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1 Cardiology, Albert Einstein College of Medicine, Bronx, New York, United States
2 Molecular and Cellular Physiology, LSUHSC, Shreveport, Louisiana, United States
* To whom correspondence should be addressed. E-mail: dlefer{at}aecom.yu.edu.
Sildenafil, a potent inhibitor of phosphodiesterase type-5 (PDE5), has recently been investigated in animal models of myocardial ischemia-reperfusion injury (MI-R). Previous studies have suggested that the protective effects of sildenafil are mediated via activation of eNOS and iNOS. To further investigate the protective mechanism of sildenafil we subjected wild-type, eNOS and iNOS null animals to 30 min. of myocardial ischemia and 24 hrs. of reperfusion. Treatment with 0.06 mg/kg sildenafil 5 min. prior to reperfusion significantly reduced myocardial infarct size in wild-type, eNOS-/- and iNOS-/- animals. Additionally the low dose utilized in this study did not alter myocardial cGMP. These results suggest that acute low dose sildenafil mediated cardioprotection is independent of eNOS, iNOS and cGMP. In a second series of experiments we investigated sildenafil in db/db diabetic mice subjected to MI-R. We found that sildenafil failed to protect diabetic mice against MI-R. However, nitric oxide donor therapy was found to significantly protect against MI-R injury in both non-diabetic and diabetic mice. Suggesting that protection could be conferred in diabetic mice and that the upstream modulator of sGC, nitric oxide, may mediate protection independent of cGMP signaling. The present study suggests that further research is needed to delineate the precise mechanisms by which sildenafil exerts cardioprotection.
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