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Antihypertensive efficacy of once daily MK-521, a new nonsulfhydryl angiotensin-converting enzyme inhibitor
Antihypertensive Efficacy of Once Daily MK-521, a New NonsulfhydrylAngiotensin-ConvertingEnzyme Inhibitor HESCHI H. ROTMENSCH, MD, PETER H. VLASSES,
PharmD, BRIAN N. SWANSON,
PhD,
JOHN D. IRVIN, MD, PhD, KATHERINE E. HARRIS, MSPH, DEBORAH G. MERRILL, BA, and ROGER K. FERGUSON, MD
The effects of the new nonsulfhydryl-containing oral converting-enzyme inhibitor MK-521 on blood pressure, heart rate, angiotensin-converting enzyme activity, plasma renin activity and plasma aldosterone concentration were assessed in 10 hypertensive patients. After a 2-week no-treatment period, patients received placebo and then 14 days each: MK-521 20 mg once daily, hydrochlorothiazide 50 mg once daily and the latter 2 in combination. During the last day of each treatment, the mean (* standard deviation) time-averaged (I- to 12-hour) standing diastolic blood pressure decreased from 106 f 8 (placebo) to 95 f 10 mm Hg with MK-521,
95 f 13 mm Hg with hydrochlorothiazide (p <0.05 vs placebo) and 88 f 11 mm Hg with the combination (p <0.05 vs all other treatments). The antihypertensive effect of MK-521 was maintained 24 hours after dosing. Heart rate did not change significantly after MK-521 treatment. MK-521 caused a marked suppression of converting enzyme activity for over 24 hours; plasma renin activity increased significantly after each active treatment and MK-521 significantly decreased the hydrochlorothiazideinduced elevation of plasma aldosterone concentration. In this short-term trial, MK-521 was well tolerated. (Am J Cardiol 1984;53:116-119)
In the last decade, the renin-angiotensin-aldosterone system has been found to play an important role in the pathophysiologic aspects of various forms of systemic hypertension and congestive heart failure. Pharmacologic blockade of the conversion process from angiotensin I to angiotensin II by angiotensin-converting enzyme (ACE) inhibition has proved highly efficacious in these conditi0ns.l Captopril, the first marketed oral ACE inhibitor, has been associated with adverse reactions such as skin rash, loss of taste, proteinuria and leukopenia.” Because these reactions resemble those of d-pencillamine and methimazole, it was suggested that the sulfhydryl moiety in the chemical structure of these compounds accounts for the specific side-effect profile.’ MK-521 is an investigational ACE inhibitor and a lysine analog of enalapril maleate (MK-421).3 Both compounds are devoid of a sulfhydryl group and in healthy volunteers and hypertensive patients are more potent
and have a longer duration of action than does captopril.“m6 This study compares the antihypertensive efficacy of MK-521, hydrochlorothiazide and their combination in patients with mild to moderate essential hypertension and correlates blood pressure responses with the biochemical changes associated with ACE inhibition. Methods Patients: Ten patients (8 men and
2 women, mean age 51 years, range 40 to 69) with mild to moderate essential hypertension (untreated, standing diastolic blood pressure between 95 and 115 mm Hg) entered and completed the study. Patients were judged to have essential hypertension without severe end-organ damage on the basis of a thorough history, physical examination and laboratory evaluation. A 150-mEq sodium and 80-mEq potassium diet was prescribed throughout the study. Study design: After at least a 2-week no-treatment period, patients were treated with placebo for 1 day and then sequentially with MK-521,20 mg once daily, hydrochlorothiazide, 50 mg once daily, and then the latter 2 in combination. Each active treatment was administered for 2 weeks. Patients were admitted to the Clinical Pharmacology Unit at 8:OOAM for evaluation on the placebo day and on the first and last days of each treatment period, except on day 1 of the hydrochlorothiazide treatment period. During the day, patients were
From the Division of Clinical Pharmacology, Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania, and Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania. Manuscript received June 8, 1983; revised manuscript received September 6, 1983, accepted September 10, 1983. Address for reprints: Heschi H. Rotmensch, MD, Division of Clinical Pharmacology (M-502), Thomas Jefferson University Hospital, 1 lth and Walnut Streets, Philadelphia, Pennsylvania 19107. 116
Januarv 1. 1984
