Beneficial renal and hemodynamic effects of omapatrilat in mild and severeheart failure

Omapatrilat is a member of the new drug class of vasopeptidase inhibitors t hat may offer benefit in the treatment of heart failure (HF through simulta neous inhibition of angiotensin-converting enzyme and neutral endopeptidase , We examined the effects of omapatrilat in a placebo-controlled crossover study using a pacing model of KF. Seven sheep were paced sequentially at 18 0 bpm (mild HF) and then 225 bpm (severe HF) for 7 days each. Omapatrilat ( 0.005 mg/kg) or vehicle was administered by intravenous bolus on days 4 to 7 of each paced period. Omapatrilat lowered mean arterial and left atrial p ressure and increased cardiac output acutely and chronically in both mild a nd severe HF (P<0.01 for all). Plasma atrial and brain natriuretic peptide and cGMP levels were stable acutely (P=NS), while brain natriuretic peptide increased after repeated dosing in severe HF (P<0.05). Plasma renin activi ty rose, whereas angiotensin II and aldosterone levels fell after acute and repeated dosing in both states (P<0.01 for all). Omapatrilat increased uri nary sodium excretion by day 7 in both mild and severe HF (P<0.05). Effecti ve renal plasma flow and glomerular filtration rate increased or were stabl e after omapatrilat in mild and severe HF after both acute and repeated dos ing. Omapatrilat exhibited pronounced acute and sustained beneficial hemody namic and renal effects in both mild and severe heart failure.