title: Drug-disease interaction: reduced verapamil response in isoproterenol-induced myocardial injury in rats.
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(-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.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Sherif
authors.initials: S
authors.lastname: Hanafy
authors.forename: Ayman O
authors.initials: AO
authors.lastname: El-Kadi
authors.forename: Fakhreddin
authors.initials: F
authors.lastname: Jamali
mesh_terms: 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*
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D012333:RNA, Messenger; D019210:Troponin I; D014700:Verapamil; D007545:Isoproterenol