Published Online
on February 7, 2005

A more recent version of this article appeared on February 15, 2005

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Submitted on July 20, 2004
Revised on September 9, 2004
Accepted on October 26, 2004

Sildenafil Prevents Endothelial Dysfunction Induced by Ischemia and Reperfusion via Opening of Adenosine Triphosphate-Sensitive Potassium Channels. A Human In Vivo Study

Tommaso Gori MD, PhD, Silvia Sicuro MD, Saverio Dragoni MD, Giovanni Donati MD, Sandro Forconi MD, and John D. Parker MD^*

From the Department of Internal, Cardiovascular, and Geriatric Medicine, Azienda Universitaria Ospedaliera Senese, Siena, Italy (T.G., S.S., S.D., G.D., S.F.), and the Division of Cardiology, Department of Medicine, Mount Sinai and University Health Network Hospitals, University of Toronto, Canada (T.G., J.D.P.).

^* To whom correspondence should be addressed. E-mail: jdp{at}ca.inter.net.

Background--Animal studies have demonstrated that administration of sildenafil can limit myocardial damage induced by prolonged ischemia, an effect that appears to be mediated by opening of adenosine triphosphate-sensitive potassium (K_ATP) channels. No study has investigated whether sildenafil can also prevent the impairment in endothelium-dependent vasodilatation induced by ischemia-reperfusion (IR) in humans.

Methods and Results--In a double-blind, placebo-controlled, crossover design, 10 healthy male volunteers (25 to 45 years old) were randomized to oral sildenafil (50 mg) or placebo. Two hours later, endothelium-dependent, flow-mediated dilatation (FMD) of the radial artery was measured before and after IR (15 minutes of ischemia at the level of the brachial artery followed by 15 minutes of reperfusion). Seven days later, subjects received the other treatment (ie, placebo or sildenafil) and underwent the same protocol. Pre-IR radial artery diameter and FMD, as well as baseline radial artery diameter after IR, were similar between visits (P=NS). After placebo administration, IR significantly blunted FMD (before IR: 7.9±1.1%; after IR: 1.2±0.7%, P<0.01). Importantly, sildenafil limited this impairment in endothelium-dependent vasodilatation (before IR: 7.0±0.9%; after IR: 6.2±1.1%, P=NS; P<0.01 compared with placebo). In a separate protocol, this protective effect was completely prevented by previous administration of the sulfonylurea glibenclamide (glyburide, 5 mg), a blocker of K_ATP channels (n=7; FMD before IR: 10.3±1.5%; after IR: 1.3±1.4%, P<0.05).

Conclusions--In humans, oral sildenafil induces potent protection against IR-induced endothelial dysfunction through opening of K_ATP channels. Further studies are needed to test the potential clinical implications of this finding.

Key words: endothelium • ischemia • reperfusion

Related Article:

Sildenafil and Endothelial Dysfunction in Humans

Garrett J. Gross
Circulation 2005 111: 721-723. [Full Text]

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