Recent experimental evidence has shown that following brief coronary artery occlusion (during which no irreversible tissue damage has occurred), recovery of contractile function of the postischemic myocardium during reperfusion may be delayed despite return of flow and electrocardiographic changes to normal. The long term goal of the proposed research is an in-depth analysis of the actions and mechanisms by which certain pharmacological agents affect regional myocardial contractile function and blood flow following transient coronary artery occlusion and reperfusion. Specifically, the effects of several structurally unrelated, slow channel calcium blocking agents (nisoldipine, KB 944, verapamil, diltiazem, AQ-A 39) on the decrement of regional function during partial or total coronary artery occlusion for brief periods of time and the subsequent recovery of function following reperfusion will be examined. These studies will be conducted in anesthetized dogs with a carotid to left anterior descending coronary artery shunt, constricted or totally occluded for 5 to 60 minutes and then reperfused for a period of 5 hours. Regional segment function will be assessed by means of ultrasonic crystals implanted in normal and ischemic myocardium, and regional myocardial blood flow will be determined by use of radioactive microspheres. Regional cardiac electrical activity, hemodynamics and arterial-coronary venous oxygen difference will be continuously recorded. Slow channel calcium blocking agents will be administered intracoronary or intravenously in multiple doses prior to the onset of occlusion or prior to reperfusion. The effects of these drugs on hemodynamics, oxygen consumption, collateral perfusion, regional electrical activity and segmental contractile function will be compared to the non-calcium antagonist vasodilator, dipyridamole. Drug-induced enhancement of recovery of segmental function or prevention of the decrement in function following coronary artery occlusion will be related to the degree of myocardial perfusion, hemodynamics or oxygen consumption during flow restriction. These studies will lend insight into the effects of coronary artery reperfusion on segmental contractile function and the effect of pharmacological agents on this process. The proposed research is timely because of the recent development of coronary artery reperfusion (both medical and surgical approaches) for the treatment of myocardial infarction and ischemia, and the findings that contractile deficits may be prolonged after restoration of blood flow.
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