free to walk within the facilities and were housed overnight in the unit. Supine and standing blood pressure and pulse rate were measured hourly for 12 hours and again 23 and 24 hours after drug ingestion by an automatic device using the Doppler principle (Dinamapm). Blood was collected from a forearm intravenous catheter in a sitting position to determine serum electrolytes, plasma renin activity, serum ACE activity and plasma aldosterone concentration before (0 hour) and at 4,8, 12 and 24 hours after drug administration on the placebo day and the first and last day of each treatment period. Urine was collected for 24 hours for electrolyte and protein determinations. Patients were carefully evaluated for side effects. Medication diaries, pill counts and ACE measurements were used to assess compliance. Laboratory analysis: Plasma renin activity, at pH 7.4, and plasma aldosterone concentrations were measured by radioimmunoassay and serum ACE activity was measured by a modified radioenzymatic method (as previously described).7mg In our laboratory, normal values (mean f standard deviation [SD]) for plasma renin activity, plasma aldosterone concentration and ACE are 1.6 f 0.4 ng/ml/hour, 11 f 4 ng/dl and 5.4 f 0.3 U (9%of hippurylglycyl-glycine substrate metabolized/min/ml). Statistical analysis: The mean standing diastolic blood pressure for the group was calculated at the various time points. In addition, the overall treatment effect for the group during t,he day was characterized by the mean of the timeaveraged (I- to 12-hour) standing diastolic blood pressure for each patient. Mean standing diastolic blood pressure and pulse rate were evaluated in a similar manner. The l- to 12hour time period was selected to minimize the effect of variability in the O-hour (predrug) values that were determined upon the patient’s arrival at the Clinical Pharmacology Unit. Differences among treatment periods were assessed using repeated measures analysis of variance. Duncan’s multiple range test was used to compare individual treatments. All tests were 2-tailed and performed at the LY= 0.05 level of significance.
Results Blood pressure and pulse rate: The time course of the mean standing diastolic blood pressure for the group on the placebo day and on the last day of each treatment is illustrated in Figure 1. In comparison with placebo, both MK-521 and hydrochlorothiazide alone decreased
THE AMERICAN JOURNAL OF CARDIOLOGY Volume 53
117
mean standing diastolic blood pressure significantly at most time points. A decrease in standing diastolic blood
pressure was apparent
within 1 hour of MK-521 inges-
tion and reached its peak at 6 hours; blood pressure was reduced for 24 hours compared with placebo. There was
no significant difference between the responses on day 1 and those on day 14 of MK-521 treatment. The addition of MK-521 to hydrochlorothiazide resulted in a further significant reduction in mean standing diastolic blood pressure which was more pronounced on day 1 of the combination than on day 14. On day 14, mean (& SD) time-averaged (l- to 12-hour) standing diastolic blood pressure was 106 f 8 mm Hg on placebo, 95 f IO mm Hg on MK-521 and 95 f 13 mm Hg on hydrochlorothiazide (Fig. 2). The responses to MK-521 and hydrochlorothiazide differed significantly (p <0.05) from those to the placebo but not from each other. The mean (3~ SD) time-averaged (l- to 12-hour) standing diastolic blood pressure on day 14 of the combination was 88 f 11 mg Hg which represents a significant (p <0.05) reduction from that with the placebo and all other treatments (Fig. 2). The mean (& SD) time-averaged (l- IO 12-hour) standing systolic blood pressure with each treatment is shown in Figure 2. In comparison to placebo, the mean (& SD) timeaveraged I- to 12.hour standing pulse rate increased from 86 f 14 to 96 f 11 beats/min on day 14 of hydrochlorothiazide therapy alone and 94 f 12 beats/ min on day 14 of the combination (p
_I t* 11
r
10
I
comblnatlon
8
c 3
4
2
4
6 Time
8
10
12
”
23
24
(Hours)
FIGURE 1. Time course of the mean standing diastolic blood pressure (SDBP) after placebo (0) and on the last day of treatment with MK-521 (A), hydrochlorothiazide (HCTZ) (A) and the combination (0).
placebo
MK-521
HCTZ
1
combination
FIGURE 2. The mean (k standard deviation) time-averaged (l- to 12hour) standing systolic and diastolic blood pressures on placebo and on the last day of the various treatments (“p <0.05 from placebo; * “p <0.05 from all other treatments). HCTZ = hydrochlorothiazide.
