Circulation Research. 2003
Published online before print March 13, 2003, doi: 10.1161/01.RES.0000066853.09821.98
Published online before print March 13, 2003, doi: 10.1161/01.RES.0000066853.09821.98
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Submitted on February 4, 2003
Revised on March 5, 2003
Accepted on March 5, 2003
Sildenafil Induces Delayed Preconditioning Through Inducible Nitric Oxide Synthase-Dependent Pathway in Mouse Heart
Fadi Salloum ;
From the Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Va.
* To whom correspondence should be addressed. E-mail: rakesh{at}hsc.vcu.edu.
Sildenafil citrate (Viagra) is the most widely used drug for treating erectile dysfunction in men. We recently demonstrated that it induces potent protective effects against ischemia-reperfusion (I-R) injury in rabbit hearts through the opening of mitochondrial ATP-dependent K+ channels. In the present study, we investigated the role of the NO-dependent signaling pathway in delayed cardioprotection by sildenafil. Adult male ICR mice were treated with saline or sildenafil (0.7 mg/kg IP) 24 hours before global I-R in the Langendorff mode. Infarct size was reduced from 27.6±3.3% in saline-treated control mice to 6.9±1.2% in sildenafil-treated mice (mean±SEM, P<0.05) without compromising cardiac function. Reverse transcription-polymerase chain reaction revealed a transient increase in endothelial and inducible NO synthase (eNOS and iNOS, respectively) mRNA in sildenafil-treated mice, peaking at 45 minutes (eNOS) and 2 hours (iNOS) after sildenafil injection. The magnitude of mRNA increase was more pronounced for iNOS than for eNOS. In addition, a significant increase in both iNOS and eNOS protein was detected 24 hours after sildenafil treatment. A selective inhibitor of iNOS, 1400W (10 mg/kg IP given 30 minutes before I-R), abolished sildenafil-induced protection (23.7±2.8%, P<0.05 versus sildenafil). These data suggest that the induction of NO synthase isoforms is an essential component of the signaling mechanism for sildenafil-induced delayed preconditioning. However, iNOS appears to be the primary isoform that mediates the robust cardioprotection.
Key words: ischemia • myocardial infarction • nitric oxide synthases • phosphodiesterase inhibitor • late preconditioning
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