angiotensin-iii and Chronic-Disease

Angiotensin-converting enzyme inhibition is not an effective antianginal therapy. Experimental data suggest that broader vasopeptidase inhibition may decrease the magnitude of demand-induced myocardial ischemia. A randomized, double-blind, placebo controlled parallel study evaluated omapatrilat, an inhibitor of angiotensin-converting enzyme and neutral endopeptidase. The primary objective was to compare maximum duration of exercise at peak plasma concentrations. Exercise treadmill studies were performed in 348 patients who had chronic angina at baseline and after 4 weeks of therapy with 80 mg/day omapatrilat or placebo. Safety data were collected and reported for all patients. Treadmill exercise duration at peak was significantly prolonged in the omapatrilat group compared with the placebo group (76.6 +/- 84.2 vs 28.7 +/- 82.2 seconds difference from baseline, p <0.001). Similar statistically significant increases were seen in time to onset of level III/IV angina and time to onset of >/=0.1-mV ST-segment depression (p <0.001). The significant improvements in exercise duration and measurements of myocardial ischemia were not sustained 20 to 28 hours after dosing. Omapatrilat was generally well tolerated in this predominantly normotensive population. The incidence of serious adverse events was 5.2% in the 2 groups. Thus, omapatrilat, an investigational vasopeptidase inhibitor, is effective in prolonging exercise duration and parameters of demand-induced myocardial ischemia in patients who have chronic angina at peak concentrations. The data confirm the proof of principle that broader vasopeptidase inhibition beyond angiotensin-converting enzyme inhibition is required to alleviate symptoms of chronic angina.

Topics: Angina Pectoris; Angiotensin II; Angiotensin III; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Chronic Disease; Double-Blind Method; Exercise Tolerance; Female; Humans; Male; Middle Aged; Neprilysin; Pyridines; Thiazepines