118
MK-52 1, A LONGACTING
ANGIOTENSIN-CONVERTING
ENZYME INHIBITOR
the 24-hour value. Hydrochlorothiazide caused a marked increase in plasma renin activity, which was increased further at all time points during combination therapy. There was no correlation between pretreatment plasma renin activity and the reduction in standing diastolic blood pressure. In comparison with placebo values, hydrochlorothiazide significantly increased mean plasma aldosterone concentration, whereas MK-521 alone had no appreciable effect. However, MK-521 in combination with hydrochlorothiazide caused a significant suppression of the diuretic-induced elevation in plasma aldosterone concentration (Fig. 3). In comparison with MK-521,
hydrochlorothiazide treatment caused a small but significant (p cO.05) reduction in mean serum potassium from 4.5 to 4.1 mEq/liter and a significant (p <0.05) increase in mean 24-hour urinary potassium excretion from 52 to 108 mEq. The addition of MK-521 to hydrochlorothiazide significantly reduced the urinary potassium loss (55 mEq) and tended to reverse serum potassium changes. Serum sodium and urinary sodium excretion remained unchanged. Adverse effects: On the first day of combination therapy, 1 patient had transient symptomatic hypotension with dizziness and blurred vision. Another patient complained of dizziness on day 1 of MK-521 administration and day 12 of hydrochlorothiazide therapy. No other clinical or laboratory abnormalities were detected. Discussion
I 0
4
8
POST
HOURS
b
8
4
0
4
8 HOURS
DRUG
12 POST
HOURS
I 24
12
12 ?OST
2’4 DRUG
2.4 DRUG
FIGURE 3. Mean angiotensin-converting enzyme activity, plasma renin activity and plasma aldosterone concentration at selected times after placebo (0) and 2 weeks of MK-521 (A), hydrochlorothiazide (A) and the combination (0). metab = metabolized.
In this study, MK-521, a new, nonsulfhydryl ACE inhibitor, reduced blood pressure in patients with mild to moderate hypertension. A single daily dose of 20 mg caused a significant (p <0.05) reduction in blood pressure for 24 hours in comparison with placebo (Fig. 1) and was associated with a very substantial suppression in ACE activity. These results confirm our previous observations that MK-521 has a considerably longer duration of action than does captopril. In a study of hypertensive patients treated with captopril, 25 mg 3 times a day, we showed that blood pressure and ACE activity returned to baseline levels within 8 hours after dosing,lO whereas ACE suppression after a single ZO-mg dose of MK-521 caused significant suppression of ACE for over 48 hours with a concomitant reduction in blood pressure.” In healthy volunteers, MK-521 and enalapril (MK-421) which are structurally similar have similar potency as ACE inhibitors and produce comparable antihypertensive effects 3; however, it appears that MK-521 has a longer duration of action. In contrast to MK-521, which is the active compound, orally administered enalapril must be bioactivated to inhibit ACE activity. In contrast to direct active arteriolar vasodilators, MK-521 did not cause a compensatory increase in heart rate, a property shared with other ACE inhibitors.4v5J1 The underlying mechanism is not well understood. However, because angiotensin II facilitates noradrenergic neurotransmission12 and produces central vagal inhibitionls a reduction in circulating angiotensin II by ACE inhibition could attenuate both sympathetic stimulation and vagal inhibition and explain the lack of reflex tachycardia. As with other ACE inhibitors, plasma renin activity increased significantly after MK-521 therapy, probably because of removal of the negative feedback effect that angiotensin II has on renal renin secretion. Alt.hough plasma aldosterone concentrations, serum potassium and urinary potassium excretion appeared to be unaffected by MK-521 alone, in combination, MK-521 counteracted the hydrochlorothiazide-induced increase in aldosterone concentration and changes in potassium homeostasis. This plus the enhanced blood pressure reduction make this combined regimen particularly
January 1, 1984
attractive. In addition, because MK-521 produced comparable blood pressure responses to those seen with hydrochlorothiazide, in patients with intolerable side effects to a diuretic it could emerge as a valuable therapeutic alternative. In conclusion, in this short-term trial, once-daily administration of MK-521 alone or in combination with hydrochlorothiazide markedly reduced blood pressure in patients with mild to moderate essential hypertension and was well tolerated. Further studies are needed to establish the efficacy and tolerability of MK-521 during long-term therapy. Acknowledgment: We express our gratitude to Teresa Mikus for excellence in preparing this manuscript.
