Interaction of the antiarrhythmic agents SR 33589 and amiodarone with the β‐adrenoceptor and adenylate cyclase in rat heart

Background-To overcome the side effects of amiodarone (AM), its noniodinated analogue, dronedarone (SR), was synthesized. In this study, its electrophysiological effects were compared with those of AM in rabbit hearts. Methods and Results-Five animal groups (nϭ7 each) for 3 weeks received daily oral treatment of 1 of these regimens:(1) control, vehicle only; (2) AM 50 mg/kg (AM50); (3) AM 100 mg/kg (AM100); (4) SR 50 mg/kg (SR50); and (5) SR 100 mg/kg (SR100). ECGs were recorded before drug and at 3 weeks of drug before euthanasia. Action potentials were recorded from isolated papillary muscle and sinoatrial node by microelectrode techniques. The short-term effects were studied in controls (nϭ5) at various concentrations of SR (0 to 10 mol/L) in tissue bath. Action potential duration at 50% (APD 50 ) and 90% (APD 90 ) repolarization and upstroke dV/dt (V max ) at various cycle lengths were compared by ANOVA with repeated measures. Compared with control, AM and SR increased RR, QT, and QTc intervals (PϽ0.0001 for all). Ventricular APD 50 and APD 90 were lengthened by 20% to 49% as a function of dose (PϽ0.005 to Ͻ0.0001) and cycle length (PϽ0.001). SR100 effects were greater than those of AM100 (PϽ0.002). V max was decreased by both AM100 (PϽ0.0001) and SR100 (PϽ0.01). Sinoatrial node automaticity was slowed in treated groups compared with that of the control group (PϽ0.0001 for all). Conclusions-The electrophysiological effects of dronedarone are similar to those of AM but more potent, despite deletion of iodine from its molecular structure, a finding of importance for the development of future class III antiarrhythmic compounds. (Circulation. 1999;100:2276-2281.)

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“…26 There is evidence that SR also interacts with ␤-adrenergic receptors of the rat heart at intracellular sites. 27 …”

Section: Potential Mechanisms Of Heart Rate Slowingmentioning

confidence: 99%

Electrophysiological Effects of Dronedarone (SR33589), a Noniodinated Benzofuran Derivative, in the Rabbit Heart

1999

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“…[23][24][25][26][27][28][29][30][31][32][33] In patch clamp experiments using human atrial myocytes, 3 mol/L of dronedarone produced potent blockade of peak sodium current, an effect 10-fold greater than that of an equal concentration of amiodarone. 23 In guinea pig ventricular myocytes, dronedarone inhibited the rapidly activating delayed-rectifier potassium current, the slowly activating delayed-rectifier potassium current, the inward rectifier potassium current, and L-type calcium current.…”

