title: Dronedarone's inhibition of If current is the primary mechanism responsible for its bradycardic effect.
abstract: BACKGROUND
  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.
  
  
  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.
authors: Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors: Lucas F
authors: LF
authors: Sobrado
authors: Bruno B
authors: BB
authors: Varone
authors: Ananda D
authors: AD
authors: Machado
authors: Bruce D
authors: BD
authors: Nearing
authors: Dewan
authors: D
authors: Zeng
authors: Luiz
authors: L
authors: Belardinelli
authors: Richard L
authors: RL
authors: Verrier
mesh_terms: D000638:Amiodarone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001919:Bradycardia / Q000139:chemically induced*; D004110:Diltiazem / Q000494:pharmacology; D000077764:Dronedarone; D007545:Isoproterenol / Q000494:pharmacology; D000077550:Ivabradine; D009200:Myocardial Contraction / Q000187:drug effects; D013552:Swine
chemical_list: D001552:Benzazepines; D000077550:Ivabradine; D004110:Diltiazem; D000077764:Dronedarone; D007545:Isoproterenol; D000638:Amiodarone
keywords: If current; contractility; dronedarone; heart rate; hemodynamics