Antihypertensive action of a novel orally active angiotensin converting enzyme inhibitor altiopril calcium (MC-838) in several hypertensive models of rats: comparison with captopril.
The antihypertensive effects of altiopril calcium (MC-838), calcium(-)-N-[(S)-3-[(N-cyclohexylcarbonyl-D-alanyl)thio]-2-methyl- propionyl]-L-prolinate, a novel inhibitor of angiotensin converting enzyme, compared with captopril, were evaluated in conscious rat models of experimental hypertension. MC-838 (3-30 mg/kg p.o.) as well as captopril (3 and 10 mg/kg p.o.) dose-dependently lowered systemic blood pressure (SBP) with no consistent changes in heart rate (HR) in two-kidney renal hypertensive rats (2 KG-RHRs) and spontaneously hypertensive rats (SHRs). However, MC-838 and captopril, unlike hydralazine, did not significantly produce hypotension in DOCA-salt hypertensive rats. The antihypertensive effect of MC-838, compared with captopril, was characterized by a slower onset and longer duration. When compared on a weight basis of 3 mg/kg, the antihypertensive effect of MC-838 was comparable to that of captopril in magnitude, but the duration of action was approximately 2 times longer than that of captopril. MC-838, like captopril, attenuated angiotensin-I (A-I)-induced pressor response, and augmented bradykinin (BK)-induced depressor one in SHRs. However, no correlation was observed between the modification of the SBP response to exogenous i.v. A-I or BK, and the SBP lowering caused by MC-838 or captopril given orally. In contrast, there was a close correlation between inhibition of lung angiotensin converting enzyme (ACE) (but not plasma ACE) and SBP reduction induced by the 2 ACE inhibitors in SHRs. When administered orally once a day for 9 weeks in 2 KG-RHRs and SHRs, MC-838 dose-dependently reduced SBP throughout the treatment period. After withdrawal of treatment with MC-838 there was no rebound increase in SBP. These studies indicate that MC-838 is a promising antihypertensive agent.
Aono
J
J
Department of Pharmacology, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
Koga
T
T
Yamazaki
T
T
Shiraki
Y
Y
Sakai
K
K
D000803:Angiotensin I / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D002216:Captopril / Q000494:pharmacology*; D003900:Desoxycorticosterone / Q000494:pharmacology; D008168:Lung / Q000187:drug effects; D008297:Male; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D012083:Renin / Q000097:blood
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D003900:Desoxycorticosterone; C048961:MC 838; D000803:Angiotensin I; D011392:Proline; D002216:Captopril; D012083:Renin; D001920:Bradykinin