been controversial (24,
25). However, some clinical studies have shown that
the blood pressure-lowering effects of these agents
are correlated to the pretreatment PRA (the higher
the PRA, the greaterthe response), supporting a role
for renin (Ang II) in hypertension (26).
The most significant advance in the understanding of the role of Ang II in cardiovascular disease
came with the development of inhibitors of Ang lI
synthesis (for reviews, see 27-29). Angiotensin II is
synthesized in a sequential fashion starting from
angiotensinogen (30). The proteolytic enzyme renin
(primarily from the kidney juxtagiomerular cells)
cleaves the terminal 10-amino acid sequence to
form the biologically inactive peptide Ang I. The proteolytic enzyme (located primarily on endothelial
cells) angiotensin-converting enzyme (ACE) then
cleaves Arg-Arg from the C-terminal of Ang I to form
the mediator of the system Ang II. Since renin is ratelimiting for Ang II synthesis from angiotensinogen,
renin inhibition was an early target for inhibiting the
"angiotensin II system". Renin inhibitors modeled
after pepstatin, and later after the active site of the
renin enzyme, have been developed. These compounds are active in vitro and inhibit the RAS in
experimental animals (for reviews, see 31-33).
Although the oral efficacy of renin inhibitors has not
been established, their effectiveness in lowering
blood pressure supports the role of Ang II in the
maintenance of blood pressure in hypertension.
Blocking Ang II synthesis by inhibiting ACE has
provided the strongest evidence that Ang II plays a
role in cardiovascular disease. The efficacy of ACE
inhibitors in the treatment of hypertension is now well
established (27, 29, 34). Importantly, these compounds have been shown to decrease mortality in
patients with congestive heart failure and have
become a standard therapy for these patients (28,
35). In addition, the renal protective effects of ACE
inhibitors in hypertensive patients with diabetes has
been demonstrated, and it is therefore likely that
inhibitors of Ang II synthesis will be protective in
other forms of renal disease (36, 37).
ACE inhibitors are, however, nonspecific inhibitors of Ang Il synthesis. ACE is also known as kininase II, and is thus responsible both for the synthesis
of Ang II and for the catabolism and inactivation of
the vasoactive peptide bradykinin. Bradykinin is a
powerful vasodilating, analgesic and proinflammatory agent (38). Unlike renin, which is substrate-specific, ACE has several natural substrates, including
enkephalin and substance P. The most widely studied nonspecific effect of ACE inhibitors has been
465
their effect on bradykinin (39). It remains controversial how important bradykinin potentiation is to the
beneficial effects of ACE inhibitors in, e.g., regression of cardiac hypertrophy in coarctation hypertension in rats, pro (40), con (41), the vascular response
to bailooon injury, pro (42), con (43, 44), or reduction
in infarct size, pro (45), con (46). It is clear, however,
that ACE inhibitors are not selective inhibitors and
block Ang II synthesis while increasing tissue levels
of bradykinin (47). Since the maximum blood pressure reductions with Ang II receptor blockade and
ACE inhibition are comparable (48) and infusion of
a bradykinin antagonist (Hoe-140) at the peak of
antihypertensive response had no effect on losartan
and little effect on the responses to the ACE inhibitors (49), it is likely that most of the blood pressurelowering effects of both classes of agents are due to
blockade of Ang II or interruption of Ang II formation,
respectively. Whether bradykinin exerts other beneficial effects remains largely speculative, but the
undesirable effects of bradykinin have been extensively studied (38, 50). Bradykinin, when applied to
isolated guinea pig tracheal preparations, stimulates
C-fiber firing rate (38, 51), and thus may be implicated in the cough observed in some patients treated
with ACE inhibitors (38).
The collective clinical efficacy of inhibitors of the
RAS provides strong evidence that Ang II is involved
both in the maintenance of blood pressure and in the
expression of the pathological changes that accompany hypertension in the heart and kidney, and possibly in other organ systems. Since it is known that
Ang II elicits its biological effects by binding to specific sites on the effector organs (vascular smooth
muscle, adrenal, kidneys) (6, 52), the most effective
and specific way to block the effects of Ang II is to
block the receptor site. Furthermore, Ang II can be
synthesized from angiotensinogen by nonrenin
pathways (e.g., tonin, chymotrypsin-like angiotensin-generating enzyme, tissue plasminogen activator) (53) or from Ang I by non-ACE or alternative
pathways (e.g., chymase) (54). Receptor blockade
may provide a more complete inhibition of the
actions of Ang II than is possible by inhibiting ACE or
renin. Based on this understanding of the "angiotensin system" and its role in cardiovascular disease, a
new drug discovery program was undertaken to find
a nonpeptide Ang II receptor antagonist (1-3).
Discovery of Losartan
Chemical strategy
The medicinal chemistry that led to the discovery
of losartan began with a focus on peptide analogs of
Ang II, but was soon replaced by exploration of a
466
MEDICAMENTOS DE ACTUALIDAD
Fig. 2. Chemical structures of some nonpeptide Ang II receptor antagonists illustrating the structural modifications of the
initial lead compounds, S-8307 and S-8308, to EXP-7711, a more potent and orally active antagonist, through the key intermediates, EXP-6155 and EXP-6803. (Reproduced with permission from Timmermans et al. The discovery of a new class
of highly specific nonpeptide angiotensin II receptor antagonists. Amer J Hypertension 1991, 4 (4, Pt. 2): 275S-281S.
series of nonpeptide molecules described in patent
literature as Ang II antagonists. These compounds,
were described as hypotensive imidazole or hypotensive imidazole-5-acetic acid derivatives, and
although no biological data were provided, they were
reported to have Ang ll-antagonist effects (55).
Examples (S-8307, S-8308) were synthesized and
shown to have only very weak binding affinity for the
Ang II receptor and displayed no significant blood
pressure-lowering effects. However, they were specific and blocked the contractile response to Ang II
while having no effect on the responses to norepinephrine or potassium chloride (56). A theoretical
model was proposed whereby the carboxy imidazole
mimicked the essential binding site of the carboxyterminal portion of the natural hormone Ang II.
Chemical modifications were then focused on the
phenylmethyl portion of the lead molecules
(S-8307). The chemical strategy and the milestone
compounds have been extensively reviewed (13). In
brief, four compounds represent the extensive
chemical synthetic effort (Fig. 2). These compounds
have progressively increasing affinity for the Ang II
receptor. The penultimate compound EXP-7711 represents the first molecule with significant oral antihypertensive activity. The chemical breakthrough
came with the synthesis of the biphenyltetrazole
molecule. The biphenyltetrazole represented completely novel chemistry and imparted high affinity
and oral bioavailability to the candidate compound
DuP-753, later designated losartan (USAN: losartan
potassium). The chemical discovery of losartan has
initiated an explosion of patents involving losartan as
a molecular model and/or including the biphenyltetrazole as an important part of the lead compounds
(57,58).
Biological strategy
The discovery of losartan was based on the need
to show that a new molecule: 1) binds to the Ang II
receptor with high affinity, 2) displays high specificity
for the Ang II receptor, 3) blocks the contractile
response of vascular smooth muscle to Ang II in
vitro, 4) blocks the pressor responses to Ang II in
vivo, 5) lowers blood pressure in renin-dependent
(Ang Il-dependent) hypertension by both the intravenous (i.v.) and oral (p.o.) routes, and 6) is free of Ang
ll-like agonist properties.
Losartan was shown to have high affinity for Ang
II receptors in competitive binding assays using
membrane receptors prepared from homogenized
tissues or in fixed tissues using autoradiography.
The concentrations producing 50% inhibition (ICso)
of Ang II binding range from 5 to 30 nM for losartan.
In contrast, losartan (10 M) had no effect on other
receptor ligands and growth factors (59). In more
recent studies, inhibition of binding to thromboxane
(60) and neurokinin NK3 (61) binding sites has been
reported at concentrations of > 15 M (> 1000-fold
DRUGS OF TODAY Vol. 31, No. 7, 1995
higher concentrations than those needed to inhibit
Ang II).
Blockade of the vascular smooth muscle
response to Ang II in vitro using rabbit aortic strips
established that losartan was a functional and competitive antagonist of Ang II receptors (48). Subsequent studies with other vascular tissues have confirmed the Ang ll-antagonist effect of losartan (62,
63). PD-123177, in contrast, has no effect on the
vascular response to Ang II (48, 64). The specificity
of losartan for the Ang II receptor was shown by the
lack of effect on the contractile responses to norepinephrine or potassium chloride (48). The specificity
of losartan was also confirmed by a study in isolated
arteries and veins. In this study, the pA2 values (negative log of antagonist concentration required to
double the agonist concentration) for losartan
against Ang ll-induced contractile responses were
8.19-8.66, whereas the responses to norepinephrine, acetylcholine, bradykinin, desArg9-bradykinin, substance P, neurokinin A, neurokinin B or
bombesin were unaffected (65).
The inhibitory effect of losartan on the pressor
response to Ang II in pithed rats showed that the
blockade of Ang II receptors was also competitive in
nature in vivo. Specificity was shown by the lack of
effect on the pressor responses to vasopressin or
norepinephrine (48).
Losartan and its predecessors (Fig. 2) were initially evaluated for antihypertensive efficacy in renal
hypertensive rats with renal artery ligation.
EXP-7711 was the first compound that demonstrated significant oral antihypertensive activity
(ED30= 11 mg/kg). Losartan was chosen after demonstrating potent antihypertensive effects by both
the i.v. and p.o. routes (ED30 = 0.8 and 0.6 mg/kg,
respectively) (66).
Preclinical Pharmacology
Blockade of the physiological effects of
angiotensin II
The basic preclinical pharmacology of losartan
and other Ang II AT1-selective antagonists is outlined in Table II. Losartan blocks all of the well-known
effects of Ang II, including constriction of vascular
and nonvascular smooth muscle, aldosterona synthesis and release, drinking (in rodents), vasopressin release, feedback inhibition of renin release, and
enhancement of norepinephrine release from sympathetic nerve endings (4,5). In isolated vascular tissue, losartan is a competitive antagonist of Ang II
while having little effect on the contractile responses
to norepinephrine or potassium. The IC50 values for
losartan range from 19 to 50 nM and the pA2 values
467
Table II: Losartan preclinical pharmacology.a
• Selectivity inhibits binding of Ang II to AT1 receptors in
vitro
Vascular smooth muscle
Kidney Adrenal Heart Brain
• Selectively inhibits responses to Ang II in vitro
Vascular contraction Aldosterone synthesis/release
Norepinephrine release from sympathetic nerves
Cardiac myocyte "growth" Vascular smooth muscle
cell "growth"
• Selectively inhibits responses to Ang II in vivo
Pressor response Aldosterone release Inhibition
of renin release Cardiac/vascular hypertrophy
Vasopressin release Drinking behavior
• Lack of Ang ll-like agonist effects
Isolated vascular and cardiac cells in vitro
Normotensive and hypertensive animals in vivo
• Lowers blood pressure (blocks endogenously released
Ang II)
Renal hypertensive rats (2-kidney, 1 clip)
Spontaneously hypertensive rats
Transgenic rats [TG(REN2)27] Reduced
renal mass-induced hypertension Coldinduced hypertension Fructose dietinduced hypertension L-NAME induced
hypertension
a
See Refs. 5, 80-82.
from 8.2 to 8.7. Likewise, in vivo in pithed rats, losartan blocked the pressor response to exogenously
administered Ang II in a competitive manner, shifting
the dose-response curve to the right without altering
the maximum response. Similar Ang ll-antagonist
effects of losartan have been demonstrated in a
number of animal species, including dogs (67, 68),
guinea pigs (69), monkeys (70) and man (71),
Angiotensin II stimulates aldosterone synthesis
in isolated adrenocortical cells in vitro and the
release of aldosterone In vivo, and losartan blocks
both effects (72). In chronic studies in spontaneously
hypertensive rats (SHR) and normotensive rats,
losartan significantly reduced the plasma aldosterone levels (73, 74).
The dipsogenic effects of Ang II can be readily
demonstrated by central or peripheral administration
in rats. In the initial study, losartan administered subcutaneously (s.c.) blocked the s.c. Ang II drinking
468
response, and when administered intracerebroventricuiarly (i.c.v.), it blocked the response to i.c.v. Ang
II. Losartan given s.c. did not block the drinking
response to i.c.v. Ang II, suggesting that losartan
does not cross the blood-brain barrier (75). The
drinking responses to Ang II have been blocked by
losartan in several other species, including cows,
rabbits and sheep (76). Conflicting data have been
reported concerning the brain penetration of losartan, but in some cases inhibition of binding and functional antagonism have been demonstrated (77-79).
Angiotensin II exerts a tonic inhibitory effect on
renin release and blockade-of Ang II synthesis or of
AT1 receptors increases circulating PRA. Losartan
increases PRA in all species tested (e.g., rats, dogs,
sheep, monkeys and man) (5). Likewise, Ang II levels rise and remain elevated throughout the duration
of dosing. No development of tolerance to the antihypertensive effects of losartan has been observed,
and no untoward effects due to the elevated circulating Ang II levels have been noted either in experimental animals or man (83). The regulation of the
Ang II receptor does not seem to follow rises or falls
in Ang II levels; infusion of Ang II increases mRNA
for the AT1 receptor in adrenal but not in other tissues, whereas nephrectomy does not seem to
change receptor number or affinity (84).
Angiotensin II is involved in vasopressin release
and this effect is blocked by losartan. The vasopressin released by i.c.v. Ang II was significantly reduced
by losartan injected into the paraventricular nucleus
(85). Losartan administered i.c.v. also blocked or
reduced the vasopressin release induced by Ang II
(86-88). There is some controversy as to whether
i.c.v. PD-123319 has an effect on vasopressin
release (87, 88).
The release of norepinephrine from sympathetic
nerve endings can be modulated by Ang II and this
effect is blocked by losartan (or its active metabolite
EXP-3174) (89, 90). Sympathetic nerve stimulationinduced release of norepinephrine from isolated cardiac and vascular tissue is enhanced by Ang II and
is mediated by the AT1 receptor. It has been shown
that atrial release of norepinephrine is suppressed in
SHR and chronic treatment with losartan normalizes
this response (91). In electrically stimulated human
kidney cortical slices, Ang II produced a concentra- <
tion-related increase in radio-labeled norepinephrine
release, which was reduced by captopril and abolished by EXP-3174 (92). In vivo in renal hypertensive rats, losartan and lisinopril lowered blood pressure and increased sympathetic nerve activity less
than the nonspecific vasodilator nitroprusside (93).
The sympathetically mediated vasoconstriction of
norepinephrine was also reduced or inhibited in
other experimental preparations (94-96).
MEDICAMENTOS DE ACTUALIDAD
The principle evidence that losartan blocks the
effects of endogenously released Ang II comes from
its ability to lower blood pressure in Ang II (renin)dependerit hypertension in rats. In rats with
elevated PRA, losartan displays a dose-related
blood pressure-lowering effect both acutely and following chronic dosing (97-99). Losartan at 30 mg/kg
for 8 weeks significantly decreased blood pressure
and reduced ventricular hypertrophy in two-kidney,
one-clip renal hypertensive rats, whereas similar
treatment with the nonspecific vasodilator hydralazine did not (100). Other "high-renin" models of
hypertension such as the transgenic rat harboring
the REN-2 gene are also sensitive to the blood pressure-lowering effects of losartan (101). In contrast,
losartan has little or no effect in normotensive animals or animals such as the Dahl salt-sensitive rat in
which Ang II is suppressed (97).
Some investigations have shown that chronic
losartan treatment did have a significant blood pressure-lowering effect in normotensive animals, suggesting a role for Ang II in maintaining basal blood
pressure levels (74, 102, 103). Normotensive animals can be made sensitive to Ang II system inhibitors by sodium depletion with diuretics or a low-sodium diet. In the sodium-depleted dog, losartan
produces a dose-related decrease in blood pressure, whereas it has very little effect in the sodiumreplete dog (104). Similar findings have been found
in man (105).
Active metabolite (EXP-3174)
Losartan is active by itself, as demonstrated both
in vitro and in vivo, but in some species, including
rats and man, it is also converted to an active metabolite, designated EXP-3174 (Fig. 3). EXP-3174 is the
free carboxylic acid of losartan and displays the
same pharmacological profile (106, 107). The
metabolite is 10-40 times more potent than losartan
in isolated vascular tissue. In pithed rats, EXP-3174
produces a nonparallel shift of the Ang II dose-response curve and decreases the maximum
response, consistent with noncompetitive blockade.
Since it is possible to displace EXP-3174 binding
with excess unlabeled material (108) and pretreatment of isolated tissue with losartan converts the
"noncompetitive" blockade of EXP-3174 to competitive blockade (63), it is likely that this reflects tight
binding or slow release from the receptor. This is further supported by the finding that EXP-3174 was
washed out of the tissue more slowly than losartan
(63). Thus, in rats and man (data discussed below),
"losartan treatment" is the net effect of AT1 receptor
blockade with losartan and EXP-3174. In the dog,
and presumably in guinea pigs and sheep, little of
this metabolite is formed and losartan is rapidly
469
a
Christen et al. (112).
Fig. 3. Pharmacokinetic highlights of losartan and its active metabolite EXP-3174 in man.
cleared as the glucuronide (109-111). This means
that studies carried out in these species must use
multiple-dose regimes or drug infusions to maintain
receptor blockade.
Selectivity for the AT1 receptor subtype
The discovery of losartan and the concurrent discovery of two other series of compounds opened the
door to our current concept of Ang II receptor heterogeneity. Although the existence of multiple Ang II
receptor subtypes had been suggested by earlier
findings (for review, see 5), it was not until losartan,
PD-123177 and CGP-42112 became available that
the existence of multiple Ang II receptors was confirmed and the complexity of Ang II receptor heterogeneity was realized (113,114). The basic observation was that losartan (or related compounds)
inhibited all of the Ang II binding in receptor preparations from vascular smooth muscle, but in adrenal
cortical receptor preparations 20-30% of the receptor sites were "resistant" to blockade. PD-123177
and CGP-42112 were found to inhibit these resistant
sites and the concept of two receptor subtypes was
reported by two independent laboratories (115,116).
After a flurry of activity to subtype every species and
tissue and to apply "novel" subtype designations, a
standardized nomenclature was proposed (117).
Accordingly, the losartan-sensitive site is the AT1
subtype and the AT2 site has affinity for the
PD-123177 series of compounds and CGP-4211.2.
Recently, this nomenclature has been extended to
include the subsequently cloned rodent AT 1 subtypes and the nonmammalian receptors that do not
fit the previous definition of AT1 or AT2 (118). It
should be noted that saralasin and other peptide
analogs of Ang II are "nonselective" and have high
affinity for both Ang II binding sites. Likewise, since
renin and AGE inhibitors block the synthesis of Ang Il
and reduce the availability of Ang II to both receptor
subtypes, they are "nonselective" inhibitors.
Losartan is the prototype of an AT1-selective
antagonist, so that if losartan inhibits a response it is
by definition an AT1-mediated response (117). Virtually all of the known effects (functions) of Ang II are
AT1-mediated, e.g., vasoconstriction, aldosterone
release, drinking, inhibition of renin release, vasopressin release and enhancement of norepinephrine
(4, 5). The early findings with losartan have now
been confirmed by published studies with a number
of new nonpeptide AT1-selective antagonists (62,
119, 120). Angiotensin II interacts with specific
receptors on effector cells (e.g., smooth muscle cells
or adrenal cortical cells) and elicits a series of intracellular events that lead to the characteristic
response of that ceil (e.g., contraction or secretion).
This hormone-synthesis-receptor-response coupling has been well studied for Ang II (121). Each
functional step in this series of events is antagonized
by losartan or related AT1-selective antagonist molecules, suggesting that they are AT1 receptor subtypemediated (Table Ill). This is confirmed by the lack of
effect of PD-123177, PD-123319 or CGP-42112.
