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.