Mechanisms of ischemic preconditioning effects on Ca²⁺paradox-induced changes in heart

Abstract

The effects of ischemic preconditioning (IP) on changes in cardiac performance and sarcoplasmic reticulum (SR) function due to Ca 2+ paradox were investigated. Isolated perfused hearts were subjected to IP (three cycles of 3-min ischemia and 3-min reperfusion) followed by Ca 2+ -free perfusion and reperfusion (Ca 2+ paradox). Perfusion of hearts with Ca 2+ -free medium for 5 min followed by reperfusion with Ca 2+ -containing medium for 30 min resulted in a dramatic decrease in the left ventricular (LV) developed pressure and a marked increase in LV end-diastolic pressure. Alterations in cardiac contractile activity due to Ca 2+ paradox were associated with depressed SR Ca 2+ -uptake, Ca 2+ -pump ATPase, and Ca 2+ -release activities as well as decreased SR protein contents for Ca 2+ -pump and Ca 2+ channels. All these changes due to Ca 2+ paradox were significantly prevented in hearts subjected to IP. The protective effects of IP on Ca 2+ paradox changes in cardiac contractile activity as well as SR Ca 2+ -pump and Ca 2+ -release activities were lost when the hearts were treated with 8-( p-sulfophenyl)-theophylline, an adenosine receptor antagonist; KN-93, a specific Ca 2+ /calmodulin-dependent protein kinase II (CaMK II) inhibitor; or chelerythrine chloride, a protein kinase C (PKC) inhibitor. These results indicate that IP rendered cardioprotection by preventing a depression in SR function in Ca 2+ paradox hearts. Furthermore, these beneficial effects of IP may partly be mediated by adenosine receptors, PKC, and CaMK II.