Comparison of the effects ofI_K,ACh,I_Kr, andI_Nablock in conscious dogs with atrial fibrillation and on action potentials in remodeled atrial trabeculae

Abstract

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of morbidity and mortality. Traditional antiarrhythmic agents used for restoration of sinus rhythm have limited efficacy in long-term AF and they may possess ventricular proarrhythmic adverse effects, especially in patients with structural heart disease. The acetylcholine receptor-activated potassium channel (I) represents an atrial selective target for future AF management. We investigated the effects of the I blocker tertiapin-Q (TQ), a derivative of the honeybee toxin tertiapin, on chronic atrial tachypacing-induced AF in conscious dogs, without the influence of anesthetics that modulate a number of cardiac ion channels. Action potentials (APs) were recorded from right atrial trabeculae isolated from dogs with AF. TQ significantly and dose-dependently reduced AF incidence and AF episode duration, prolonged atrial effective refractory period, and prolonged AP duration. The reference drugs propafenone and dofetilide, both used in the clinical management of AF, exerted similar effects against AF in vivo. Dofetilide prolonged atrial AP duration, whereas propafenone increased atrial conduction time. TQ and propafenone did not affect the QT interval, whereas dofetilide prolonged the QT interval. Our results show that inhibition of I may represent a novel, atrial-specific target for the management of AF in chronic AF.

Antiarrhythmic and cardiac electrophysiological effects of SZV-270, a novel compound with combined Class I/B and Class III effects, in rabbits and dogs

“…The effects of SZV-270 on AF in this model were comparable to those of the selective I Kr blocker dofetilide, which is known as an effective compound for rhythm control in AF (Kirchhof 2016;Piccini and Fauchier 2016). Dofetilide also reduced AF incidence and increased AERP in the present study, and was shown to prolong atrial APD in atrial trabeculae isolated from dogs with chronic tachypacing induced atrial remodeling (Juhász et al, 2018).…”

“…The pH of the solution was set between 7.35 and 7.4 when saturated with the mixture of 95% oxygen and 5% CO 2 at 37 ºC. Isolated right atrial trabeculae were obtained, individually mounted in a tissue chamber and stimulated as decribed previously (Juhász et al, 2018). The maximal rate of depolarization (V max ), maximum diastolic potential, action potential amplitude, and action potential duration measured at 90% of repolarization (APD 90 ) were evaluated off-line, applying stimulation with a constant basic cycle length (BCL) of 500 ms.…”

Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior

“…It is difficult to measure I Kr and I Ks in atrial myocytes, most likely because of the cell isolation techniques (252). Regardless of that, I Kr block significantly lengthens atrial repolarization, in both animal and human studies (558,559). On the other hand, the role of I Ks in atria is not well explored.…”

“…Based on this finding, K ir 3 subunits were speculated to be involved as the channel background of this current, and it was suggested that it may play a significant role in atrial pathophysiology (579). This current, I K, ACh , was enhanced in a conscious tachypaced dog AF model, and its inhibition by tertiapin-Q resulted in a marked reduction in the incidence of AF episodes (558).…”

New Strategies for the Treatment of Atrial Fibrillation

“…However, our recent study questioned this hypothesis. In an experimentally induced tachypaced dog model of permanent AF (ATR) we have revealed that the real amplitude of I KA,Ch_Const does not seem to be large enough to contribute substantially to the shortening of APD and thus to the shortening of atrial ERP [ 13 , 123 , 124 ]. Therefore, we have proposed the following new concept [ 13 ]: under physiological condition, in vivo, “background” vagal stimulation is always present, thereby it is probable that the acetylcholine-activated potassium channels are active in atrial myocytes either in SR or in AF.…”