Mechanisms of ischemic preconditioning effects on Ca21 paradox-induced changes in heart

Kawabata, Ken-Ichi, Thomas Netticadan, Mitsuru Osada, Kohji Tamura, and Naranjan S. Dhalla. Mechanisms of ischemic preconditioning effects on Ca21 paradoxinduced changes in heart. Am. J. Physiol. Heart Circ. Physiol. 278: H1008–H1015, 2000.—The effects of ischemic preconditioning (IP) on changes in cardiac performance and sarcoplasmic reticulum (SR) function due to Ca21 paradox were investigated. Isolated perfused hearts were subjected to IP (three cycles of 3-min ischemia and 3-min reperfusion) followed by Ca21-free perfusion and reperfusion (Ca21 paradox). Perfusion of hearts with Ca21-free medium for 5 min followed by reperfusion with Ca21-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 Ca21 paradox were associated with depressed SR Ca21uptake, Ca21-pump ATPase, and Ca21-release activities as well as decreased SR protein contents for Ca21-pump and Ca21 channels. All these changes due to Ca21 paradox were significantly prevented in hearts subjected to IP. The protective effects of IP on Ca21 paradox changes in cardiac contractile activity as well as SR Ca21-pump and Ca21-release activities were lost when the hearts were treated with 8-(p-sulfophenyl)-theophylline, an adenosine receptor antagonist; KN-93, a specific Ca21/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 Ca21 paradox hearts. Furthermore, these beneficial effects of IP may partly be mediated by adenosine receptors, PKC, and CaMK II.