4. 5.
6. 7.
6. 9.
10.
References 11. 1. Vlasses PH, Ferguson RK, Chatterjee K. Captopril: clinical pharmacology and benefit-to-risk ratio in hypertension and congestive heart failure. Pharmacotherapy 1982;2:1-17. 2. Rotmensch HH, Vlasses PH, Ferguson RK. Resolution of captopril-induced rash after substitution of enalapril. Pharmacotherapy 1983;3:131-133. 3. Millar JA, Derkx FHM, McLean K? Reid JL. Pharmacodynamics of converting enzyme inhibition: the cardiovascular endocrine and automatic ef-
12.
THE AMERICAN
JOURNAL OF CARDIOLOGY
Volume 53
119
fects of MK-421 (enalapril) and MK-521. Br J Clin Pharmacol 1982; 14: 347-355. Gavras H,, Waeber 6, Gavras I, Biollaz J, Brunner HA, Davies RO. Antihypertensive effect of the new oral angiotensin converting enzyme inhibitor “MK-421”. Lancet 1981;2:543-546. Vlasses PH, Rotmensch HH, Swanson BN, Irvin JD. Lee RB, Koplin JR, Ferguson RK. Comparative antihypertensive effects of enalapril maleate and hydrochlorothiazide, alone and in combination. .J Clin Pharmacol 1983;23:227-233. Rotmensch HH. Vincent M. Vlasses PH. Swanson BN. Irvin JD. Hichens M, Harris KE, F&guson RK. initial evaluatan of the non-shlfhydryl donverting enzyme inhibitor MK-521 in hypertensive man. Fed Proc, in press. Haber E. Koerner D. Paae LB. Kliman B. Purnode A. Aoolication of a radioimmunoassay for angigtensin I to the ph;siologic meas&ement of plasma renin activity in normal human subjects. J Clin Endocrinol 1969;29: 1349-1355. Ito T, Woo J, Haning R, Horton R. A radioimmunoassay for aldosterone in human peripheral plasma including a comparison of alternate techniques. J Clin Endocrinol 1972;34:106-112. Swanson BN, Hichens f$ Mojaverian P, Ferguson RK, Vlasses PH, Dudash M. Angiotensin converting enzyme activity in human serum: relationship to enzyme inhibitor in vivo and in vitro. Res Comm Chem Path Pharmacol 1981;33:525-536. Vlasses PH, Rotmensch HH, Swanson BN, Mojaverian P, Ferguson RK. Low dose captopril. Its use in mild to moderate hypertension unresponsive to diuretic treatment. Arch Intern Med 1982;142:1098-1102. lmai Y, Abe K, Sato M, Haruyama T, Hiwatari M, Goto T, Sato K, Kasai K, Tajima J, Yoshinaga K. Evaluation of the chronotropic property of captopril in hypertensive patients. Am Heart J 1982;104:1339-1345. Malik KU, Nasjletti A. Facilitation of adrenergic neurotransmission by locally ;;yerrted angiotensin II in rat mesenteric arteries. Circ Res 1976;38:
13. Lee WB, lsmay MJ, Lumbers ER. Mechanisms by which angiotensin II affects the heart rate of the conscious sheep. Circ Res 1980;47:286-292.
