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, placebo-controlled, 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) 0.3 mg/kg q.i.d., and 3) 0.1 mg/kg q.i.d. Each patient received an
intravenous infusion every 6 hours for 1 week. Placebo infusions were used to mimic the 4 times/day dosing schedule. Blood pressure was measured periodically via 24-hour automated monitoring equipment. Mean plasma
renin activity in the patient groups ranged from 1.58 to 2.68 ng
angiotensin I/ml/hr. Plasma
renin activity was promptly suppressed in all groups receiving
enalkiren. Prolonged duration of plasma
renin activity suppression (greater than or equal to 24 hours) was demonstrated after the administration of 1.2 mg/kg
enalkiren. The 0.3 mg/kg q.i.d. and 1.2 mg/kg quotid. regimens produced statistically significant reductions (p less than or equal to 0.05) in systolic and diastolic blood pressures with clear evidence of persistent
antihypertensive activity for 12 hours or more when compared with the placebo group. Despite relatively large reductions in mean systolic and diastolic blood pressure, mean pulse rates were essentially unchanged. The prolonged reduction in blood pressure with
enalkiren without evidence of tachyphylaxis after 1 week of treatment suggests that
renin inhibitors may emerge as useful therapeutic agents for the treatment of
hypertension.