Reversible Inhibition of Adenylate Cyclase Activity in the Ischemic Myocardium

Abstract

Adenylate cyclase (AC) function was studied in homogenate and particulate preparations of ischemic rat heart obtained from three models: anoxic-ischemic incubations, coronary artery ligation, and global low-flow perfusion of isolated hearts. Both basal activity and the function of AC measured in the presence of NaF (8 X 10(-3)M), Gpp(NH)p (10(-5)M), and L-(-)-isoprenaline (10(-8)-10(-4)M) were reduced to 50% of the control value in homogenates of hearts incubated under anoxic-ischemic conditions for 10 min. Comparable results were obtained with homogenates from the ischemic area 20 min after coronary artery ligation in anesthetized open-chest rats with artificial ventilation. Reduced AC activity of the anoxic-ischemic hearts was completely reversible by aerobic reperfusion, provided the ischemic period did not exceed 20 min. AC activity in homogenates of isolated hearts perfused at low-flow was not changed, indicating a nonuniform alteration of AC system in nonperfused and low-flow perfused areas of the ischemic heart. Depression of myocardial AC function during severe ischemia was avoided by reducing Ca2+ in the incubation buffer, in combination with addition of EGTA during the homogenization step, and by pretreating the animals with verapamil. It is suggested that the depressed AC function is caused mainly by an increase in intracellular Ca2+, which inhibits the enzyme at its catalytic site. A negative feedback control of AC function by Ca2+ is postulated that may operate especially in the ischemic myocardium.