PharmD, BRIAN N. SWANSON,
PhD,
JOHN D. IRVIN, MD, PhD, KATHERINE E. HARRIS, MSPH, DEBORAH G. MERRILL, BA, and ROGER K. FERGUSON, MD
The effects of the new nonsulfhydryl-containing oral converting-enzyme inhibitor MK-521 on blood pressure, heart rate, angiotensin-converting enzyme activity, plasma renin activity and plasma aldosterone concentration were assessed in 10 hypertensive patients. After a 2-week no-treatment period, patients received placebo and then 14 days each: MK-521 20 mg once daily, hydrochlorothiazide 50 mg once daily and the latter 2 in combination. During the last day of each treatment, the mean (* standard deviation) time-averaged (I- to 12-hour) standing diastolic blood pressure decreased from 106 f 8 (placebo) to 95 f 10 mm Hg with MK-521,
95 f 13 mm Hg with hydrochlorothiazide (p <0.05 vs placebo) and 88 f 11 mm Hg with the combination (p <0.05 vs all other treatments). The antihypertensive effect of MK-521 was maintained 24 hours after dosing. Heart rate did not change significantly after MK-521 treatment. MK-521 caused a marked suppression of converting enzyme activity for over 24 hours; plasma renin activity increased significantly after each active treatment and MK-521 significantly decreased the hydrochlorothiazideinduced elevation of plasma aldosterone concentration. In this short-term trial, MK-521 was well tolerated. (Am J Cardiol 1984;53:116-119)
In the last decade, the renin-angiotensin-aldosterone system has been found to play an important role in the pathophysiologic aspects of various forms of systemic hypertension and congestive heart failure. Pharmacologic blockade of the conversion process from angiotensin I to angiotensin II by angiotensin-converting enzyme (ACE) inhibition has proved highly efficacious in these conditi0ns.l Captopril, the first marketed oral ACE inhibitor, has been associated with adverse reactions such as skin rash, loss of taste, proteinuria and leukopenia.” Because these reactions resemble those of d-pencillamine and methimazole, it was suggested that the sulfhydryl moiety in the chemical structure of these compounds accounts for the specific side-effect profile.’ MK-521 is an investigational ACE inhibitor and a lysine analog of enalapril maleate (MK-421).3 Both compounds are devoid of a sulfhydryl group and in healthy volunteers and hypertensive patients are more potent
and have a longer duration of action than does captopril.“m6 This study compares the antihypertensive efficacy of MK-521, hydrochlorothiazide and their combination in patients with mild to moderate essential hypertension and correlates blood pressure responses with the biochemical changes associated with ACE inhibition. Methods Patients: Ten patients (8 men and
2 women, mean age 51 years, range 40 to 69) with mild to moderate essential hypertension (untreated, standing diastolic blood pressure between 95 and 115 mm Hg) entered and completed the study. Patients were judged to have essential hypertension without severe end-organ damage on the basis of a thorough history, physical examination and laboratory evaluation. A 150-mEq sodium and 80-mEq potassium diet was prescribed throughout the study. Study design: After at least a 2-week no-treatment period, patients were treated with placebo for 1 day and then sequentially with MK-521,20 mg once daily, hydrochlorothiazide, 50 mg once daily, and then the latter 2 in combination. Each active treatment was administered for 2 weeks. Patients were admitted to the Clinical Pharmacology Unit at 8:OOAM for evaluation on the placebo day and on the first and last days of each treatment period, except on day 1 of the hydrochlorothiazide treatment period. During the day, patients were
From the Division of Clinical Pharmacology, Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania, and Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania. Manuscript received June 8, 1983; revised manuscript received September 6, 1983, accepted September 10, 1983. Address for reprints: Heschi H. Rotmensch, MD, Division of Clinical Pharmacology (M-502), Thomas Jefferson University Hospital, 1 lth and Walnut Streets, Philadelphia, Pennsylvania 19107. 116
Januarv 1. 1984
