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(Hypertension. 2003;41:963.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Long-Acting Ca²⁺ Blockers Prevent Myocardial Remodeling Induced by Chronic NO Inhibition in Rats

Shoji Sanada; Koichi Node; Tetsuo Minamino; Seiji Takashima; Akiko Ogai; Hiroshi Asanuma; Hisakazu Ogita; Yulin Liao; Masanori Asakura; Jiyoong Kim; Masatsugu Hori; Masafumi Kitakaze

From the Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine (S.S., K.N., T.M., S.T., H.A., H.O., Y.L., M.A., M.H.), Suita; and the Cardiovascular Division of Medicine, National Cardiovascular Center (A.O., J.K., M.K.), Suita, Japan.

Correspondence to Masafumi Kitakaze, MD, Cardiovascular Division of Medicine, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita Osaka 565-8565, Japan. E-mail kitakaze{at}zf6.so-net.ne.jp

Chronic inhibition of nitric oxide (NO) synthesis induces cardiac remodeling independent of systemic hemodynamic changes in rats. We examined whether long-acting dihydropyridine calcium channel blockers block myocardial remodeling and whether the activation of 70-kDa S6 kinase (p70S6K) and extracellular signal-regulated kinase (ERK) are involved. Ten groups of Wistar-Kyoto rats underwent 8 weeks of drug treatment consisting of a combination of NO synthase inhibitor N^G-nitro-L-arginine methyl ester (L-NAME), an inactive isomer (D-NAME), amlodipine (1 or 3 mg/kg per day), or benidipine (3 or 10 mg/kg per day). In other groups, L-NAME was also used in combination with a p70S6K inhibitor (rapamycin), a MEK inhibitor (PD98059), and hydralazine. Systolic blood pressure (SBP), heart rate, and left ventricular weight (LVW) were measured, together with histological examinations and kinase assay. L-NAME increased SBP and LVW (1048±22 versus 780±18 mg, P<0.01) compared with the control, showing a significant increase in cross-sectional area of cardiomyocytes after 8 weeks. Amlodipine, benidipine, or hydralazine equally attenuated the increase in SBP induced by L-NAME. However, both amlodipine and benidipine but not hydralazine attenuated the increase in LVW by L-NAME (789±27, 825±20 mg, P<0.01, and 1118±29 mg, NS, respectively), also confirmed by histological analysis. L-NAME caused a 2.2-fold/1.8-fold increase in p70S6K/ERK activity in myocardium compared with the control, both of which were attenuated by both amlodipine and benidipine but not hydralazine. Both rapamycin and PD98059 attenuated cardiac hypertrophy in this model. Thus, long-acting dihydropyridine calcium channel blockers inhibited cardiac hypertrophy induced by chronic inhibition of NO synthesis by inhibiting both p70S6K and ERK in vivo.

Key Words: hypertrophy • nitric oxide • L-NAME • calcium channel blockers • kinase

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