Submitted on August 8, 2008
Revised on November 5, 2008
Accepted on November 10, 2008
Na+/H+ Exchange Inhibitor Cariporide Attenuates Skeletal Muscle Infarction When Administered Before Ischemia or Reperfusion
Sandra E. McAllister1, Michael A. Moses2, Kunaal Jindal3, Homa Ashrafpour4, Neil J. Cahoon5, Ning Huang4, Peter C. Neligan6, Christopher R. Forrest1, Joan E. Lipa2, and Cho Y. Pang4*
1 Research Institute, The Hospital for Sick Children
2 University of Toronto
3 University of Manitoba
4 The Hospital for Sick Children
5 The Hospital for Sick Children, University of Toronto
6 University of Washington
* To whom correspondence should be addressed. E-mail: pang{at}sickkids.ca.
Administration of Na+/H+ exchange isoform-1 (NHE-1) inhibitors before ischemia has been shown to attenuate myocardial infarction in several animal models of ischemia/reperfusion (I/R) injury. However, controversy still exists as to the efficacy of NHE-1 inhibitors in protection of myocardial infarction when administered at the onset of reperfusion. Furthermore, the efficacy of NHE-1 inhibition in protection of skeletal muscle from infarction (necrosis) has not been studied. This information has potential clinical applications in prevention or salvage of skeletal muscle from I/R injury in elective and trauma reconstructive surgery. The objective of this research project is to test our hypothesis that the NHE-1 inhibitor Cariporide is effective in protection of skeletal muscle from infarction when administered at the onset of sustained ischemia or reperfusion, and to study the mechanism of action of Cariporide. In our studies, we observed that intravenous administration of Cariporide 10 min before ischemia (1 or 3 mg/kg) or reperfusion (3 mg/kg) significantly reduced infarction in pig latissimus dorsi muscle flaps compared with the control when these muscle flaps were subjected to 4h of ischemia and 48h of reperfusion (p < 0.05; n = 5 pigs/group). Both preischemic and postischemic Cariporide treatment (3 mg/kg) induced a significant decrease in muscle myeloperoxidase activity and mitochondrial free Ca2+ content and a significant increase in muscle ATP content within 2h of reperfusion (p < 0.05; n = 4 pigs/group). Preischemic and postischemic Cariporide treatment (3 mg/kg) also significantly inhibited muscle NHE-1 protein expression within 2h of reperfusion after 4h of ischemia, compared with the control (p<0.05; n=3 pigs/group). These observations support our hypothesis that Cariporide attenuates skeletal muscle infarction when administered at the onset of ischemia or reperfusion and the mechanism involves attenuation of neutrophil accumulation, and mitochondrial free Ca2+ overload and preservation of ATP synthesis in the early stage of reperfusion.
