Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
Pharmacology. 2010;86(4):196-202. doi: 10.1159/000318852. Epub 2010 Sep 7.
Inflammation is involved in the pathogenesis of cardiovascular diseases. We investigated whether the response to verapamil is altered in experimental acute myocardial injury (AMI). Two groups of male Sprague-Dawley rats (230-280 g) were divided into control (n = 8) and post-AMI (n = 13). Myocardial injury was induced by 2 daily doses of 150 mg·kg(-1) isoproterenol (ISP). Subcutaneous ECG leads were implanted, and 2 days following the second injection, each rat was dosed with 25 mg·kg(-1) verapamil per os, and an ECG was recorded over 4 h after dosing. The animals were euthanized and blood samples collected for analysis of inflammatory mediators and cardiac troponin I (cTnI). Cardiac L-type calcium channel (Ca(v)1.2) protein levels and mRNA were determined by Western blot and real-time PCR, respectively. ISP treatment caused a 170% increase in serum cTnI, J point elevation, R wave amplitude reduction and Q wave development. Cardiac injury caused a 75% reduction in verapamil potency by prolonging the PR interval and reducing the heart rate. Cardiac tissue injury also caused a significant reduction in the Ca(v)1.2 protein level. Verapamil response was significantly correlated with cTnI. The reduced potency of verapamil in myocardial injury appears to result from a reduction in the drug target protein Ca(v)1.2. If extrapolated to humans, our observations may suggest that downregulation of calcium channel proteins is a contributory factor in the poor outcome in myocardial infarction.
炎症参与了心血管疾病的发病机制。我们研究了维拉帕米的反应是否在实验性急性心肌损伤（AMI）中发生改变。将两组雄性 Sprague-Dawley 大鼠（230-280 g）分为对照组（n = 8）和 AMI 后组（n = 13）。通过 2 天给予 150 mg·kg(-1)异丙肾上腺素（ISP）诱导心肌损伤。植入皮下心电图导联，在第二次注射后第 2 天，每只大鼠口服给予 25 mg·kg(-1)维拉帕米，并在给药后 4 小时记录心电图。处死动物并采集血液样本，用于分析炎症介质和心肌肌钙蛋白 I（cTnI）。通过 Western blot 和实时 PCR 分别测定心脏 L 型钙通道（Ca(v)1.2）蛋白水平和 mRNA。ISP 处理导致血清 cTnI 增加 170%，J 点抬高，R 波幅度降低和 Q 波发展。心脏损伤通过延长 PR 间隔和降低心率导致维拉帕米效力降低 75%。心脏组织损伤还导致 Ca(v)1.2 蛋白水平显著降低。维拉帕米的反应与 cTnI 显著相关。心肌损伤中维拉帕米的效力降低似乎是由于药物靶标蛋白 Ca(v)1.2 的减少所致。如果外推至人类，我们的观察结果可能表明钙通道蛋白的下调是心肌梗死不良结局的一个促成因素。
