title: Calcium channel blockade limits cardiac remodeling and improves cardiac function in myocardial infarction-induced heart failure in rats.
abstract: Calcium channel antagonists (CCAs) have been proposed to prevent cardiac events after myocardial infarction (MI). However, unwanted effects, such as negative inotropy, limit their use in many cases. The aim of this study was to compare the effects of long-term treatment with the CCAs, mibefradil, verapamil, and amlodipine, administered before and after chronic MI on myocardial remodeling and cardiac function. MI was induced by permanent ligation of the left coronary artery in male Wistar rats. Infarcted animals were treated with placebo, mibefradil (10 mg/kg/d po), verapamil (8 mg/kg bid po), or amlodipine (4 mg/kg/d po). Treatment was started 7 days before or 3 h after MI induction. Six weeks after MI, mean arterial blood pressure (MAP), heart rate (HR), left ventricular end diastolic pressure (LVEDP), and cardiac contractility (dP/dt(max)) were measured. Morphometric parameters such as infarct size (IS), left ventricular dilation (LVD), septal thickness (ST), and cardiac fibrosis were determined in picrosirius red-stained hearts. Six weeks after MI, MAP and dP/dt(max) were decreased, whereas LVEDP and HR were increased in placebo-treated controls. The hearts featured an IS of 45%, left ventricular dilation, cardiac fibrosis, and septal thinning. MAP of all CCA-treated animals was increased, whereas LVEDP was decreased and dP/dt(max) increased 7-day pre- and 3-h post-MI started in mibefradil- and amlodipine-treated animals, but not in verapamil-treated animals. In contrast to amlodipine treatment, before and after MI started mibefradil and verapamil treatment decreased HR. Pretreatment with all CCA reduced IS and increased ST, whereas only mibefradil and amlodipine pretreatment prevented LVD and cardiac fibrosis. After MI started treatment with mibefradil and amlodipine reduced IS and cardiac fibrosis, and increased ST. Long-term treatment with the CCAs mibefradil, verapamil, and amlodipine reduced myocardial remodeling and improved cardiac function in MI-induced heart failure in rats.
authors.affiliation: Institute of Pharmacology, Christian-Albrechts-University of Kiel, Germany. s.sandmann@pharmakologie.uni-kiel.de
authors.forename: S
authors.initials: S
authors.lastname: Sandmann
authors.forename: R
authors.initials: R
authors.lastname: Claas
authors.forename: J P
authors.initials: JP
authors.lastname: Cleutjens
authors.forename: M J
authors.initials: MJ
authors.lastname: Daemen
authors.forename: T
authors.initials: T
authors.lastname: Unger
mesh_terms: D017311:Amlodipine / Q000494:pharmacology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D006333:Heart Failure / Q000188:drug therapy; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy; D008297:Male; D020748:Mibefradil / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000188:drug therapy; D009206:Myocardium / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology; D014700:Verapamil / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D017311:Amlodipine; D020748:Mibefradil; D014700:Verapamil