© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
The bradycardic agent zatebradine enhances baroreflex sensitivity and heart rate variability in rats early after myocardial infarction
aDepartment of Cardiology, University of Heidelberg, Bergheimer Strasse 58, D-69115 Heidelberg, Germany
bDepartment of Physiology I, University of Heidelberg, Heidelberg, Germany
* Corresponding author. Tel.: +49-6221-568-611; fax: +49-6221-565-515 carsten_krueger{at}med.uni-heidelberg.de
Objective: The bradycardic agent zatebradine (UL-FS 49) reduces heart rate without negative inotropic or proarrhythmic effects. The aim was to experimentally characterize the influence of zatebradine on arterial baroreflex sensitivity (BRS) and heart rate variability (HRV) which are generally considered as estimates of vagal activity and have prognostic value in patients after myocardial infarction (MI). Methods: Conscious rats were studied 3 days after left coronary artery ligation or sham-operation (SH). BRS was determined by linear regression analysis of RR-interval and mean arterial pressure changes evoked by intravenous (i.v.) injections of methoxamine and nitroprusside. HRV at rest was calculated from high-resolution electrocardiogram-recordings. Results: In MI-rats heart rate was similar to SH-rats, mean arterial pressure was lower and both BRS and HRV were markedly reduced. Zatebradine (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 increased in SH-rats by the drug. Effects of 0.05, 0.5 and 5 mg/kg zatebradine revealed 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 reduced in rats early after MI, indicating a depressed reflex and tonic vagal activity. Treatment with zatebradine enhances both BRS and HRV. These data suggest that the drug has both peripheral and central effects, leading to an increase of vagal control of heart rate.
KEYWORDS ANOVA: analysis of variance; ANP: atrial natriuretic peptide; BRS: baroreflex sensitivity; C.V.: coefficient of variance; ECG: electrocardiogram; FFT: fast Fourier transform; HF: high frequency; HR: heart rate; HRV: heart rate variability; LF: low frequency; LVEDP: left ventricular end-diastolic pressure; MAP: mean arterial pressure; MI: myocardial infarction; RR-interval: interval between heart beats; NN-interval: interval between normal heart beats; SDNN: standard deviation of the mean interval between normal heart beats; SH: sham-operation
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