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

BACKGROUND: 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. METHODS AND RESULTS: 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). CONCLUSIONS: 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.

Clinical pharmacology of enalkiren, a novel, dipeptide renin inhibitor.

Enalkiren (A-64662), a potent, dipeptide renin inhibitor, mimics the transition state of the human renin substrate, angiotensinogen. Enalkiren has been shown to produce dose-related suppression of plasma renin activity (PRA) and angiotensin II when administered intravenously. Doses of enalkiren of less than 0.1 mg/kg induced little hemodynamic response in normotensive and hypertensive volunteers despite marked suppression of PRA. However, at doses of 0.3 and 1.2 mg/kg, enalkiren produced significant, dose-related decreases in systolic and diastolic blood pressure (BP) in hypertensive patients, and the BP response was enhanced by pretreatment with hydrochlorothiazide. The effects of enalkiren on PRA and BP are prolonged despite its relatively short elimination phase plasma half-life (1.6 h). Persistent pharmacologic activity without evidence of tachyphylaxis was demonstrated during 1 week of treatment in hypertensive patients. The observed dissociation between suppression of PRA and BP response and the recruitment of dose-related BP decrements, despite complete suppression of PRA, are unexplained phenomena. The results of clinical trials with enalkiren are encouraging, and suggest that renin inhibitors may be safe, useful therapeutic agents in the management of hypertension.