It should be noted that CGP-42112 is a peptide and
has been described as an agonist (118), but may act
as an AT2 antagonist or an AT1 antagonist at high
concentrations (122).
MEDICAMENTOS DE ACTUALIDAD
470
Table III: AT1 -selective blockade of the Ang II receptor response coupling.
Ang II "response"
Receptor binding
Antagonist
L, S
Reference
123

G-protein coupling

Second messenger

Intracellular response

Cell/tissue/organ response

Whole animal response
GTP S
-Adenylate cyclase
-  PLC
-  PLD
L (not CGP or PD)
L (not PD)
L (not CGP)
IP3 hydrolysis
Ca2+ transient
L (not CGP)
L (not PD)
124,125
72
126
127
128, 129
130
Contraction
L(notPD)
48
Secretion
Transport
Proliferation
L, S (not PD)
L (not PD)
L (not PD)
131
132
133
 Blood pressure
L (not PD)
48
  Renal function
 Drinking
L, S (not PD?)
L (not PD)
134, 135
48, 136
L = losartan; S = saralasin; CGP=CGP-42112; PD = PD-123177 or PD-123319; GTP S = guanosine thio-triphosphate;
IP3 = inositol triphosphate; PLC = phospholipase C; PLD = phospholipase D. (Reproduced with permission from Timmermanns et a/., in press.)
The role of the AT2 receptor is not well understood. PD-123177-like compounds do not lower
blood pressure or block the vasoconstrictor effects
of Ang II, so the functional role of this binding site in
hypertension or blood pressure control remains to
be determined (48,104). The AT2 receptor has been
cloned and the structure is 32-34% homologous to
the AT1 receptor. The AT2 receptor is not G-proteincoupled and it remains controversial how it is
coupled to protein tyrosine phosphatase (137, 138).
The abundance of AT2 sites in fetal and reproductive
organs such as the uterus has suggested a growth
or developmental role, but a functional response has
not been determined (139, 140). The increased
expression in rat skin wounds suggested a repair
function, but AT2 sites were not found in rapidly dividing cell cultures (141). Studies from co-cultures of
brain stem and hypothalamus from 1-day-old rats
suggest that Ang II has an effect on a potassium current that is selectively blocked by PD-123177, but
the meaning of this finding is unknown (142, 143).
That the AT2 site has a growth-inhibitory role has
been suggested by two reports. In the first, overexpression of the AT2 receptor at the site of balloon
injury in rats suppressed neointimal formation (144).
In this rat balloon injury model, AT1 receptor blockade also suppressed the neointimal response and
addition of PD-123177 had no further effect (44,145,
146). In the pig, neither AT1 blockade nor the combination of AT 1 and AT2 blockade had any effect on
the vascular response to balloon injury (147). It has
recently been reported that Ang II acting through an
AT2 site inhibits the proliferation of coronary endothelial cells cultured from SHR (148). If this is confirmed, it would mean that losartan and related
AT1-selective antagonists would be antiproliferative
by blocking Ang II directly at the AT1 receptor (the
majority of effect) and indirectly through stimulation
of the unblocked AT2 site by the elevated circulating
Ang II levels. Preliminary data from balloon vascular
injury in dogs suggest that AT1 receptor blockade
inhibits neointimal formation, whereas ACE inhibition is ineffective. This is presumably due not to differences in effect on subtype, but rather to blockade
of non-ACE-generated Ang II (149).
Antihypertensive and antihypertrophic effects in
experimental models of hypertension
The efficacy of losartan in experimental models
of hypertension provides the basis of the clinical
trials in hypertensive patients and its subsequent
marketing for the treatment of hypertension (5,150).
The initial findings with AT1-selective blockade with
losartan have now been confirmed with many other
AT1 -selective antagonists, including candesartan
(TCV-116) (62), irbesartan (SR-47436) (119) and
valsartan (120). As described above, losartan has
acute antihypertensive effects in renal hypertensive
rats in which PRA (and presumably Ang II levels) are
elevated (97). Rats infused with Ang II (30 mg/min)
for 2 weeks develop hypertension and cardiac
hypertrophy, which is blocked by losartan but not by
enalapril. In contrast, lowering of blood pressure-with
hydralazine does not block the hypertrophy (151). In
DRUGS OF TODAY Vol. 31, No. 7, 1995
renal hypertensive rats (two-kidney, one-clip) dosed
for 2 weeks, losartan lowered blood pressure and
reduced both cardiac and vascular hypertrophy (98,
99). In rats made hypertensive by aortic constriction
above the renal arteries, losartan, but not
PD-123319, reduced cardiac hypertrophy and transforming growth factor-1, (TGF- 1) levels (152).
Losartan and ramipril were comparable and both
were superior to hydralazine in reducing cardiac
hypertrophy in rats with ascending aorta constriction
(153).
Losartan has been extensively studied in SHR,
which have low PRA (Ang II levels). In the initial
study of losartan and captopril dosed for 14
days, both compounds produced comparable
reductions in blood pressure (154). Importantly,
after termination of treatment, the blood pressure
slowly returned toward the pretreatment (vehicle)
values, such that no rebound hypertension was
observed. Ten-week treatment of 3-week-old SHR
with either losartan or captopril significantly
lowered blood pressure and resulted in longlasting reductions in cardiac and vascular
hypertrophy (155). In these studies, the
reductions in cardiovascular hypertrophy were
assessed 17 weeks after the termination of
treatment,
suggesting
that
AT 1 selective
blockade lowers blood pressure and affects the
vascular and cardiac
tissue
changes
associated
with
the development and/or
maintenance
of
hypertension.
Significant
reductions in vascular and cardiac hypertrophy
were observed 2 weeks after dosing with
losartan,
whereas
comparable
blood
pressure reductions with hydralazine did not alter
the cardiovascular hypertrophy (156). As expected,
the acute antihypertensive effects of losartan are
not bradyki-nin-dependent. In SHR, ramiprilat,
captopril and losartan produced comparable
reductions in arterial blood pressure. Infusion of the
bradykinin antagonist Hoe-140 produced small
reversals of the effects of the ACE inhibitors, but
had no effect on the response to losartan (49).
The antihypertensive effects of selective AT1
receptor blockade in SHR (young, old) are now well
established, and the reduction in blood pressure is
accompanied by decreases in cardiac and
vascular hypertrophy (for review, see 82).
Angiotensin II as a growth factor acting via the AT1
receptor subtype
The growth-stimulatory effects of Ang II were first
observed in 3T3 cells (157), and have subsequently
been observed in a variety of cell types, including
vascular smooth muscle cells, cardiac myocytes,
mesangial cells, fibroblasts and endothelial cells
(158, 159). Each of the cell types has important
potential implications for cardiovascular hypertrophy
and tissue remodeling. In vitro, Ang II stimulates the
471
expression of proto-oncogenes (e.g., c-fos), DNA
synthesis (thymidine incorporation), protein synthesis or accumulation, and in some cases it increases
cell number (Table IV). In each case, the "growth
effects" of Ang II are blocked by losartan, but not by
PD-123319 or CGP-42112 (see above). In vivo, the
growth-stimulatory effect of Ang II is difficult to separate from the blood pressure effect. Angiotensin II
infusion increases blood pressure and induces cardiac hypertrophy, and blocking the increase in blood '
pressure with hydralazine does not block the cardiac
hypertrophy (151). Losartan, in contrast, blocks both
responses, suggesting a pressure-independent
effect of Ang II. In most studies in which losartan
reduced or prevented cardiovascular hypertrophy,
there was a significant reduction in blood pressure
(99, 160). In Dahl salt-sensitive rats and strokeprone SHR, losartan has been shown to reduce ventricular hypertrophy while having much less effect on
blood pressure, suggesting a dissociation between
pressure and growth (161, 162). In newborn pigs,
Ang II appears to have a trophic effect on heart
weight, as the rapid increase in normal growth in
heart weight is reduced by enalapril or losartan
(163). As discussed above, the neointimal growth in
response to balloon injury in normotensive rats and
rabbits is blocked by losartan, suggesting that AT1
receptors are involved (for review, see 81).
Activity in models of cardiovascular disease
Hypertension is the primary indication for losartan and AT1selective antagonists. The efficacy of
these molecules in experimental hypertension has
been well documented (see above). In addition,
losartan lowers blood pressure and/or exerts tissueprotective effects in models of renal failure, cardiac
failure and stroke (Table V). Importantly, losartan,
like ACE inhibitors, appears to increase survival in
coronary artery-ligated "heart failure" rats (164), and
in stroke-prone SHR (162) and Dahl salt-sensitive
rats (161). The confirmation of these initial studies
with losartan with other ATrselective antagonists
points to the emerging concept that Ang II acts as a
pathological factor to: 1) cause vasoconstriction, 2)
induce tissue damage, and 3) decrease survival
(Fig. 4).
In the kidney, Ang II has multiple sites of action
on afferent and efferent arterioles, proximal tubular
cells, mesangial cells, JG cells, vascular endothelial
cells, adipocytes and sympathetic neurons. The distribution and type (AT1 vs. AT2) of Ang II receptors
appear to vary somewhat from species to species
(192). In rat kidney, AT1 receptors predominate and
are localized in the glomerulus, renal tubules and
renal vasculature. In human kidney, the AT1 receptor
predominates, although AT2 receptors are present in
MEDICAMENTOS DE ACTUALIDAD
472
Table IV: The angiotensin II receptor subtype (or "growth" is AT1.
Angiotensin response
Species tissue or cell
Proto-oncogene expression
Rat hepatocytes
Rat mesenteric artery
Rat aortic smooth muscle cells
Rat brain
Rat heart fibroblasts
Bovine adrenal cells
Rat heart endothelial cells
Growth factor expression
(TGF-1, endothelin-1)
Growth DNA synthesis
(thymidine incorporation)
Growth protein accumulation
Growth heart weight
Receptor subtype
Reference
AT1
AT1
AT1
AT1
AT1
AT1
165
166
167
168
169
170
AT1
171, 172
AT1
173, 174
AT1
AT1
AT1
AT1
175
131
176
177
AT1
178, 179
AT1
AT1
AT1
180
181
182
AT1
183
Rat aortic smooth muscle cells
Mouse mesangialcells
Bovine adrenal cortical cells
Rat, human mesangial cells
Human mesangial cells
Rat cardiomyocytes
Rat aortic smooth muscle ceils
Rat aortic segments
Rat mesangial cells
Pig (newborn) heart
TGF- 1 = transforming growth factor- 1. (Reproduced with permission from Smith and Timmermans. Human angiotensin
receptor subtypes. Curr Opin Nephrol Hypertension 1994, 3: 112-122.)
Table V: Efficacy of losartan in experimental models of cardiovascular diseasesa.
Referencea
"Disease"
Model
Finding
Hypertension
SHR, renal
 MAP, no rebound hypertension,  SBP,
 Cardiac and vascular hypertrophy
154, 184
Renal failure
Reduced renal mass
Streptozotocin
 SBP,  proteinuria
 Proteinuria,  glomerular sclerosis, improved hernodynamics
185-187
Cardiac failure
Aortocaval shunt
Coronary ligation
 Cardiac hypertrophy
 LVEDP, cardiac hypertrophy, survival
164, 188-190
Stroke
Stroke-prone SHR
 SBP, survival, cerebral infarction
162, 191
SHR = Spontaneously hypertensive rats; MAP = mean arterial pressure; SBP = systolic blood pressure; LVEDP = left ventricular end-diastolic pressure. aSee Ref. 5 for additional references.
large preglomerular vessels in the renal cortex and
tubulointerstitium (193). Angiotensin II appears to
exert a complex modulatory role on normal basal
renal function (194, 195), and under normal conditions, Ang II system inhibitors may have limited net
effects (104, 196). However, when renal tissue is
damaged by toxins or pressure load, or when the
functional renal mass is reduced below that necessary to maintain normal sodium balance, the remaining JG cells are stimulated to release renin to
increase circulating and tissue Ang II levels. Progressive reductions in glomerular filtration rate
(GFR), sodium retention, proteinuria and glomerular
sclerosis follow the rise in Ang II. Blockade of Ang II
synthesis with ACE inhibitors has provided the best
evidence that Ang II exerts a pathological effect in
the kidney (197). The nonspecific actions of these
compounds, e.g., bradykinin potentiation, however,
complicate such interpretations. Since bradykinin is
a potent vasodilator of afferent arterioles, ACE inhibitors, by blocking Ang II synthesis, may have a
greater and potentially adverse effect on GFR (198,
199).
AT1 receptor blockade with losartan or the
related molecules A-81988 or TCV-116 blocks or
attenuates the severe proteinuria observed in rats
with reduced renal mass (185, 200), or in SHR with
reduced renal mass (201). In the latter study, AT1
DRUGS OF TODAY Vol. 31, No. 7, 1995
473
Hypertension "Pressure
dependent"
Progressive tissue deterioration (loss
of vascular, renal, cardiac, and
cerebral function)
"Pressure dependent" and "Nonpressure dependent"
Increased deaths (strokes, myocardial,
infarction, renal failure)
"Pressure dependent" and "Nonpressure dependent"
Fig. 4. The role of Ang II in cardiovascular disease.
blockade with TCV-116 was reported to increase
survival (201). In stroke-prone SHR, losartan or
TCV-11974 reduced proteinuria and increased survival (202, 203). After uninephrectomy, streptozotocin or puromycin treatment, losartan reduced the
proteinuria noted in untreated animals (115,
204-206). The reductions in GFR following unilateral
urethral obstruction or ochratoxin were also
reversed by losartan at doses of 10-20 mg/kg/day
p.o. (207, 208). The elevated blood pressure, proteinuria and glomerulosclerosis characteristic of
genetically hyperlipidemic (Imai) rats were blocked
by both enalapril and losartan, suggesting that Ang
II acting through the AT1 receptor plays a pathological role (209). In a model of passive Heymann
nephritis, the decrease in GFR and proteinuria were
blocked more by enalapril than losartan, suggesting
that enalapril acts through a non-Ang II mechanism
(210). Recently, TCV-116 has been shown to inhibit
the decrease in GFR following antiglomerular basement membrane antibody-induced nephritis if given
2 hours before the antibody injection, but not if given
for 1 week starting from day 3. The benefit appears
to be dependent on the state of activation of the RAS
(211). From the collective experience to date, Ang II
appears to exert significant renal tissue-damaging
effects where renal mass or cellular function is compromised. It is not clear how much is "pressure-dependent" and how much is "pressure-independent".
It is clear, however, that AT1-selective blockade produces significant renal tissue protection in the majority of experimental models. The relative lack of effect
of losartan in passive Heymann nephritis suggests
that Ang II may not be involved in this model.
In cardiac tissue, Ang II has multiple sites of
action, including myocytes, fibroblasts, sympathetic
nerves, adipocytes and coronary vascular endothelial and smooth muscle cells (212-214). The Ang II
subtype and the distribution of receptors vary with
species and functional state (e.g., normal vs. failing
heart). The heart appears capable of generating its
own Ang II (so-called cardiac tissue RAS) (214) and,
in addition, may generate Ang II by non-ACE pathways (e.g., chymase) (215, 216). The relative contribution of locally generated or non-ACE-generated
Ang II to the overall actions of Ang II in the normal
and/or failing heart is largely unknown. Unlike in the
kidney where the functional role of Ang II has been
more clearly established, the role of Ang II in the
heart is not fully understood. The increase in survival
in patients with heart failure treated with inhibitors of
Ang II synthesis (SOLVD, CONSENSUS, SAVE
trials; for review, see 28), however, has suggested
that Ang II has an important pathological role. Ang II
induces a number of cellular changes in isolated
myocytes involving IP3 concentrations, intracellular
calcium release, cAMP levels and proto-oncogene
expression (81), and each of these responses to Ang
II is blocked by losartan.
Cardiac sympathetic nerves release norepinephrine and Ang II enhances this release, presumably through a presynaptic effect. In isolated guinea
pig left atria, losartan (1 M), but not PD-123319
(100 M), blocked the Ang ll-enhanced release
474
(217). Likewise, in human right atrial appendages,
AT1 blockade with EXP-3174 or nonspecific blockade with saralasin inhibited the enhanced norepinephrine release (90). Interestingly, as described
above, untreated SHR display an abnormal
response to Ang II, which can be reversed by chronic
losartan treatment (218).
The inotropic effects of Ang II in vivo are not well
understood. In isolated rat papillary muscle, the
maximum response is 41-75% of the response to
isoproterenol. This response is blocked by losartan,
but not by PD-123319 or PD-121981 (219, 220). In
isolated human atrial tissue, Ang II has positive
inotropic effects, but not in right or left ventricular tissue (221, 222). The response to Ang II was blocked
by losartan or saralasin, but not by propranolol or
prazosin (222).
Fibroblasts are abundant in the failing heart and
participate in the cardiac remodeling of the failing
heart (223). In cultured neonatal rat heart fibroblasts,
Ang II increases DNA and protein synthesis and
mitogen-activated kinase (224-226). In a preliminary
report using adult rat fibroblasts, both losartan and
PD-123177 (AT2) had an inhibitory effect (227). In
cultures of human fibroblasts, Ang II increased collagen synthesis ([3H]-proline incorporation), and this
response was blocked by PD-123319, but not by ICID8731 (a nonpeptide AT1 antagonist), suggesting an
involvement of the AT2 site. In vivo, however, losartan and ACE inhibition (nonseiective) produced
comparable reductions in collagen content in rats
after coronary ligation (228, 229). A recent report, ••
however, shows that cultures of human fibroblasts
have a growth response to Ang II, which is not
blocked by either losartan or PD-123319, suggesting
an alternative, as yet uncharacterized, receptor
subtype (230).
AT1 receptor antagonism in experimental models of
heart failure
"Heart failure" (broadly defined as a progressive
loss of cardiac function or rise in left ventricular enddiastolic pressure [LVEDP]) can be induced in a variety of animal species by a variety of methods (212,
231). Although none of these models perfectly
reflects the human clinical syndrome of heart failure,
they can provide insight into the potential pathological role of Ang II and the beneficial effects of Ang II
receptor antagonists. The degenerative cardiac
changes observed in S40 virus-treated mice are
reduced by TCV-116, suggestive of a role of Ang II
(232). In genetically myopathic hamsters, AT1
receptor blockade with SR-47436 prevents the progressive loss of ventricular function (233). In socalled "high-output" failure induced by aortocaval
shunt, AT1 receptor blockade with losartan reverses
MEDICAMENTOS DE ACTUALIDAD
the hemodynamic and hypertrophic changes characteristic of this model (234, 235). Similar results
were reported for ACE inhibitors and other AT1
receptor antagonists (236-238). Treatment with
losartan (10 mg/kg/day twice daily by gavage) and
captopril (1 g/l in the drinking water) for 3 weeks
beginning 7-8 days after aortocaval shunt surgery
improved hemodynamics, decreased water retention
and reversed cardiac hypertrophy (239). These data
show that Ang II has an important pathological role in
this model of heart failure.
Cardiac failure produced by rapid ventricular
pacing is characterized by marked elevation in
LVEDP and reduced cardiac output (CO) in both
sheep and dogs (240-242). Losartan given as bolus
injections produced marked but short-lived reductions in LVEDP and increases in CO in sheep. The
magnitude of the changes was the same as noted
with captopril (240). The short duration of action
reflects the limited half-life of losartan in sheep. In
dogs, losartan, EXP-3174, SR-74736 and TCV-116
have all been shown to have beneficial effects. However, each is a biphenyltetrazole and has a limited
duration of action in dogs (241-245). These studies
should be repeated with chronic infusions of these
agents to assure 24-hour AT1 receptor blockade.
