Dronedarone's inhibition of If current is the primary mechanism responsible for its bradycardic effect

J Cardiovasc Electrophysiol. 2013 Aug;24(8):914-8. doi: 10.1111/jce.12155. Epub 2013 May 3.


Introduction: 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).

Conclusions: 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.

Keywords: If current; contractility; dronedarone; heart rate; hemodynamics.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amiodarone / analogs & derivatives*
  • Amiodarone / pharmacology
  • Analysis of Variance
  • Animals
  • Arterial Pressure / drug effects
  • Benzazepines / pharmacology
  • Blood Pressure / drug effects
  • Bradycardia / chemically induced*
  • Diltiazem / pharmacology
  • Dronedarone
  • Isoproterenol / pharmacology
  • Ivabradine
  • Myocardial Contraction / drug effects
  • Swine


  • Benzazepines
  • Ivabradine
  • Diltiazem
  • Dronedarone
  • Isoproterenol
  • Amiodarone