Reflex-Hemodynamic Adjustments and Baroreflex
Sensitivity During Converting Enzyme Inhibition
with MK-421 in Normal Humans
HANS IBSEN, M.D.,
D . M . S c , BRENT EGAN, M.D.,
ARTHUR VANDER, M.D.,
KARL OSTERZIEL,
AND STEVO JULIUS, M.D.,
M.D.,
Sc.D.
SUMMARY Invasive hemodynamic measurements and determination of baroreflex sensitivity were
carried out in 12 mildly sodium-depleted normotensive volunteers in a randomized double-blind
crossover study with a single dose of converting enzyme inhibitor, MK-421, and placebo. In supine
humans at rest, MK-421 caused a reduction in blood pressure through a fall in total peripheral
resistance and an increase in arterial compliance. Thus, MK-421 appears to dilate both resistance
vessels and larger arteries. Cardiac output increased, but contrary to the effects of other vasodilators,
the increase was due to a higher stroke volume with an unchanged heart rate. The lack of heart rate
response may well reflect enhanced central parasympathetic cardiac inhibition. Head-up tilt on MK421 caused an additional decrease in blood pressure in 65% of the subjects. The major determinant
for the blood pressure fall during tilt and converting enzyme inhibition was a decrease in cardiac
performance, while the reflex increase of arteriolar and venous tone was largely unimpaired. The
decreased stroke volume may be secondary to elimination of a positive inotropic effect of angiotensin II
(All). It is also conceivable that in the absence of AH the inotropic response to sympathetic activation
is inadequate during tilt in these sodium-depleted normotensive individuals. Baroreflex sensitivity to
blood pressure increase (i.v. phenylephrine) was enhanced after MK 421. Arterial compliance was
increased, and this may explain the altered baroreceptor sensitivity. However, a possible central
nervous enhancement of baroreceptor sensitivity after MK-421 could not be ruled out in this study.
(Hypertension 5 (supp I): 1-184—1-191, 1983)
KEY WORDS
•
adrenergic system
• angiotensin II
• baroreflex
• blood pressure
hemodynamics
A
NGIOTENSIN II (All) has been shown to facilitate the cardiovascular effect elicited by
stimulation of the sympathetic nervous system.1"-1 These effects of All are exerted on the peripheral as well as the central part of the adrenergic system1 2
and involve a facilitation of ganglionic transmission
through an increased norepinephrine release at the presynaptic level and to a minor degree by prevention of
reuptake. Some data also suggest that All potentiates
the effect of norepinephrine on postsynaptic receptors.' 4 Finally, All enhances the neuronally-mediated
release of catecholamines from the adrenal medulla.2
This potentiating action of All has been investigated
mainly in isolated animal preparations,-^ and very
little is known as to the functional importance of this
complicated interaction between the renin-angiotensin
system (RAS) and the adrenergic system in humans.7 8
Angiotensin II antagonists and converting enzyme
inhibitors (CEI) are useful tools in evaluating the importance of the RAS in cardiovascular homeostasis.9""
The absence of a significant increase in heart rate during a blood pressure fall due to All antagonists or CEI
have directed some investigators to examine baroreflex mechanisms;12"17 some have proposed an increase12 14 and some a decrease11 in baroreflex sensitivity during CEI.
The purpose of the present study was to examine: 1)
to what extent the absence of All might impair reflex
hemodynamic adjustments to head-up tilt in normal
humans; and 2) whether changes in baroreflex sensitivity are involved in the hemodynamic response to CEI.
A single dose of MK-421,18- l9 a new orally active CEI,
was administered to normotensive male volunteers.
From the Division of Hypertension. Department of Internal
Medicine, and Department of Physiology. University of Michigan
Medical School. Ann Arbor. Michigan
Supported in part by Grants HL 21893 and HL 18575 from the
National Institutes of Health.
Address for reprints: Stevo Julius. M.D.. Division of Hypertension. Box 48. R6669 Kresge Building, University of Michigan
Medical Center. Ann Arbor, Michigan 48109.
I-184
HEMODYNAMICS AND CONVERTING ENZYME INHIBITION//*^ et al.
