Levitra (vardenafil) Info

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.

But to treat patients with acute myocardial infarction with an infarct-reducing agent, it would be much more feasible to apply the drug at reperfusion rather than before the ischemic event. Therefore, PDE-5 inhibitors were tested in a similar manner for their cardioprotective properties when applied at the onset of reperfusion. Salloum et al. (2007) were able to demonstrate that the PDE-5 inhibitors sildenafil and vardenafil limited myocardial infarction when administered at reperfusion in a model of ischemia/reperfusion in in situ rabbit hearts. Further, they could block this infarct-limiting effect with the putative mitochondrial KATP (mKATP) channel blocker 5-hydroxydecanoate (5-HD), suggesting a role for mKATP in this protective scenario. Opening of mKATP is thought to be mediated via PKG, which would complete the picture of cGMP playing a major role in protection at reperfusion. Nevertheless, cGMP often has opposite effects on cAMP, and it is not known whether the effects of PDE-5 inhibition work exclusively through cGMP and PKG, or the regulation of the cAMP/PKA pathway is needed as well.

We therefore set out to determine (1) if we could reproduce the cardioprotective effects of vardenafil in a rat isolated heart model and what concentrations of the drug are effective, (2) whether vardenafil (Levitra Professional) signals solely through PKG. For this purpose, we used the specific PKG inhibitor KT-5823 and the highly specific PKG-blocking peptides DT-2 and DT-3. Further, we asked if the soluble GC, blocked with the highly specific inhibitor ODQ, is required to propagate the protective signaling.

These protective pathways are thought to exert their protection by inhibiting the formation of lethal mitochondrial permeability transition pores (mPTPs) in the initial minutes of reperfusion. To test that hypothesis, we also studied the ability of vardenafil (Levitra Plus) to inhibit Ca++-induced permeability pore formation in a cardiac-derived cell line. We were able to further test for participation of GC and PKG in the cell model by using the highly selective peptide inhibitors of PKG.