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Am J Physiol Heart Circ Physiol 286: H1281-H1288, 2004; doi:10.1152/ajpheart.00390.2003
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Heart rate reduction by zatebradine reduces infarct size and mortality but promotes remodeling in rats with experimental myocardial infarction

Kai Hu,1 Anne Naumann,1 Daniela Fraccarollo,1 Peter Gaudron,2 Jens J. Kaden,1 Stefan Neubauer,3 and Georg Ertl1

1Medizinische Universitätsklinik, Universität Würzburg, 97080 Würzburg; 2Krankenhaus St. Georg, Innere Medizin und Kardiologie, D-31812 Bad Pyrmont, Germany; and 3Department 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).




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