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Attenuation of extracellular ATP response in cardiomyocytes isolated from hearts subjected to ischemia-reperfusion

Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, and Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Canada

Submitted 2 February 2005 ; accepted in final form 1 April 2005

Extracellular ATP is known to augment cardiac contractility by increasing intracellular Ca²⁺ concentration ([Ca²⁺]_i) in cardiomyocytes; however, the status of ATP-mediated Ca²⁺ mobilization in hearts undergoing ischemia-reperfusion (I/R) has not been examined previously. In this study, therefore, isolated rat hearts were subjected to 10–30 min of global ischemia and 30 min of reperfusion, and the effect of extracellular ATP on [Ca²⁺]_i was measured in purified cardiomyocytes by fura-2 microfluorometry. Reperfusion for 30 min of 20-min ischemic hearts, unlike 10-min ischemic hearts, revealed a partial depression in cardiac function and ATP-induced increase in [Ca²⁺]_i; no changes in basal [Ca²⁺]_i were evident in 10- or 20-min I/R preparations. On the other hand, reperfusion of 30-min ischemic hearts for 5, 15, or 30 min showed a marked depression in both cardiac function and ATP-induced increase in [Ca²⁺]_i and a dramatic increase in basal [Ca²⁺]_i. The positive inotropic effect of extracellular ATP was attenuated, and the maximal binding characteristics of ³⁵S-labeled adenosine 5'-[-thio]triphosphate with crude membranes from hearts undergoing I/R was decreased. ATP-induced increase in [Ca²⁺]_i in cardiomyocytes was depressed by verapamil and Cibacron Blue in both control and I/R hearts; however, this response in I/R hearts, unlike control hearts, was not affected by ryanodine. I/R-induced alterations in cardiac function and ATP-induced increase in [Ca²⁺]_i were attenuated by treatment with an antioxidant mixture and by ischemic preconditioning. The observed changes due to I/R were simulated in hearts perfused with H₂O₂. The results suggest an impairment of extracellular ATP-induced Ca²⁺ mobilization in I/R hearts, and this defect appears to be mediated through oxidative stress.

isolated cardiomyocytes; oxidative stress; ischemic preconditioning

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