Drug-disease interaction: reduced verapamil response in isoproterenol-induced myocardial injury in rats.
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.
Hanafy
Sherif
S
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
El-Kadi
Ayman O
AO
Jamali
Fakhreddin
F
D000818:Animals; D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D004195:Disease Models, Animal; D004562:Electrocardiography; D007545:Isoproterenol; D008297:Male; D009203:Myocardial Infarction / Q000503:physiopathology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019210:Troponin I / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D012333:RNA, Messenger; D019210:Troponin I; D014700:Verapamil; D007545:Isoproterenol