Reactive cardiomyocyte hypertrophy after myocardial infarction is an important risk factor for arrhythmias. Myocardial ATP-sensitive potassium (KATP) channels have been implicated in attenuating cardiac hypertrophyby inhibition of 70-kDa S6 kinase. We investigated the effect of pravastatin on ventricular hypertrophy during remodeling after myocardial infarction and whether the attenuated hypertrophic effect was via activation of myocardial KATP channels. Twenty-four hours after ligation of the anterior descending artery, male Wistar rats were randomized to either vehicle, nicorandil (an agonist of KATP channels), pravastatin, glibenclamide (an antagonist of KATP channels), or a combination of nicorandil and glibenclamide orpravastatin and glibenclamide for 4 weeks. Infarct size and mortality weresimilar among the infarcted groups. Cardiomyocyte sizes isolated by enzymatic dissociation after infarction significantly increased at the border zonein vehicle-treated infarcted rats compared with sham-operated rats. Rats inthe nicorandil- and pravastatin-treated groups significantly attenuated cardiomyocyte hypertrophy, as compared with the vehicle-treated group. Arrhythmicscores during programmed stimulation mirrored those of cardiomyocyte hypertrophy. Increased 70-kDa S6 kinase mRNA expression in cardiac remodeling was confirmed by reverse transcription-polymerase chain reaction, consistent with the results of immunohistochemistry and Western blot for the phosphorylation of 70-kDa S6 kinase. Nicorandil-induced effects were abolished by administering glibenclamide. Similarly, the beneficial effects of pravastatin were abolished by administering glibenclamide, implicating KATP channels as the relevant target. Activation of KATPchannels by pravastatin administration can attenuate ventricular remodeling through a S6 kinase-dependent pathway after infarction.
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