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.