Myocardial postconditioning is lost in vascular nitrate tolerance

J Cardiovasc Pharmacol. 2013 Sep;62(3):298-303. doi: 10.1097/FJC.0b013e3182993ae0.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Coronary Circulation / drug effects
  • Coronary Vessels / drug effects*
  • Coronary Vessels / metabolism
  • Coronary Vessels / pathology
  • Drug Tolerance*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Enzyme Activation / drug effects
  • Heart / drug effects*
  • Heart / physiopathology
  • In Vitro Techniques
  • Ischemic Postconditioning*
  • MAP Kinase Signaling System / drug effects
  • Male
  • Myocardial Ischemia / metabolism
  • Myocardial Ischemia / pathology
  • Myocardial Ischemia / therapy
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocardium / enzymology
  • Myocardium / metabolism
  • Myocardium / pathology
  • Nitric Oxide Synthase Type III / metabolism
  • Nitroglycerin / pharmacology*
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Rats
  • Rats, Wistar
  • Vasodilator Agents / pharmacology*


  • Vasodilator Agents
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • Nitroglycerin