Losartan has been studied in rats with coronary
artery ligation-induced heart failure. The results
have been inconsistent. The first report showed that
losartan and captopril given for 2 weeks starting 2
weeks after ligation produced comparable reductions in LVEDP (189). A subsequent study showed
that losartan administered s.c. via osmotic pump
reduced left ventricular hypertrophy and collagen
synthesis, but did not affect DNA synthesis or restore
the hemodynamic response to saline infusion (228).
The latter group had shown that captopril, but not
benzapril, restored the functional response to saline
(246). In a study in which losartan or captopril was
administered in the drinking water for 2 weeks starting 3 weeks after coronary artery ligation, both
agents lowered arterial pressure, but only captopri!
reduced renal vascular resistance (247). In a more
recent study, moexipril or losartan was given for 1
week before coronary artery ligation and then for an
additional 6 weeks. In this study, moexipril lowered
LVEDP and reduced infarct size, whereas losartan
had no effect on either parameter (248). In a comparative trial of enalapril, losartan and placebo, the
treatments were begun 7 days after coronary artery
ligation and continued for 6 weeks. In this study,
interstitial fibrosis determined from the perfusionfixed heart was elevated in the placebo-treated animals and reduced by both enalapril and losartan.
Both methods of RAS inhibition also restored the
minimal coronary vascular resistance (229). AT 1
DRUGS OF TODAY Vol. 31, No. 7, 1995
receptor blockade with TCV-116 and delapril has
also been reported to decrease left ventricular
hypertrophy and LVEDP, Importantly, treatment of
rats with coronary artery ligation for up to 1 year with
either losartan or captopril has been completed. The
preliminary results indicate that the losartan-treated
animals have a mean survival time of 246 days versus
149 days for the captopril group (249). This study
provides important support for the ongoing trial of
losartan in heart failure.
Commentary
At the time of its 1994 market introduction in
Europe, losartan had been studied more extensively
than any previous antihypertensive dug. This
reflects scientific and clinical interest in the "Ang II
system" and the fact that losartan is the first specific
nonpeptide Ang II receptor antagonist that is devoid
of intrinsic agonist activity. The oral activity and long
duration of action of losartan have greatly facilitated
chronic studies in rats. Losartan has proven highly
useful as a prototype of the AT1 antagonist as a tool
to explore Ang II receptor heterogeneity. Although a
role for the AT2 site remains elusive, the search for
its physiological role continues (250, 251). The use
of losartan and other AT1 -selective antagonists to
more precisely characterize the Ang ll-dependent
effects of ACE inhibitors has only just begun.
Theoretically, AT1 receptor antagonists should block
Ang II generated by both ACE and non-ACE (alternative pathways) synthesis, and do not affect bradykinin. While decreasing Ang II production, ACE inhibition blocks the availability of Ang II to both receptor:
subtypes and potentiates bradykinin. The majority of
data generated to date show that AT1 receptor blockers and ACE inhibitors produce equivalent effects
both in vitro and in vivo, suggesting that AT1 receptors mediate the principal physiological and pathophysiological effects of Ang II. These findings in preclinical studies have now been confirmed in early
human clinical trials. Acutely, losartan (and other AT1
antagonists) antagonize Ang II and lower blood pressure in hypertensive patients. The long-term studies
of losartan in hypertensive patients with and without
nephropathy and patients with heart failure will provide a further refinement of our understanding of the
pathological role of Ang II and the therapeutic value
of specific AT1 receptor blockers.
Clinical Experience with Losartan and
Other AT1-Selective Antagonists
The majority of human clinical trials of AT1 -selective
antagonists completed to date have been with
losartan (Table VI). Clinical trials with a number of
other AT1-selective antagonists are now under way
475
(Table VII). The general goal for the phase I clinical
trials has been to establish safety and tolerability,
oral bioavailability and the blockade of Ang II pressor
effects in normal volunteers. From these studies, the
range of doses for short-term safety and efficacy
trials in hypertensive patients was determined. The
results of the dose-finding trials in hypertensive
patients (phase II) then provided the dosing parameters for the longer term, multicenter trials (phase III)
and studies in special populations (e.g., severe
hypertension, renally impaired, elderly) or trials versus other comparative compounds. In addition, studies
with concomitant administration of hydrochlorothiazide were also performed (252-254). Losartan
has been studied in 16 double-blind, placebo-controlled trials. At the time of regulatory submission of
the New Drug Application (NDA) with the Federal
Drug Administration (FDA) (December, 1993), data
from more than 3300 subjects were included. Currently, more than 1700 patients have received losartan for more than 1 year. Efficacy and safety data
have been collected from over 4058 patients/subjects enrolled in clinical trials (302).
Clinical trials in normal subjects
Losartan is an orally active Ang II antagonist in
man. The blockade of Ang ll-induced pressor effects
in man was demonstrated in two studies performed
in normal subjects in whom the blood pressure
response to i.v. infusion of Ang I or Ang II repeated
several times over 24 hours was monitored by photoplethysmography (Finapres; Ohmeda, Englewood,
CO, USA). In the initial study, single oral doses of
losartan (2.5, 5,10, 20 and 40 mg) were studied versus placebo. Doses of 10, 20 and 40 mg of losartan
produced dose-related inhibition of the systolic
blood pressure response to Ang I (converted to Ang
II). Demonstrable inhibition of Ang II was evident at
24 hours with the 40-mg dose. At these doses,
plasma levels of immunoactive Ang II rose, whereas
the fall in plasma aldosterone was not different from
placebo (112, 255). In the second study, losartan (20
and 40 mg) was given orally to volunteers once a day
for 8 days. The i.v. Ang II challenge was given several times on days 2, 4 and 8. Losartan produced a
dose-related inhibition of the systolic and diastolic
blood pressure response to Ang II. Similar maximum
inhibition of Ang II was achieved on days 2, 4 and 8,
suggesting that acute tolerance to the receptor
antagonism did not develop. The 20- and 40-mg
doses of losartan significantly elevated PRA and
Ang II levels on days 1 and 8 (268).
Pharmacokinetic studies were also carried out in
normal volunteers. Plasma was analyzed for losartan and the active metabolite EXP-3174. Because of
MEDICAMENTOS DE ACTUALIDAD
476
Table VI: Summary of clinical experience.
Patient description
Clinical observation
Normotensive volunteers
Ang II antagonism
Pharmacokinetics
PRA and Ang II levels
Renal function
Forearm blood flow
255
256, 257
258
105,259
260
Essential hypertensives
PRA, Ang II, aldosterone
Renal hemodynamics
Ambulatory blood pressure
261
262, 263
264
Antihypertensive effect
Heart failure patients
References
263, 265-271
Chronic renal insufficiency
Effect on proteinuria
Insulin sensitivity
Cough
Circadian periodicity of BP
Safety
EXP-3174 i.v. hemodynamics
272
273
274
275, 276
277
83
278
Acute hemodynamic effects
12-Week hemodynamic effects
Exercise performance
279, 280
281
282
Ang II - angiotensin II; PRA = plasma renin activity; BP = blood pressure.
Table VII: Selective AT1 receptor antagonists in clinical trials.
Compound
Other designation
Status
Losartan
DuP-753, MK-954
Marketed in U.S., some countries in Europe
References
Candesartan
TCV-116
Phase III
283-285
Valsartan
CGP-48933
Phase III
286
(see Table VI)
Irbesartan
SR-47436/BMS-18295
Phase III
287, 294
Telmisartan
BIBR-0277
Phase II
295, 296
Eprosartan
SK&F-108566
Phase II
297
SC-52458
Phase I
298, 299
TAK-536
Phase I
300
Other drugs in clinical trials without published data include E-4177, HN-65021, GR-117289 (zolasartan), UP-2696, LRB/081, MK-996 (L-158,282) and ANA-756.
its slow clearance, EXP-3174 gave high plasma
levels based on the AUC and had a longer
terminal half-life (t1/2). Because blood levels of
EXP-3174 paralleled the antagonism of Ang II,
the authors concluded that the long-lasting Ang
Il blockade following losartan is largely due to the
active metabolite EXP-3174 (256) (Fig. 5).
Unlike ACE inhibitors, losartan does not
potentiate
the
vasodilator
response
to
bradykinin in the human forearm (260). On
different occasions, eight normal subjects
received single doses of losartan 20
mg, losartan 100 mg, enalapril 10 mg and placebo
in a double-blind, four-period crossover study
(260). Forearm blood flow was measured by
venous
occlusion
plethysmography
during
infusions of Ang I, Ang II and bradykinin. At 4-6
hours after dosing, losartan inhibited the
vasoconstrictor responses to Ang I and Ang II in a
dose-related manner, but it did not potentiate the
vasodilator response to bradykinin. Enalapril, in
contrast, selectively blocked the vasoconstrictor
response to Ang I (without changing Ang II) and
significantly
augmented
the
vasodilator
response to
DRUGS OF TODAY Vol. 31, No. 7, 1995
477
Fig. 5. Top: Time profile of the mean plasma concentrations of the parent compound (closed symbols) and its active metabolite EXP-3174 (open symbols) after single oral administration of losartan (squares, 40 mg; diamonds, 80 mg; triangles,
120 mg) in six volunteers. For purposes of clarity, SD values are reported for the highest oral dose and for the active metabolite only. Bottom: Time profile of the mean response to exogenous angiotensin II challenge in six volunteers receiving
placebo (no symbols) and three doses of losartan (asterisks, 40 mg; diamonds, 80 mg; triangles, 120 mg). The ordinate
is expressed as a percentage of the baseline predose response. For purpose of clarity, SEM are reported for placebo and
120 mg only. (Reproduced with permission from Munafo et al. Drug concentration response relationships in normal volunteers after oral administration of losartan, an angiotensin II receptor antagonist. Clin Pharmacol Ther 1992, 51:513-521.)
bradykinin. These data are consistent with the lack
of effect of losartan on ACE activity and on the
smooth muscle effects of bradykinin (154, 302).
Losartan increases PRA and Ang II levels in normal subjects (258), presumably through inhibition of
the negative feedback mechanism in the kidney.
Losartan 100 mg/day was administered for 8 days.
PRA (expressed as ng of Ang I generated/ml/h) was
measured by radioimmunoassays and Ang II levels
were measured by high-performance liquid chromatography (HPLC) plus a radioimmunoassay during
the run-in period and 6 hours after dosing. The PRA
increased from 1.2 ± 0,6 (run-in) to 12.0 ± 6.3 (after
the first dose) and to 9.6 ± 4.9 (after the last dose).
The Ang II levels increased from 4.3 ± 1.7 ng/ml
(run-in) to 77.4 ± 33 ng/ml (after the first dose) and
to 45.7 ±14.1 ng/ml (after the last dose). Thus, the
incremental increase in Ang II was somewhat less
after the last dose than after the first dose (p < 0.05).
Similar changes in the RAS hormones have been
observed in hypertensive patients (261). In these
studies, losartan 25 and 100 mg/day
478
MEDICAMENTOS DE ACTUALIDAD
Fig. 6. Graphs show geometric mean plasma angiotensin II measurements at placebo run-in visit and geometric mean fold
changes of angiotensin II during treatment. At 0 hours, changes in the 100-mg losartan group were significantly different
from run-in at weeks 2 and 6 and significantly different from the placebo group at week 2. In the 20-mg enalapril group,
changes were significantly different from run-in and the placebo group at week 6. (Reproduced with permission from
Hypertension, Copyright 1995, American Heart Association, Ref. 261.)
increased PRA and Ang II levels at 4 hours, and the
increase in both parameters was less pronounced at
week 6 than at week 2 (Fig. 6).
The absorption, distribution, metabolism and
excretion characteristics of losartan include: .1) good
bioavailability, e.g., 30%, 2) conversion to EXP-3174
via cytochrome P-450 in the liver, and 3) elimination
of losartan and EXP-3174 via both the hepatic and
renal routes. Losartan is highly protein-bound
(98.6-98.8%) (1.4 ± 0.2 to 1.2 ± 0.1% unbound at
concentrations of 0.5-5.0 g/ml). EXP-3174 is more
than 99.7% bound (0.2 ± 0.0% unbound at concentrations of 0.1-10 g/ml). Binding to -acid glycoprotein is negligible. In vitro concentrations of warfarin up to 20 g/ml, diazepam up to 35 g/ml,
naproxen up to 50 g/ml or ibuprofen up to 20 g/ml
did not affect losartan binding. Supratherapeutic
concentrations of acetylsalicylic acid (ASA; 300 or
3000 g/ml), naproxen (500 g/ml) or ibuprofen
(200 g/ml) did significantly increase the percent of
free losartan (303). In formal interaction studies in
man, the blood levels of losartan were not affected by
phe-nobarbital, cimetidine or ketoconazole.
Losartan and EXP-3174 have a volume of
distribution of 34 and 12 liters, respectively (301).
Losartan is converted to the free carboxylic acid
EXP-3174, which is a potent AT1 receptor antagonist
(see above), in rats and man (256). In these two species, losartan undergoes extensive first-pass metabolism by hepatic P-450 enzymes (110). In human
liver slices, the major metabolite is EXP-3174. In
dogs, the glucuronide is the primary product, with
little EXP-3174 formed (109). The extent of conversion is approximately 14% in man, 20% in rats and
< 1% in dogs. In these studies, a sensitive (5 ng/ml
for plasma and 10-20 ng/ml for urine) HPLC assay
for the simultaneous detection of both compounds
was described (304).
Losartan is excreted in man via both the bile and
the urine, and following oral [14C]-losartan, approximately 35% of the radioactivity is recovered in the
urine and about 60% in the feces. The plasma levels
of losartan (AUCs) in patients with a creatinine clearance of 30 ml/min or less were increased by 50% and
were 2-fold greater in patients on hemodialysis; however, no dose adjustment is recommended (301)
unless volume depletion is present. In patients with
mild to moderate hepatic impairment, the blood levels (AUCs) of losartan and the metabolite EXP-3174
have been shown to be elevated 5- and 1.7-fold,
respectively, and reduction of the starting dose has
been recommended (301).
Clinical trials in salt-depleted volunteers
Losartan has been shown to lower blood pressure in sodium-depleted normal subjects (105,259).
Subjects were studied following a single dose of
losartan on four occasions 2 weeks apart. Each was
pretreated with furosemide (40 mg twice daily) for 3
days prior to the study day, and then given placebo
salt replacement ("salt-depleted") or active salt
replacement ("salt-replete") (105). During salt depletion, a single dose of losartan 100 mg significantly
lowered both supine (-24 ± 9 mmHg) and erect (-33
± 1 5 mmHg) blood pressure. In contrast, when the
subjects were salt-repleted, losartan had no significant effect on blood pressure compared to placebo.
Creatinine clearance was transiently reduced by
losartan in salt-depleted subjects (47 ± 54 ml/min
for losartan, 161 ±37 ml/min for placebo), but not in
salt-replete subjects. Activation of the RAS by the
low-salt diet was confirmed with the demonstration
DRUGS OF TODAY Vol. 31, No. 7, 1995
479
that PRA was significantly elevated by salt depletion. It
was concluded that care should be taken in treating
vigorously salt-depleted patients (105).
In the second normal volunteer study, losartan or
placebo was administered to 23 healthy subjects on
a high-sodium (200 mmol/day) or low-sodium (50
mmol/day) diet in a randomized, double-blind, crossover design (259). To maintain adequate urinary flow
rates, the patients were hydrated throughout the
study day. When the subjects were on a low-sodium
diet, losartan significantly increased urinary sodium
excretion (from 115 ± 9 to 207 ± 21 mmol/min) and
potassium excretion (from 3.5 ± 0.2 mmol/min to
11.1 ± 0.5 mmol/min). During the high-sodium diet,
losartan produced somewhat smaller effects, which
did not reach statistical significance. Uric acid excretion increased to 9.66 ± 0.6 mmol/min from a baseline of 3.1 ± 0.2 mmol/min. In these water-loaded
patients, losartan did not acutely affect blood pressure, GFR or renal blood flow under either dietaiy
sodium condition.
Uricosuric effect
One surprising finding during the clinical development programs was the observation of a transient
uricosuria following treatment with losartan. Losartan
has been shown to increase the urinary excretion of
uric acid in normal subjects (256) and hypertensive
patients (269). The uricosuric effect of losartan does
not appear to be related to AT1 receptor blockade or
renin status. The early time course of the transient
increase in uric acid excretion suggests that it is an
effect of losartan rather than the metabolite (259).
This is supported by the apparent lack of effect on uric
acid excretion of EXP-3174 when administered i.v.
(278). Analysis of the overall experience with
losartan in controlled clinical trials showed that
plasma uric acid decreased by approximately 0.4
mg/dl (301). The mechanism of this uricosuric effect
is unknown. Losartan does not appear to inhibit xanthine oxidase or to stimulate intestinal water transport (305).
Antihypertensive effects
The results of several large multicenter trials with
losartan in hypertensive patients have been published (263, 270) (see Table VI). The clinical database for losartan includes the results of 16 doubleblind controlled trials totaling 2805 losartan-treated
patients (302).
The efficacy and safety of once-daily losartan
(10,25,50,100 or 150 mg) have been demonstrated
in an 8-week, double-blind trial in patients with mila
to moderate essential hypertension (Fig. 7) (263).
Five hundred and seventy-six patients were
randomly allocated to receive different doses of
Fig. 7. Graphs show changes in diastolic and systolic
pressure by weeks in patients with mild to moderate
essential hypertension. Shown is the mean change
(mmHg) in trough (24 hours after dosing) supine blood
pressure by week. Top: changes in diastolic pressure;
Bottom: changes in systolic pressure. LOS = oral losartan
potassium (doses are in mg once daily); ENAL 20 = enalapril maleate (∆ , 20 mg given once daily);● , placebo; ▲,
LOS, 10;■ , LOS 25; ♦, LOS 50; ▼ , LOS 100; O, LOS
150). (Reproduced with permission from Hypertension,
Copyright 1995, American Heart Association, Ref. 263.)
losartan, placebo or the positive control enalapril (20
mg). After 8 weeks of treatment, mean reductions
from baseline in supine systolic/diastolic pressure
24 hours after dosing (trough) for losartan 10,25, 50,
100 and 150 mg were 7.6/7.9, 7.8/6.8, 13.0/10.1,
8.9/9.9 and 10,5/9.7 mmHg, respectively. The values for enalapril and placebo were 14.7/11.2 and
3.8/5.6 mmHg, respectively. Losartan doses of 10
and 25 mg did not result in clinically significant differences from placebo (263). As shown in Figure 7, the
blood pressure changes are essentially identical to
those observed with enalapril at a dose of 20 mg.
The placebo-corrected trough-to-peak ratios of the
mean changes in supine diastolic blood pressure
after 8 weeks were 78% (10 mg), 23% (25 mg), 60%
(50 mg), 72% (100 mg) and 49% (150 mg) for losar-
480
tan, indicating a sustained 24-hour effect, which is
not a result of excessive effects at peak (4-6 hours).
Losartan was generally very well tolerated and no
dose-related trends in adverse experiences were
noted. Headache was the most common adverse
effect in most treatment groups, including the placebo group (263).
Antihypertensive effects of EXP-3174
In patients with essential hypertension, the acute
hemodynamic and renal effects of EXP-3174 administered i.v. appear to be consistent with AT1 receptor
blockade. EXP-3174 (20 mg infused over 4 hours)
significantly reduced diastolic pressure compared to
placebo beginning approximately 100 minutes after
the initiation of the infusion (278). The maximum
blood pressure reduction did not occur until 8 hours
after initiation of the infusion, even though the maximum blood levels (324 ng/ml) were achieved within
the first 20 minutes of infusion. The reason for this
delayed onset is not presently known, but may reflect
the low volume of distribution (12 l vs. 34 I for losartan) and the delay in equilibrating with different tissue compartments. Only modest changes (not-significant) in PRA were observed. Urinary excretion of
uric acid, Na+, K+ or chloride was not significantly
altered.
