Myocardial postconditioning is lost in vascular nitrate tolerance

Abstract

Organic nitrates play an important role in the therapy of ischemic heart disease, however, their clinical application is limited by the development of vascular nitrate tolerance. We have previously shown attenuation of the cardioprotective effect of preconditioning in vascular nitrate tolerance. Here we studied whether the development of vascular nitrate tolerance affects the infarct size limiting effect of ischemic postconditioning in the myocardium, and whether the activation of survival kinases plays a role in the molecular mechanism of postconditioning in the presence or absence of vascular nitrate tolerance. Male Wistar rats were treated with nitroglycerin/vehicle for 3 days to induce vascular nitrate tolerance. On the fourth day, isolated hearts were subjected to 30min coronary occlusion followed by 120min reperfusion with or without ischemic postconditioning. In non-tolerant hearts, postconditioning significantly decreased infarct size as compared to ischemia/reperfusion, however, postconditioning failed to decrease infarct size in hearts of nitrate tolerant rats. Phosphorylation of ERK 1/2, Akt or eNOS showed no significant differences between groups at the 10 min of reperfusion. Vascular nitrate tolerance interferes with the infarct size limiting effect of ischemic postconditioning. Activation of survival kinases is not crucial in the molecular mechanism of postconditioning which remains unaffected in nitrate tolerance.