Dronedarone's Inhibition of If Current Is the Primary Mechanism Responsible for Its Bradycardic Effect

Authors


  • This investigation was funded by a grant from Gilead Sciences, Inc., to Beth Israel Deaconess Medical Center; R.L. Verrier, Principal Investigator.

  • D. Zeng and L. Belardinelli are employees of Gilead Sciences, Inc. Other authors: No disclosures.

Address for correspondence: Richard L. Verrier, Ph.D., F.A.C.C., Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, 99 Brookline Avenue, RN-301, Boston, MA 02215, USA. Fax: +617-975-5270, E-mail: rverrier@bidmc.harvard.edu

Dronedarone's Bradycardic Effect

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.

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