Vardenafil protects isolated rat hearts at reperfusion dependent on GC and PKG. Introduction
Recent studies have implicated that PDE-5 inhibitors, such as sildenafil, vardenafil or tadalafil, induce preconditioning-like effects in the heart and protect against ischemia/reperfusion injury. PDE-5 inhibition has been shown to enhance the accumulation of the cyclic nucleotide cGMP, which in turn acts as a second messenger in many signaling events in healthy and diseased myocardium. Intracardiac cGMP is produced by two isoforms of GC: particulate GC, which is activated by natriuretic peptides (atrial, brain and C-type natriuretic peptides) and soluble GC, which is activated by nitric oxide. On GC activation, cGMP accumulates and interacts with several targets, including the cGMP-dependent PKG. The cGMP/PKG pathway has been shown in many reports to be involved in the protective signaling of preconditioning, for example, direct PKG activation with a cell-permeant cGMP analogue proved to be protective, as well as receptor-mediated preconditioning could be blocked with the GC inhibitor 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ). Therefore, it seems only logical that PDE-5 inhibitors would protect the heart against ischemia/reperfusion injury when administered before ischemia. A detailed summary of the attenuation of increased cGMP during ischemia/reperfusion can be found in a recent review from Burley et al. Although there is increasing evidence that the heart is protected against ischemia/reperfusion injury due to elevated cGMP or PKG activity, considerably less is known whether this is exclusively related to myocytes or other compartments (for example, endothelium) play a partial or even major role.