We have demonstrated that activation of ATP-sensitive potassium (K(ATP)) channels can attenuate sympathetic hyperinnervation. Sildenafil, a phosphodiesterase-5 inhibitor, has been shown to provide a preconditioning-like cardioprotective effect via opening of K(ATP) channels. The aim of this study was to investigate whether chronic administration of sildenafil attenuates cardiac sympathetic hyperinnervation after myocardial infarction through activation of K(ATP) channels and to compare it with the nitric oxide donor isosorbide dinitrate. Male Wistar infarcted rats induced by ligation of the anterior descending artery were randomized to either vehicle, nicorandil, sildenafil, isosorbide dinitrate, glibenclamide, or a combination of nicorandil and glibenclamide, or sildenafil and glibenclamide. Myocardial norepinephrine levels revealed a significant elevation in vehicle-treated rats compared with sham-operated rats, consistent with sympathetic hyperinnervation after infarction assessed by immunohistochemical analysis for tyrosine hydroxylase, growth associated factor 43 and neurofilament and by protein expression and mRNA of nerve growth factor. Sympathetic hyperinnervation was reduced after administering either nicorandil or sildenafil. Arrhythmic scores during programmed stimulation in the sildenafil-treated rats were significantly lower than those treated with the vehicle. Furthermore, the beneficial effects of sildenafil-induced were reversed by the addition of either glibenclamide or 5-hydroxydecanoate, implicating mitochondrial K(ATP) channels as the relevant target. Isosorbide dinitrate failed to confer similar antiarrhythmia. 1H-[1,2,4]oxadiazolo[4,3-α]quinoxalin-1-one, a soluble guanylyl cyclase inhibitor, did not influence the effect of sildenafil on the nerve growth factor. These data indicate that sildenafil after infarction attenuated sympathetic hyperinnervation and arrhythmias by activation of mitochondrial K(ATP) channels through a guanylyl cyclase-cGMP-independent pathway.
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