Heart rate reduction by zatebradine reduces infarct size and mortality but promotes remodeling in rats with experimental myocardial infarction

• Published in: American journal of physiology. Heart and circulatory physiology 2004-04, Vol.286 (4), p.H1281-H1288
• Main Authors: Hu, Kai, Naumann, Anne, Fraccarollo, Daniela, Gaudron, Peter, Kaden, Jens J, Neubauer, Stefan, Ertl, Georg
• Format: Article
• Language: English
• Subjects: Animals; Benzazepines - pharmacology; Body Weight - drug effects; Cardiotonic Agents - pharmacology; Catecholamines - blood; Chromatography, High Pressure Liquid; Creatine Kinase - metabolism; Dilatation, Pathologic - prevention & control; Dose-Response Relationship, Drug; Energy Metabolism - drug effects; Female; Heart Rate - drug effects; Hemodynamics - drug effects; Hormones - blood; Isoenzymes - metabolism; L-Lactate Dehydrogenase - metabolism; Myocardial Infarction - mortality; Myocardial Infarction - pathology; Myocardial Infarction - prevention & control; Myocardium - enzymology; Oxygen Consumption - drug effects; Rats; Rats, Wistar; Ventricular Function, Left - drug effects; Ventricular Remodeling - drug effects
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00390.2003

1 Medizinische Universitätsklinik, Universität Würzburg, 97080 Würzburg; 2 Krankenhaus St. Georg, Innere Medizin und Kardiologie, D-31812 Bad Pyrmont, Germany; and 3 Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford University, Oxford OX3 9DU, United Kingdom Submitted 28 April 2003 ; accepted in final form 21 November 2003 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·kg –1 ·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. neurohumoral systems; heart failure; bradycardia Address for reprint requests and other correspondence: G. Ertl, Medizinische Universitätsklinik, Universität Würzburg, Josef-Schneider Strasse 2, 97080 Würzburg, Germany (E-mail: g.ertl{at}medizin.uni-wuerzburg.de ).