Dose-dependent effects of the renin inhibitor zankiren HCl after a single oral dose in mildly sodium-depleted normotensive subjects

• Published in: Circulation (New York, N.Y.) Vol. 91; no. 2; pp. 330 - 338
• Main Authors: MENARD, J, BOGER, R. S, MOYSE, D. M, GUYENE, T. T, GLASSMAN, H. N, KLEINERT, H. D
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 15.01.1995
• Subjects: Adult; Antihypertensive agents; Biological and medical sciences; Blood Pressure; Cardiovascular system; Dose-Response Relationship, Drug; Double-Blind Method; Drug Tolerance; Furosemide - pharmacology; Heart Rate; Humans; Hypotension, Orthostatic - chemically induced; Hypotension, Orthostatic - diagnosis; Male; Medical sciences; Pharmacology. Drug treatments; Piperazines - administration & dosage; Piperazines - blood; Piperazines - pharmacokinetics; Renin - antagonists & inhibitors; Renin - blood; Renin-Angiotensin System - drug effects; Renin-Angiotensin System - physiology; Thiazoles - administration & dosage; Thiazoles - blood; Thiazoles - pharmacokinetics; Human; Enzyme; Single dose; Oral administration; Exploration; Chemotherapy; Renin; Treatment; Follow up study; Hydrolases; Antihypertensive agent; Arterial pressure; Aspartic endopeptidases; Inhibitor; Proteinases
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.cir.91.2.330

Zankiren HCl (A-72517) is a potent renin inhibitor shown to have substantial bioavailability in several animal species and to produce dose-related reductions in blood pressure, plasma renin activity, and angiotensin II (Ang II) in salt-depleted dogs. The present study was designed to evaluate the hemodynamic effects of oral zankiren HCl administration in healthy volunteers and to characterize the response of the renin-angiotensin system (RAS) to specific blockade by this new renin inhibitor. Twenty-four male volunteers participated in a double-blind randomized, placebo-controlled in-hospital study to evaluate the effects of zankiren HCl (10 to 250 mg). All subjects were pretreated with 40 mg furosemide 12 hours before study drug administration. Blood pressure and heart rate were monitored by an automated oscillometric device, and blood samples were obtained for active renin, total renin, plasma renin activity, angiotensin I (Ang I), Ang II, aldosterone, and plasma zankiren concentration. Satisfactory absorption of zankiren HCl was demonstrated by the results of plasma drug concentration determinations, and renin inhibitory activity was confirmed by dose-related suppression of plasma renin activity, Ang I, Ang II, and aldosterone and increases in plasma active renin concentration. Furthermore, hypotensive activity was readily observed in these normotensive subjects, as evidenced by statistically significant dose-related blood pressure reductions (P < .01). Results from this study demonstrate for the first time that oral administration of a renin inhibitor can dose-dependently decrease blood pressure and circulating components of the RAS in normotensive volunteers as a result of documented absorption.