Effect of pravastatin on sympathetic reinnervation in postinfarcted rats

We assessed whether pravastatin attenuates cardiac sympathetic reinnervation after myocardial infarction through the activation of ATP-sensitive K⁺ (K_ATP) channels. Epidemiological studies have shown that men treated with statins appear to have a lower incidence of sudden death than men without statins. However, the specific factor for this has remained disappointingly elusive. Twenty-four hours after ligation of the anterior descending artery, male Wistar rats were randomized to groups treated with either vehicle, nicorandil (a specific mitochondrial K_ATP channel agonist), pinacidil (a nonspecific K_ATP channel agonist), pravastatin, glibenclamide (a K_ATP channel blocker), or a combination of nicorandil and glibenclamide, pinacidil and glibenclamide, or pravastatin and glibenclamide for 4 wk. Myocardial norepinephrine levels revealed a significant elevation in vehicle-treated rats at the remote zone compared with sham-operated rats (2.54 ± 0.17 vs. 1.26 ± 0.36 μg/g protein, P <0.0001), consistent with excessive sympathetic reinnervation after infarction. Immunohistochemical analysis for tyrosine hydroxylase, growth-associated factor 43, and neurofilament also confirmed the change of myocardial norepinephrine. This was paralleled by a significant upregulation of tyrosine hydroxylase protein expression and mRNA in vehicle-treated rats, which was reduced after the administration of either nicorandil, pinacidil, or pravastatin. Arrhythmic scores during programmed stimulation in vehicle-treated rats were significantly higher than those treated with pravastatin. In contrast, the beneficial effects of pravastatin were reversed by the addition of glibenclamide, implicating K_ATP channels as the relevant target. The sympathetic reinnervation after infarction is modulated by the activation of K_ATP channels. Chronic use of pravastatin after infarction, resulting in attenuated sympathetic reinnervation by the activation of K_ATP channels, may modify the arrhythomogenic response to programmed electrical stimulation.