Antiproteinuric effects in nondiabetic hypertensives
Losartan demonstrated beneficial effects on
urinary protein excretion in nondiabetic hypertensive
patients (273) with creatinine clearance of > 60 ml/
min and protein excretion exceeding 2 g in 24 hours.
In an open-label, crossover study, losartan (50 and
100 mg) and enalapril (10 and 20 mg) (Fig. 8) produced comparable reductions in protein excretion,
reduction in blood pressure (15.1% vs. 17.3%),
increase in effective renal plasma flow (ERPF;
13.3% vs 13.1%) and decrease in filtration fraction
(15.1% vs. 14.6%).
These findings have been extended to an
11-month, single-blind study comparing losartan 50
or 100 mg/day to placebo (306). In this study, urinary
excretion of total protein, albumin and immunoglobulin G (IgG) was decreased in a dose-dependent
manner. At the high dose, serum uric acid fell from
0.43 ± 0.02 mmol/l to 0.39 ± 0.02 mmol/l, and
serum potassium decreased from 4.7 ±0.1 mmol/l
to 4.6 ± 0.1 mmol/l.
Concomitant administration with
hydrochlorothiazide
Diuretics are known to produce additive blood
pressure effects when combined with other antihypertensive drugs, particularly those that inhibit the
RAS. A fixed-dose combination of losartan (50 mg)
MEDICAMENTOS DE ACTUALIDAD
and hydrochlorothiazide (12.5 mg) has been_
approved for the treatment of hypertension in the
United States. This was based on the results of three
double-blind, placebo-controlled trials. In one study,
hydrochlorothiazide (6.25,12.5 or 25 mg) was given
to patients who did not achieve a target diastolic
pressure of 93 mmHg after 4 weeks of losartan 50
mg alone. Statistically significant additional reductions in diastolic and systolic pressures (compared
to placebo) were achieved only with 12.5 or 25 mg
hydrochlorothiazide, e.g., systolic/diastolic: -12/-9
mmHg and -16/-11 mmHg, respectively (253). Similar findings were reported in another study in which
losartan 25, 50 or 100 mg was given to patients who
did not achieve target blood pressure on hydrochlorothiazide 25 mg (270). The concomitant administration of losartan 50 mg and hydrochlorothiazide 12.5
mg has been evaluated by Arcuri et al. (254). By
extrapolation to other studies, this study demonstrated an approximately 50% increase in efficacy
over losartan monotherapy. The increases in serum
glucose, uric acid and potassium induced by
hydrochlorothiazide appeared to be reduced in the
losartan-treated patients compared to placebo (Fig.
9) (264).
Safety and tolerability
Losartan is very well tolerated in patients with
essential hypertension. Approximately 2800
patients/subjects have been treated with losartan
alone or in combination with other antihypertensive
agents in double-blind clinical trials. On the basis of
data pooled from these trials, it was concluded that
losartan has an excellent tolerability profile comparable to placebo (83). Table VIII summarizes clinical
adverse experiences. The most frequent clinical
adverse effects considered by the investigator to be
drug-related were headache (4.2%), dizziness
(2.4%) and asthenia/fatigue (2.0%). Only dizziness
occurred more often in losartan-treated than in placebo-treated patients (2.4% vs. 1.3%). Withdrawals
due to adverse events occurred in 2.3% of patients
receiving losartan alone and in 2.8% of those receiving losartan plus hydrochlorothiazide. Withdrawals
occurred in 3.7% of the placebo-treated patients and
in 2.5% of the ACE inhibitor-treated patients. In contrast, the incidence of withdrawals was 8.8% for blockers and 9.3% for calcium channel blockers.
In patients with a history of "ACE cough" who
were subsequently challenged with lisinopril, losartan was associated with significantly less cough than
lisinopril (276). In this trial, hypertensive patients with
a history of ACE inhibitor-associated cough were
first challenged with lisinopril to confirm the presence
of cough, then dechallenged with placebo during the
washout period, during which time the cough had to
DRUGS OF TODAY Vol. 31, No. 7, 1995
481
Fig. 8. The effects (median with 95% Cl) of angiotensin II receptor antagonism (50 and 100 mg once daily) and ACE inhibition
(10 and 20 mg once daily) in 11 patients with proteinuria due to no nondiabetic renal disease. Shaded areas represent study
periods in which active treatment (Ang II, angiotensin II antagonist; ACE inhibition) was given, while nonshaded areas
represent study periods in which placebo was given. Changes in blood pressure ( ■ ) and urinary protein excretion (●) are
depicted in the upper panel, changes in glomerular rate (∆ ), effective renal plasma flow (□ ) and filtration fraction (O) are
depicted in the lower panel. Parameters are expressed as percentage change from baseline. *p < 0.05 vs. baseline (two-way
ANOVA, Friedman). (Reproduced with permission from Gansevoort et al. Is the antiproteinuric effect of ACE inhibition
mediated by interference in the renin angiotensin system? Kidney Int 1994, 45(3): 861-867. Ref. 273.)
disappear. Patients were then randomized in a
double-blind fashion to lisinopril, hydrochlorothiazide (a negative control) or losartan. The incidence,
severity and frequency of cough were assessed by
a self-administered questionnaire and visual analog
scale (275). The results indicated that the incidence
of cough with losartan (29.2%) was significantly less
than with lisinopril (71.7%) and was similar to that
with hydrochlorothiazide (34.1%). These results
confirmed differences between ACE inhibition and
losartan in the large phase III trial database for spontaneous reports of cough (ACE inhibitors 8.8% vs.
losartan 3.1%) (Table VIII).
Clinical trials in patients with heart failure
Losartan is not approved for the treatment of
heart failure, but it is currently under evaluation in
such patients. Acute and multiple-dose hemodynamic studies and two pilot exercise studies have
been completed (280, 281). Two multicenter exercise efficacy trials and an efficacy and tolerability
study in elderly patients with heart failure versus captopril (ELITE Trial, Evaluation of Losartan in the
Elderly) are ongoing (see below).
Losartan produced beneficial acute hemodynamic effects in patients with heart failure consistent
with Ang II system blockade (280). The acute hemodynamic and neurohumoral response to single
doses of losartan (5,10,25,75 or 150 mg) or placebo
was studied in 66 patients with New York Heart
Association functional class II, III or IV heart failure
and an ejection fraction of < 40% (280). Hemodynamic and neurohumoral measurements were
obtained at selected times for 24 hours post-treat-
482
Fig. 9. Mean serum concentrations of potassium, glucose
and uric acid at baseline, after 4 weeks of monotherapy
with placebo or various dosages of losartan, and after an
additional 2 weeks during which hydrochlorothiazide,
12.5 mg/day, was given in combination with the previous
treatment. (Reproduced with permission from Arch Intern
Med 1995, 155(4): 405-411, Copyright 1995, American
Medical Association, Ref. 264.)
ment. Losartan produced a dose-related fall in
mean arterial blood pressure and capillary wedge
pressure at doses up to 25 mg. The 75- or 150mg doses of losartan had no additional effect.
Modest increases in cardiac index were noted at
all doses. Heart rate was not changed by any of
the doses of losartan evaluated. Plasma renin
activity and Ang II levels increased in a doserelated fashion up to 150-mg. Maximum values
were observed at 4-6 hours post-treatment and
remained elevated for 24 hours. Modest
reductions in plasma norepinephrine and aldosterone were noted.
The acute and chronic hemodynamic
responses to 12-week treatment with losartan
(2.5,10, 25 or 50 mg once daily) were assessed
in 134 patients with
MEDICAMENTOS DE ACTUALIDAD
symptomatic heart failure and impaired left
ventricular function (ejection fraction < 40%) (281).
Invasive 24-hour hemodynamic assessment was
performed after the first dose and after 12 weeks
of
treatment.
Acutely,
systemic
vascular
resistance (SVR) and mean arterial pressure
were significantly reduced following the 50-mg
dose. The 25-and 50-mg doses of losartan
increased PRA and Ang II levels consistent with
the previously reported study (280). After 12 weeks,
similar effects were seen on SVR and blood
pressure (maximum decrease in SVR compared
to placebo at 5 hours with 50 mg). In addition,
pulmonary capillary wedge pressure fell with 2.5,25
and 50 mg, cardiac index rose with 25 and 50 mg,
and heart rate was lower in all treatment groups.
Losartan was well tolerated, with persistent
beneficial hemodynamic effects at 12 weeks, the
greatest effect being seen with 50 mg.
The published experience with losartan in
heart failure is limited at this time. In general, it
appears
that
losartan
has
beneficial
hemodynamic
effects
in
patients
with
symptomatic heart failure. The decrease in
pulmonary capillary wedge pressure after 12
weeks of treatment and the lack of effect of
losartan on heart rate are consistent with prior
experience with ACE inhibitors. In addition, a
higher incidence of progression of heart failure
was observed in the placebo and low-dose groups
compared to the higher dose groups, suggesting
that losartan may exert a beneficial effect in heart
failure.
At the present time, there are no published
data on other AT1-selective antagonists in
patients with heart failure. Clinical trials with
losartan in heart failure are continuing with
exercise studies and a safety study in elderly
patients (the ELITE trial). Results of a 12-week
pilot trial with losartan at 25 and 50 mg versus
enalapril at 10 mg b.i.d. suggested that losartan is
well tolerated in patients with heart failure, and
exercise capacity and clinical status were
similar after treatment with losartan or enalapril
(307).
Conclusions
Losartan is the first of a new class of therapeutic
agents. A large number of related molecules are at
present in various stages of development (57, 58).
Although many of these compounds are more
potent than losartan (lower doses producing
maximum inhibition of Ang II), full blockade of AT1
receptors is achieved by all losartan-related
molecules. Comparative trials with various AT 1
antagonists are not yet available, but it is
anticipated
that
all
agents
will
produce
approximately equal antihypertensive efficacy. As
with the development of the ACE inhibitor
class of agents, it is likely, however, that studies
will be available in the near future that will
attempt to
DRUGS OF TODAY Vol. 31, No. 7, 1995
483
Table VIII: Percentage of patients reporting clinical adverse experiences.
Losartan
(n = 2085)
Losartan
+
HCTZ
(n = 858)
Placebo
(n = 535)
ACE
inhibitors
(n = 239)
46.8
45.0
52.0
50.6
57.4
53.5
48.3
Percentage with any
15.3
drug-related adverse experience
14.8
15.5
24.7
26.5
23.3
18.1
Percentage with any
adverse experience
-Blocker
(n = 68)
Calcium
channel
blocker
(n = 43)
HCTZ
(n = 271)
Asthenia/fatigue
3.8
2.9
3.9
6.7
5.9
0.0
5.5
Cough
3.1
2.6
2.6
8.8
0.0
2.3
4.1
Diarrhea
1.9
1.5
1.9
2.9
0.0
4.7
Dizziness
4.1
5.7
2.4
6.3
7.4
2.3
Edema
1.7
1.3
1.9
1.7
1.5
14.0
19.1
14.0
14.1
7.7
17.2
10.9
Upper respiratory
infection
Headache
6.5
6.1
5.6
5.4
Insomnia
1.1
0.5
0.7
0.8
1.5
4.4
7.0
2.3
0.4
4.1
1.8
14.0
5.5
1.1
ACE - angiotensin-converting enzyme; HCTZ = hydrochlorothiazide. *During treatment or within 14 days after discontinuing the test drug. (Adapted with permission from Amer J Cardiol, Ref. 83.)
differentiate newer agents on the basis of bioavailability, onset of action, duration of action, tissue
penetration, or whether an active metabolite is
required for full biological activity. From a practical
point of view, losartan is a once-a-day drug that
blocks all of the cardiovascular effects of Ang II
whether formed by the classical RAS pathway or
through alternative biosynthetic pathways.
The specific site of action of losartan at the AT1
receptor appears to provide both the desired blockade of the Ang II system and an excellent tolerability
profile. The hypothetical concern about elevated circulating Ang II during losartan treatment interacting
with AT2 sites does not appear to be justified based
on current clinical experience (301). Although the
role of the AT2 sites remains largely unknown, therapeutic doses (50 or 100 mg/day) for periods of up to
2 years in patients with hypertension have continued
to show good tolerance (83).
Losartan lowers blood pressure comparable to
other classes of currently used antihypertensive
agents, including ACE inhibitors, calcium channel
blockers, -blockers and diuretics (308). Fewer
adverse reactions have been noted with losartan
than with felodipine, hydrochlorothiazide or atenolol.
Although ACE inhibitors were generally well tolerated in comparative trials with losartan, the incidence of dry cough was significantly greater (8.8%
for ACE inhibitors, and 2.6 and 3.1 % for placebo and
losartan, respectively) (83).
The long-term benefits of losartan in patients
with hypertension are unknown. Although more than
1700 patients have taken losartan for more than 1
year in extensions of clinical trials and for which
adverse experiences have been recorded, no morbidity/mortality data are currently available. A wealth
of preclinical data supports the probable efficacy of
the chronic use of losartan in hypertensive patients
and in heart failure. A 5-year endpoint (cardiovascular morbidity and mortality) trial is, however, under
way in Scandinavia and the United States, This trial,
designated the LIFE Trial (Losartan intervention for
Endpoint Reduction), is a double-blind, comparative
trial of losartan- and atenolol-based regimens in
hypertensive patients with left ventricular hypertrophy identified by sensitive ECG criteria. This trial will
include approximately 8300 patients and is scheduled to be completed by the end of the year 2000.
Beneficial effects of fosartan on renal function
and proteinuria have been demonstrated in an openlabel, short-term study in patients with proteinuria
(273). In addition, a number of preclinical studies
have shown that losartan and other AT1-selective
antagonists have beneficial effects in various models pf renal dysfunction (see above). Extrapolating
the results from preclinical studies, it is anticipated
484
MEDICAMENTOS DE ACTUALIDAD
(48-week) trial of losartan treatment in elderly
patients with congestive heart failure (CHF) is under
way. In this trial, designated ELITE, the effect of
losartan on renal safety parameters in elderly
patients will be compared to captopril.
Losartan is the first of a rapidly expanding class
of antihypertensive agents. For the first time, it is
possible to selectively inhibit the "angiotensin II system". The results of the long-term studies with losartan and with the other AT1-selective antagonists to
follow should clearly define the pathological role of
Ang II. From what we know from the early clinical
trials with losartan and from the wealth of preclinical
data, Ang II acting through the AT1 receptor: 1)
behaves as a potent vasoconstrictor, increasing
pressure and decreasing blood flow, 2) effects tissue
damage at the cellular level in blood vessels, kidney,
heart, and possibly brain, and 3) may result in a detrimental cascade of effects resulting in decreased survival. AT1 receptor blockade holds the possibility of
preventing or attenuating each of these effects.
Fig. 10. Losartan in heart failure. Plots of mean change
in pulmonary capillary wedge pressure (mmHg) from pretreatment baseline levels (A) after short-term therapy and
(B) after 12 weeks of therapy (placebo,  ; losartan 2.5,
O; losartan 10 mg, ; losartan 25 mg, Δ ; losartan 50 mg,
◊). Shaded symbols indicate a significant difference (p 
0.05) between losartan and placebo groups. (Reproduced with permission from Circulation, Copyright 1995,
American Heart Association, Ref. 281.)
that losartan will have long-term beneficial effects in
clinical syndromes of renal dysfunction, e.g., diabetic nephropathy and nephropathies of other etiologies, but this will require extensive clinical trials.
The long-term effects of losartan in heart failure
have not been established. Preclinically, losartan
has been shown to have beneficial effects on hemodynamics, ventricular remodeling and survival in
rodent models of heart failure. In clinical trials in
patients with heart failure, losartan produces beneficial hemodynamic effects both acutely (309) and
after 12 weeks of treatment (281). A long-term
References
1. Timmermans, P.B.M.W.M., Carini, D.J., Chiu,
AT., Duncia, J.V., Price, W.A., Wells, G.J.,
Wong, PC., Wexler, R.R., Johnson, A.L. Angio
tensin II receptor antagonists: From discovery to
antihypertensive drugs. Hypertension 1991,
18(Suppl. Ill, No. 5): III-136-42.
2. Duncia, J.V., Carini, D.J., Chiu, AT., Johnson,
A.L., Price, W.A., Wong, PC., Wexler, R.R., Tim
mermans, P.B.M.W.M. The discovery of DuP
753, a potent, orally active nonpeptide angioten
sin II receptor antagonist. Med Res Rev 1992,
12(2): 149-91.
3. Carini, D.J., Duncia, J.V. The discovery and
development of the nonpeptide angiotensin II
receptor antagonists. Adv Med Chem 199.3, 2:
153-95.
4. Smith, R.D., Chiu, AT., Wong, P.C., Herblin,
W.F., Timmermans, P.B.M.W.M. Pharmacology
of nonpeptide angiotensin II receptor antago
nists. Annu Rev Pharmacol Toxicol 1992, 32:
135-65.
5. Timmermans, P.B.M.W.M., Wong, P.C., Chiu,
AT, Herblin, W.F., Benfield, P., Carini, D.J., Lee,
R.J., Wexler, R.R., Saye, J.M., Smith, R.D.
Angiotensin II receptors and angiotensin II
receptor antagonists. Pharmacol Rev 1993,
45(2): 205-51.
6. Peach, M.J., Dostal, D.E. The angiotensin II
receptor and the actions of angiotensin II. J Cardiovasc Pharmacol 1990, 16(Suppl. 4): S25-30.
7. Ferrario, C.M. Importance of the renin-angiotensin-aldosterone system (RAS) in the physiology
DRUGS OF TODAY Vol. 31, No. 7, 1995
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
and pathology of hypertension. Drugs 1990,
39(Suppl. 2): 1-8.
Alderman, M.H., Madhovan, S., Qoi, W.L.,
Cohen, H., Sealey, J.E., Laragh, J.H. Associa
tion of the renin-sodium profile with the risk of
myocardial infarction in patients with hyperten
sion. New Engl J Med 1991, 324: 1098-104.
Goldblatt, H., Lynch, J., Hanzel, R.E., Summerville, W.W. Studies on experimental hyperten
sion: II. The production of persistent elevation of
systolic blood pressure by means of renal ische
mia. J Exp Med 1934, 59: 347-79.
Bright, R. Tabular view of the morbid appear
ances in 100 cases connected with albuminous
urine with observations. Guy's Hospital Rep
1836,1:380-400.
Tigerstedt, R., Bergman, P.G. Kidney and Circ
Scand Arch Physiol 1898, 7-8: 223-71.
Page, I.H., Helmer, O.M. A crystalline pressor
substance (angiotonin) resulting from the reac
tion between renin and renin activator. J Exp
Med 1940, 71:29-42.
Braun-Mendez, E., Fasciolo, E., Leloir, J.C.,
Munoz, J.M. The substance causing
renal hypertension. J Physiol (London)
1940, 98:283-98,
Peart, W.S. The isolation of a hypertensin, BiochemJ 1956, 62:520-7.
Skeggs, L.T. Jr.,Kahn, J.R., Shumway, N.P.
The purification of hypertensin II. J Exp Med
1956,103:301-7.
Bumpus, F.M., Schwartz, H., Page, I.H. Synthe
sis and pharmacology of the octapeptide
angiotensin. Science 1957, 125: 886-7.
Schwyzer, R., Iselin, B., Kappelei, H., Riniker, B.
Uber die partielle hydrolyse von hypertensinasp- -amiden zu den entsprechenden dicarbonsauren - Hypertensin ll-analoge. Chimica
1957,11:335-6.
Khosla, M.C., Smeby, R.R., Bumpus, F.M.
Structure-activity relationship in angiotensin II
analogs. In: Handbook of Experimental Phar
macology, Vol. XXXVII, Angiotensin. Page, I.H.,
Bumpus, F.M. (Eds.). Springer-Verlag, Berlin
1974,126-61.
Khosla, M.C., Bachynsky, E., Forgac, S.,
Lakios-Cherpas, C., Bumpus, F.M. Angiotensin
analogues that selectively augment the force of
contraction of the isolated heart. Hypertension
1988, ll(Suppl. I): 138-41.
