Comparison of Acute Hemodynamic Effects of MC-838, a New Angiotensin-Converting Enzyme Inhibitor, with Captopril in Anesthetized Dogs

Effects of a new angiotensin-converting enzyme inhibitor, N-[3-(N-cyclohexanecarbonyl-D-alanylthio)-2-methylpropanoyl] -L-proline calcium (MC-838), on the systemic and coronary circulation were evaluated in anesthetized dogs, and the effects were compared with those of captopril. Administration of MC-838 (0.1, 0.3, 1.0 and 3.0 mg/kg, i.v.) produced a gradual and dose-dependent decline in aortic pressure associated with no marked changes in coronary blood flow, heart rate and LVdP/dt. Captopril (0.01, 0.03, 0.1 and 0.3 mg/kg, i.v.) also caused a dose-related decrease in aortic pressure, but the significant hypotension appeared more rapidly than that of MC-838. Both MC-838 and captopril inhibited selectively the pressor response to angiotensin I in a dose-related manner. The doses of MC-838 and captopril to lower mean aortic pressure by 10 mmHg from the pre-drug value were 2.8 mg/kg and 0.03 mg/kg, respectively; those of these drugs to cause 50% inhibition of angiotensin I-pressor response were 1.0 mg/kg and 0.04 mg/kg, respectively. When administration of MC-838 (3.0 mg/kg) was repeated three times at a 30 min-interval, the second and third injections caused no additional hypotension, while each of the repeated injections of captopril (0.3 mg/kg) produced significant hypotension. These results indicate that MC-838 inhibits angiotension I-conversion and decreases systemic blood pressure more slowly and persistently than captopril in anesthetized dogs.