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EXPERIMENTAL STUDY

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

Shoji Sanada, MD^*, Koichi Node, MD^*, Hiroshi Asanuma, MD^*, Hisakazu Ogita, MD^*, Seiji Takashima, MD^*, Tetsuo Minamino, MD^*, Masanori Asakura, MD^*, Yulin Liao, MD^*, Akiko Ogai, BS, Jiyoong Kim, MD, Masatsugu Hori, MD, FACC^* and Masafumi Kitakaze, MD, FACC^,*

^* Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan
Cardiology Division of Medicine, National Cardiovascular Center, Suita, Japan

Manuscript received April 4, 2001; revised manuscript received April 26, 2002, accepted May 24, 2002.

^* Reprint requests and correspondence: Dr. Masafumi Kitakaze, Cardiovascular Division of Medicine, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita Osaka 565-8565, Japan.
kitakaze{at}hsp.ncvc.go.jp

OBJECTIVES: We examined whether the adenosine triphosphate (ATP)-sensitive potassium (K_ATP) 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 N-nitro-L-arginine methyl ester (L-NAME), the inactive isomer D-nitro-L-arginine methyl ester, KCOs (nicorandil, 3 and 10 mg/kg per day, or JTV-506, 0.3 mg/kg per day), or the K_ATP channel blocker glibenclamide. The L-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 L-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 L-NAME. The L-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 L-NAME.

CONCLUSIONS: The KCOs modulate p70S6K, not ERK, to attenuate myocardial hypertrophy induced by long-term inhibition of NO synthesis in vivo.

Abbreviations and Acronyms   ANOVA   analysis of variance   ATP   adenosine triphosphate   BW   body weight   D-NAME   D-nitro-L-arginine methyl ester   ERK   extracellular signal-regulated kinase   KATP   adenosine triphosphate-sensitive potassium   KCO   adenosine triphosphate-sensitive potassium channel opener   L-NAME   N-nitro-L-arginine methyl ester   LVW   left ventricular weight   NO   nitric oxide   p70S6K   70-kDa S6 kinase   PKC   protein kinase C

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