Antihypertensive effects of fasidotril, a dual inhibitor of neprilysin andangiotensin-converting enzyme, in rats and humans

The aim of this study was to assess the antihypertensive activity of fasido tril, a dual inhibitor of neprilysin (NEP) and angiotensin I-converting enz yme (ACE), in various models of hypertension in rats (spontaneously hyperte nsive rats [SHR]; renovascular Goldblatt 2-kidney, 1-clip rats; and deoxyco rticosterone acetate [DOCA]-salt hypertensive rats) and in patients with mi ld-to-moderate essential hypertension. Fasidotril treatment (100 mg/kg PO t wice daily for 3 weeks) resulted in a progressive and sustained decrease in systolic blood pressure (-20 to -30 mm Hg) in SHR and Goldblatt rats compa red with vehicle-treated rats and prevented the progressive rise in blood p ressure in DOCA-salt hypertensive rats. After a 4-week placebo run-in perio d, 57 patients with essential hypertension were included in a randomized do uble-blind, placebo-controlled, parallel-group study and received orally ei ther Fasidotril (100 mg twice daily) or placebo for 6 weeks. Blood pressure was measured during the 6 hours after the first intake and then at trough (12 hours after the last intake) on days 7, 28, and 42. The first dose of f asidotril had no significant effect on blood pressure. After 42 days, compa red with placebo, fasidotril lowered supine systolic and diastolic blood pr essures by 7.4/5.4 mm Hg and standing blood pressure by 7.6/6.8 mm Hg. Fasi dotril, a dual NEP/ACE inhibitor, was an effective oral antihypertensive ag ent during chronic treatment in high-renin renovascular rats, normal-renin SHR, and low-renin DOCA-salt hypertensive rats and in patients with essenti al hypertension.