The bradycardic agent zatebradine enhances baroreflex sensitivity and heart rate variability in rats early after myocardial infarction

Objective: The bradycardic agent zatebradine (UL-FS 49) reduces heart rate without negative inotropic or proarrhythmic effects. The aim was to experim entally characterize the influence of zatebradine on arterial baroreflex se nsitivity (BRS) and heart rate variability (HRV) which are generally consid ered as estimates of vagal activity and have prognostic value in patients a fter myocardial infarction (MI). Methods: Conscious rats were studied 3 day s after left coronary artery ligation or sham-operation (SH). BRS was deter mined by linear regression analysis of RR-interval and mean arterial pressu re changes evoked by intravenous (i.v.) injections of methoxamine and nitro prusside. HRV at rest was calculated from high-resolution electrocardiogram -recordings. Results: In MI-mts heart rate was similar to SH-rats, mean art erial pressure was lower and both BRS and HRV were markedly reduced. Zatebr adine (0.5 mg/kg i.v.) reduced heart rate in MI-rats from 400+/-15 to 350+/ -19 and in SH-rats from 390+/-19 to 324+/-6 beats/min without changing mean arterial pressure. Both BRS and HRV were restored in MI- and further incre ased in SH-rats by the drug. Effects of 0.05, 0.5 and 5 mg/kg zatebradine r evealed a dose-dependency of heart rate reduction. The lowest dose enhanced reflex bradycardia despite little effect on heart rate and lack of effect on both reflex tachycardia and HRV. Conclusions: Both BRS and HRV are reduc ed in rats early after MI, indicating a depressed reflex and tonic vagal ac tivity. Treatment with zatebradine enhances both BRS and HRV. These data su ggest that the drug has both peripheral and central effects, leading to an increase of vagal control of heart rate. (C) 2000 Elsevier Science B.V. All rights reserved.