Hypertensive Wistar-Kyoto Rats Research Articles

Captopril (SQ 14,225) ( d-3-mercapto-2-methylpropanoyl- l-proline): A novel orally active inhibitor of angiotensin-converting enzyme and antihypertensive agent

Relatively potent and specific in vitro and in vivo (oral or intravenous) inhibition of angiotensin-converting enzyme by a nonpeptidic compound, captopril (SQ 14,225; d-3-mercapto-2-methylpropanoyl- l-poline), was demonstrated in excised guinea pig ileum and in rats, rabbits, cats, dogs, and monkeys. The design of captopril was based on a hypothetical model of the active site of the enzyme. Captopril, in vitro or in vivo, was about ten times as potent as teprotide. Inhibition of angiotensin-converting enzyme was evaluated in vitro and in vivo by inhibition of the contractile or vasopressor activity of angiotensin I or by augmentation of the contractile or vasodepressor activity of bradykinin. Acute of subacute dosage with captopril moderately to markedly lowered the blood pressure of the renin-dependent aorticligated and the conscious two-kidney Goldblatt hypertensive rat; in the latter, the effect was intensified by concomitant dosage with a thiazide diuretic. Furthermore, the life-prolonging effects of captopril in renal hypertensive rats were augmented by a thiazide diuretic. In the two-kidney Goldblatt rat, acute captopril (p.o.) was about ten times as potent as teprotide (s.c.) in lowering blood pressure. Acute or subacute oral doses of captopril moderately reduced the blood pressure of the spontaneously hypertensive Wistar-Kyoto rat; chronic dosage almost normalized blood pressure. Captopril produced little or no hypotension in the saltreplete normotensive Wistar-Kyoto rat. Bilateral nephrectomy virtually abolished the hypotensive activity of captopril in the spontaneous hypertensive rat. The results suggest that captopril acts in large part by inhibiting the renin-angiotensin-aldosterone system to reduce elevated blood pressure, especially in renindependent models of hypertension; the roles of the kallikrein-kinin-prostaglandin systems and sodium balance remain to be elucidated. Captopril also lowers blood pressure in apparently non-renin-dependent types of hypertension by mechanisms that are as yet undefined.