Prolonged duration of blood pressure response to enalkiren, the novel dipeptide renin inhibitor, in essential hypertension.

Abstract

The effects of sustained renin inhibition by repeated administration of enalkiren (A-64662), the novel dipeptide renin inhibitor, were evaluated in a randomized, double-blind, placebocontrolled, parallel-group study of 32 inpatients (eight per group) with essential hypertension who were maintained on a diet containing 60 meq/day sodium. Three different dosage regimens of enalkiren were studied: 1) 1.2 mg/kg quotid., 2) 03 mg/kg q.i. T he renin-angiotensin system is an important modulator of blood pressure and extracellular fluid volume. Manipulation of the reninangiotensin system has emerged as a valuable tool in the evaluation of physiological mechanisms of blood pressure control and fluid and electrolyte homeostasis 1 -2 and as a new therapeutic approach to the management of hypertension 3 " 5 and congestive heart failure.6 ' 7 Angiotensin converting enzyme inhibitors block the conversion of angiotensin I (Ang I) to angiotensin II (Ang II). However, angiotensin converting enzyme inhibitors also exert actions on other endogenous systems, such as the kallikrein-kinin system, 8 and prostaglandins 910 and therefore are not specific physiological probes of the renin-angiotensin system.

Signal transduction of the (pro)renin receptor as a novel therapeutic target for preventing end-organ damage

“…59,63,64 The 34-fold increase might be overestimated because of an assay artefact: by binding to prorenin, aliskiren causes a conformational change in this molecule, which is then detected as (immuno-re)active renin, that is, aliskiren allows the false detection of prorenin as renin. [65][66][67] Nevertheless, renin inhibition can cause a greater increase in plasma renin compared with AT1R blockade at dosages with comparable antihypertensive effects.…”

Hemodynamic Effects of Renin Inhibitors

“…PRA would be suppressed long after plasma levels of drug are no longer detectable and longer than the hemodynamic effect of renin inhibition is observed. PRA inhibition has been shown to be sustained during chronic intravenous treatment in an imal models [19] and in hypertensive patients [27].…”

“…2). Multiple dosing studies with renin inhibitors in patients with mild-to-moderate hypertension have resulted in doserelated reductions in blood pressure of significant duration and inhibition of plasma renin activity, without tachycardia or tachyphylaxis [27], A reactive rise in immunoreactive renin that accompa nies hypotension and renin inhibition is elicited by these drugs [28], No remarkable safety issues were reported in any of the studies.…”

Pharmacokinetics and pharmacodynamics of CI-992 following intravenous and oral administration to cynomolgus monkeys

“…Renin is the enzyme which catalyzes the first and rate-determining step in angiotensin II formation. Thus it is not surprising that renin inhibitors have significant antihypertensive activity in patients with essential hypertension [3,4].…”