Material and Methods
Fifteen normotensive men with a mean age of 29
years (range 21-39 years) were studied. The study was
approved by the Human Use Committee at the University of Michigan Hospitals, and its nature and purpose
were explained to the volunteers, who gave written
consent. Each individual had a medical history taken
and underwent a physical examination. Routine blood
and urine analyses were performed prior to and at the
termination of the study. All investigations were carried out on an outpatient basis. The design was a randomized, single-dose double-blind crossover study
with MK-421 20 mg and placebo.
The individuals were placed on a diet containing
approximately 20 mmol of sodium per day for 5 days
prior to the hemodynamic measurements, in order to
obtain a mild degree of sodium depletion. Adherence
to the diet was checked by a 24-hour urine collection
terminated on the morning of the day of the hemodynamic measurements. The individuals kept a food record, enabling them to adhere to the same diet prior to
the second procedure.
On the day of the hemodynamic measurements, the
individuals came to the laboratory for clinical examination at 0800 hours after a light breakfast. After remaining supine for 1 hour, they had blood samples
drawn through an indwelling needle for determinations
of plasma renin activity (PRA), plasma angiotensin II
concentration (PAII), plasma norepinephrine (PNE),
plasma epinephrine (PE), and plasma angiotensin I
converting enzyme concentration (P-ACE). At the
same time, MK-421 or placebo was administered orally. Blood pressure and heart rate were recorded. Two
hours later, after a light meal, the individuals were
placed supine on a tilt table for insertion of catheters
under local anesthesia. A short plastic cannula was
introduced percutaneously into the brachial artery and
connected to a pressure transducer. A Swan-Ganz
catheter or a polyethylene, PE-50 catheter was introduced percutaneously into an antecubital vein and advanced to the right atrium. Heart rate was monitored
by electrocardiogram. Intraarterial blood pressure,
right atrial pressure, and heart rate were monitored
continuously.
While resting in the recumbent position 4 hours after
intake of the tablet and at least 30 minutes after all
catheters were introduced, the subjects underwent
blood sample collections and hemodynamic measurements. After 20 minutes of 25° head-up tilt, the hemodynamic measurements were repeated, followed by
blood sampling just before termination of the tilt procedure. At least 20 minutes later, the experimental
procedure was concluded by determination of baroreflex sensitivity.
Exactly the same procedure was repeated 2 weeks
later, preceded by the low salt diet for 5 days.
Cardiac output was determined by dye dilution (Cardiogreen). Details of the procedure have been published elsewhere.20-2I An average of two to three determinations was used. The central blood volume (CBV)
was calculated by multiplication of cardiac output by
1-185
mean transit time, corrected for the delayin the withdrawal system. The ratio of stroke volume to pulse
pressure (SV/PP) was used as a measure of arterial
compliance. Forearm blood flow was determined by
venous occlusion plethysmography and a mercury in
Silastic strain gauge.20 Venous distensibility was also
measured by venous occlusion plethysmography.22
Baroreflex sensitivity was determined by the ramp
method described by Smyth et al." An intravenous
bolus of phenylephrine 50-200 /ig was administered.
The PRA was measured by radioimmunoassay of
generated AI after 60 minutes of incubation at pH
6.0,20 PAII by radioimmunoassay,24 and PNE and PE
by a single isotope radioenzymatic method.20 Measurement of P-ACE was based on the enzyme's ability to
release dipeptides from a radio-labeled tripeptide25 a n c j
expressed as the amount of released hippuric acid per
milliliter per minute. All blood samples from each
individual were analyzed in a single assay run.
A mild degree of sodium depletion and head-up tilt
(25°) were chosen in an attempt to avoid fainting episodes, necessitating termination of the procedures before hemodynamic measurements could be obtained.
In spite of this precaution, three individuals experienced fainting episodes during the first procedure,
two during introduction of catheters, and one after 1
minute of tilt. They were all on active treatment and
had a very low urine sodium excretion (2-10 mmol/24
hr). They did not return for a second procedure. Furthermore, in three of the remaining 12 cases, fainting
episodes occurred during tilt and required active treatment before hemodynamic measurements could be obtained. No fainting episodes were seen during placebo
procedures.
Statistical calculations were carried out by means of
t test for paired data. Linear regression analyses were
also used. Results are presented as means ± SEM.
Results
Recumbent Data
Humoral Effects
The humoral effects of MK-421 in the recumbent
position before and 4 hours after intake of the tablet are
summarized in table 1. The predrug values for PRA as
well as PAII were normal in spite of the low salt diet.