Pals, D.T., Mascucci, F.D., Denning, G.S.,
Sipos, F., Fessler, D.C. Role of the pressor
action of angiotensin II in experimental hyper
tension. Circ Res 1971, 29: 673-81.
Anderson, G.H. Jr., Dalakos, T.G., Elias, A.,
Tomycz, N., Streeten, D.H.P. Diuretic therapy
485
and response of essential hypertension to saralasin. Ann Intern Med 1977, 87: 183-7.
22. Anderson, G.H. Jr., Streeten, D.H.P, Dalakas,
T.G. Pressor responses to 1-Sar-8-Ala-angiotensin II (saralasin) in hypertensive: subjects.
Circ Res 1977, 40(3): 243-50.
23. Buhler, F.R., Laragh, J.H., Baer, L., Vaughan,
E.D. Jr., Brunner, H.R. Propranolol inhibition of
renin secretion. A specific approach to diagno
sis and treatment of renin dependent hyperten
sive diseases. New Engl J Med 1972, 287:
1209-14.
24. McDevitt, D.G. Pharmacological characteristics
of (3 blockers and their role in clinical practice. J
Cardiovasc Pharmacol 1986, 8(Suppl. 6):
S5-11.
25. McDevitt, D.G. Position Paper: Different fea
tures of beta adrenoreceptor blocking drugs
for therapy. In: Frontiers in Hypertension
Research. Laragh, J.H., Buhler, F.R., Seldin,
D.W. (Eds.). Springer-Verlag, New York 1981,
473-81.
26. Buhler, F.R. Position Paper:Antihypertensive
actions of beta-blockers. In: Frontiers in Hyper
tension Research. Laragh, J.H., Buhler,
F.R., Seldin, D.W. (Eds.). Springer-Verlag,
New York 1981,423-35.
27. Leonetti, G., Cuspidi, C. Choosing the right
ACE inhibitor - A guide to selection. Drugs
1995,49(4): 516-35.
28. Young, J.B. Reduction of ischemic events with
angiotensin converting enzyme inhibitors: Les
sons and controversy emerging from recent
clinical trials. Cardiovasc Drug Ther 1995, 9(1):
89-102.
29. Burris, J.F. The expanding role of angiotensin
converting enzyme inhibitors in the manage
ment of hypertension. J Clin Pharmacol 1995,
35(4): 337-42.
30. Skeggs, L.T. Jr. Historical overview of the reninangiotensin system. In: Hypertension and the
Angiotensin System: Therapeutic Approaches.
Doyle, A.E., Beam, A.G. (Eds.). Raven Press,
New York 1984, 31-45.
31. Siegl, P.K.S., Kivlighn, S.D., Broten, T.P., Schaffer, L.W. Pharmacology of angiotensin II recep
tor antagonists: Comparison with renin inhibi
tors and angiotensin-converting enzyme
inhibitors. Unpublished 1994.
32. Kleinert, H.D., Stein, H.H. Specific renin inhibi
tors: Concepts and prospects. In: Hypertension:
Pathophysiology, Diagnosis, and Management,
2nd Ed. Laragh, J.H., Brenner, B.M. (Eds.).
Raven Press, New York 1995, 3065-77.
33. Lunney, E.A., Humblet, C. Renin inhibitor design
though molecular modeling. In: Medicinal
Chemistry of tha Renin Angiotensin System,
486
21st Ed. Timmermans, P.B.M.W.M., Wexier,
R.R. (Eds.). Elsevier, Lausanne 1994, 73-101.
34. Unger, T., Gohike, P. Converting enzyme inhibi
tors in cardiovascular therapy: Current status
and future potential. Cardiovasc Res 1994,
28(2): 146-58.
35. Struthers, A.D. The clinical pharmacology, of
angiotensin converting enzyme inhibitors in
chronic heart failure. Pharmacol Ther 1992, 53:
187-97.
36. Keilani, T., Schlueter, W., Batlle, D. Selected
aspects of ACE inhibitor therapy for patients
with renal disease: Impact on proteinuria, lipids
and potassium. J Clin Pharmacol 1995, 35(1):
87-97.
37. Weidmann, P. Differential effects of antihypertensive drugs on hypertension - Associated risk
factors. Cardiology 1994, 85(S1): 78-83.
38. Hall, J.M. Bradykinin receptors: Pharmacologi
cal properties and biological roles. Pharmacol
Ther 1993, 56: 131-90.
39. Sunman, W., Sever, P.S. Nonangiotensin
effects of angiotensin converting enzyme inhibi
tors. Clin Sci 1993, 85: 661-70.
40. Linz, W., Henning, R., Scholkens, B.A. Role of
angiotensin II receptor and converting enzyme
inhibition in the progression and regression of
cardiac hypertrophy in rats. J Hypertens 1992,
9(Suppl. 6): 400-1S.
41. Rhaleb, N.E., Yang, X.P., Scicli, A.G., Carretero,
O.A. Role of kinins and nitric oxide in the antihypertrophic effect of ramipril. Hypertension 1994,
23(Pt. 2): 865-8.
42. Farhy, R.D., Carretero, O.A., Ho, K.L., Scicli,
A.G. Role of kinins and nitric oxide in the effects
of angiotensin converting enzyme inhibitors on
neointima formation. Circ Res 1993, 72(6):
1202-10.
43. Barnes, J.M., Barber, P.C., Barnes, N.M. Char
acterisation of angiotensin II receptor subtypes
in human cerebellar membranes. Brit J Pharma
col 1992, 106(Suppl.): 135P (Abst).
44. Prescott, M.F., Webb, R.L., Reidy, M.A. Angio
tensin converting enzyme inhibitor versus
angiotensin II, AT1 receptor antagonist. Amer J
Pathol 1992, 139(6): 1291-6.
45. Hartman, J.C., Hullinger, T.G., Wall, T.M., Shebuski, R.J. Reduction of myocardial infarct size
by ramiprilat is independent of angiotensin II
synthesis inhibition. Eur J Pharmacol 1993,
234(2-3): 229-36.
46. Miki, T., Miura, T., Shamamoto, K., Urabe, K.,
Sakamoto, J., limura, O. Do angiotensin con
verting enzyme inhibitors limit myocardial infarct
size?Clin Exp Pharmacol Physiol 1993, 20(6):
429-34.
MEDICAMENTOS DE ACTUALIDAD
47. Campbell, D J., Kladis, A., Duncan, A.M. Effects
of converting enzyme inhibitors on angiotensin
and bradykinin peptides. Hypertension 1994,
23(4): 439-49.
48. Wong, P.C., Hart, S.D., Zaspel, A., Chiu, AT.,
Smith, R.D., Timmermans, P.B.M.W.M. Functional studies of nonpeptide angiotensin II
receptor subtype-specific ligands: DuP 753
(AII-1) and PD123177(AII-2). J Pharmacol Exp
Ther 1990, 255(2): 584-92.
49. Cachofeiro, V., Sakakibara, T., Nasjletti, A.
Kinins, nitric oxide, and the hypotensive effect of
captopril and ramiprilat in hypertension. Hyper
tension 1992, 19(2): 138-45.
50. Geppetti, P. Sensory neuropeptide release by
bradykinin: Mechanisms and pathophysiological implications. Regul Pept 1993, 47: 1-23.
51. Ogilvie, R.I. Research report - Acute effects of
captopril, DuP 532 and Ro 44-9375 on hemodynamics and total vascular capacitance in exper
imental acute heart failure. Unpublished 1994.
52. Peach, M.J. Renin-angiotensin system: Bio
chemistry and mechanisms of action. Physiol
Rev 1977,57:313-70.
53. Phillips, M.I., Speakman, E.A., Kimura, B. Tis
sue renin angiotensin systems. In: Cellular and
Molecular Biology of the Renin Angiotensin Sys
tem. Raizada, M.K., Phillips, M.I., Sumners, C.
(Eds.). CRC Press, Inc., Boca Raton 1993,
97-130.
54. Husain, A. The chymase angiotensin system in
humans. J Hypertens 1993, 11: 1155-9.
55. Furakawa, Y., Kishimoto, S., Nishikawa, K.
(Takeda Chem. Inds., Ltd.). Hypotensive imidazole derivatives and hypotensive imidazole-5-acetic acid derivatives. US 4340598, US
4355040.
56. Wong, P.O., Chiu, A.T., Price, W.A., Thoolen,
M.J.M.C., Carini, D.J., Johnson, A.L., Taber,
R.I., Timmermans, P.B.M.W.M. Nonpeptide
angiotensin II receptor antagonists. I. Pharma
cological characterization of 2-n-butyl-4-chloro1-(2-chlorobenzyl)imidazole-5-acetic
acid,
sodium salt (S-8307). J Pharmacol Exp Ther
1988,247:1-7.
57. Bovy, P.R., Olins, G.M. Recent advances in nonpeptidic angiotensin II receptor antagonists. In:
Current Drugs: Renin Angiotensin System. Cur
rent Patents, Ltd. 1992, B17-34.
58. Buhlmayer, P. Angiotensin II antagonists: Pat
ent activity since the discovery of DuP 753. Curr
Opin Ther Pat 1992, 2(1): 1693-718.
59. Wong, P.C., Tam, S.W., Herblin, W.F., Timmer
mans, P.B.M.W.M. Further studies on the selec
tivity of DuP 753, a nonpeptide angiotensin II
DRUGS OF TODAY Vol. 31, No. 7, 1995
receptor antagonist. Eur J Pharmacol 1991,
196:201-3.
60. Liu, E.C.K., Hedberg, A., Goldenberg, H.J., Har
ris, D.N., Webb, M.L. DuP 753, the selective
angiotensin II receptor blocker, is a competitive
antagonist to human platelet thromboxane
A2/prostaglandin H 2 (TP) receptors. Prostaglandins 1992, 44(2): 89-99.
61. Chretien, L, Guillemette, G., Regoli, D. Nonpeptide angiotensin receptor antagonists bind
to tachykinin NK3 receptors of rat and guinea pig
brain. Eur J Pharmacol 1994, 256(1): 73-8.
62. Shibouta, Y., Inada, Y, Ojima, M., Wada, T.,
Noda, M., Sanada, T., Kubo, K., Kohara, Y,
Naka, T., Nishikawa, K. Pharmacological profile
of a highly potent and long acting angiotensin II
receptor antagonist [(2'-(1H-tetrazol-5-yl)biphenyl - 4 - yl)methyl] - 1H- benzimidazole - 7 - carboxylic acid (CV-11974), and its prodrug, (±)-i(cyclohexyloxycarbonyloxy)-ethyl 2-ethoxy-1 1(2' - (1H - tetrazol - 5 - yl)biphenyl - 4 - yl)methyl] - 1H - benzimidazole - 7 - carboxylate
(TCV-116). J Pharmacol ExpTher 1993,266(1 ):
114-20.
63. Wienen, W., Mauz, A.B.M., VanMeel, J.C.A.,
Entzeroth, M. Different types of receptor interac
tion of peptide and nonpeptide angiotensin llantagonists revealed by receptor binding and
functional studies. Mol Pharmacol 1992, 41(6):
1081-8.
64. Criscione, L., Thomann, H., Whitebread, S.,
DeGasparo, M., Buhlmayer, P., Herold, P,
Ostermayer, F, Kamber, B. Binding characteris
tics and vascular effects of various angiotensin
II antagonists. J Cardiovasc Pharmacol 1990,
16(Suppl.4):S56-9.
65. Rhaleb, N.E., Rouissi, N., Nantel, R, D'OrleansJuste, P., Regoli, D. DuP 753 is a specific antag
onist for the angiotensin receptor. Hypertension
1991, 17:480-4.
66. Timmermans, P.B.M.W.M., Wong, PC., Chiu ;
AT., Herblin, W.R Nonpeptide angiotensin II
receptor antagonists. Trends Pharmacol Sci
1991, 12:55-62.
67. MacFadyen, R.J., Tree, M., Lever, A.F, Reid,
J.L. Effects of the angiotensin II receptor antag
onist losartan (DuP 753/MK 954) oh arterial
blood pressure, heart rate, plasma concentra
tions of angiotensin II and renin and the pressor
response to infused angiotensin II in the salt
deplete dog.Clin Sci 1992, 83: 549-56.
68. Chan, D.P., Sandok, E.K., Aarhus, L.L., Heublein, D.M., Burnett, J.C. Jr. Renal specific
actions of angiotensin II receptor antagonism in
the anesthetized dog. Amer J Hypertens 1992,
5:354-60.
487
69. ElAmrani, A.I.K., Menard, J., Gonzales, M.F,
Michel, J.B. Effects of blocking the angiotensin
II receptor, converting enzyme, and renin activ
ity on the renal hemodynamics of normotensive
guinea pigs. J Cardiovasc Pharmacol 1993,
22(2): 231-9.
70. DeGraaf, G.L, Pals, D.T., Couch, S.J., Lawson,
J.A. Hormonal and cardiovascular effects of
losartan (DuP 753), an angiotensin receptor
antagonist, in nonhuman primates. J Pharmacol
ExpTher 1993, 264(1): 6-66.
71. Smid, S.D., Hime, N.J., Frewin, D.B., Head, R.J.
Losartan reverses the angiotensin II mediated
facilitation of sympathetic nerve transmission in
the perfused rat mesenteric preparation. Clin
Exp Pharmacol Physiol 1992, Suppl. 21: 65
(Abst).
72. Balla, T, Baukal, A.J., Eng, S., Catt, K.J. Angio
tensin II receptor subtypes and biological
responses in the adrenal cortex and medulla.
Mol Pharmacol 1991, 40: 401-6.
73. Tofovic, S., Pong, A., Jackson, E.K. Effects of
angiotensin subtype 1 and subtype 2 receptor
antagonists in normotensive versus hyperten
sive rats. Hypertension 1991, 18(6): 774-82.
74. Mizuno, K., Niimura, S., Tani, M., Haga, H.,
Gomibuchi, T, Sanada, H., Fukuchi, S. Antihypertensive and hormonal activity of MK 954 in
spontaneously hypertensive rats. Eur J Phar
macol 1992,215:305-8.
75. Wong, PC., Price, W.A., Chiu, AT., Carini, D.J.,
Duncia, J.V., Johnson, A.L., Wexler, R.R., Tim
mermans, P.B.M.W.M. Nonpeptide angiotensin
II receptor antagonists: Studies with EXP 9270
and DuP 753. Hypertension 1990, 15: 823-34.
76. Blair-West, J.R., Burns, P., Denton, D.A., Ferraro, T, McBurnie, M.I., Tarjan, E., Weisinger,
R.S. Thirst induced by increasing brain sodium
concentration is mediated by brain angiotensin.
Brain Res 1994, 637(1-2): 335-8.
77. Li, Z., Ferguson, A.V. Electrophysiological evi
dence that subfornical organ efferents to the
paraventricular nucleus utilize angiotensin as
an excitatory neuretransmitter in the rat. Unpub
lished 1993.
78. Matsuo, K., Kumagai, K., Onon, M., Yamanouchi, Y, Handa, K., Nakashima, Y, Arakawa, K.
Protective effects of MK954 on reperfusion arr
hythmias in the dog. Unpublished 1992.
79. Song, K., Zhuo, J., Mendelsohn, F.A.O. Access
of peripherally administered DuP 753 to rat brain
angiotensin II receptors. Brit J Pharmacol 1991,
104:771-2.
80. Smith, R.D., Timmermans, P.B.M.W.M. Human
angiotensin receptor subtypes. Curr Opin Nephrol Hypertens 1994, 3: 112-22.
488
81. Timmermans, P.B.M.W.M., Smith, R.D. Angiotensin II receptor subtypes: Selective antago
nists and functional correlates. Eur Heart J
1994, 15(Suppl. D): 79-87.
82. Timmermans, P.B.M.W.M., Wong, P.C., Chiu,
AT., Smith, R.D. The preclinical basis of the
therapeutic evaluation of losartan. J Hypertens
1995, 13(Suppl. 1): S1-13.
83. Goldberg, A.I., Dunlay, M.C., Sweet, C.S.
Safety and tolerability of losartan potassium, an
angiotensin II receptor antagonist, compared
with hydrochlorothiazide, atenolol, felodipine
ER, and angiotensin-converting enzyme inhibi
tors for the treatment of systemic hypertension.
Amer J Cardiol 1995, 75(12): 793-5.
84. Inagami, T, Guo, D.F., Kitami, Y. Molecular biol
ogy of angiotensin II receptors: An overview. J
Hypertens 1994, 12(S10): S83-94.
85. Veltmar, A., Culman, J., Qadri, F, Rascher, W.,
Unger, T. Involvement of adrenergic and angiotensinergic receptors in the paraventricular
nucleus in the angiotensin II induced vasopressin release. J Pharmacol Exp Ther 1992,
263(3): 1253-74.
86. Toney, G.M., Porter, J.P. Functional role of brain
AT1 andAT 2 receptors in the central angiotensin
II pressor response. Brain Res 1993, 603(1):
57-63.
87. Toney, G.M., Porter, J.P. Functional roles of
brain AT1 andAT 2 receptors in the central angio
tensin II pressor response in conscious young
spontaneously hypertensive rats. Dev Brain
Res 1993, 71: 193-9.
88. Hogarty, D.C., Speakman, E.A., Puig, V., Phil
lips, M.I. The role of angiotensin, AT 1 and AT 2
receptors In the pressor, drinking and vasopressin responses to central angiotensin. Brain Res
1992, 586(2): 289-94.
89. Rippetoe, P.E., Fitz, R., Painter, D., Soltis, E.,
Gillespie, M.N., Cassis, L. Angiotensin (AII) and
monocrotaline (MCT)-induced pulmonary
hypertension: Effect of DuP 753, a nonpeptide
AII-1 receptor antagonist. FASEB J 1991, 5(4,
Pt. I): A535 (Abst).
90. Rump, L.C., Schwertfeger, E., Schaible, U.,
Fraedrich, G., Schollmeyer, P. 2 Adrenergic
receptor and angiotensin II receptor modulation
of sympathetic neurotransmission in human
atria. Circ Res 1994, 74(3): 434-40.
91. Foucart, S., Patrick, S.K., Oster, L., DeChamplain, J. Effects of chronic treatment with losar
tan and enalaprilat on [ 3 H]-noradrenaline from
isolated atria of WKY and SHR rats. Unpub
lished 1994.
MEDICAMENTOS DE ACTUALIDAD
92. Rump, L.C. Angiotensin (A) II receptor blockade
and neurotransmission in human kidney cortex.
J Hypertens 1994, 12(Suppl. 3): 868 (Abst).
93. Niederberger, M., Nussberger, J., Brunner,
H.R., Waeber, B. Effects of ACE inhibition,
angiotensin II receptor blockade and Na-nitroprusside on sympathetic nerve activity of renal
hypertensive rats. Circulation 1990, 82(4):
III-684 (Abst).
94. Wong, PC., Bernard, R., Timmermans,
P.B.M.W.M. Effect of blocking angiotensin II
receptor subtype on rat sympathetic nerve function. Hypertension 1992, 19(6, Pt. 2): 663-7.
95. Hilgers, K.F., Veelken, R., Ganten, D., Luft, F.C.,
Geiger, H., Mann, J.F.E. Vascular angiotensin
formation and the sympathetic nervous system
in Ren-2 transgenic hypertensive and control
rats. Hypertension 1993, 22(3): 424 (Abst).
96. Schwieler, J.H., Kahan, T, Nussberger, J.,
Hjemdahl, P. Converting enzyme inhibition mod
ulates sympathetic neurotransmission in vivo
via multiple mechanisms. Amer J Physiol 1993,
264(27): E631-7.
