Circulation Research. 2003;92:595-597
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
© 2003 American Heart Association, Inc.
Reports |
Sildenafil Induces Delayed Preconditioning Through Inducible Nitric Oxide Synthase–Dependent Pathway in Mouse Heart
From the Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Va.
Correspondence to Rakesh C. Kukreja, PhD, Division of Cardiology, Box 980281, Virginia Commonwealth University, Richmond, VA 23298. E-mail rakesh{at}hsc.vcu.edu
Abstract
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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