(5)
Angiotensin Converting Enzyme
Inhibitors (Captopril)
IN
HYPERTENSION AND CONGESTIVE HEART
FAILURE
Essay
Submitted In Partial Fulfijmeni For The Master
Degree
( Cardiology )
BY
Abdel Kader Ali Hassan Marrie M. B. B. Ch.
Faculty of Medicine - Zagazig University
1984
There is no evidence to suggest that captopril exerts
all of its pharmacological effects through any other mechanism
except inhibition of ACE. It is not a vasodilator, has no direct
effects on sympathetic or parasympathetic nerve function,
does not interfere with receptor activation of any
angonist tested, nor does it enter the brain. Cqse .et al. ,
(1978).
Although inhibition of ACE seems a clear and simple
enough explanation for how captopril exerts its cardiovascular
effects,
the consequences of such inhibition are,
in fact,
complicated and surprising . Undoubtedly, the most important
practical
aspect
of ACE
inhibition has been its striking
efficacy in hypertension. Thus, the effectiveness of captopril in
both human and animal hypertension with low or normal
plasma renin activity has provided strong evidence that the
renin-angiotensin system
is a contributing and/or causative
factor in almost all forms of hypertension; as a corollary,
plasma renin activity is a poor indicator of such a contribution
if it is not obviously high. Fortunately, from the clinical
standpoint, this means that measurements of plasma renin
activity are not necessary in order to predict responders to captopril since the effectiveness of the drug is poorly correlated with
pre-drug planar renin activity.
In renovascular hypertension where high plasma renin
activity is often apparent, reductions in blood pressure by
inhibition of ACE with captopril is rapid ( Case et al. , 1978 )
and consistent with the onset of inhibition of pressor responses
to AI (Ferguson et al., 1977). Furthermore, antagonists of All
receptors such as serializing (Hollenberg; et al., 1979), are also
effective
in
reducing
blood
pressure
in
renovascular
hypertension with high PRA.
The effectiveness of captopril in hypertension associated
with low or normal PRA is, however, not so readily understood.
Thus, while it is tempting to suggest that captopril acts to reduce
blood pressure in chronic renal hypertension by the same
mechanism as in acute renal hypertension.
Several possible mechanisms of the antihypertensive
activity still related to ACE inhibition may account for the
effectiveness of captopril in low or normal renin states of
hypertension:
1) Arterial wall rennin . Arterial vascular tissue of several
species including man contains all
of the
components
necessary for the local generation of All Ganten et
al.
,(1976) . This local vascular All formation is of functional
significance responds to typical stimuli, thus, inhibition
of locally generated All might explain how renin inhibitors
and captopril reduce blood pressure in these models,
(Antonaccio jst al., 1979) . All antagonists may not be
effective because of their relatively large molecular bulk,
which does not allow them to penetrate to the local vascular
site of All formation. Support for such a hypothesis
is
provided by studies in which acute bilateral nephrectomy
either raised or had no effect on blood pressure, Swales,
(1976), whereas ACE inhibition by teprotide Brunner et al.,
(1978) still caused reductions in the acutely nephrectomized
hypertensive rats Swales, (1976).
2) Bradykinin accumulation, ACE is the same enzyme as
kininase II, which is responsible for the inactivation of
bradykinin, inhibition of which causes marked potentiation
of the cardiovascular effects of BK. Thus, it is conceivable
that accumulation of BK might occur with chronic
inhibition of ACE and be partially responsible for some
of its effects.
This is a very difficult hypothesis to test
since local accumulation of BK might not be reflected in
circulating plasma or urine levels but which could have very
profound cardiovascular effects through renal vasodilation,
diuresis, natiuresis, and inhibition of sympathetic function.
Unfortunately, the literature is not consistent in relation
to BK levels after captopril, some investigators reporting
increases in kinin levels McKinstry et al., (1978).
3) Prostaglandin
release
Enhanced
cardiovascular
responsiveness to BK administration has been shown in one
study to be partially mediated through the release of renal
prostaglandins Murthy et al. , (1978). Furthermore,
captopril
did not change urinary PGE2 levels in
renovascular hypertensive human patients Bravo et al. ,
(1979).
4) Aldosterone. Captopril has been consistently shown to
decrease aldosterone secretion in hypertensive animals
McCaa et al. , (1978) and humans Case, et al. , (1978).
Since this is undoubtedly a consequence of inhibition of
All formation, it is difficult to determine how much of the
antihyper-tensive action of captopril is directly related to
reductions in All formation compared with how much is due
to reductions in aldosterone secretion. Certainly, the acute
antihypertensive effects of captopril are not due to
aldosterone inhibition since reductions in blood pressure
were unaltered after bilateral adrenalectomy either prior to
or following captopril administration Adler et al. , (1979).
On the other hand, the reductions of blood pressure in
sodium-depleted normotensive dogs after chronic captopril
could be reversed by simultaneous administration of
aldosterone sufficient to raise plasma levels to normal
McCaa jat al.,
effects-perhaps
(1978). It seems likely that the chronic
the secondary reduction
in
pressure
observed in human patients-of captopril in hypertensive
patients involves inhibition of aldosterone release.
5) Sodium and water excretion. Captopril has been shown to
cause increases in sodium and water excretion and therefore
might decrease blood pressure by reducing sodium content
and/or flux in vessels, as well as by reducing plasma
volume. However, this appears unlikely since the diuretic
and natiuretic actions of captopril can be dissociated from
changes in blood pressure. In both animals Antonaccio et
al., (1979) and human hypertension Atlas et al. , (1979).
captopril can reduce blood pressure with associated
increases, decreases, or unaltered excretion of sodium.
Also, captopril does not reduce plasma volume Cody et al.,
(1978).
In conclusion, captopril is an effective anti-hypertensive
agent in most forms of hypertension. Its only mechanism of
action appears to be inhibition of ACE but the consequences of
this inhibition are complicated and not clarified as yet.
Degrees of blood pressure reduction are poorly correlated with
pre-drug ERA but greater reductions in blood pressure are
observed in high renin hypertensive states.