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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.

Original publication

DOI

10.1152/ajpheart.00390.2003

Type

Journal article

Journal

Am J Physiol Heart Circ Physiol

Publication Date

04/2004

Volume

286

Pages

H1281 - H1288

Keywords

Animals, Benzazepines, Body Weight, Cardiotonic Agents, Catecholamines, Chromatography, High Pressure Liquid, Creatine Kinase, Dilatation, Pathologic, Dose-Response Relationship, Drug, Energy Metabolism, Female, Heart Rate, Hemodynamics, Hormones, Isoenzymes, L-Lactate Dehydrogenase, Myocardial Infarction, Myocardium, Oxygen Consumption, Rats, Rats, Wistar, Ventricular Function, Left, Ventricular Remodeling