Sildenafil and endothelial dysfunction in humans.

Although it is well established that ischemic preconditioning (IPC) and pharmacological preconditioning (PPC) protect cardiac myocytes against reversible and irreversible injury and the genesis of cardiac arrhythmias1 in all animal species and humans, the effect of IPC and PPC on endothelial dysfunction has been less thoroughly studied. In this regard, the first article to clearly establish that IPC can protect endothelium against injury was published by DeFily and Chilian in 1993.2 They demonstrated in dogs that IPC preserved the endothelial-mediated coronary dilator responses to 2 endothelial-dependent vasodilators, serotonin and acetylcholine, in the absence of any damage to the smooth muscle cells mediating the dilator response. From a mechanistic standpoint, it has also been known since 19923 that adenosine triphosphate (ATP)–sensitive potassium channels (KATP channels) are an integral part of both acute and delayed IPC against myocardial infarction in animals and man.4 Subsequently, Katnik and Adams5 demonstrated that an ATP-sensitive potassium channel was present in rabbit endothelium that was inhibited by the KATP channel antagonists tolbutamide and glibenclamide. That endothelial KATP channels may be involved as a trigger in IPC to protect isolated guinea pig hearts against endothelial dysfunction was demonstrated recently by Beresewicz et al.6 These authors showed that the opening of mitochondrial KATP channels by IPC or diazoxide protected the endothelium by reducing the burst of reactive oxygen species, particularly the superoxide anion, which occurs at reperfusion.6 Thus, strong evidence in animal models indicates the presence of a KATP channel in endothelial cells and suggests that its activation resulting from IPC and PPC results in a protective effect to alleviate endothelial dysfunction after ischemia/reperfusion (I/R) injury.