We have demonstrated that myocardial ATP-sensitive potassium (K_ATP) channels are implicated in the development of cardiac hypertrophy in hyperlipidemic rabbits. We investigated the effect of pravastatin on development of ventricular hypertrophy in male normolipidemic Wistar rats with two-kidney one clip (2K1C) hypertension and whether the attenuated hypertrophic effect was via activation of K_ATP channels. Twenty-four hours after the left renal artery was clipped, rats were treated with one of the following therapies for 8 weeks: vehicle, nicorandil (an agonist of K_ATP channels), pravastatin, glibenclamide (an antagonist of K_ATP channels), hydralazine, nicorandil + glibenclamide, or pravastatin + glibenclamide. Systolic blood pressure, relative LV weight, and cardiomyocyte sizes significantly increased in vehicle-treated 2K1C rats compared with those in sham-operated rats. Treatment with either nicorandil or pravastatin significantly attenuated LV hypertrophy/body weight, as compared with the vehicle, which was further confirmed by downregulation of LV atrial natriuretic peptide mRNA. Nicorandil-induced effects were abolished by administering glibenclamide. Similarly, pravastatin-induced beneficial effects were reversed by the addition of glibenclamide, implicating K_ATP channels as the relevant target. A dissociation between the effects of blood pressure and cardiac structure was noted because pravastatin and hydralazine reduced arterial pressure similarly. These results suggest a crucial role of cardiac K_ATP channel system in the development of ventricular hypertrophy in the 2K1C hypertensive rats. Pravastatin is endowed with cardiac antihypertrophic properties probably through activation of K_ATP channels, independent of lipid and hemodynamic changes.