As stated above, we were not aiming at a severe degree
of sodium depletion, and the urinary sodium excretion
(UNa) reflects the mild degree of sodium depletion
obtained. The predrug control values for PRA, PAII,
and UNa were identical in the two situations: Similarly, there was no difference between P-ACE, PNE, and
PE in the placebo and MK-421 situations before intake
of the tablet. A high degree of CEI induced by MK-421
was documented by the marked increase in PRA and a
significant fall in PAII. P-ACE was dramatically reduced, in most cases to an undetectable level. A small
but statistically significant increase in PNE was found
on MK-421 while PE did not change.
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1982 BLOOD PRESSURE COUNCIL
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MARCH-APRIL
1983
TABLE 1. Humoral Effects of MK-421 in 12 Normotensive Men at Rest Supine
Placebo
PRA (ng/ml/hr)
P-ACE (nmol/liter)
PA II (pg/ml)
PNE (pg/ml)
PE (pg/ml)
UNa (mmol/24 hr)
MK-421
Control
Placebo
P
Control
1.37±0.3
218±16
I3.7±2.2
197 ±30
34 + 4
55±11
1.11+0.2
218+18
11.6±1.7
225 + 29
49±9
n.s.
n.s.
<0 03
—
—
1.88±0.4
219±19
15.0±2.7
204 ±24
37 ±7
48±9
n.s.
n.s.
MK-421
P
9.0±0.9
253 ±28
49 ±10
< 0.002
< 0.0001
<0.05
< 0.01
n.s.
—
—
9.32±2.2
6±3
No significant differences were observed between the two control periods (mean ± SEM).
PRA = plasma renin activity; P-ACE = plasma angiotensin I converting-enzyme concentration; PA II (n = 8) =
plasma angiotensin II concentration; PNE = plasma norepinephrine; PE = plasma epinephrine; UNa = 24-hour urinary
sodium excretion.
Hemodynamic Effects
Hemodynamic results are illustrated in figures 1 and
2. As compared to placebo, MK-421 caused a significant fall in blood pressure. This was due to a decrease
in total peripheral resistance (TPR) and took place in
spite of an increase in cardiac output (CO) and stroke
volume (SV). There was no change in heart rate (HR).
Right atrial pressure (RAP) and central blood volume
(CBV) did not change significantly. Not shown in figures 1 and 2 are forearm blood flow (FBF), forearm
vascular resistance (FVR), and venous distensibility.
All of these variables did not change significantly after
MK-421.
Baroreflex sensitivity, expressed as the slope of the
regression line between SBP and the change in RR
interval during phenylephrine injection, was 23.6 ±
2.8 msec/mm Hg before and 28.3 ± 4.1 msec/mm Hg
after MK-421. This increase of baroreceptor sensitivity was significant ip < 0.02). The correlation coefficient for the individual regression lines varied between
r = 0.70 and r = 0.96. The ratio of stroke volume to
pulse pressure (SV/PP) was 1.76 ± 0.1 on placebo
and 2.04 ± 0.1 on MK-421. This increase in the compliance index on MK-421 was significant (p < 0.01).
Tilt Data
Humoral Effects
Tilt results are summarized in figure 3. The PRA
increased significantly during tilt, more markedly so
on MK-421 compared to placebo. The PAII increased
by 85% on placebo but did not change on MK-421,
indicating an effective CEI also during the tilt procedure. The PNE increased significantly to a similar degree on MK-421 and placebo while PE did not change
consistently.
Hemodynamic Effects
Three individuals fainted during tilt on MK-421 before we could measure C O , FBF, and venous distensibility. The changes reported in BP, HR, and RAP are
the values obtained just before termination of tilt in all
TPR
HR
beats/mm
n.s.
70-
RAP
mmHg
O
n.s.
MAP
mm Hg
lOOn p<:.001
p<.001
20-
9060-
15-
8070-
106050-1
,
P
i
MK
FIGURE 1. Heart rate (HR), mean arterial pressure (MAP),
and right atrial pressure (RAP) in normal men at rest supine on
placebo (P) and on MK-421 (MK).
MK
FIGURE 2. Cardiac output (CO), stroke volume (SV), and total peripheral resistance (TPR) in normal men at rest supine on
placebo (P) and on MK-421 (MK).
HEM0DYNAM1CS AND CONVERTING ENZYME INHIBITION//foen et al.
