Sildenafil (Viagra) induces powerful cardioprotective effect via opening of mitochondrial K_ATPchannels in rabbits

Abstract

Sildenafil citrate (Viagra) is the pharmacological agent used to treat erectile dysfunction in men. Because this drug has a vasodilatory effect, we hypothesized that such an action may induce a preconditioning-like cardioprotective effect via opening of mitochondrial ATP-sensitive K (K(ATP)) channels. Rabbits were treated with sildenafil citrate (0.7 mg/kg iv) either 30 min (acute phase) or 24 h (delayed phase) before 30 min of ischemia and 3 h of reperfusion. Mitochondrial K(ATP) channel blocker 5-hydroxydecanoate (5-HD, 5 mg/kg iv) was given 10 min before ischemia-reperfusion. Infarct size was measured by tetrazolium staining. Sildenafil caused reduction in arterial blood pressure within 2 min of treatment, which returned to nearly baseline levels 3 min later. The infarct size (% risk area, means +/- SE) reduced from 33.8 +/- 1.7 in control rabbits to 10.8 +/- 0.9 during the acute phase (68% reduction, P < 0.05) and 19.9 +/- 2.0 during the delayed phase (41% reduction, P < 0.05). 5-HD abolished protection with an increase in infarct size to 35.6 +/- 0.4% and 36.8 +/- 1.6% during the acute and delayed phase, respectively (P < 0.05). Similar acute and delayed cardioprotective effects were observed when sildenafil was administered orally. Systemic hemodynamics also decreased after oral administration of the drug. However, these changes were mild and occurred slowly. For the first time, we demonstrate that sildenafil induces acute and delayed protective effects against ischemia-reperfusion injury, which are mediated by opening of mitochondrial K(ATP) channels.

The phosphodiesterase-5 inhibitor tadalafil reduces myocardial infarct size

“…Whereas the involvement of the mK ATP channels has been demonstrated for the cardioprotective effect of sildenafil, the possibility of the same mechanism of action being involved for the tadalafil effect, at least in view of our results, will require further investigation. 10,13 It has been suggested that elevated levels of cGMP, caused by PDE5 inhibitors, could inhibit PDE3, an enzyme responsible for the hydrolysis of cyclic adenosine monophosphate (cAMP) and increase cAMP levels, resulting in elevated HR and contractility. 19 Our results showed that tadalafil did not increase HR nor induce arrhythmias.…”

“…[7][8][9] Recent studies have shown that these medicines improve endothelial function and may also have vascular and myocardial protective effects. [10][11][12][13] Tadalafil differs from sildenafil and vardenafil by its pharmacokinetic profile, 17.5 h half-life, maximum plasma concentration at 2 h and efficacy for up to 36 h after dosing. 14 As there is no previous information on tadalafil in the setting of myocardial infarction, we studied the effects of tadalafil on infarct size (IS), hemody-namics and regional myocardial blood flow (RMBF) after myocardial ischemia and reperfusion.…”

“…15,16 As studies on sildenafil have implicated the mitochondrial ATP-sensitive K (mK ATP ) channels in the cardioprotective effect of the drug, we also investigated whether tadalafil's protective effects on the heart occur through an mK ATP channel mechanism. 10,13 Materials and methods …”

Anti-ischemic effects of sildenafil, vardenafil and tadalafil in heart

“…4 The present study demonstrates the protective effect of a longer acting PDE-5 inhibitor suggesting that the differences in half-life of the three PDE-5 inhibitors has little, if any impact on the cardioprotective effect, at least during the acute time-window of treatment 30 min before I-R. The degree of infarct size reduction was, however, lower with tadalafil (B22%) 1 as opposed to sildenafil (68%) 3 or vardenafil (58%) 4 in rabbits as reported previously from our laboratory. These differences may be attributed to the animal species studied (rat versus rabbit) or lower potency of tadalafil (IC 50 6.74 nM) as compared to sildenafil (IC 50 3.5 nM) and vardenafil (IC 50 0.14 nM).…”

“…2 In 2002, we first reported a powerful protective effect of sildenafil against myocardial infarction in a rabbit model of I-R in vivo. 3 Since then, several laboratories across the world reproduced these findings in various animal models of I-R injury as summarized in Table 1. Moreover, a recent study from our laboratory showed that vardenafil (Levitra), another potent PDE-5 inhibitor, was equally effective as sildenafil in reducing infarct size following I-R injury in rabbits.…”