An Orally Active Inhibitor of Renin
作者:
DONALD PALS,
Suvrr THAISRIVONGS,
JUDY LAWSON,
WARREN KATI,
STEVE TURNER,
GARRY DEGRAAF,
DOUGLAS HARRIS,
GARLAND JOHNSON,
期刊:
Hypertension
(OVID Available online 1986)
卷期:
Volume 8,
issue 12
页码: 1105-1112
ISSN:0194-911X
年代: 1986
出版商: OVID
关键词: renin inhibition;blood pressure;plasma renin activity;hog renininfused rat;cynomolgus monkey
数据来源: OVID
摘要:
A potent renin inhibitor, U-71038 (BK-Pro-Phe-JV-MeHis-Leuψ[CHOHCH2]Val-Ile-Amp), was tested for oral effectiveness. Enzyme kinetic studies indicated that U-71038 was a competitive inhibitor of hog renin with an inhibitor constant (K1) value of 12 nM. Intravenous as well as oral administration of U-71038 to anesthetized, ganglion-blocked rats infused with hog renin elicited doserelated hypotensive responses. Intravenous administration of U-71038 to conscious, sodium-depleted monkeys caused dose-related decreases of blood pressure and plasma renin activity without affecting heart rate. Similarly, the oral administration of U-71038 at 50 mg/kg to conscious, sodium-depleted monkeys elicited a pronounced hypotension and decrease in plasma renin activity that persisted for 5 hours. The hypotensive responses elicited by intravenous and oral administration of U-71038 to hog renin-infused rats and sodium-depleted monkeys were shown to be due entirely to inhibition of the renin-angiotensin system. A comparison of the results obtained after the intravenous administration of U-71038 with the results obtained after the oral administration of U-71038 implied that at least 10% of the orally administered U-71038 must have been absorbed to cause the observed effects in hog renin-infused rats and sodium-depleted monkeys. The studies demonstrated that an inhibitor of renin with a long duration of action and with oral effectiveness is a feasible entity.
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