A
10l
PRA
ng Aj/ml/h
0J
10n
A
PA 11
P9/ml
5-
A
SVml
A200PNE
n
g/mf
100-
-10
J.
10
20
A
MAP
mmHg
-20
0J
n.s.
n
0J
-4Q-
9/ml
50-
-60- 1 FIGURE 5. Correlation between changes in stroke volume
(ASV) and mean arterial pressure (AMAP) in normal men during tilt and MK-421.
0-
MK
FIGURE 3. Changes in plasma renin activity (PRA), plasma
angiotensin II concentration (PAH), plasma norepinephrine
(PNE), and plasma epinephrine (PE) in normal men during tilt
on placebo (P) and MKA2I (MK).
12 cases. The results on CO, SV, TPR, CBV, and FBF
consist of data from the nine subjects who were without fainting episodes. Results are summarized in table
2 and figure 4.
Compared to the changes during placebo, the BP
decreased significantly during tilt on MK-421. The
individual changes varied markedly from severe hypotension to no BP change. The RAP and CBV decreased
to a similar degree on placebo and MK-421. The decrease in CO tended to be more pronounced on MK421 but not statistically significant, while the reduction
in SV was significantly higher on MK-421. HR and
ASBP
-20
r = 0.67
p<.05
1-187
ADBP
mmHg
•20n
TPR increased to a similar degree on placebo and on
MK-421. FBF decreased significantly during tilt on
placebo, but not on MK-421. However, the changes on
placebo and on MK-421 did not differ significantly.
Similarly, FVR increased significantly on placebo but
not on MK-421. Venous distensibility did not change
consistently. The decrease in MAP during tilt and
MK-421 correlated with the decrease in SV (r = 0.67,
p < 0.05) (fig. 5).
The hemodynamic results in the nine complete cases
were analyzed in more detail. Using the change in
MAP during tilt as the criterion, we divided the group
into two, consisting of one group of five individuals
whose BP fell, and one group of four whose BP remained the same during tilt and MK-421 (figs. 6 and
7). The BP fall was due to a decrease in CO and SV,
p<001
AMAP
mmHg
• 20-|
• 20-
• 10-
• 10-
o-
o-
•10-
o-10-
-10-
-10-
-20-
-20J
-20-30-
FIGURE 4. Changes in systolic (SBP), diastolic (DBP), and mean arterial blood pressure (MAP) in normal men
during tilt on placebo and on MK-421 (four individuals showed no fall in MAP on MK-421).
1-188
1982 BLOOD PRESSURE COUNCIL
A 20
SBP
mmHg
SUPP I, HYPERTENSION, VOL 5, No 2, MARCH-APRIL 1983
n.s.
A
1-1
n.s.
h
CO
0l/min
-1
OH
-20J
-20J
20-.
i
i
P
MK
l/min
-1-
-2
-2-
-3-
-3-
<.O2
sv
-20
SV
ml
-20-
-40-
-40-
ml
i
i
MK
P
A 20-|
MAP
mmHg
-60
i
P
n.s.
n.s.
A
TPR
0-
Units
-20BP-Resp.
MK
BP-Non Resp.
FIGURE 6.
Changes in systolic (SBP), diastolic (DBP), and
TABLE 2.
HR (bpm)
SBP (mm Hg)
DBP (mm Hg)
MAP (mm Hg)
CO (liter/min)
SV (ml)
RAP (mm Hg)
TPR (units)
FVR (units)
5-
BP-Non Resp.
FIGURE 7.
Changes in cardiac output (CO), stroke wlume
(SV), and total peripheral resistance (TPR) during tilt on placebo (P) and MK-421 (MK) in five normal men with and four
without BP fall during tilt and MK-421.
Changes in Hemodynamic Measurements during Head-Up Tilt in Subjects on Placebo (P) and MK-421
Hemodynamic
measurement
CBV (ml)
n.s.
0J
0J
BP-Resp.
mean arterial blood pressure (MAP) during tilt on placebo (P)
and MK-421 (MK) in five normal men who showed a BPfall and
four who showed no BP fall during tilt and MK-421.
i
MK
i
P
A
TPR
5-
Units
10-
-60-
i
MK
MK
n.s.
