[Angiotensin converting enzyme inhibitory activity of MK-0521 in vivo and antihypertensive effect of its single oral administration on blood pressure and effect on the renin-angiotensin system in 2-kidney Goldblatt hypertensive dogs].
Angiotensin converting enzyme (ACE) inhibitory activity of MK-0521 in dogs and the effects of its single oral administration on blood pressure and the renin-angiotensin system in 2-kidney Goldblatt hypertensive dogs were compared with those of captopril and MK-421. MK-0521 at 0.001-0.1 mg/kg, i.v., or 0.01-1 mg/kg, p.o., attenuated the pressor effect of angiotensin I without affecting that of angiotensin II and augmented the depressor effect of bradykinin. The potency of MK-0521 to reduce the pressor effect of angiotensin I was 9.8 times that of captopril by intravenous administration, and by oral administration, it was 15.9-32.1 times that of captopril and approximately 3 times that of MK-421. When administered orally, the onset of action and the time to peak effectiveness were more rapid than those of MK-421, but slower than those of captopril. Duration of the action of MK-0521 was longer than that of captopril and equal or longer than that of MK-421. The inhibition of ACE was well correlated with serum MK-0521 levels. MK-0521 produced a dose-dependent antihypertensive effect in 2-kidney Goldblatt hypertensive dogs at over 0.3 mg/kg, p.o., without affecting the heart rate. The antihypertensive effect of MK-0521 was persistent and approximately 3 times more potent than that of captopril. MK-0521 inhibited the serum ACE activity and increased the plasma renin activity, while it had a tendency to decrease plasma aldosterone level. These changes were parallel to the time course of the antihypertensive effect. These results suggest that the main mechanism of the antihypertensive effect of MK-0521 is the suppression of angiotensin II production due to the inhibition of the ACE.
Oda
M
M
Research Laboratories, Torii & Co., Ltd., Chiba, Japan.
Ino
Y
Y
Suzuki
K
K
Sato
T
T
Iwamoto
S
S
Iwaki
M
M
D000284:Administration, Oral; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002216:Captopril / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006978:Hypertension, Renovascular / Q000188:drug therapy*; D017706:Lisinopril; D008297:Male; D012084:Renin-Angiotensin System / Q000187:drug effects*
D000806:Angiotensin-Converting Enzyme Inhibitors; D004656:Enalapril; D002216:Captopril; D017706:Lisinopril