二氢吡啶类钙通道拮抗剂抗心肌肥厚作用依赖于其对N-型钙通道的阻断能力

Antihypertrophic effect of dihydropyridines calcium channel blockers is dependent on their potential of blocking N-type calcium channel

目的比较三种兼有不同N-型钙通道阻滞力的二氢吡啶类钙通道阻断剂(CCB)的抗心肌肥厚作用并分析其可能机制。方法在C57BL/6小鼠上缩窄主动脉弓(TAC)制作心肌肥厚模型,7d后检测血浆儿茶酚胺水平以明确交感神经系统是否被激活。分别用长效CCB氨氯地平、贝尼地平和短效CCB硝苯啶治疗TAC小鼠7d后评价心肌肥厚程度。培养新生大鼠心肌细胞,检测上述三种CCB对苯肾上腺素(Phe)刺激的蛋白合成有无抑制作用。结果TAC7d后,小鼠血浆肾上腺素、去甲肾上腺素和多巴胺浓度均显著上升。三种CCB的抗心肌肥厚作用的强弱与其对N-型钙通道的阻滞能力相一致,氨氯地平最明显。即使在持续缓释给药的情况下,硝苯啶对心肌肥厚无抑制作用。在培养的心肌细胞种,对Phe刺激的蛋白合成,三种CCB的抑制作用与在体实验结果一致。结论二氢吡啶类CCB抗心肌肥厚的作用依赖于其对N-型钙通道阻滞力,其机制可能与抑制交感神经有关。

Objective To compare the effects of amlodipine,benidipine and nifedipine on myocardial hypertrophy and evaluate the underlying mechanism.Methods Myocardial hypertrophy model was created by transverse aortic constriction （TAC） in C57 BL/6 mice,and plasma catecholamine concentrations were measured 7 days after surgery to confirm the sympathetic activation.The 3 drugs were administered in TAC mice for 7 days and cardiac hypertrophy was evaluated according to the heart-to-body weight ratio （HW/BW）.Effects of those drugs on the protein synthesis stimulated by phenylephrine in cultured neonatal cardiac myocytes were also examined.Results HW/BW and plasma concentrations of catecholamine were significantly increased in TAC mice one week after surgery in camparison with to sham-operated mice.One week after TAC,the HW/BW ratio was significantly lower in the amolodipine but not nifedipine-treated group than in the TAC group.Administration of nifedipine via minipump infusion for one week did not decrease HW/BW ratio.Treatment with amlodpine or benidipine,but not nifedipine,decreased the neonatal rat myocyte protein synthesis induced by phenylephrine stimulation.Conclusion Antihypertrophic effect of DHEs on myocardium is dependent on their potential of blocking N-type calcium channel,and the underlying mechanism involves the sympathetic inhibition.