Antihypertensive Effects of the Novel Converting-Enzyme Inhibitor YS 980 in Spontaneously Hypertensive Rats

Abstract

The converting-enzyme inhibitor (CEI) YS 980 (50 mg/kg/day) was administered orally to 7 week old stroke-prone spontaneously hypertensive rats (SHR-sp) and to age and sex-matched normotensive Wistar Kyoto (WKY) rats over a period of three months.

The development of hypertension was markedly delayed in SHR-sp. Systolic but not diastolic blood pressure was lowered in WKY rats. Heart rate remained unchanged in both strains. Plasma renin and angiotensin I (ANG I) were elevated in both strains, but plasma angiotensin II (ANG II) was not decreased. Plasma norepinephrine levels rose in SHR-sp but not in WKY rats. Urinary aldosterone decreased in both strains. Body weight, total fluid intake, urine volume, urinary sodium and potassium excretion and urinary kallikrein activity were unaltered.

At the end of the treatment period, the animals were challenged with intravenous (i.v.) and intracerebroventricular (i.c.v.) injections of ANG I and bradykinin. The pressor responses to i.v. ANG I were diminished and the depressor effects of i.v. bradykinin were potentiated in SHR-sp and WKY rats. The pressor responses to injections of ANG I and bradykinin into the lateral brain ventricle were unchanged in SHR-sp. In WKY rats, however, chronic oral treatment with YS 980 significantly diminished the pressor responses to i.c.v. ANG I.

It is concluded that the orally active CEI YS 980 is a potent blood pressure-lowering compound in SHR-sp. Inhibition of the plasma renin-angiotensin system or of the sympathetic nervous system cannot fully explain its antihypertensive actions. Central antihypertensive effects cannot be ruled out and local tissue actions, which are not reflected in plasma and urinary hormones, need to be investigated.