Abstract-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 angiotensin I-conversion and decreases systemic blood pressure more slowly and persistently than captopril in anesthetized dogs.it causes significant hypotension in normal volunteers (5). However, effects of MC-838 on the systemic and coronary circulation have not fully investigated.Thus, this study was designed to evaluate acute hemodynamic effects of MC-838 and to compare them with those of captopril as a standard drug.
Materials and MethodsMongrel dogs of either sex weighing 11 to 25 kg were anesthetized with pentobarbital Na (25 mg/kg, i.v.) and were ventilated by an artificial respirator (Harvard, Model 607). A catheter filled with heparinized physio logical saline (0.9% NaCI) was inserted through the left carotid artery into the aortic root and connected to a pressure transducer (Statham, P231 D) to measure the aortic pressure. A catheter-tip manometer (Millar, PC-350) was introduced through the right femoral artery into the left ventricle to measure the left ventricular pressure. Left thoracotomy was performed through the fifth intercostal space. The pericardium was opened, and the heart was suspended in a pericardial cradle. The proximal portion of the left circumflex coronary artery (LCX) was carefully dissected free from the surrounding tissues. An electro magnetic flow probe (Statham, SP751 5) was placed around the LCX, and it was connected to an electromagnetic flowmeter (Statham, SP2204) for the measurement of coronary blood flow. The zero reference was checked by temporary occlusions of the LCX just distal to the probe with a snare occluder.Mean coronary blood flow was obtained by an electronic-capacitance filter with a 2 second time constant. Left ventricular dP/dt (LVdP/d...