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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL032911-03
Application #
3344472
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1985-09-02
Project End
1989-03-31
Budget Start
1987-09-02
Budget End
1989-03-31
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Pagel, P S; Proctor, L T; Devcic, A et al. (1998) A novel alpha 2-adrenoceptor antagonist attenuates the early, but preserves the late cardiovascular effects of intravenous dexmedetomidine in conscious dogs. J Cardiothorac Vasc Anesth 12:429-34
Arkonac, B M; Kersten, J R; Wynsen, J C et al. (1996) Differential hemodynamic effects of the nitric oxide donor pirsidomine in comparison to SIN-1, nitroprusside and nitroglycerin. Pharmacology 52:92-100
Hettrick, D A; Pagel, P S; Warltier, D C (1995) Differential effects of isoflurane and halothane on aortic input impedance quantified using a three-element Windkessel model. Anesthesiology 83:361-73
Pagel, P S; Tessmer, J P; Warltier, D C (1994) Systemic and coronary hemodynamic effects of repetitive cocaine administration in conscious dogs. J Cardiovasc Pharmacol 24:443-53
Pagel, P S; Hettrick, D A; Warltier, D C (1994) Left ventricular mechanical consequences of dihydropyridine calcium channel modulation in conscious and anesthetized chronically instrumented dogs. Anesthesiology 81:190-208
Kenny, D; Coughlan, M G; Pagel, P S et al. (1994) Transforming growth factor beta 1 preserves endothelial function after multiple brief coronary artery occlusions and reperfusion. Am Heart J 127:1456-61
Harkin, C P; Pagel, P S; Kersten, J R et al. (1994) Direct negative inotropic and lusitropic effects of sevoflurane. Anesthesiology 81:156-67
Pagel, P S; Warltier, D C (1994) Mechanical consequences of calcium channel modulation during volatile anesthetic-induced left ventricular systolic and diastolic dysfunction. Adv Pharmacol 31:125-43
Wynsen, J C; O'Brien, P D; Warltier, D C (1994) Zatebradine, a specific bradycardic agent, enhances the positive inotropic actions of dobutamine in ischemic myocardium. J Am Coll Cardiol 23:233-41
Kenny, D; Coughlan, M G; Kampine, J P et al. (1994) Cultured endothelial cells restore vasodilator responses to coronary arteries with impaired endothelial function and alter the response to a nitric oxide donor. Pharmacology 49:249-56

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