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02 July 2004

Atrial-selective antiarrhythmic actions of novel Ikur vs. Ikr, Iks, and IKAch class Ic drugs and beta blockers in pigs

Karsten Knobloch, Joachim Brendel, Björn Rosenstein, Markus Bleich, Andreas E. Busch, Klaus J. Wirth

Med Sci Monit 2004; 10(7): BR221-228 :: ID: 11700

Abstract

Background:The Kv1.5 channel, underlying I[sub]Kur[/sub], is supposed to be atrial selective in pigs and humans. We investigated the effects of different potassium channel blockers, i.e. the IKur blockers AVE 0118, S9947 and S20951, with amiodarone (AM), dofetilide (DO), azimilide (AZ), ibutilide (IB), the I[sub]Ks[/sub] blocker HMR 1556, atropine (ATR), flecainide (FL), propafenone (PR), d,l-sotalol (SO), atenolol (ATE), and esmolol (ES), on the left and right atrial and ventricular refractoriness and left atrial vulnerability (LAV) in vivo in pigs.Material/Methods:In pentobarbital-anesthetized pigs (n=81), atrial and ventricular effective refractory periods (ERPs) were measured with the S1-S2-extrastimulus-method and QTc time from electrocardiograms. LAV was assessed after S2-extrastimulus to the left atrium.Results:All I[sub]Kur[/sub] blockers prolonged left stronger than right atrial ERP and did not change QTc. All I[sub]Kr[/sub] blockers predominantly prolonged the right vs. left atria. AM prolonged both atria equally, and ATR the left only. Pure beta blockers acted predominantly on the left atrium, as did FL and PR, while d,l-sotalol acted predominantly on the right. AVE 0118, S9947, S20951, ibutilide, and d,l-sotalol significantly decreased LAV (–100%, –100%, –82%, –53%, –42%; p<0.05), in contrast to all other drugs.
Conclusions: The IKur blockers exhibited stronger effects on the left atrium, which itself has shorter refractoriness, but strikingly with no effect on ventricular repolarization, while IKr blockers, IKs blockers, and d,l-sotalol exerted predominantly right atrial effects and known ventricular effects. IKur blockers inhibited atrial tachyarrhythmias stronger than all available drugs. Therefore, IKur blockers seem to be promising new atrial-selective antiarrhythmic drugs.

Keywords: Piperazines - pharmacology, Adrenergic beta-Antagonists - pharmacology, Amiodarone - pharmacology, Anti-Arrhythmia Agents - pharmacology, Atrial Function - physiology, Atropine - pharmacology, Biphenyl Compounds - pharmacology, Chromans - pharmacology, Flecainide - pharmacology, Heart Atria - drug effects, Imidazoles - pharmacology, Imidazolidines, Phenethylamines - pharmacology, Piperazines - pharmacology, Potassium Channel Blockers - pharmacology, Potassium Channels - physiology, Propafenone - pharmacology, Propanolamines - pharmacology, Sotalol - pharmacology, Sulfonamides - pharmacology, Swine, Ventricular Function - physiology

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