97. Wong, PC., Price, W.A., Chiu, A.T., Duncia, J.V.,
Carini, D.J., Wexler, R.R., Johnson, A.L., Tim
mermans, P.B.M.W.M. Nonpeptide angiotensin
II receptor antagonists. IX. Antihypertensive
activity in rats of DuP 753, an orally active antihypertensive agent. J Pharmacol Exp Ther
1990,252(2): 726-32.
98. Ling, Q., Guo, Z.G., Su, Z., Guo, X. Regression
of cardiac hypertrophy and myosin isoenzyme
patterns by losartan and captopril in renovascular hypertensive rats. Acta Pharmacol Sin 1994,
15(3): 206-10.
99. Wilm, C., Lues, I., Schelling, P. Regression of
vascular hypertrophy in renal hypertensive rats
treated with the angiotensin II antagonist losar
tan. J Hypertens 1994, 12(Suppl. 3): S90.
100. Schudeck, R., Jalil, J.E., Vio, C., Nalli, A., Cespedes, C., Ebensperger, R. Regression of renal
fibrosis and damage in experimental renovascular hypertension using an angiotensin type 1
receptor antagonist. J Amer Coll Cardiol 1994,
Special Issue: 332A (Abst).
101. Tabrizchi, R., Lupichuk, S.M. The effects of
losartan and captopril on vasopressor actions of
cirazoline in the absence and presence of
SZL-49 and nifedipine. J Cardiovasc Pharmacol
1995,26(1): 137-44.
102. Bunkenburg, B., Schnell, C., Baum, H.P,
Cumin, F, Wood, J.M. Prolonged angiotensin II
antagonism in spontaneously hypertensive rats
DRUGS OF TODAY Vol. 31, No. 7, 1995
- Hemodynamic and biochemical consequences. Hypertension 1991, 18(3): 278-88.
103. Soltis, E.E., Jewell, A.L., Dwoskin, L.P., Cassis,
L.A. Acute and chronic effects of losartan (DuP
753) on blood pressure and vascular reactivity
in normotensive rats. Clin Exp Hypertension
1993, 15(1): 171-84.
104. Wong, P.C., Hart, S.D., Duncia, J.V., Timmermans, P.B.M.W.M. Nonpeptide angiotensin II
receptor antagonists. XIII. Studies with DuP 753
and EXP3174 in dogs. Eur J Pharmacol 1991,
202: 323-30.
105. Doig, J.K.,MacFadyen,R.J., Sweet, C.S., Reid,
J.L. Hemodynamic and renal responses to oral
losartan potassium during salt depletion in nor
mal human volunteers. J Cardiovasc Pharmacol
1995, 25(1): 511-7.
106. Wong, P.C., Price, W.A., Chiu, AT, Duncia,
J.V., Carini, D.J., Wexler, R.R., Johnson, A.L.,
Timmermans, P.B.M.W.M. Pharmacology of
EXP3174, a metabolite of DuP 753, an orally
active nonpeptide angiotensin II (All) receptor
antagonist. J Hypertens 1990, 8(Suppl. 3): S42
(Abst).
107. McMahon, T.J., Kaye, A.D., Hood, J.S., Minkes,
R.K., Nossaman, B.D., Kadowitz, P.J. Inhibitory
effects of DuP 753 and EXP3174 on responses
to angiotensin II in pulmonary vascular bed of
the cat. J Appl Physiol 1992, 73(5): 2054-61.
108. Chiu, AT., Leung, K.H., Smith, R.D., Timmer
mans, P.B.M.W.M. Defining angiotensin recep
tor subtypes. In: Cellular and Molecular Biology
of the Renin Angiotensin System. Raizada,
M.K., Phillips, M.I., Sumners, C. (Eds.). CRC
Press, Inc., Boca Raton 1993, 245-71.
109. Christ, D.D., Wong, PC., Wong, Y.N., Hart,
S.D., Quon, C.Y., Lam, G.N. The pharmacokinetics and pharmacodynamics of the angioten
sin II receptor antagonist losartan potassium
(DuP 753/MK954) in the dog. J Pharmacol Exp
Ther 1994, 268(3): 1199-205.
110. Stearns, R.A., Miller, R.R., Doss, G.A., Chakravarty, P.K., Rosegay, A., Gatto, G.J., Chiu,
S.H.L. The metabolism of DuP 753, a nonpep
tide angiotensin II receptor antagonist, by rat,
monkey and human liver slices. Drug Metab
Dispos 1992, 20(2): 281-7.
111. Krieter, P.A., Colletti, A.E., Miller, R.R,, Stearns,
R.A. Absorption and glucuronidation of the
angiotensin II receptor antagonist losartan by
the rat intestine. J Pharmacol Exp Ther 1995,
273(2): 816-22.
112. Christen, Y, Waeber, B., Nussberger, J., Porchet, M., Lee, R., Maggon, K., Shum, L., Tim
mermans, P.B.M.W.M., Brunner, H.R., Borland,
R.M. Oral administration of DuP 753, a specific
489
angiotensin II antagonist, to normal male volunteers: Inhibition of pressor response to exogenous angiotensin I and II. Circulation 1991,
83(4): 1333-42.
113. Timmermans, P.B.M.W.M., Chiu, AT., Herblin,
W.F., Wong, P.C., Smith, R.D. Angiotensin II
receptor subtypes. Amer J Hypertens 1992, 5:
406-10.
114. Timmermans, P.B.M.W.M., Benfield, P., Chiu,
AT., Herblin, W.F., Wong, P.C., Smith, R.D.
Angiotensin II receptors and functional corre
lates. Amer J Hypertens 1992, 5: 221-35S.
115. Chiu, AT., Herblin, W.F., Ardecky, R.J., McCall,
D.E., Carini, D.J., Duncia, J.V., Pease, L.J.,
Wexler, R.R., Wong, P.C., Johnson, A.L., Tim
mermans, P.B.M.W.M. Identification of angio
tensin II receptor subtypes. Biochem Biophys
Res Commun 1989, 165(1): 196-203.
116. Whitebread, S., Mele, M., Kamber, B., DeGasparo, M. Preliminary biochemical characteriza
tion of two angiotensin II receptor subtypes. Bio
chem Biophys Res Commun 1989,163:284-91.
117. Bumpus, F.M., Catt, K.J., Chiu, AT., DeGasparo, M., Goodfriend, T, Husain, A., Peach,
M.J., Taylor, D.G. Jr., Timmermans, P.B.M.W.M.
Nomenclature for angiotensin receptors. Hyper
tension 1991, 17(5): 720-1.
118. DeGasparo, M., Husain, A., Alexander, W.,
Catt, K.J., Chiu, AT, Drew, M., Goodfriend, T,
Harding, J.W., Inagami, T., Timmermans,
P.B.M.W.M. Proposed update of the angiotensin
receptor nomenclature. Hypertension 1995,
25(5): 924-7.
119. Cazaubon, C., Gougat, J., Bousquet, F., Guiraudou, P., Gayraud, R., Lacour, C., Roccon, A.,
Galindo, G., Barthelemy, G. Pharmacological
characterization of SR 47436, a new nonpeptide
AT1 subtype angiotensin II receptor antagonist.
J Pharmacol Exp Ther 1993, 265(2): 826-34.
120. Criscione, L., DeGasparo, M., Buhlmayer, P.,
Whitebread, S., Ramjoue, H.P., Wood, J.M.
Pharmacological profile of valsartan: A potent,
orally active, nonpeptide antagonist of the
angiotensin II AT1 receptor subtype. Brit J Phar
macol 1993, 110(2): 761-71.
121. Catt, K.J., Sandberg, K., Balla, T. Angiotensin II
receptors and signal transduction mechanisms.
In: Cellular and Molecular Biology of the Renin
Angiotensin System. Raizada, M.K., Phillips,
M.I., Sumners, C. (Eds.). CRC Press, Inc., Boca
Raton 1993, 307-56.
122. Macari, D., Bottari, S.P., Whitebread, S.,
DeGasparo, M., Levens, N. Renal actions of the
selective angiotensin AT2 receptor ligands CGP
42112B and PD 123319 in the sodium depleted
rat. Eur J Pharmacol 1993, 249(1): 85-93.
490
123. Chiu, AT., McCall, D.E., Ardecky, R.J., Duncia,
J.V., Nguyen, T.T., Timmermans, P.B.M.W.M.
Angiotensin. II receptor subtypes and their
selective nonpeptide ligands. Receptor 1990,1:
33-40.
124. Crawford, K.W., Frey, E.A., Cote, T.E. Angiotensin II receptor recognized by DuP753 regulates
two distinct guanine nucleotide-binding protein
signaling pathways. Mol Pharmacol 1992,
41(1): 154-62.
125. Ohyama, K., Yamano, Y, Chaki, S., Kondo, T.,
Inagami, T. Domains for G-protein coupling in
angiotensin II receptor type 1: Studies by site-di
rected mutagenesis. Biochem Biophys Res
Commun 1992, 189(2): 677-83.
126. Wintersgiil, H.P., Warburton, P., Bryson, S.E.,
Ball, S.G., Balmforth, A.J. Characterization of
the angiotensin II receptor expressed by the
human hepatoma cell line, PLC-PRF-5. Eur J
Pharmacol 1992, 227: 283-91.
127. Pfeilschifter, J., Huwiler, A., Merriweather, C.,
Briner, V.A. Angiotensin II stimulation of phospholipase D in rat renal mesangial cells is
mediated by the AT 1 receptor subtype. Eur J
Pharmacol 1992, 225(1): 57-62.
128. Pfeilschifter, J. Angiotensin II B-type receptor
mediates phosphoinositide hydrolysis in
mesangial cells. Eur J Pharmacol 1990, 184:
201-2.
129. Ko, Y, Gorg, A., Appenheimer, M., Wieczorek,
A.J., Dusing, R., Vetter, H., Sachinidis, A. Losartan inhibits the angiotensin II induced stimula
tion of the phosphoinositide signaling system in
vascular smooth muscle cells. Eur J Pharmacol
1992, 227(2): 215-9.
130. Poggioli, J., Lazar, G., Houillier, P., Gardin, J.P.,
Achard, J.M., Paillard, M. Effects of angiotensin
II and nonpeptide receptor antagonists on the
transduction pathways in rat proximal tubule.
Amer J Physiol 1992, 263(32): C750-8.
131. Clyne, C.D., Nicol, M.R., MacDonald, S., Wil
liams, B.C., Walker, S.W. Angiotensin II stimu
lates growth and steroidogenesis in zona fasciculata/reticularis cells from bovine adrenal
cortex via the AT1 receptor subtype. Endocrinol
ogy 1993, 132(5): 2206-12.
132. Hajnoczky, G., Csordas, G., Hunyady, L, Kalapos, M.P., Balla, T., Enyedi, P., Spat, A. Angio
tensin II inhibits sodium/potassium pump in rat
adrenalglomerulosa cells: Possible contribution
to stimulation of aldosterone production. Endo
crinology 1992, 130(3): 1637-44.
133. Bunkenburg, B., VanAmelsvoort, T., Rogg, H.,
Wood, J.M. Receptor mediated effects of angio
tensin II on growth of vascular smooth muscle
MEDICAMENTOS DE ACTUALIDAD
cells from spontaneously hypertensive rats.
Hypertension 1992, 20(6): 746-54.
134. Keiser, J.A., Bjork, F.A., Hodges, J.C., Taylor,
D.G. Jr. Renal hemodynamic and excretory
responses to PD123319 and losartan, nonpep
tide AT1 and AT2 subtype specific angiotensin II
ligands. J Pharmacol Exp Ther 1992, 262(3):
1154-60.
135. Macari, D., Whitebread, S., Cumin, R, DeGasparo, M., Levens, N. Renal actions of the angio
tensin AT 2 receptor ligands CGP42112 and
PD 123319 after blockade of the renin angioten
sin system. Eur J Pharmacol 1994, 259(1):
27-36.
136. Stephenson, K.N., Steele, M.K. Brain angioten
sin II receptor subtypes and the control of luteinizing hormone and prolactin secretion in
female rats. J Neuroendocrinol 1992, 4(4):
441-7.
137. Mukoyama, M., Nakajima, M., Horiuchi, M.,
Sasamura, H., Pratt, R.E., Dzau, V.J. Expres
sion cloning of type 2 angiotensin II receptor
reveals a unique class of seven transmembrane
receptors. J Biol Chem 1993, 268(33):
24539-42.
138. Kambayashi, Y, Bardhan, S., Takahashi, K.,
Tsuzuki, S., Inui, H., Hamakubo, T., Inagami, T.
Molecular cloning of a novel angiotensin II
receptor isoform involved in phosphotyrosine
phosphatase inhibition. J Biol Chem 1993,
268(33): 24543-6.
139. Cox,B.E., Ipson, M.A., Shaul, P.W., Kamm,
K.E., Rosenfeld, C.R. Myometrial angiotensin II
receptor subtypes change during ovine preg
nancy. J Clin Invest 1993, 92: 2240-8.
140. Cox, B.E., Williams, C.E., Roy, T.A., Rosenfeld,
C.R. Angiotensin II (ANG II) may not directly
vasoconstrict the uteroplacental circulation in
pregnant ewes. FASEB J 1995, 9(4): A896
(Abst).
141. Grady, E.F., Kalinyak, J.E. Expression of AT2
receptors in rat fetal subdermal cells. Regul
Pept 1993, 44(2): 171-80.
142. Kang, J., Sumners, C., Posner, P. Angiotensin
II type 2 receptor modulated changes in potas
sium currents in cultured neurons. Amer J
Physiol 1993, 265(3): C607-16.
143. Kang, J., Posner, P., Sumners, C. Angiotensin
II type 2 receptor stimulation of neuronal K + cur
rents involves an inhibitory GTP binding protein.
Amer J Physiol 1994, 267(5, Pt. 1): C1389-97.
144. Morishita, R., Gibbons, G.H., Ellison, K.E., Lee,
W., Zhang, L., Yu, H., Kaneda, Y, Ogihara, T.,
Dzau, V.J. Evidence for direct local effect of
angiotensin in vascular hypertrophy in vivo gene
DRUGS OF TODAY Vol. 31, No. 7, 1995
transfer of angiotensin converting enzyme. J
Clin Invest 1994, 94(3): 978-84.
145. Kauffman, R.F., Bean, J.S., Zimmerman, K.M.,
Brown, R.F., Steinberg, M.I. Losartan, a nonpeptide angiotensin II (ANG II) receptor antago
nist, inhibits neointima formation following bal
loon injury to rat carotid arteries. Life Sci 1991,
49(25): PL223-8.
146. Bourgeois, R., Laporte, S., Escher, E. The myoproliferative response of vascular smooth
muscle after injury is angiotensin II mediated
through the AT1 receptor. FASEB J 1993, 7(3):
A47 (Abst).
147.Huckle, W.R., Drag, M.D., Acker, W.R., Powers,
M., Holder, D.J., Kim, D., Mantlo, N.B., Greenlee, W.J., Johnson, R.G. Neither an AT1 -selec
tive nor a balanced AT 1/AT 2 angiotensin II
receptor antagonist reduces neointimal thicken
ing in a porcine coronary artery injury model.
Unpublished 1994.
148. Stoll, M., Steckelings, U.M., Paul, M., Bottari,
S.P., Metzger, R., Unger, T. The angiotensin
AT2-receptor mediates inhibition of cell prolifer
ation in coronary endothelial cells. J Clin Invest
1995,95:651-7.
149. Okunishi, H., Shiota, N., Fukamizu, A., Takai,
S., Murakaml, K., Miyazaki, M. Angiotensin II
antagonist, non ACE inhibitor, prevents neointima formation on injured canine arteries. J
Hypertens 1994, 12(Suppl. 3): Abst 725.
150. Wong, P.C. Angiotensin antagonist in models of
hypertension. In: Angiotensin Receptors. Saavedra, J.M., Timmermans, P.B.M.W.M. (Eds.).
Plenum Press, New York 1994, 319-36.
151. Dostal, D.E., Baker, K.M. Angiotensin II stimula
tion of left ventricular hypertrophy in adult rat
heart. Amer J Hypertens 1992, 5: 276-80.
152. Everett, A.D., Tufro-McReddie, A., Fisher, A,,
Gomez, R.A. Angiotensin receptor regulates
cardiac hypertrophy and transforming growth
factor 1 expression. Hypertension 1994, 23(5):
587-92.
153. Bruckschlegel, G., Holmer, S.R., Jandeleit, K.,
Ackermann, B., Riegger, G.A.J, Schunkert, H.
The role of cardiac angiotensin conversion
enzyme in experimentally induced myocardial
hypertrophy in the rat. Nier Hochdruckkrank
1994, 23(4): 144-6.
154. Wong, P.C., Price, W.A., Chiu, AT., Duncia,
J.V., Carini, D.J., Wexler, R.R., Johnson, A.L.,
Timmermans, P.B.M.W.M. In vivo pharmacol
ogy of DuP 753. Amer J Hypertens 1991, 4(4):
288-98S.
155. Morton, J. J. Inhibiting the effects of angiotensin
II on cardiovascular hypertrophy in experimen
tal hypertension. In: Angiotensin Receptors.
491
Saavedra, J.M., Timmermans, P.B.M.W.M.
(Eds.). Plenum Press, New York 1994, 221-34.
156. Soitis, E.E. Alterations in vascular structure and
function after short term losartan treatment in
spontaneously hypertensive rats. J Pharmacol
Exp Ther 1993, 266(2): 642-6.
157. Ganten, D., Schelling, P., Flugel, R.M., Fischer,
H. Effect of angiotensin and the angiotensin
antagonist P113 on iso-renin and cell growth in
3T3 mouse cells. IRCS Med Sci Biochem 1975,
3:327.
158. Huckle, W.R., Earp, H.S. Regulation of cell pro
liferation and growth by angiotensin II. Prog
Growth Factor Res 1994, 5(2): 177-94.
159. Wolf, G. Regulation of renal tubular cell growth:
Effects of angiotensin II. Exp Nephrol 1994,
2(2): 107-14.
160. Wu, J.N., Edwards, D., Berecek, K.H. Changes
in renal angiotensin II receptors in sponta
neously hypertensive rats by early treatment
with the angiotensin converting enzyme inhibi
tor captopril. Hypertension 1994, 23(Pt 2):
819-22.
161. VonLutterotti, N., Camargo, M.J.F., Mueller,
F.B., Timmermans, P.B.M.W.M., Laragh, J.H.
Angiotensin II receptor antagonist markedly
reduces morbidity in salt-loaded Dahl S rats.
Amer J Hypertens 1991, 4(4, Pt. 2): 346-9S.
162. Camargo, M.J.F., VonLutterotti, N., Pecker,
M.S., James, G.D., Timmermans, P.B.M.W.M.,
Laragh, J.H. DuP 753 increases survival in
spontaneously hypertensive stroke-prone rats
fed a high sodium diet. Amer J Hypertens 1991,
4(4, Pt. 2):341-5S.
163. Beinlich, C.J., Morgan, H.E. Control of growth in
neonatal pig hearts. Mol Cell Biochem 1993,
119(1-2): 3-9.
164. Milavetz, J.J., Raya, T.E., Morkin, E., Goldman,
S. Survival after large myocardial infarction in
rats: Comparison of ACE inhibition with captopril versus direct angiotensin II blockade with
losartan. 44th Annu Sci Sess Amer Coll Cardiol
1994.
165. Gonzalez-Espinosa, C., Garcia-Sainz, J.A.
Angiotensin II and active phorbol esters induce
proto-oncogene expression in isolated rat hepatocytes. Biochim Biophys Acta 1992, 1136:
309-14.
166. Lyall, F., Dornan, E.S., McQueen, J., Boswell,
F, Kelly, M. Angiotensin II increases protooncogene expression and phosphoinositide
turnover in vascular smooth muscle cells via the
angiotensin II AT1 receptor. J Hypertens 1992,
10(12): 1463-70.
