Acute Effects of Zatebradine on Cardiac Conduction and Repolarization

Abstract

Zatebradine, a potent bradycardic agent, is believed to act selectively at the sinoatrial node. The selectivity of such a property relative to various electrophysiologic classes of action is not well defined. To characterize the electrophysiologic properties of zatebradine, the corrected sinus node recovery time, sinoatrial conduction time, conduction intervals, atrial effective refractory period and monophasic action potential duration in the ventricle were measured before and after incremental doses of zatebradine (0.1-1.5 mg/kg) in 15 anesthetized dogs. The electrophysiologic effects of zatebradine developed immediately after a single i.v. bolus dose, reaching steady-steady-state at 15 minutes with the maximum effect evident at 0.75 mg/kg. The IC(50) was 0.23 mg/kg. There was no significant effect on the sinus node recovery time. The PR interval on the electrocardiogram was significantly increased when the dose was higher than 0.25 mg/kg. The duration of the P wave and the PA interval were not changed. Zatebridine greatly increased the AH (from 135 to 178 milliseconds) without changing the HH and HV intervals in His bundle recordings. The EC(50) of this effect was 0.58 mg/kg. The QRS interval was not changed. The QTc was significantly increased from 0.43 to 0.56 s(1/2) (P < 0.05). The action potential duration was significantly increased by high dose zatebradine (> 0.5 mg/kg), the EC(50) for this effect was 0.76 mg/kg. The atrium effective refractory period was significantly increased (31%) with an EC(50) 0.69 mg/kg. These results indicate that zatebradine selectively inhibits sinus node automaticity at low doses. The inhibition of the AV nodal conduction and the lengthening of the refractory period and repolarization in the atria and the ventricles occur at higher dose.

Heart Rate Dependence of Aortic Pulse Wave Velocity at Different Arterial Pressures in Rats

“…Drugs may induce systemic effects that can directly or indirectly affect arterial stiffness. However, studies have shown that zatebradine selectively acts on the If current [28][29][30] and does not affect cardiovascular function directly. 31 In addition, the use of vasoactive agents phenylephrine and sodium nitroprusside may be suspected to have an independent effect on the aorta.…”

“…Although we decreased HR pharmacologically using zatebradine, all of the PWV measurements were taken at paced HRs. Moreover, studies have shown that zatebradine selectively acts on the If current [28][29][30] and does not affect cardiovascular function directly. 31 Therefore, it is presumed that the changes in PWV observed in this study were related to changes in HR alone.…”

Selektive If-Kanal-Hemmung: eine Alternative in der Behandlung der koronaren Herzkrankheit?

“…In höheren Dosierungen traten verlängerte Refraktärperioden und verlängerte Repolarisationsphasen in Vorhof und Ventrikel sowie eine Blockierung der AV-Überleitung auf [164]. Bei der Untersuchung der Frage, ob Zatebradin ischämieinduzierten Arrhythmien vorbeugen kann, zeigte sich, dass der herzfrequenzreduzierende Effekt allein nicht ausreichte, diesen wünschenswerten Effekt zu erzeugen [23].…”

“…Diese Ergebnisse lassen vermuten, dass Zatebradin nicht nur eine elektrophysiologische, sondern auch eine intrinsisch-autonome Aktivität hat und möglicherweise das sympathovagale Ungleichgewicht nach Myokardinfarkt korrigieren kann[105]. Allerdings zeigte sich experimentell eine Verlängerung des Aktionspotentials im Sinne einer QTc-Zeit-Verlängerung[164].Bei Probanden mit chronisch stabiler Angina pectoris wurde trotz des herzfrequenzsenkenden Effekts nur eine minimale antiischämische Wirkung festgestellt. Auch bei diesem Modell wurde die subendokardiale Durchblutung im minderperfundierten Bereich durch Zatebradin deutlich verbessert[70], was erneut auf eine verlängerte Diastolendauer zurückgeführt wurde[60].…”

Antiarrhythmic drugs: new agents and evolving concepts

“…In anaesthetised dogs, intravenous zatebradine prolonged PR and AH intervals without affecting HV and QRS width. At higher doses, it also prolonged QTc interval and atrial refractory period [168]. In animal models of myocardial ischaemia, zatebradine decreases the rate of ventricular ectopy [169]; this is likely related to the presence of a form of I f current in the Purkinje fibres and ventricular muscle [170][171][172].…”