The Mechanism of Atrial Antiarrhythmic Action of RSD1235

Fedida, David; Orth, Peter; Chen, Janet Y.C.; Lin, Shunping; Plouvier, Bertrand; Jung, Grace; Ezrin, Alan M.; Beatch, Gregory N.

doi:10.1111/j.1540-8167.2005.50028.x

Cited by 191 publications

(179 citation statements)

References 42 publications

(73 reference statements)

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“…Blockade of the ultrarapid delayed rectifier current I Kur (or Kv1.5) channel has been proposed as a novel target for the development of safer and potentially more effective atrial antiarrhythmic agents. 39 Four structurally distinct synthesized antiarrhythmic agents have been described as possessing I Kur block as part of their spectrum of actions: NIP-141, 40 AVE0118, 41,42 RSD1235, 43 and DPO-1. 44 The present study demonstrates that acacetin, a natural flavone I Kur blocker, also blocks I to and I KACh .…”

Section: Discussionmentioning

confidence: 99%

Acacetin, a Natural Flavone, Selectively Inhibits Human Atrial Repolarization Potassium Currents and Prevents Atrial Fibrillation in Dogs

et al. 2008

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Background-The development of atrium-selective antiarrhythmic agents is a current strategy for inhibiting atrial fibrillation (AF). The present study investigated whether the natural flavone acacetin from the traditional Chinese medicine Xuelianhua would be an atrium-selective anti-AF agent. Methods and Results-The effects of acacetin on human atrial ultrarapid delayed rectifier K ϩ current (I Kur ) and other cardiac ionic currents were studied with a whole-cell patch technique. Acacetin suppressed I Kur and the transient outward K ϩ current (IC 50 3.2 and 9.2 mol/L, respectively) and prolonged action potential duration in human atrial myocytes. The compound blocked the acetylcholine-activated K ϩ current; however, it had no effect on the Na ϩ current, L-type Ca 2ϩ current, or inward-rectifier K ϩ current in guinea pig cardiac myocytes. Although acacetin caused a weak reduction in the hERG and hKCNQ1/hKCNE1 channels stably expressed in HEK 293 cells, it did not prolong the corrected QT interval in rabbit hearts. In anesthetized dogs, acacetin (5 mg/kg) prolonged the atrial effective refractory period in both the right and left atria 1 to 4 hours after intraduodenal administration without prolongation of the corrected QT interval, whereas sotalol at 5 mg/kg prolonged both the atrial effective refractory period and the corrected QT interval. Acacetin prevented AF induction at doses of 2.5 mg/kg (50%), 5 mg/kg (85.7%), and 10 mg/kg (85.7%). Sotalol 5 mg/kg also prevented AF induction (60%). Conclusions-The present study demonstrates that the natural compound acacetin is an atrium-selective agent that prolongs the atrial effective refractory period without prolonging the corrected QT interval and effectively prevents AF in anesthetized dogs after intraduodenal administration. These results indicate that oral acacetin is a promising atrium-selective agent for the treatment of AF.

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Section: Discussionmentioning

confidence: 99%

Acacetin, a Natural Flavone, Selectively Inhibits Human Atrial Repolarization Potassium Currents and Prevents Atrial Fibrillation in Dogs

et al. 2008

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“…7,8 In animal models of AF and in a recent clinical study, vernakalant selectively prolonged the atrial refractory period without affecting ventricular refractoriness. [7][8][9] Vernakalant effectively converted acute-onset AF (AF lasting 3 to 72 hours) in a placebo-controlled phase 2 trial (nϭ56). 10 …”