A 20]
DBP
mmHg
0-
-20J
i
P
Placebo
+ 7.0±1.6
0.0+1.6
+ 7.5+1.3
+ 2.9+1.8
-0.88 + 0.2
-23.7±4.3
-5.4±0.4
-282 + 37
+ 3.4±0.7
+ 8.1±1.3
MK-421
P
a 0.001
NS
c 0.001
NS
C 0.005
C 0.001
C 0.001
C 0.001
C 0.001
C 0.001
P
+ 8.0 + 0.9
-11.4 + 3.7
-0.5 + 2.5
-2.5 + 3.0
-1.3 + 0.3
-31.1+3.9
-5.4 + 0.8
-387 + 77
+ 2.9 + 0.5
+ 6.2 + 5.0
C 0.001
C0.01
NS
NS
C 0.001
c: o.ooi
=: 0.001
=: 0.001
c 0.001
NS
Difference P
vs MK-421
P
NS
< 0.01
< 0.001
<0.02
NS
<0.05
NS
NS
NS
NS
Values are means ± SEM. HR = heart rate; SBP = systolic blood pressure; DBP = diastolic blood pressure; MAP =
mean arterial blood pressure; CO = cardiac output; SV = stroke volume; RAP = right atrial pressure; CBV = central
blood volume; TPR = total peripheral resistance; FVR = forearm vascular resistance.
HEMODYNAMICS AND CONVERTING ENZYME INHIBITION///^ et al.
while the four individuals who were able to maintain
BP levels also maintained their levels of CO and S V as
compared to placebo. The changes in HR and TPR
were similar in the two subgroups. The changes in the
remaining variables also did not differ significantly
between the two groups.
Discussion
The present results verify that a single dose of MK421 induces a high degree of CEI:18 l9 P-ACE was
reduced to an undetectable level. This led to a marked
rise in PRA and a fall in PAII. This pattern was accentuated during head-up tilt.
Acute CEI caused an approximately 10% decrease
in resting BP, in accordance with other investigations.26-27 However, the hemodynamic mechanism of
this decrease in normotensive individuals in our study
was different than that in other studies on hypertensive
subjects. In hypertension, no change28"30or even a decrease30 3I in CO and SV were found. In one study of
hypertensives, a slight increase32 in CO during CEI has
been reported. In our study of normal subjects, the BP
decreased through a fall of vascular resistance, which
exceeded the moderate CO increase. Data on normal
humans are very scarce, but our results are in agreement with those of Niarchos et al., 26 who reported an
increase in SV and CO in six sodium-depleted normal
volunteers during acute CEI with teprotide.
In our study, CEI caused a decrease of vascular
resistance. In addition, the arterial compliance increased after MK-421. Both of these effects led to a
substantial decrease of the cardiac afterload. The usual
response to an acute decrease in afterload is a reflex
increase of CO, predominantly through an increase in
HR. After MK-421, however, the response to the decreased afterload was an increase in SV, without
tachycardia.
The absence of tachycardia after MK-421 cannot be
attributed to an absence of sympathetic activation,
since we observed a small but significant increase in
PNE values after MK-421. There are two possible
explanations for this absence of tachycardia: 1) the
absence of angiotensin blunts postjunctional sympathetic responses;4-5 or 2) CEI elicits a central increase
in the parasympathetic chronotropic inhibition.16-l7-31
With a relatively fixed heart rate, MK-421 elicited an
increase of CO through a higher SV. The right atrial
pressure and the cardiopulmonary blood volume did
not increase, indicating that the cardiac preload remained unchanged after MK-421. Consequently, we
believe that the increase of SV reflects a mechanical
improvement of ejection in response to the MK-421induced decrease in afterload.
In anticipation of fainting episodes, we only used a
mild degree of tilt and sodium depletion. In spite of our
precautions, syncope occurred in three subjects, with a
very pronounced BP fall during tilt and MK-421 before
CO measurements could be obtained. However, it
seems unlikely that these three individuals responded
qualitatively differently compared to the remaining in-
1-189
dividuals with a BP fall during CEI and tilt, as, until
the point of faintness, their changes in HR and right
atrial pressure followed the same pattern as the remaining subjects. An analysis of the individual BP changes
during tilt and MK-421 in the nine complete cases
revealed that the subjects could be divided into five
individuals with and four without BP fall. In the five
cases, the BP fall during tilt was obviously due to a
marked decrease in SV as well as CO while the increase in TPR was similar during placebo and MK421. CEI affected the BP response to head-up tilt in
this study. Since there was no evidence for increased
venous pooling of blood in the tilted position after
MK-421, the decrease of SV discloses an impairment
of cardiac function in subjects who responded with a
BP decrease. Apparently after CEI these subjects were
unable to maintain a normal SV against the tilt-induced
increase in afterload. The BP response to MK-421 in
all normotensive subjects fully depends on their capability to maintain a SV, a fact clearly demonstrated in
the correlation of these variables (fig. 5).