free to walk within the facilities and were housed overnight in the unit. Supine and standing blood pressure and pulse rate were measured hourly for 12 hours and again 23 and 24 hours after drug ingestion by an automatic device using the Doppler principle (Dinamapm). Blood was collected from a forearm intravenous catheter in a sitting position to determine serum electrolytes, plasma renin activity, serum ACE activity and plasma aldosterone concentration before (0 hour) and at 4,8, 12 and 24 hours after drug administration on the placebo day and the first and last day of each treatment period. Urine was collected for 24 hours for electrolyte and protein determinations. Patients were carefully evaluated for side effects. Medication diaries, pill counts and ACE measurements were used to assess compliance. Laboratory analysis: Plasma renin activity, at pH 7.4, and plasma aldosterone concentrations were measured by radioimmunoassay and serum ACE activity was measured by a modified radioenzymatic method (as previously described).7mg In our laboratory, normal values (mean f standard deviation [SD]) for plasma renin activity, plasma aldosterone concentration and ACE are 1.6 f 0.4 ng/ml/hour, 11 f 4 ng/dl and 5.4 f 0.3 U (9%of hippurylglycyl-glycine substrate metabolized/min/ml). Statistical analysis: The mean standing diastolic blood pressure for the group was calculated at the various time points. In addition, the overall treatment effect for the group during t,he day was characterized by the mean of the timeaveraged (I- to 12-hour) standing diastolic blood pressure for each patient. Mean standing diastolic blood pressure and pulse rate were evaluated in a similar manner. The l- to 12hour time period was selected to minimize the effect of variability in the O-hour (predrug) values that were determined upon the patient’s arrival at the Clinical Pharmacology Unit. Differences among treatment periods were assessed using repeated measures analysis of variance. Duncan’s multiple range test was used to compare individual treatments. All tests were 2-tailed and performed at the LY= 0.05 level of significance.
Results Blood pressure and pulse rate: The time course of the mean standing diastolic blood pressure for the group on the placebo day and on the last day of each treatment is illustrated in Figure 1. In comparison with placebo, both MK-521 and hydrochlorothiazide alone decreased
THE AMERICAN JOURNAL OF CARDIOLOGY Volume 53
117
mean standing diastolic blood pressure significantly at most time points. A decrease in standing diastolic blood
pressure was apparent
within 1 hour of MK-521 inges-
tion and reached its peak at 6 hours; blood pressure was reduced for 24 hours compared with placebo. There was
no significant difference between the responses on day 1 and those on day 14 of MK-521 treatment. The addition of MK-521 to hydrochlorothiazide resulted in a further significant reduction in mean standing diastolic blood pressure which was more pronounced on day 1 of the combination than on day 14. On day 14, mean (& SD) time-averaged (l- to 12-hour) standing diastolic blood pressure was 106 f 8 mm Hg on placebo, 95 f IO mm Hg on MK-521 and 95 f 13 mm Hg on hydrochlorothiazide (Fig. 2). The responses to MK-521 and hydrochlorothiazide differed significantly (p <0.05) from those to the placebo but not from each other. The mean (3~ SD) time-averaged (l- to 12-hour) standing diastolic blood pressure on day 14 of the combination was 88 f 11 mg Hg which represents a significant (p <0.05) reduction from that with the placebo and all other treatments (Fig. 2). The mean (& SD) time-averaged (l- IO 12-hour) standing systolic blood pressure with each treatment is shown in Figure 2. In comparison to placebo, the mean (& SD) timeaveraged I- to 12.hour standing pulse rate increased from 86 f 14 to 96 f 11 beats/min on day 14 of hydrochlorothiazide therapy alone and 94 f 12 beats/ min on day 14 of the combination (p
_I t* 11
r
10
I
comblnatlon
8
c 3
4
2
4
6 Time
8
10
12
”
23
24
(Hours)
FIGURE 1. Time course of the mean standing diastolic blood pressure (SDBP) after placebo (0) and on the last day of treatment with MK-521 (A), hydrochlorothiazide (HCTZ) (A) and the combination (0).
placebo
MK-521
HCTZ
1
combination
FIGURE 2. The mean (k standard deviation) time-averaged (l- to 12hour) standing systolic and diastolic blood pressures on placebo and on the last day of the various treatments (“p <0.05 from placebo; * “p <0.05 from all other treatments). HCTZ = hydrochlorothiazide.
