Abstract
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<sup>–1</sup> isoproterenol (ISP). Subcutaneous ECG leads were implanted, and 2 days following the second injection, each rat was dosed with 25 mg·kg<sup>–1</sup> 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<sub>v</sub>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<sub>v</sub>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<sub>v</sub>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.
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