This investigation was funded by a grant from Gilead Sciences, Inc., to Beth Israel Deaconess Medical Center; R.L. Verrier, Principal Investigator.
Dronedarone's Inhibition of If Current Is the Primary Mechanism Responsible for Its Bradycardic Effect
Article first published online: 3 MAY 2013
© 2013 Wiley Periodicals, Inc.
Journal of Cardiovascular Electrophysiology
Volume 24, Issue 8, pages 914–918, August 2013
How to Cite
SOBRADO, L. F., VARONE, B. B., MACHADO, A. D., NEARING, B. D., ZENG, D., BELARDINELLI, L. and VERRIER, R. L. (2013), Dronedarone's Inhibition of If Current Is the Primary Mechanism Responsible for Its Bradycardic Effect. Journal of Cardiovascular Electrophysiology, 24: 914–918. doi: 10.1111/jce.12155
D. Zeng and L. Belardinelli are employees of Gilead Sciences, Inc. Other authors: No disclosures.
- Issue published online: 22 JUL 2013
- Article first published online: 3 MAY 2013
- Accepted manuscript online: 8 APR 2013 06:05AM EST
- Manuscript Accepted: 26 FEB 2013
- Manuscript Revised: 23 FEB 2013
- Manuscript Received: 5 FEB 2013
- Gilead Sciences, Inc.
- heart rate;
- If current;
Dronedarone's Bradycardic Effect
The mechanism(s) whereby dronedarone reduces sinus rate are not well understood, although L-type calcium channel antagonism, beta-adrenergic blockade, and inhibition of If are plausible.
Methods and Results
In anesthetized pigs, we compared the effects of dronedarone to the prototypical If inhibitor, ivabradine, and the L-type calcium channel antagonist diltiazem on heart rate, mean arterial blood pressure (MAP), and contractility. Dronedarone's effects on the phenylephrine-induced rise in MAP and on the chronotropic response to isoproterenol were also investigated. Cumulative doses of dronedarone (0.5 mg/kg, i.v., and 5.0 mg/kg, i.v.; plasma level: 80 ± 16.1 nM) progressively reduced heart rate (P < 0.02) without changes in MAP or contractility as assessed by LV dP/dt (N = 6). Ivabradine (0.5 mg/kg, i.v.) similarly reduced heart rate (P < 0.01) without change in MAP (N = 6). Diltiazem (0.8 mg/kg, i.v.) reduced heart rate and MAP and decreased contractility (N = 6). Dronedarone blunted phenylephrine's alpha-receptor-mediated increase in MAP but did not alter the marked beta-adrenergic receptor (BAR)-mediated increase in heart rate induced by isoproterenol. When dronedarone injection was preceded by ivabradine, no further decrease in heart rate or change in MAP was observed (N = 6).
Dronedarone reduced heart rate without affecting MAP or contractility, effects that differ from L-type calcium channel blockade. Dronedarone did not antagonize BAR stimulation, and its heart-rate lowering effects were eliminated by prior administration of ivabradine. Thus, dronedarone's bradycardic action is likely due to inhibition of If and not to blockade of either L-type calcium channels or BAR.