118
MK-52 1, A LONGACTING
ANGIOTENSIN-CONVERTING
ENZYME INHIBITOR
the 24-hour value. Hydrochlorothiazide caused a marked increase in plasma renin activity, which was increased further at all time points during combination therapy. There was no correlation between pretreatment plasma renin activity and the reduction in standing diastolic blood pressure. In comparison with placebo values, hydrochlorothiazide significantly increased mean plasma aldosterone concentration, whereas MK-521 alone had no appreciable effect. However, MK-521 in combination with hydrochlorothiazide caused a significant suppression of the diuretic-induced elevation in plasma aldosterone concentration (Fig. 3). In comparison with MK-521,
hydrochlorothiazide treatment caused a small but significant (p cO.05) reduction in mean serum potassium from 4.5 to 4.1 mEq/liter and a significant (p <0.05) increase in mean 24-hour urinary potassium excretion from 52 to 108 mEq. The addition of MK-521 to hydrochlorothiazide significantly reduced the urinary potassium loss (55 mEq) and tended to reverse serum potassium changes. Serum sodium and urinary sodium excretion remained unchanged. Adverse effects: On the first day of combination therapy, 1 patient had transient symptomatic hypotension with dizziness and blurred vision. Another patient complained of dizziness on day 1 of MK-521 administration and day 12 of hydrochlorothiazide therapy. No other clinical or laboratory abnormalities were detected. Discussion
I 0
4
8
POST
HOURS
b
8
4
0
4
8 HOURS
DRUG
12 POST
HOURS
I 24
12
12 ?OST
2’4 DRUG
2.4 DRUG
FIGURE 3. Mean angiotensin-converting enzyme activity, plasma renin activity and plasma aldosterone concentration at selected times after placebo (0) and 2 weeks of MK-521 (A), hydrochlorothiazide (A) and the combination (0). metab = metabolized.
In this study, MK-521, a new, nonsulfhydryl ACE inhibitor, reduced blood pressure in patients with mild to moderate hypertension. A single daily dose of 20 mg caused a significant (p <0.05) reduction in blood pressure for 24 hours in comparison with placebo (Fig. 1) and was associated with a very substantial suppression in ACE activity. These results confirm our previous observations that MK-521 has a considerably longer duration of action than does captopril. In a study of hypertensive patients treated with captopril, 25 mg 3 times a day, we showed that blood pressure and ACE activity returned to baseline levels within 8 hours after dosing,lO whereas ACE suppression after a single ZO-mg dose of MK-521 caused significant suppression of ACE for over 48 hours with a concomitant reduction in blood pressure.” In healthy volunteers, MK-521 and enalapril (MK-421) which are structurally similar have similar potency as ACE inhibitors and produce comparable antihypertensive effects 3; however, it appears that MK-521 has a longer duration of action. In contrast to MK-521, which is the active compound, orally administered enalapril must be bioactivated to inhibit ACE activity. In contrast to direct active arteriolar vasodilators, MK-521 did not cause a compensatory increase in heart rate, a property shared with other ACE inhibitors.4v5J1 The underlying mechanism is not well understood. However, because angiotensin II facilitates noradrenergic neurotransmission12 and produces central vagal inhibitionls a reduction in circulating angiotensin II by ACE inhibition could attenuate both sympathetic stimulation and vagal inhibition and explain the lack of reflex tachycardia. As with other ACE inhibitors, plasma renin activity increased significantly after MK-521 therapy, probably because of removal of the negative feedback effect that angiotensin II has on renal renin secretion. Alt.hough plasma aldosterone concentrations, serum potassium and urinary potassium excretion appeared to be unaffected by MK-521 alone, in combination, MK-521 counteracted the hydrochlorothiazide-induced increase in aldosterone concentration and changes in potassium homeostasis. This plus the enhanced blood pressure reduction make this combined regimen particularly
January 1, 1984
attractive. In addition, because MK-521 produced comparable blood pressure responses to those seen with hydrochlorothiazide, in patients with intolerable side effects to a diuretic it could emerge as a valuable therapeutic alternative. In conclusion, in this short-term trial, once-daily administration of MK-521 alone or in combination with hydrochlorothiazide markedly reduced blood pressure in patients with mild to moderate essential hypertension and was well tolerated. Further studies are needed to establish the efficacy and tolerability of MK-521 during long-term therapy. Acknowledgment: We express our gratitude to Teresa Mikus for excellence in preparing this manuscript.