167. Millet, D., Desgranges, C., Campan, M.,
Gadeau, A., Costerousee, O. Effects of angio-
492
tensins on cellular hypertrophy and c-fos
expression in cultured arterial smooth muscle
cells. Eur J Biochem 1992, 206(2): 367-72.
168. Rydzewski, B., Wozniak, M., Baker,
S.P.,Sumners, C., Raizada, M.K. Angiotensin II
(All) stimulation of c-fos gene expression in
neuronal and astroglial cultures from the brain.
Hypertension 1992, 20(3): 412 (Abst).
169. Schorb, W., Booz, G.W., Dostal, D.E., Chang,
K.C., Baker, K.M. Angiotensin II receptor
mediated growth of cardiac fibroblasts. Circula
tion 1992, 86(4): 1-89 (Abst).
170. Viard, l, , Jaillard, C., Ouali, R., Saez, J.M.
Angiotensin II induced expression of proto
oncogene (c-fos, jun-B and c-jun) mRNA in
bovine adrenocortical fasciculata cells (BAC) is
mediated by AT 1 receptors. FEBS Lett 1992,
313(1): 43-6.
171. Chua, B.H.L., Chua, C.C., Diglio, C.A., Siu, B.B.
Induction of TGF-beta 1 by angiotensin II in rat
heart endothellal cells. FASEB, J 1993, 7(3):
A133 (Abst).
172. Scheuer, DA, Kitzen, J.M., Perrone, M.H. Role
of nitric oxide release in the arterial pressure
response to angiotensin. FASEB J 1993, 7(4):
A765 (Abst).
173. Chiu, AT., Roscoe, W.A., McCall, D.E., Timmermans, P.B.M.W.M. The type of angiotensin
II receptors found in rat, aortic smooth muscle
cells. J Hypertens 1990, 8(Suppl. 3): 167 (Abst).
174. Sachinidis, A., Ko, Y., Weisser, P., Brickwedde,
M.K.M.Z., Dusing, R., Christian, R., Wieczorek,
A.J., Vetter, H. EXP3174, a metabolite of losartan (MK-954, DuP 753) is more potent than
losartan in blocking the angiotensin II induced
responses in vascular smooth muscle cells. J
Hypertens 1993, 11(2): 155-62.
175. Anderson, P.W., Do, Y.S., Hsueh, W.A. Angio
tensin II causes mesangial cell hypertrophy.
Hypertension 1993, 21(1): 29-35.
176. Chansel, D., Badre, L., Czekalski, S. Intrinsic
properties of the nonpeptide angiotensin II (All)
antagonist losartan in glomeruli and mesangial
cells (MC) at high concentrations. J Amer Soc
Nephrol 1992, 3(3): 434 (Abst),
177. DeLaGarza, M., Bhandaru, S., Bakris, G.L.
Angiotensin II (All) induced mitogenesis in
human mesangial cells (HMO): Role for endothelin. J Amer Soc Nephrol 1992, 3(3): 466
(Abst).
178. Kessler-lcekson, G., Schlesinger, H., Cohen, F.
Effect of angiotensin II and losartan on protein
accumulation in cultured heart myocytes and
non-myocytes. FASEB J 1992, 6(5): A1872
(Abst).
MEDICAMENTOS DE ACTUALIDAD
179. Schunkert, H., Weinberg, E.G., Izumo, S., Riegger, G., Lorell, B.H. Angiotensin II mediated
rapid increase in cardiac protein synthesis in
adult hearts is not associated with induction of
c-fos, c-jun, and c-myc protooncognees.
FASEB J 1993, 7(4): A751 (Abst).
180. Wamsley, J.K., Herblin, W.F., Hunt, M. Use of
nonpeptide angiotensin H receptor antagonists
to demonstrate All receptor subtypes in brain.
Soc Neuro Sci 1990, 16(1): 685 (Abst).
181. Holycross, B.J., Peach, M.J., Owens, G.K.
Angiotensin II stimulates increased protein syn
thesis, not increased DNA synthesis, in intact rat
aortic segments, in vitro. J Vase Res 1993, 30:
80-6.
182. Madhun, Z., Ernsberger, P., Ke, F.C., Zhou, J.,
Hopfer, U., Douglas, J.G. Signal
transduction mediated by angiotensin II
receptor subtypes expressed in rat renal
mesangial cells. Regul Pept 1993,44(2):
149-57.
183. Beinlich, C.J., White, G.J., Baker, K.M., Mor
gan, H.E. Angiotensin II and left
ventricular growth in newborn pig heart. J
Mol Cell Cardiol 1991 , 23(9): 1031-8.
184. Morton, J.J., Beattie, E.G., MacPherson, F.
Angiotensin II receptor antagonist losartan has
persistent effects on blood pressure in the
young spontaneously hypertensive rat: Lack of
relation to vascular structure. J Vase Res 1992,
29(3): 264-9.
185. Lafayette, R.A., Mayer, G., Park, S.K., Meyer,
T.W. Angiotensin II receptor blockade limits
glomerular injury in rats with reduced renal
mass. J Clin Invest 1992, 90(3): 766-71.
186. Pollock, D.M., Divish, B.J., Polakowski, J.S.,
Opgenorth, T.J. Angiotensin II receptor block
ade improves renal function in rats with reduced
renal mass. J Pharmacol Exp Ther 1993,
267(2): 657-63.
187. Remuzzi, A., Perico, N., Amuchastegui, C.S.,
Malanchini, B., Mazerska, M., Battaglia, C., Bertani, T., Remuzzi, G. Short and long term effect
of angiotensin II receptor blockade in rats with
experimental diabetes. J Amer Soc Nephrol
1993,4:40-9.
188. Ruzicka, M., Yuan, B., Harmsen, E., Leenen,
F.H.H. The renin angiotensin system and vol
ume overload-induced cardiac hypertrophy in
rats. Circulation 1993, 87(3): 921-30.
189. Raya, T.E., Fonken, S.J., Lee, R.W., Daugherty,
S., Goldman, S., Wong, P.C., Timmermans,
P.B.M.W.M., Morkin, E. Hemodynamic effects of
direct angiotensin II blockade compared to con-.
verting enzyme inhibition in rat model of heart
DRUGS OF TODAY Vol. 31, NO. 7, 1995
failure. Amer J Hypertens 1991, 4(4, Pt.
2): 334-40S.
190. Capasso, J.M., Li, P., Meggs, L.G., Herman,
M.V., Anversa, P. Efficacy of angiotensin con
verting enzyme inhibition and AT 1 receptor
blockade on cardiac pump performance after
myocardial infarction in rats. J Cardiovasc Pharmacol 1994, 23(4): 584-93.
191. Okada, M., Kobayashi, M., Satoh, N., Nishikibe,
M., Ikemoto, F. Effect of chronic treatment with
losartan on development of hypertension in
stroke prone spontaneously hypertensive rats
(SHRSP): Comparative study with enalapril and
hydralazine. Hypertens Res 1993, 16: 49-55.
192. Chang, R.S.L., Lotti, V.J. Angiotensin receptor
subtypes in rat, rabbit and monkey tissues: Rel
ative distribution and species dependency. Life
Sci 1991,49(20): 1485-90.
193. Grone, H.J., Simon, M., Fuchs, E. Autoradiographic characterization of angiotensin receptor
subtypes in fetal and adult human kidney. Amer
J Physiol 1992, 262(2): F326-31.
194. Burns, K.D., Homma, T., Harris, B.C. The
intrarenal renin angiotensin system. Semin
Nephrol 1993, 13(1): 13-30.
195. Hall, J.E., Guyton, A.C., Brands, M.W. Control
of sodium excretion and arterial pressure
by intrarenal mechanisms and the renin
angiotensin system. In: Hypertension:
Pathophysiology, Diagnosis, and
Management, 2nd Ed. Laragh,
J.H., Brenner, B.M. (Eds.). Raven Press,
New York 1995, 1451-75.
196. Fenoy, F.J., Milicic, I., Smith, R.D., Wong, P.C.,
Timmermans, P.B.M.W.M., Roman, R.J.
Effects of DuP 753 on renal function of
normotensive and spontaneously
hypertensive rats. Amer J Hypertens 1991,
4(4, Pt. 2): 321-6S.
197. Schmieder, R.E. Nephroprotection by antihypertensive agents. J Cardiovasc Pharmacol
1994, 24(Suppl.2):S55-64.
198. Tanaka, R., Kon, V., Yoshioka, T., Ichikawa, I.,
Fogo, A. Angiotensin converting enzyme inhibi
tor modulates glomerular function and structure
by distinct mechanisms. Kidney Int 1994, 45:
537-43.
199. Jover, B., Mimran. A. Angiotensin II receptor
antagonists versus angiotensin converting
enzyme inhibitors: Effects on renal function. J
Hypertens 1994, 12(9): 3-9S.
200. Levine, D.Z., lacovitti, M., Buckman, S., Burns,
K. D. Response of rat late distal tubule bicarbon
ate flux to changes in the renin angiotensin sys
tem in vivo. Unpublished 1995.
201. Tobe, T.J.M., deLangen, C.D.J, Weersink,
E.G.L, Wijngaarden, J.V., Bel, K.J.,
deGraeff, P.A., Gilst, W.H.V., Wesseling, H.
The angioten-
493
sin converting enzyme inhibitor perindopril
improves survival after experimental myocardial
infarction in pigs. J Cardiovasc Pharmacol
1992, 19:732-40.
202. Camargo, M.J.F., VonLutterotti, N., Campbell,
W.G., Pecker, M.S., James, G.D., Timmermans,
P.B.M.W.M. Control of blood pressure and end
organ damage in maturing salt loaded stroke
prone spontaneously hypertensive rats by oral
angiotensin II receptor blockade. J Hypertens
1993, 11(1): 31-40.
203. Honma, H., Nakamura, T., Ikeda, Y., Kuroyanagi, R., Takano, H., Yoshida, Y, Tamura, K.
Renal protective effects of the angiotensin //
antagonist CV-11974 in spontaneously hyper
tensive rats stroke prone. J Hypertens 1994,
12(Suppl. 3): 2075 (Abst).
204. Saladini, D., Jover, B., Ribstein, J. Renal com
pensation to uninephrectomy (UNX) and the
renin angiotensin system. J Amer Soc Nephrol
1992, 3(3): 478 (Abst).
205. Jackson, E.K., Inagami, T. Blockade of the preand postjunctional effects of angiotensin in vivo
with a nonpeptide angiotensin receptor antago
nist. Life Sci 1990, 46: 945-53.
206. Yayama, K., Kawao, M., Tujii, H., Itoh, N., Okamoto, H. DuP 753 prevents the development of
puromycin aminonucleoside induced nephrosis. Eur J Pharmacol 1993, 236: 337-8.
207. Pimentel, J.L., Wang, S., Martinez-Maldonado,
M. Regulation of the renal angiotensin II recep
tor gene in acute unilateral ureteral obstruction.
Kidney Int 1994, 45(6): 1614-21.
208. Gekle, M., Silbernagl, S. Mechanism of ochratoxin A induced reduction of glomerular filtration
rate in rats. J Pharmacol Exp Ther 1993, 267(1):
316-21.
209. Sakemi, T., Baba, N. Effects of an angiotensin
II receptor antagonist on the progression of
renal failure in hyperlipidemic Imai rats. Nephron 1993, 65(3): 426-32.
210. Hutchison, F.N. Hormonal modulation of proteinuria in the nephrotic syndrome. Amer J Neph
rol 1993, 13(5): 337-46.
211. Yayama, K., Matsui.T., Takano, M., Hayashi, K.,
Nagamatsu, T., Suzuki, Y, Okamoto, H. Activa
tion of the renin-angiotensin system in antiglomerular basement membrane antibody induced
glomerulonephritis. Biol Pharm Bull 1995,18(3):
411-5.
212. Smith, R.D., Timmermans, P.B.M.W.M. Inhibi
tion of the renin angiotensin system in conges
tive heart failure. Curr Drugs 1992, A127-A150.
213. Baker, K.M., Booz, G.W., Dostal, D.E. Cardiac
actions of angiotensin H: Role of an intracardiac
494
renin angiotensin system. Annu Rev Physiol
1992,54:227-41.
214. Johnston, C.I. Tissue angiotensin converting
enzyme in cardiac and vascular hypertrophy,
repair, and remodeling. Hypertension 1994,
23(2): 258-68.
215. Urata, H., Ganten, D. Cardiac angiotensin II
formation: The angiotensin I converting enzyme
and human chymase. Eur Heart J 1993,
14(Suppl. I): 177-82.
216. Urata, H., Hoffmann, S., Ganten, D. Tissueangiotensin II system in the human heart. Eur
Heart J 1994, 15(D): 68-78.
217. Brasch, H., Sieroslawski, L, Dominiak, P.
Angiotensin II increases norepinephrine release
from atria by acting on angiotensin subtype 1
receptors. Hypertension 1993, 22: 699-704.
218. Foucart, S., Patrick, S.K., Oster, L., DeChamplain, J. Effect of chronic treatment with losartan
and enalaprilat on [3H]-noradrenaline release
from isolated atria of SHR rats. J Hypertens
1994, 12(Suppl. 3): 488 (Abst).
219. Scott, A.L., Chang, R.S.L., Lotti, V.J., Siegl,
P.K.S. Cardiac angiotensin receptors: Effects of
selective angiotensin II receptor antagonists,
DuP 753andPD121981, in rabbit heart. J Pharmacol Exp Ther 1992, 261(3): 931-5.
220. Ishihata, A., Endoh, M. Pharmacological char
acteristics of the positive inotropic effect of
angiotensin II In the rabbit ventricular myocar
dium. Brit J Pharmacol 1993, 108: 999-1005.
221. Zerkowski, H.R., Broede, A., Kunde, K., Hillemann, S., Schafer, E., Vogelsang, M., Michel,
M.C., Brodde, O.E. Comparison of the positive
inotropic effects of serotonin, histamine, angio
tensin H, endothelin and isoprenaline in the iso
lated human right atrium. Naunyn-Schmied
Arch Pharmacol 1993, 347: 347-52.
222. Holubarsch, C., Hasenfuss, G., SchmidtSchweda, S., Knorr, A., Pieske, B., Ruf, T.,
Fasol, R., Just, H. Angiotensin I and II exert
inotropic effects in atrial but not in ventricular
human myocardium. Circulation 1993, 88:
1228-37.
223. Weber, K.T., Sun, Y., Guarda, E. Structural
remodeling in hypertensive heart disease and
the role of hormones. Hypertension 1994,23(Pt.
2): 869-77.
224. Guarda, E., Myers, P.R., Brilla, C.G., Tyagi,
S.C., Weber, K.T. Endothelial cell induced mod
ulation of cardiac fibroblast collagen metabo
lism. Cardio Res 1993, 27(6): 1004-8.
225. Sadoshima, J.I., Izumo, S. Molecular character
ization of angiotensin II induced hypertrophy of
cardiac myocytes and hyperplasia of cardiac
fibroblasts. Circ Res 1993, 73: 413-23.
MEDICAMENTOS DE ACTUALIDAD
226. Schorb, W., Singer, H.A., Baker, K.M. Angioten
sin II is a potent stimulator of MAP-kinase activ
ity in neonatal rat cardiac fibroblasts. FASEB J
1993, 7(3): A492 (Abst).
227. Brilla, C.G., Matsubara, L., Weber, K.T. Inhibi
tion of collagenase activity in cultured cardiac
fibroblasts by angiotensin II. Eur Heart J 1992,
13(Suppl.): 111 (Abst).
228. Smits, J.F.M., VanKrimpen, C., Schoemaker,
R.G., Cleutjens, J.P.M., Daemen, M.J.A.P.
Angiotensin II receptor blockade after myocardial infarction in rats: Effects on hemodynamics,
myocardial DNA synthesis, and interstitial colla
gen content. J Cardiovasc Pharmacol 1992, 20:
772-8.
229. Schieffer, B., Wirger, A., Meybrunn, M., Setiz,
S., Holtz, J., Riede, U.N., Drexler, H. Compara
tive effects of chronic angiotensin converting
enzyme inhibition and angiotensin H type 1
receptor blockade on cardiac remodeling after
myocardial infarction in the rat. Circulation
1994, 89(5): 2273-82.
230. Neuss, M., Regitz-Zagrosek, V., Hildebrandt,
A., Fleck, E. Human cardiac fibroblasts
express an angiotensin receptor with unusual
binding characteristics which is coupled to cellular
proliferation. Biochem Biophys Res Commun
1994, 204(3): 1334-9.
231. Smith, H.J., Nuttall, A. Experimental models of
heart failure. Cardio Res 1985, 19: 181-6.
232. Matsumori, A., Tanaka, A., Wang, W., Sasayama, S. Angiotensin II receptor antagonist,
TCV-116 improves virus induced myocardial
injury in an animal model. Amer Heart Assoc
1994,90(4, Pt. 2): 1452 (Abst).
233. Trippodo, N.C., Panchal, B.C., Fox, M. Repres
sion of angiotensin II and potentiation of bradykinin contribute to the synergistic effects of dual
metalloprotease inhibition in heart failure. J
Pharmacol Exp Ther 1995, 272(2): 619-27.
234. Ruzicka, M., Yuan, B., Leenen, F.H.H. Effects of
enalapril versus losartan on regression of vol
ume overload induced cardiac hypertrophy in
rats. Circulation 1994, 90: 484-91.
235. Ruzicka, M., Keeley, F.W., Leenen, F.H.H. The
renin angiotensin system and volume overload
induced changes in cardiac collagen and elastin. Circulation 1994, 89(4): 1989-96.
236. Nishikimi, T., Ohmura, T., Tani, T., Yamagishi,
H., Yanagi, S., Yoshiyama, M., Toda, I., Akioka,
K., Teragaki, M., Takeuchi, K., Takeda, T. Role
of angiotensin II type I receptor on the develop
ment of heart failure in rats. J Amer Coll Cardiol
1993, 21(2): 27A (Abst).
237. Jiang, G.W., Mulroney, S.E., Opgenorth, T.,
Hoffman, A., Winaver, J., Haramati, A. Effects of
DRUGS OF TODAY Vol. 31, No. 7, 1995
an angiotensin II receptor antagonist on urinary
sodium excretion and cardiac hypertrophy in
rats with experimental congestive heart failure.
Xllth Cong Nephrol 1993, 242 (Abst).
238. Fujimori, A., Shibasaki, M., Kusayama, T., Okazaki, T., Matsuda, Y, Inagaki, O., Yanagisawa,
I., Sato, N., Takenaka, T. YM358, a novel angio
tensin II receptor (AT1) antagonist, prevents vol
ume overload induced cardiac hypertrophy in
rats. Can J Physiol Pharmacol 1994, 72(Suppl.
1): 120 (Abst).
239. Qing, G., Garcia, R. Chronic captopril and
losartan (DuP 753) administration in rats with
high output heart failure. Amer J Physiol 1992,
263(3): 833-40H.
240. Fitzpatrick, M.A., Rademaker, M.T., Charles,
C.J., Yandle, T.G., Espiner, E.A., Ikram, H.
Angiotensin II receptor antagonism in ovine
heart failure: Acute hemodynamic, hormonal,
and renal effects. Amer J Physiol 1992, 263:
H250-6.
241. Murakami, M., Suzuki, H., Naitoh, M., Ichihara,
A., Matsumoto, A., Tsujimoto, G., Saruta, T. Cardioprotective action of ACE inhibitor in failing
heart. J Hypertens 1992, 10(Suppl. 4): S74
(Abst).
242. Ito, K., Kitayoshi, T., Igata, H., Goto, Y, Kito, G.
Effect of TCV-116,a novel nonpeptide angioten
sin II receptor antagonist, on chronic congestive
heart failure. Can J Physiol Pharmacol 1994,
72(Suppl. 1): 120 (Abst).
243. Garcia-Sainz, J.A., Olivares-Reyes, J.A. Glycyl-histidine-lysine interacts with the angioten
sin II AT1 receptor. Unpublished 1995.
