title: Heart rate reduction by zatebradine reduces infarct size and mortality but promotes remodeling in rats with experimental myocardial infarction.
abstract: The importance of heart rate for left ventricular remodeling and prognosis after myocardial infarction is not known. We examined the contribution of heart rate reduction by zatebradine, a direct sinus node inhibitor without negative inotropic effects on left ventricular function and dilatation, on mortality, energy metabolism, and neurohormonal changes in rats with experimental myocardial infarction (MI). Thirty minutes after left coronary artery ligation or sham operation, the rats were randomized to receive either placebo or zatebradine (100 mg x kg(-1) x day(-1) per gavage) continued for 8 wk. Mortality during 8 wk was 33.3% in the placebo and 23.0% in the zatebradine group (P < 0.05); MI size was 36 +/- 2% and 30 +/- 1% (means +/- SE, P < 0.05), respectively. Zatebradine improved stroke volume index in all treated rats but increased left ventricular volume in rats with small MI (2.43 +/- 0.10 vs. 1.81 +/- 0.10 ml/kg, P < 0.05) but not in rats with large MI (2.34 +/- 0.09 vs. 2.35 +/- 0.11 ml/kg, not significant). Zatebradine reduced left and right ventricular norepinephrine and increased left and right ventricular 3,4-dihydroxyphenyl ethylene glycol-to-norepinephrine ratio suggesting aggravation of cardiac sympathetic activation by zatebradine after MI. Creatine kinase and lactate dehydrogenase isoenzymes in rats with MI remained unchanged by zatebradine. Lowering heart rate per se reduces mortality and MI size in this model but induces adverse effects on left ventricular remodeling in rats with small MI.
authors.affiliation: Medizinische Universitätsklinik, Universität Würzburg, 97080 Würzburg, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Hu
authors.forename: Anne
authors.initials: A
authors.lastname: Naumann
authors.forename: Daniela
authors.initials: D
authors.lastname: Fraccarollo
authors.forename: Peter
authors.initials: P
authors.lastname: Gaudron
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Kaden
authors.forename: Stefan
authors.initials: S
authors.lastname: Neubauer
authors.forename: Georg
authors.initials: G
authors.lastname: Ertl
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002395:Catecholamines / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D003402:Creatine Kinase / Q000378:metabolism; D004108:Dilatation, Pathologic / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D006728:Hormones / Q000097:blood; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009203:Myocardial Infarction / Q000401:mortality / Q000473:pathology* / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D001552:Benzazepines; D002316:Cardiotonic Agents; D002395:Catecholamines; D006728:Hormones; D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase; C043636:zatebradine