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- Title
Dronedarone's Inhibition of I<sub>f</sub> Current Is the Primary Mechanism Responsible for Its Bradycardic Effect.
- Authors
SOBRADO, LUCAS F.; VARONE, BRUNO B.; MACHADO, ANANDA D.; NEARING, BRUCE D.; ZENG, DEWAN; BELARDINELLI, LUIZ; VERRIER, RICHARD L.
- Abstract
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.
- Subjects
AMIODARONE; ANALYSIS of variance; ANIMAL experimentation; BRADYCARDIA; CARDIOTONIC agents; ELECTROCARDIOGRAPHY; ELECTRODES; HEART beat; HEART conduction system; ARTIFICIAL implants; MYOCARDIAL depressants; RESEARCH funding; STATISTICS; SWINE; T-test (Statistics); DATA analysis; REPEATED measures design; DESCRIPTIVE statistics; DILTIAZEM
- Publication
Journal of Cardiovascular Electrophysiology, 2013, Vol 24, Issue 8, p914
- ISSN
1045-3873
- Publication type
Article
- DOI
10.1111/jce.12155