Section: Clinical Perspective P 1525mentioning

confidence: 99%

Vernakalant Hydrochloride for Rapid Conversion of Atrial Fibrillation

Pratt²,

et al. 2008

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Background-The present study assessed the efficacy and safety of vernakalant hydrochloride (RSD1235), a novel compound, for the conversion of atrial fibrillation (AF). Methods and Results-Patients were randomized in a 2:1 ratio to receive vernakalant or placebo and were stratified by AF duration of 3 hours to 7 days (short duration) and 8 to 45 days (long duration). A first infusion of placebo or vernakalant (3 mg/kg) was given for 10 minutes, followed by a second infusion of placebo or vernakalant (2 mg/kg) 15 minutes later if AF was not terminated. The primary end point was conversion of AF to sinus rhythm for at least 1 minute within 90 minutes of the start of drug infusion in the short-duration AF group. A total of 336 patients were randomized and received treatment (short duration, nϭ220; long duration, nϭ116

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“…Most drugs currently in use for treatment of atrial fibrillation are indiscriminate, targeting channels in both atrial and ventricular tissue and are therefore associated with life-threatening (ventricular) arrhythmias. Vernakalant (RSD1235) is a mixed voltage-and frequencydependent Na ϩ and atria-preferred K ϩ channel blocker (Roy et al, 2004;Fedida et al, 2005) under development for the acute conversion of atrial fibrillation to sinus rhythm. In recent phase II and III clinical trials, vernakalant has shown promise as an intravenous antiarrhythmic agent for rapid conversion of atrial fibrillation to sinus rhythm with an overall rate close to 52% within 90 min of infusion, compared with a placebo conversion rate of just 3.8% (Roy et al, 2005;Pratt et al, 2006;Stiell et al, 2006;Fedida, 2007).…”

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confidence: 99%

The Molecular Basis of High-Affinity Binding of the Antiarrhythmic Compound Vernakalant (RSD1235) to Kv1.5 Channels

Eldstrom¹,

Wang²,

Xu³

et al. 2007

Mol Pharmacol

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Vernakalant (RSD1235) is an investigational drug recentlyshown to convert atrial fibrillation rapidly and safely in patients (J Am Coll Cardiol 44:2355-2361. Here, the molecular mechanisms of interaction of vernakalant with the inner pore of the Kv1.5 channel are compared with those of the class IC agent flecainide. Initial experiments showed that vernakalant blocks activated channels and vacates the inner vestibule as the channel closes, and thus mutations were made, targeting residues at the base of the selectivity filter and in S6, by drawing on studies of other Kv1.5-selective blocking agents. Block by vernakalant or flecainide of Kv1.5 wild type and mutants was assessed by whole-cell patch-clamp experiments in transiently transfected human embryonic kidney 293 cells. The mutational scan identified several highly conserved amino acids, Thr479, Thr480, Ile502, Val505, and Val508, as important residues for affecting block by both compounds. In general, mutations in S6 increased the IC 50 for block by vernakalant; I502A caused an extremely local 25-fold decrease in potency. Specific changes in the voltage-dependence of block with I502A supported the crucial role of this position. A homology model of the pore region of Kv1.5 predicted that, of these residues, only Thr479, Thr480, Val505, and Val508 are potentially accessible for direct interaction, and that mutation at additional sites studied may therefore affect block through allosteric mechanisms. For some of the mutations, the direction of changes in IC 50 were opposite for vernakalant and flecainide, highlighting differences in the forces that drive drug-channel interactions.

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The Mechanism of Atrial Antiarrhythmic Action of RSD1235

Abstract: These data suggest that RSD1235's clinical selectivity and AF conversion efficacy result from block of potassium channels combined with frequency- and voltage-dependent block of INa.

Cited by 191 publications

References 42 publications

Acacetin, a Natural Flavone, Selectively Inhibits Human Atrial Repolarization Potassium Currents and Prevents Atrial Fibrillation in Dogs

Acacetin, a Natural Flavone, Selectively Inhibits Human Atrial Repolarization Potassium Currents and Prevents Atrial Fibrillation in Dogs

Vernakalant Hydrochloride for Rapid Conversion of Atrial Fibrillation

The Molecular Basis of High-Affinity Binding of the Antiarrhythmic Compound Vernakalant (RSD1235) to Kv1.5 Channels

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