Objectives: We examined whether the ATP-sensitive potassium(KATP) channel openers (KCOs) block myocardial hypertrophy, and whether the 70 kDa S6 kinase(p70S6K)-or extracellular signal-regulated kinase(ERK)-dependent pathway is involved.
Background: Chronic inhibition of nitric oxide (NO) synthesis induces cardiac hypertrophy independent of blood pressure by increasing protein synthesis in vivo. KCOs attenuate calcium overload and confer cardioprotection against ischemic stress, and thereby prevent myocardial remodeling.
Methods: Twelve Wistar-Kyoto rat groups underwent 8 weeks of the drug treatment in combination with NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME), an inactive isomer D omega-nitro-L-arginine methyl ester(D-NAME), KCOs(nicorandil; 3 and 10 mg/kg/day, or JTV-506; 0.3 mg/kg/day), or a KATP channel blocker glibenclamide. L-NAME was also treated with hydralazine, p70S6K inhibitor (rapamycin) or MAP kinase kinase inhibitor(PD98059). Finally, left ventricular weight-to-body weight ratio(LVW/BW) was quantified followed by histological examinations and kinase assay.
Results: L-NAME increased blood pressure and LVW/BW compared with the control. KCOs and hydralazine equally cancelled the increase in blood pressure, whereas only KCOs blocked the increase in LVW/BW and myocardial hypertrophy induced by L-NAME. The L-NAME group showed both p70S6K and ERK activation in the myocardium compared with the control(2.3-fold and 2.0-fold, respectively), which was not reversed by hydralazine. Selective inhibition of either P70S6K or ERK blocked myocardial hypertrophy. KCOs prevented the increase in activity only of p70S6K. Glibenclamide reversed the effect of nicorandil in the presence of L-NAME.
Conclusions: KCOs modulate p70S6K, not ERK, to attenuate myocardial hypertrophy induced by chronic inhibition of nitric oxide synthesis in vivo.