244.Barbe, F., Jinbo, S., Guyenne, T.T., Laplace, M.,
Menard, J., Crozatier, B., Hittinger, L. The hypotensive effect of the angiotensin II antagonist
EXP3174 depends upon the renin-angiotensin
system activation in conscious dogs with heart
failure. J Amer Coll Cardiol 1995, 371A (Abst).
245. Spinale, F.G., Hird, R.B., Mukherjee, R.,
Walker, J.D., Holzgrefe, H.H., Child, M.J., Koster, W.H. Chronic angiotensin II receptor block
ade (AT1AT-II) affects myocyte sarcolemmal
function and electrophysiology in dilated cardiomyopathy. J Amer Coll Cardiol 1995, 235A
(Abst).
246. Smits, J.F.M., Schoemaker, R.G., Daemen,
M.J.A.P., Debets, J.J.M. Haemodynamic conse
quences of interference with the renin-angioten
sin system following myocardial infarction in
rats. Brit J Pharmacol 1991, 102(Suppl.): 9.9P
(Abst).
247. Deck, C.C., Gaballa, M.A., Raya, T.E. Renal
function in rats with experimental heart failure:
Angiotensin II blockade versus converting
495
enzyme inhibition. Circulation 1993, 88(4, Pt. 2,
Suppl.): 1-514 (Abst).
248. Stauss, H.M., Zhu, Y.C.; Redlich, T., Adamiak,
D., Mott, A., Kregel, K.C., Unger, T. Angiotensin
converting enzyme inhibition in infarct
induced
heart failure in rats: Bradykinin versus angioten
sin II. J Cardiovasc Risk 1994, 1: 255-62.
249. Milavetz, J.J., Raya, T.E., Morkin, E., Goldman,
S, Survival after large myocardial infarction in
rats: Comparison of ACE inhibition with capto
pril versus direct angiotensin II blockade with
losartan. J Amer Coll Cardiol 1995,221A (Abst).
250. Kambayashi, Y, Takahashi, K., Bardhan, S.,
Inagami, T. Molecular structure and function of
angiotensin type 2 receptor. Kidney Int 1994,
46(6): 1502-4.
251. DeGasparo, M., Bottari, S.P., Levens, N.R.
Characteristics of angiotensin II receptors and
their role in cell and organ physiology. In: Hyper
tension: Pathophysiology, Diagnosis, and Man
agement, 2nd Ed. Laragh, J.H., Brenner, B.M.
(Eds.). Raven Press, Ltd., New York 1995,
1695-720.
252. Stadler, T., Veltmar, A., Qadri, F., Unger, T.
Angiotensin II evokes noradrenaline release
from the paraventricular nucleus in conscious
rats. Brain Res 1992, 569(1): 117-22.
253. Simpson, R.L., Morlin, C., Ton, J., Snavely,
D.B., Nelson, E.B., Goldberg, A.I. Efficacy and
safety of losartan combined with hydrochlorothiazide in patients with mild to severe hyperten
sion. Amer J Hypertens 1994, 7(4): A17 (Abst).
254. Arcuri, K., Harm, S., Nelson, E.B., Snapinn, S.
Efficacy and safety of concomitant losartan/
hydrochlorothiazide therapy in patients with
essential hypertension. Amer J Hypertens
1994,7(4): I48 (Abst).
255. Christen, Y, Waeber, B., Nussberger, J., Lee,
R.J., Timmermans, P.B.M.W.M., Brunner, H.R.
Dose-response relationships following oral
administration of DuP 753 to normal humans.
Amer J Hypertens 1991, 4(4, Pt. 2): 350-3S.
256. Munafo, A., Christen, Y, Nussberger, J., Shum,
L., Borland, R.M., Lee, R J., Waeber, B., Biollaz,
J., Brunner, H.R. Drug concentration response
relationships in normal volunteers after oral
administration of losartan, an angiotensin II
receptor antagonist. Clin Pharmacol Ther 1992,
51:513-21.
257. Ohtawa, M., Takayama, F., Saitoh, K., Yoshinaga, T, Nakashima, M. Pharmacokinetics and
biochemical efficacy after single and multiple
oral administration of losartan, an orally active
nonpeptide angiotensin II receptor antagonist,
in humans. Brit J Clin Pharmacol 1993, 35:
290-7.
496
258. Goldberg, M.R., Tanaka, W., Barchowsky, A.,
Bradstreet, T.E., McCrea, J., Lo, M.W., McWilliams, E.J., Bjornsson, T.D. Effects of losartan
on blood pressure, plasma renin activity, and
angiotensin II in volunteers. Hypertension 1993,
21 (5): 704-13.
259.Burnier, M., Rutschmann, B., Nussberger, J.,
Versaggi, J., Shahinfar, S., Waeber, B., Brunner,
H.R. Salt dependent renal effects of an angio
tensin II antagonist in healthy subjects. Hyper
tension 1993, 22(3): 339-47.
260. Cockcroft, J.R., Sciberras, D.G., Goldberg,
M.R., Ritter, J.M. Comparison of angiotensin
converting enzyme inhibition with angiotensin II
receptor antagonism in the human forearm. J
Cardiovasc Pharmacol 1993, 22(4): 579-84.
261. Goldberg, M.R., Bradstreet, T.E., McWilliams,
E.J. et al. Biochemical effects of losartan, a nonpeptide angiotensin II receptor antagonist, on
the renin angiotensin aldosterone system in
hypertensive patients. Hypertension 1995, 25:
37-46.
262. Erley, C.M., Bader, B., Scheu, M., Wolf, S.,
Braun, N., Risler, T. Renal hemodynamics in
essential hypertensives treated with losartan.
Clin Nephrol 1995, 43(S1): S8-11.
263. Gradman, A.M., Arcuri, K., Goldberg, A.I.,
Ikeda, L.S., Nelson, E.B., Snavely, D.B., Sweet,
C.S. A randomized, placebo controlled, double
blind, parallel study of various doses of losartan
potassium compared with enalapril maleate in
patients with essential hypertension. Hyperten
sion 1995, 25(6): 1345-50.
264.Weber, M.A., Byyny, R.L., Pratt, J.H., Faison,
E.P., Snavely, D.B., Goldberg, A.I., Nelson, E.B.
Blood pressure effects of the angiotensin II
receptor blocker, losartan. Arch Intern Med
1995, 155(4): 405-11.
265. Nelson, E., Merrill, D., Sweet, C.S. et al. Effi
cacy and safety of oral MK-954 (DuP 753), an
angiotensin receptor antagonist, in essential
hypertension. J Hypertens 1991, 9(Suppl. 6):
S468-S469 (Abst).
266. Hagino, T., Abe, K., Tsunoda, K., Yoshinaga, K.
Antihypertensive effect of a nonpeptide angio
tensin II receptor antagonist, MK954, in patients
with essential hypertension. Jpn J Nephrol
1992,34(2): 133-40.
267. Weber, M.A. Clinical experience with the angio
tensin II receptor antagonist losartan. A prelimi
nary report. Amer J Hypertens 1992, 5(12, Pt.
2): 247-51S.
268. Brunner, H.R., Christen, Y, Munafo, A., Lee,
R.J., Waeber, B., Nussberger, J. Clinical experi
ence with angiotensin II receptor antagonists.
Amer J Hypertens 1992, 5(12, Pt. 2): 243-6S.
MEDICAMENTOS DE ACTUALIDAD
269. Tsunoda, K., Abe, K., Hagino, T., Omata, K.,
Misawa, S., Imai, Y, Yoshinaga, K. Hypotensive
effect of losartan, a nonpeptide angiotensin II
receptor antagonist, in essential hypertension.
Amer J Hypertens 1993, 6(1): 28-32.
270. Soffer, B.A., Wright, J.T., Pratt, J.H., Wiens, B.,
Goldberg, A.I., Sweet, C.S. Effects of losartan
on a background of hydrochlorothiazide in
patients with hypertension. Hypertension 1995,
26(1): 112-7.
271. Dahlof, B., Keller, S.E., Makris, L, Goldberg,
A.I., Sweet, C.S., Lim, N.Y Efficacy and tolerability of losartan potassium and atenolol in
patients with mild-to-moderate essential hyper
tension. Amer J Hypertens 1995, 8(6): 578-83.
272. Shultz, P., Raij, L., Cook, M.E., Pearce, C., Buonagura, A., Wallin, J., Bauer, J. Effects of losar
tan on renal function in patients with chronic
renal insufficiency. Amer Soc Nephrol 1993,540
(Abst).
273. Gansevoort, R.T., DeZeeuw, D., DeJong, P.E.
Is the antiproteinuric effect of ACE inhibition
mediated by interference in the renin angioten
sin system? Kidney int 1994, 45(3): 861-7.
274. Moan, A., Risanger, T., Eide, I., Kjeldsen, S.E.
The effect of angiotensin II receptor blockade on
insulin sensitivity and sympathetic nervous sys
tem activity in primary hypertension. Blood
Pressure 1994, 3(3): 185-8.
275. Lacourciere, Y, Lefebvre, J., Nakhle, G., Fai
son, E.P., Snavely, D.B., Nelson, E.B. Associa
tion between cough and angiotensin converting
enzyme inhibitors versus angiotensin II antago
nists: The design of a prospective, controlled
study. J Hypertens 1994, 12(2): S49-53.
276. Lacourciere, Y, Brunner, H., Irwin, R., Karlberg,
B.E., Ramsay, L.E., Snavely, D.B., Dobbins,
T.W., Faison, E.P., Nelson, E.B. Effects of modu
lators of the renin-angiotensin-aldosterone system on cough. J Hypertens 1994, 12(12):
1387-93.
277. Hayashi, H. Effect of MK-954 (losartan potas
sium) on the circadian variation of ambulatory
blood pressure - Investigation by the periodic
analysis of covariance. Ther Res 1994, 15(12):
479-90.
278. Sweet, C.S., Bradstreet, D.C., Berman, R., Jallad, N.S., Saenz, A., Weidler, D.J. Pharmacodynamic activity of intravenous E 3174, an angio
tensin II antagonist, in patients with essential
hypertension. Amer J Hypertens 1994, 7(12):
1035-40.
279. Gottlieb, S.S., Dickstein, K., Fleck, E., Kostis,
J., Levine, T.B., LeJemtel, T., DeKock, M.
Hemodynamic and neurohormonal effects of
the angiotensin II antagonist losartan in patients
497
with congestive heart failure. Circulation 1993,
88(4):1602-9.
280. Dickstein, K., Gottlieb, S., Fleck, E., Kostis, J.,
Levine, B., DeKock, M., LeJemtel, T. Hemodynamic and neurohumoral effects of the angiotensin II antagonist losartan in patients with
heart failure. J Hypertens 1994, 12(2): S31-5.
281.Crozier, I., Ikram, H., Awan, N., Cleland, J., Ste
phen, N., Dickstein, K., Frey, M., Young, J.,
Klinger, G., Makris, L., Rucinska, E. Losartan in
heart failure: Hemodynamic effects and tolerability. Circulation 1995, 91: 691-7.
282. Dickstein, K., Chang, P., Willenheimer, R.,
Haunso, S., Remes, J., Hall, C., Kjekshus, J.
Comparison of the effects of losartan and enalapril on clinical status and exercise performance
in patients with moderate or severe chronic
heart failure. J Amer Coll Cardiol 1995, 26(2):
438-45.
283. Ogihara, T., Mikami, H., Higaki, J. et al. TCV
116: Pharmacodynamics. Rinsho lyaku 1993,
9(5): 1031-63.
284. Ogihara, T., Higashimori, K., Masuo, K.,
Mikami, H. Pilot study of a new angiotensin II
receptor antagonist, TCV-116: Effects of a
single dose on blood pressure in patients with
essential hypertension. Clin Ther 1993, 15:
684-91.
285. Strodter, D., Zeissig, I., Heath, R., Federlin, K.
Angiotensin II antagonist CGP 48933 (valsartan) - Results of a double-blind, placebo con
trolled multicenter study. Nier Hochdruckkrank
1994, 23(5): 217-20.
286. Muller, P., Cohen, T., DeGasparo, M., Sioufi, A.,
Racine-Poon, A., Howald, H. Angiotensin II
receptor blockade with single doses of valsartan
in healthy, normotensive subjects. Eur J Clin
Pharmacol 1994, 47(3): 231-45.
287. Sissmann, J., Bouradian, M., Armagnac, C.,
Donazollo, Y., Latreille, M., Panis, R. Angioten
sin II blockade in healthy volunteers: Tolerability
and impact on renin angiotensin system compo
nents of single and repeated doses of a new
angiotensin II receptor antagonist SR 47436
(BMS 186295). J Hypertens 1994,12(Suppl. 3):
Abst 510.
288. VanDenMeiracker, A., Janssen, J., Admiraal,
P.J.J., deRonde, W., Kroodsma, J., Blankestijn,
P.J., Sissmann, J. Dose finding study with angio
tensin II receptor antagonist SR 47436 (BMS
186295) in essential hypertension. J Hypertens
1994, 12(Suppl. 3): 520 (Abst).
289. Burnier, M., Hagmann, M., Delacretaz, E.,
Brouard, R., Armagnac, C., Nussberger, J.,
Waeber, B., Brunner, H.R. The angiotensin II
antagonist SR 47436 (BMS 186295) increases
dose dependently urinary sodium excretion but
not uric acid in healthy normotensive volunteers. J Hypertens 1994, 12(Suppl. 3): 545
(Abst).
290. Ribstein, J., Sissmann, J., Picard, A.Bouroudian, M., Mimran, A. Effects of the angiotensin
II antagonist SR 47436 (BMS 186295) on the
pressor response to exogenous angiotensin II
and the renin angiotensin system in sodium
replete normal subjects. J Hypertens 1994,
12(Suppl.3):2191 (Abst).
291. Hagmann, M., Burnier, M., Nussberger, J.,
Leenhardt, A.F., Brouard, R., Waeber, B., Brun
ner, H.R. Natriuretic and hormonal effects of SR
47436 (BMS 186295), a new angiotensin II
receptor antagonist in normotensive volunteers.
Amer J Hypertens 1994, 7(4): 1370 (Abst).
292. Ribstein, J., Sissmann, J., Picard, A., Mimran,
A. Prolonged blockade of the pressor response
to exogenous angiotensin II by the angiotensin
II antagonist SR 4 7436 (BMS 186295) in sodium
replete normal subjects. Nephrol Dialysis
Transplant 1994, 9(7): 928.
293. VanDenMeiracker, A.H., Admiraal, P.J.J., Janssen, J.A., Kroodsma, J.M., DeRonde, W.A.M.,
Boomsma, F, Sissmann, J., Blankestijn, P.J.,
Mulder, P.G.M., Man in't Veld, A.J., Schalekamp, M.A.D.H. Hemodynamic and biochemi
cal effects of the AT 1 receptor antagonist irbesartan in hypertension. Hypertension 1995, 25:
22-9.
294. Burnier, M., Hagman, M., Nussberger, J., Biollaz, J., Armagnac, C., Brouard, R., Waeber, B.,
Brunner, H.R. Short term and sustained renal
effects of angiotensin II receptor blockade in
healthy subjects. Hypertension 1995, 25(4):
P602-P609.
295. Su, C.A.P.F., VanHeiningen, P.N.M., Vanlier,
J.J., de Bruin, H., Kirchgaessler, K.U., Cornelissen, P.J.G. Pharmacodynamics of the All antagonist BIBR0277SE. Clin Pharmacol Ther 1994,
55(2): 205 (Abst).
296. VanHeiningen, P.N.M., VanLier, J.J., deBruin,
H., Su, C.A.P.F, Kirchgasessler, K.U., Cornelissen, P.J.G. Single dose study on the pharmacodynamics and pharmacokinetics of the angiotensin H antagonist BIBR0277SE. Pharm
World Sci 1994, 16(3, Suppl. D): D4.
297. White, W.B., Mansoor, G.A., Lessem, J.,
Schusterman, N. Evaluation of the angiotensin,
H receptor antagonist, eprosartan, by casual
and ambulatory BP monitoring. Clin Res 1994,
42(3): 447A (Abst).
298. Naudin, R.B., Hagmann, M., Nussberger, J.,
Brunner, H.R. Oral administration of SC52458,
a specific angiotensin II receptor antagonist, to
498
healthy male volunteers. J Hypertens 1994,
12(Suppl. 3): 517 (Abst).
299.Hagmann, M., Delacretaz, E., Nussberger, J.,
Naudin, R.B., Burns, T.S., Karim, A, Waeber,
B., Brunner, H.R. Clinical and hormonal assess
ment of SC-52458, a new orally active angiotensin II receptor antagonist in normotensive volun
teers. Amer J Hypertens 1994, 7(4): B17 (Abst).
300.Buclin, T, Biollaz, J., Kung, S., Appenzeiler, M.,
Nussberger, J., Higgins, T., Obayashi, M., Brun
ner, H.R. Tolerability, pharmacokinetics and
pharmacodynamics of the angiotensin II (Ang II)
antagonist TAK-536 in healthy volunteers. Clin
Pharmacol Ther 1995, 57(2): P204.
301.Anonymous. Cozaar (losartan potassium tab
lets). Merck & Co., Inc. 1995, 1-3.
302.Chiu, A.T., McCall, D.E., Price, W.A., Wong,
P.C., Carini, D.J., Duncia, J.V., Wexier, R.R.,
Yoo, S.E., Johnson, A.L., Timmermans,
P.B.M.W.M. In vitro pharmacology of DuP 753,
a nonpeptide All receptor antagonist. Amer J
Hypertens 1991, 4(4, Pt. 2): 282-7S.
303. Christ, D.D. Human plasma protein binding of
the angiotensin If receptor antagonist losartan
potassium (DuP 753/MK 954) and its pharma
cologically active metabolite EXP3174. J Clin
Pharmacol 1995, 35: 515-20.
304. Furtek, C.I., Lo, M.W.J. Simultaneous deter
mination of a novel angiotensin II receptor block
ing agent, losartan, and its metabolite in human
plasma and urine by high-performance liquid
chromatography. J Chromatogr Biomed Appl
1992, 573(2): 295-301.
MEDICAMENTOS DE ACTUALIDAD
305. Hatch, M., Freel, R.W., Vaziri, N.D. Intestinal
transport and renal excretion of urate is altered
by a specific angiotensin II antagonist, DuP 753.
Unpublished 1994.
306.Gansevoort, R.T., DeZeeuw, D., Shahinfar, S.,
Redfield, A., DeJong, P.E. Effects of the angio
tensin II antagonist losartan in hypertensive
patients with renal disease. J Hypertens 1994,
12(2): S37-42 (Abst).
307.Lang, R.M., Yeilen, L.G., McKelvie, R.S., Vaughan, D., Ney, D.E., Makris, L, Chang, P.I. Com
parative effects of losartan and enal april on
exercise capacity and clinical status in patients
with heart failure. Circulation 1994, 90 (4, Pt. 2):
I-602 (Abst).
308. Goldberg, A.l., Dunlay, M.C., Sweet, C.S. The
safety and tolerability of losartan potassium, an
angiotensin II receptor antagonist in compari
son with hydrochlorothiazide, atenolol, felodipine ER and ACE-inhibitors for the treatment of
systemic hypertension. Unpublished 1995.
309. Baboolal, K., Meyer, T.W. Acute angiotensin II
receptor blockade does not reverse systemic or
glomerular capillary hypertension in remnant
kidney rats. J Amer Soc Nephrol 1992,3(3): 557
(Abst).
310. Timmermans, P.B.M.W.M., Carini, D.J., Chiu,
A.T., Duncia, J.V., Price, W.A., Wells, G.J.,
Wong, P.C., Wexler, R.R., Johnson, A.L. The
discovery of a new class of highly specific non
peptide angiotensin II receptor antagonists.
Amer J Hypertens 1991, 4(4, Pt. 2): 275-81S.