Opening of the adenosine triphosphate-sensitive potassium channel attenuates cardiac remodeling induced by long-term inhibition of nitric oxide synthesis: Role of 70-kDa S6 kinase and extracellular signal-regulated kinase

Objectives We examined whether the adenosine triphosphate (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 Long-term inhibition of nitric oxide (NO) synthesis induces cardiac hypertrophy independent of blood pressure, by increasing protein synthesis in vivo. The KCOs attenuate calcium overload and confer cardioprotection against ischemic stress, thereby preventing myocardial remodeling. Methods Twelve Wistar-Kyoto rat groups underwent eight weeks of the drug treatment in combination with the NO synthase inhibitor Nω-nitro-image-arginine methyl ester (image-NAME), the inactive isomer imageω-nitro-image-arginine methyl ester, KCOs (nicorandil, 3 and 10 mg/kg per day, or JTV-506, 0.3 mg/kg per day), or the KATP channel blocker glibenclamide. The image-NAME was also used with hydralazine, the p70S6K inhibitor rapamycin, or the mitogen-activated protein kinase inhibitor PD98059. Finally, the left ventricular weight (LVW) to body weight (BW) ratio was quantified, followed by histologic examination and kinase assay. Results The image-NAME increased blood pressure and LVW/BW, as compared with the control agent. The KCOs and hydralazine equally cancelled the increase in blood pressure, whereas only KCOs blocked the increase in LVW/BW and myocardial hypertrophy induced by image-NAME. The image-NAME group showed both p70S6K and ERK activation in the myocardium (2.3-fold and 2.0-fold increases, respectively), as compared with the control group, which was not reversed by hydralazine. Selective inhibition of either p70S6K or ERK blocked myocardial hypertrophy. The KCOs prevented the increase in activity only of p70S6K. Glibenclamide reversed the effect of nicorandil in the presence of image-NAME. Conclusions The KCOs modulate p70S6K, not ERK, to attenuate myocardial hypertrophy induced by long-term inhibition of NO synthesis in vivo.