mc-838 and Hypertension

Patients with essential hypertension were studied to clarify the role of the kallikrein-kinin system in the hypotensive actions of angiotensin I converting enzyme inhibitors. Captopril, alacepril, ramipril, and altiopril administered in single doses rapidly decreased blood pressure and plasma angiotensin II levels, and increased plasma and urinary kinins as well as plasma renin activity. Following administration of captopril for 14 days, similar effects were observed. Urine volume and urinary sodium excretion were augmented after acute and chronic administration of captopril. The patients who received ramipril and altiopril were divided into renin subgroups. In the normal-renin group, the change in blood pressure was accompanied by an increase in plasma kinin level and a decrease in plasma angiotensin II level. However, in the low-renin group, although these drugs reduced blood pressure and increased plasma kinin, no significant change was observed in plasma angiotensin II levels. These findings suggest that (a) in patients with normal renin activity, the hypotensive effect of converting enzyme inhibitors might be caused by an increase in plasma kinin and a decrease in plasma angiotensin II, but in the low-renin group, the increase in plasma kinin levels may be more important; and (b) the augmentation of urine volume and urinary sodium excretion may also be related to the hypotensive effects of the converting enzyme inhibitors during long-term administration.

Topics: Adult; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Bridged Bicyclo Compounds; Humans; Hypertension; Kallikreins; Kinins; Middle Aged; Proline; Radioimmunoassay; Ramipril; Renin; Sodium

The effect of a new orally active angiotensin converting enzyme (ACE) inhibitor, calcium (-)-N-[(S)-3-[(N-cyclohexylcarbonyl-D-alanyl)thio]-2-methylpropionyl+ ++]-L- prolinate (MC-838, altiopril calcium), on systemic blood pressure (SBP) and tissue ACE activity has been examined in conscious spontaneously hypertensive rats (SHRs). MC-838 (3 mg kg-1) given orally to SHRs elicited a long-lasting hypotension lasting over 24 h. With the development of the hypotension, MC-838 significantly reduced ACE activity in the lung, kidney and aorta, but not in the brain and heart. Suppression of plasma ACE and rise of plasma renin activity occurred only transiently at an earlier stage.

Topics: Animals; Antihypertensive Agents; Hypertension; Male; Peptidyl-Dipeptidase A; Proline; Rats; Rats, Inbred SHR; Renin

MC-838, calcium (-)-N-[(S)-3-(N-cyclohexylcarbonyl-D-alanyl) thio]-2-methylpropionyl]-L- prolinate, is a new orally active angiotensin converting enzyme (ACE) inhibitor in which the mercapto-group is taken up in a stable thiolester linkage. The linkage was relatively resistant against enzymatic hydrolysis by rat liver homogenates. The ACE prepared from rabbit lung was inhibited by MC-838 in a concentration-dependent manner. In isolated rat aortic ring and guinea-pig ileum preparations, MC-838 was highly specific in suppressing the contractile response to angiotensin-I (A-I) an in augmenting the contractile one to bradykinin. However, the ACE inhibitory activity of MC-838 was 30-100 times less potent than that of captopril. In conscious two-kidney (2 KG), renal hypertensive rats and spontaneously hypertensive rats (SHRs), MC-838 (3 and 10 mg/kg) given orally caused a long-lasting hypotensive effect with a slow onset. When compared on a weight basis (3 mg/kg), the antihypertensive effect of MC-838 was comparable to that of captopril in magnitude, but the duration of action of MC-838 was approximately 2 times longer than that of captopril.

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Blood Vessels; Dogs; Female; Guinea Pigs; Hypertension; In Vitro Techniques; Liver; Lung; Male; Mice; Muscle, Smooth; Proline; Rats; Rats, Inbred SHR; Rats, Inbred Strains