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Dronedarone's Inhibition of I f Current Is the Primary Mechanism Responsible for Its Bradycardic Effect
Author(s) -
SOBRADO LUCAS F.,
VARONE BRUNO B.,
MACHADO ANANDA D.,
NEARING BRUCE D.,
ZENG DEWAN,
BELARDINELLI LUIZ,
VERRIER RICHARD L.
Publication year - 2013
Publication title -
journal of cardiovascular electrophysiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.193
H-Index - 138
eISSN - 1540-8167
pISSN - 1045-3873
DOI - 10.1111/jce.12155
Subject(s) - ivabradine , dronedarone , medicine , heart rate , diltiazem , contractility , chronotropic , phenylephrine , cardiology , anesthesia , blood pressure , calcium , atrial fibrillation , amiodarone
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 I f are plausible. Methods and Results In anesthetized pigs, we compared the effects of dronedarone to the prototypical I f 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 I f and not to blockade of either L‐type calcium channels or BAR.