4. 5.
6. 7.
6. 9.
10.
References 11. 1. Vlasses PH, Ferguson RK, Chatterjee K. Captopril: clinical pharmacology and benefit-to-risk ratio in hypertension and congestive heart failure. Pharmacotherapy 1982;2:1-17. 2. Rotmensch HH, Vlasses PH, Ferguson RK. Resolution of captopril-induced rash after substitution of enalapril. Pharmacotherapy 1983;3:131-133. 3. Millar JA, Derkx FHM, McLean K? Reid JL. Pharmacodynamics of converting enzyme inhibition: the cardiovascular endocrine and automatic ef-
12.
THE AMERICAN
JOURNAL OF CARDIOLOGY
Volume 53
119
fects of MK-421 (enalapril) and MK-521. Br J Clin Pharmacol 1982; 14: 347-355. Gavras H,, Waeber 6, Gavras I, Biollaz J, Brunner HA, Davies RO. Antihypertensive effect of the new oral angiotensin converting enzyme inhibitor “MK-421”. Lancet 1981;2:543-546. Vlasses PH, Rotmensch HH, Swanson BN, Irvin JD. Lee RB, Koplin JR, Ferguson RK. Comparative antihypertensive effects of enalapril maleate and hydrochlorothiazide, alone and in combination. .J Clin Pharmacol 1983;23:227-233. Rotmensch HH. Vincent M. Vlasses PH. Swanson BN. Irvin JD. Hichens M, Harris KE, F&guson RK. initial evaluatan of the non-shlfhydryl donverting enzyme inhibitor MK-521 in hypertensive man. Fed Proc, in press. Haber E. Koerner D. Paae LB. Kliman B. Purnode A. Aoolication of a radioimmunoassay for angigtensin I to the ph;siologic meas&ement of plasma renin activity in normal human subjects. J Clin Endocrinol 1969;29: 1349-1355. Ito T, Woo J, Haning R, Horton R. A radioimmunoassay for aldosterone in human peripheral plasma including a comparison of alternate techniques. J Clin Endocrinol 1972;34:106-112. Swanson BN, Hichens f$ Mojaverian P, Ferguson RK, Vlasses PH, Dudash M. Angiotensin converting enzyme activity in human serum: relationship to enzyme inhibitor in vivo and in vitro. Res Comm Chem Path Pharmacol 1981;33:525-536. Vlasses PH, Rotmensch HH, Swanson BN, Mojaverian P, Ferguson RK. Low dose captopril. Its use in mild to moderate hypertension unresponsive to diuretic treatment. Arch Intern Med 1982;142:1098-1102. lmai Y, Abe K, Sato M, Haruyama T, Hiwatari M, Goto T, Sato K, Kasai K, Tajima J, Yoshinaga K. Evaluation of the chronotropic property of captopril in hypertensive patients. Am Heart J 1982;104:1339-1345. Malik KU, Nasjletti A. Facilitation of adrenergic neurotransmission by locally ;;yerrted angiotensin II in rat mesenteric arteries. Circ Res 1976;38:
13. Lee WB, lsmay MJ, Lumbers ER. Mechanisms by which angiotensin II affects the heart rate of the conscious sheep. Circ Res 1980;47:286-292.