Why does elimination of All lead to BP fall during
tilt, mainly through a decrease in cardiac performance?
An attenuation of venous return does not seem to be
involved since the decrease in RAP and CBV during
tilt was similar on placebo and MK-421. Furthermore,
venous distensibility did not change in a consistent
way. It is known that All has a pronounced positive
inotropic effect on the isolated myocardium.33 This
effect is not detectable during All infusion in vivo,
probably due to baroreceptor response to increased
vascular resistance and BP. '6 In the recumbent position
in the present study, an elimination of the inotropic
effect of All could not be uncovered; in fact, an increase in CO and SV was found. However, contrary to
the findings during tilt, a reduction in afterload by CEI
might well override a negative inotropic influence in
recumbency. The decrease in SV and BP during tilt
and CEI was not counterbalanced by augmentation of
reflex adrenergic activity. The increase in HR and vascular resistance was the same on placebo and MK-421.
This suggests that reflex sympathetic adjustments to
tilt are less potent during CEI, which is in accordance
with the results from animal research.3-* The lack of
accentuation of HR increase in spite of BP fall might
not solely be explained by decreased adrenergic function, but increased vagal tone could also be involved.31
Animal data indicate decreased adrenergic activity34 as
well as increased vagal activity35 during sodium depletion. Furthermore, the central potentiating effects of
All on the cardiovascular system involve both enhanced sympathetic activity and withdrawal of vagal
tone.2-16-1? Consequently, All blockade during sodium
depletion might well lead to increased vagal tone.
A decrease in BP without a reflex increase in HR
might also occur if at the same time an alteration in
baroreflex sensitivity or a change in the setpoint12-l4 of
the baroreflexes takes place. We found an increase in
baroreflex sensitivity in response to increases in systolic BP during bolus injections of phenylephrine. The
slope of the regression line between systolic BP and
1-190
1982 BLOOD PRESSURE COUNCIL
increase in RR interval was slightly, but significantly
steeper during CEI with MK-421. It is well known that
baroreflex sensitivity is closely related to arterial compliance.36 The ratio SV/PP serves as an index of arterial
compliance.37 The increase in SV/PP indicates an increase in arterial compliance during CEI, and this
might explain the increase in BRS. Another possible
explanation for the increase in baroreflex sensitivity is
that All antagonizes baroreflexes at a central level;15"17
consequently CEI, with an attendant fall in All, leads
to increases in baroreflex sensitivity.15 Contrary to our
study, Mancia et al.14 found that, in patients with severe hypertension, the sensitivity to BP reduction with
nitroglycerine was increased, while the sensitivity to
BP elevation with phenylephrine was unchanged.
Conclusions
Acute CEI with MK-421 in mildly sodium-depleted
normal men leads to a BP fall through a reduction in
TPR, in spite of an increase in CO and SV. The increase in CO and SV is probably due to a reduction in
afterload.
The major determinant for the additional BP fall
during tilt and CEI was a decrease in cardiac performance. We propose a dual mechanism responsible for
this BP fall: CEI with a decrease in All level leads to an
elimination of a positive inotropic effect of All. The
attendant decrease in S V and CO is insufficiently counterbalanced because of an impairment of reflex adrenergic function. This is, in turn, caused by an attentuation of an All-mediated facilitation on the sympathetic
nervous system. The hypothesis needs to be substantiated by more detailed measurements of left ventricular
function during tilt and blockade of the RAS.
Baroreflex sensitivity to BP increases was enhanced. This might be due to the increase in arterial
compliance, but a central mechanism could also be
responsible. A possible practical importance of this
finding during long-term treatment in hypertension remains to be determined.
Acknowledgments
MK-421 was generously placed at our disposal by Dr. Richard
Davies, Merck Sharp & Dohme Research Laboratories, West Point,
Pennsylvania.
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