Section: Electrophysiological Properties Of Dronedarone In Vitro Expementioning

confidence: 99%

Dronedarone

2009

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Abstract-Amiodarone is the most effective antiarrhythmic drug for maintaining sinus rhythm for patients with atrial fibrillation. Extra-cardiac side effects have been a limiting factor, especially during chronic use, and may offset its benefits. Dronedarone is a noniodinated benzofuran derivative of amiodarone that has been developed for the treatment of atrial fibrillation and atrial flutter. Similar to amiodarone, dronedarone is a potent blocker of multiple ion currents, including the rapidly activating delayed-rectifier potassium current, the slowly activating delayed-rectifier potassium current, the inward rectifier potassium current, the acetylcholine activated potassium current, peak sodium current, and L-type calcium current, and exhibits antiadrenergic effects. It has been studied for maintenance of sinus rhythm and control of ventricular response during episodes of atrial fibrillation. Dronedarone reduces mortality and morbidity in patients with high-risk atrial fibrillation, but may be unsafe in those with severe heart failure. This article will review evidence of safety and effectiveness of dronedarone in patients with atrial fibrillation. Key Words: amiodarone Ⅲ arrhythmia Ⅲ atrial fibrillations Ⅲ dronedarone A trial fibrillation (AF) is the most common arrhythmia in clinical practice and a usual cause for hospitalization and consultation. 1,2 It is an epidemic. It is projected that by 2050, more than 15 million people will contract AF in the United States alone. 2,3 Nearly 1 in every 10 persons aged 80 years and older has AF, 1,4,5 predisposing them to stroke, heart failure, and death. 6,7 A recent report from Centers for Medicare and Medicaid Services suggested that AF accounted for 1 765 304 hospitalizations in 1999. 8 The cost of medical care for patients with AF is almost 5 times higher than the care of patients without AF. 9,10 Despite improvements in primary and secondary prevention of ischemic heart disease and hypertension, the US age-adjusted death rate due to AF increased from 27.6 in 1980 to 69.8 per 100 000 in 1998. 2,11 Current therapy for AF is multidimensional and complicated. 12 There is some consensus on the benefits of anticoagulation in patients with AF, but debate continues about the relative value of rate versus rhythm control. Recent clinical trials have failed to demonstrate superiority of sinus rhythm maintenance, 13-18 but antiarrhythmic therapy is important for patients with severe symptoms. Conventional antiarrhythmic drugs have limited efficacy and safety. In fact, data suggest that the benefit of restoring and maintaining sinus rhythm in AF may be offset by significant cardiac and extracardiac side effects of currently used drugs. 19 -21 Improvement in the current approach to AF is clearly necessary. This review focuses on dronedarone, a new antiarrhythmic drug for AF suppression (Figure 1). Electrophysiological Properties of Dronedarone In Vitro ExperimentsIn vitro electrophysiological properties of dronedarone and its comparison with amiodarone are summarized in Table...

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“…10 In vitro it decreases the binding capacity to ␤-receptors and increases the dissociation rate from these receptors. 11 It inhibits the adenylate cyclase activity in a noncompetitive way. 11 In patients, amiodarone blunts the effects of isoproterenol administration.…”

Section: Discussionmentioning

confidence: 99%

“…11 It inhibits the adenylate cyclase activity in a noncompetitive way. 11 In patients, amiodarone blunts the effects of isoproterenol administration. 12 However, all these effects of amiodarone could increase the effects of a partial ␤-receptor blockade, especially the decrease in the number of receptors, by making a suboptimal dose of ␤-blocker more active.…”

Section: Discussionmentioning

confidence: 99%

Amiodarone Interaction With β-Blockers

et al. 1999

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the EMIAT and CAMIAT InvestigatorsBackground-Investigations with in vitro and animal models suggest an interaction between amiodarone and ␤-blockers.The objective of this work was to explore if an interaction with ␤-blocker treatment plays a role in the decrease of cardiac arrhythmic deaths with amiodarone in patients recovered from an acute myocardial infarction. Methods and Results-A pooled database from 2 similar randomized clinical trials, the European Amiodarone Myocardial Infarction Trial (EMIAT) and the Canadian Amiodarone Myocardial Infarction Trial (CAMIAT), was used. Four groups of post-myocardial infarction patients were defined: ␤-blockers and amiodarone used, ␤-blockers used alone, amiodarone used alone, and neither used. All analyses were done on an intention-to-treat basis. Unadjusted and adjusted relative risks for all-cause mortality, cardiac death, arrhythmic cardiac death, nonarrhythmic cardiac death, arrhythmic death, or resuscitated cardiac arrest were lower for patients receiving ␤-blockers and amiodarone than for those without ␤-blockers, with or without amiodarone. The interaction was statistically significant for cardiac death and arrhythmic death or resuscitated cardiac arrest (Pϭ0.05 and 0.03, respectively). Findings were consistent across subgroups. Conclusions-These findings are based on a post hoc analysis. However, they confirm prior results from in vitro and animal experiments suggesting an interaction between ␤-blockers and amiodarone. In practice, not only is the adjunct of amiodarone to ␤-blockers not hazardous, but ␤-blocker therapy should be continued if possible in patients in whom amiodarone is indicated. (Circulation. 1999;99:2268-2275.)

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Interaction of the antiarrhythmic agents SR 33589 and amiodarone with the β‐adrenoceptor and adenylate cyclase in rat heart

Cited by 72 publications

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Electrophysiological Effects of Dronedarone (SR33589), a Noniodinated Benzofuran Derivative, in the Rabbit Heart

Electrophysiological Effects of Dronedarone (SR33589), a Noniodinated Benzofuran Derivative, in the Rabbit Heart

Dronedarone

Amiodarone Interaction With β-Blockers

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