Copyright © 2004, European Society of Cardiology
Benidipine, a long-acting calcium channel blocker, inhibits cardiac remodeling in pressure-overloaded mice
aDepartment of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0781, Japan
bCardiovascular Division of Internal Medicine, National Cardiovascular Center (M.K.), 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan
* Corresponding author. Tel.: +81 6 6833 5012x2225; fax: +81 6 6836 1120. Email address: kitakaze{at}zf6.so-net.ne.jp
Objective: The effects of long-acting calcium channel blockers (CCBs) on pressure overload-induced cardiac remodeling are seldom studied in animals. We evaluated the effects of benidipine, a long-acting CCB, on cardiac remodeling.
Methods: Rat neonatal cardiac myocytes were used to examine the influence of benidipine on protein synthesis. Cardiac remodeling was induced in C57 B6/J mice by transverse aortic constriction (TAC). Then the effects of benidipine (10 mg/kg/d) were assessed on myocardial hypertrophy and heart failure, cardiac histology, and gene expression.
Results: Benidipine significantly inhibited protein synthesis by cardiac myocytes stimulated with phenylephrine (PE), and this effect was partially abolished by cotreatment with a nitric oxide synthase (NOS) inhibitor [N(G)-nitro-L-arginine methylester (L-NAME)]. Four weeks after the onset of pressure overload, benidipine therapy potently inhibited cardiac hypertrophy and prevented heart failure. The heart to body weight ratio was 6.89 ± 0.48 mg/g in treated mice vs. 8.76 ± 0.33 mg/g in untreated mice (P<0.01), and the lung to body weight ratio was 7.39 ± 0.93 mg/g vs. 10.53 ± 0.99 mg/g, respectively (P<0.05). Left ventricular fractional shortening (LVFS) was improved on echocardiography. Plasma NO levels were increased, while B type natriuretic peptide, protein inhibitor of neuronal NOS, and procollagen IV alpha were down-regulated in benidipine-treated mice.
Conclusion: These results indicate that benidipine inhibits cardiac remodeling due to pressure overload at least partly by acting on the nitric oxide signaling pathway.
KEYWORDS Calcium channel blocker; Heart failure; Hypertrophy; Gene expression
Time for primary review 19 days
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