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 (IPost) 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 30-minute coronary occlusion followed by 120-minute reperfusion with or without IPost. In nontolerant hearts, postconditioning significantly decreased infarct size as compared with ischemia/reperfusion; however, postconditioning failed to decrease infarct size in hearts of nitrate tolerant rats. Phosphorylation of ERK 1/2, Akt, or endothelial nitric oxide synthetase showed no significant differences between the groups at the 10th minute of reperfusion. Vascular nitrate tolerance interferes with the infarct size limiting effect of IPost. Activation of survival kinases is not crucial in the molecular mechanism of postconditioning, which remains unaffected in nitrate tolerance.

The role of gasotransmitters NO, H2S and CO in myocardial ischaemia/reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning

“…Phosphorylation of ERK1/2, Akt or eNOS showed no significant differences in hearts being responsive to PostC or lacking protection due to nitrate tolerance (Fekete et al, 2013).…”

Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning

“…Since then, little progress has been made in this field. Nevertheless, Fekete et al (2013) recently showed that the presence of nitrate tolerance inhibits the infarct size limiting effect of postconditioning in rats. Moreover, in a recent human study, Gori et al (2010) reported that the endothelial preconditioning effect of a single dose of nitroglycerin is lost upon a prolonged exposure to nitroglycerin.…”

Time to Give Up on Cardioprotection?

“…215,216 While a patient with coronary artery disease who suffers an AMI or undergoes a cardiovascular intervention will likely have one or more of the above drugs on board, nitrates, opioids, and purinergic receptor 2Y 12 (P2Y 12 ) antagonists would be administered acutely to induce coronary vasodilation and control blood pressure, to reduce pain, and to inhibit platelet aggregation. Although chronic nitrate use and nitrate tolerance abrogate protection by conditioning interventions, 217,218 the acute use of nitrates during surgical coronary revascularization does not interfere with protection by remote ischemia preconditioning. 219 Opioids are triggering molecules in ischemic preconditioning and remote postconditioning, 108,[220][221][222] but there is no unequivocal evidence that acute opioid treatment reduces infarct size in patients (for review see Kleinbongard and Heusch 30 ).…”