Electrophysiologic Effects of an Antiarrhythmic Agent, Bidisomide, on Sodium Current in Isolated Rat Ventricular Myocytes: Comparison With Mexiletine and Disopyramide

Abstract

ABSTRACT-The effects of bidisomide, an antiarrhythmic agent, on sodium current (INa) in isolated rat ventricular myocytes were investigated using a whole cell voltage clamp method. Bidisomide blocked INa with a Ki of 214 mM at a holding potential of -140 mV. The blockade of INa was enhanced at a less negative holding potential of -100 mV with a Ki of 21 mM. Bidisomide shifted the steady state inactivation curve to a negative potential direction by 20 mV without a significant change in the slope factor. Bidisomide slowed the time course of recovery of INa at a holding potential of -140 mV with a slow recovery phase. The time constant of recovery phase for bidisomide, disopyramide and mexiletine were 2703, 1858 and 757 ms, respectively. The development of the block of INa consisted of two phases in the presence of bidisomide. The fast and slow time constants were 11 and 648 ms. Bidisomide produced a use-dependent block of INa when the depolarizing pulse was repeated at 1 -3 Hz. Our results indicate that bidisomide binds to rat cardiac sodium channels and that the dissociation kinetics of bidisomide from the inactivated sodium channel is slower than that of disopyramide.Keywords: Bidisomide, Sodium current, Cardiac myocyte An antiarrhythmic agent, bidisomide, (±)-a-{2-[acetyl(1-methylethyl)amino]ethyl}-a-(2-chlorophenyl)-1-piperidinebutanamide, was developed as an analogue of disopyramide, a class I antiarrhythmic drug. The pyridyl residue of disopyramide was replaced with a pyperidine residue in bidisomide and a halogen (chloride) was introduced to the ortho position of the benzene ring. These chemical changes produced a beneficial property; i.e., little side effect on the cardiovascular profile because of the weak negative inotropic effect and the low anticholinergic effect (1, 2). Although disopyramide is an established and widely-used class I antiarrhythmic agent, congestive heart failure and/or anticholinergic actions, such as urinary retention, dry mouth and constipation, are its side effects, which limited the clinical efficacy of disopyramide. When the negative inotropic effect was assessed in anesthetized dogs, bidisomide showed less decrease in the maximum left ventricular dP/ dt than disopyramide (2, 3). Binding studies using the muscarinic radioligand [3 H]-quinuclidinylbenzylate also showed that the affinity of bidisomide to the muscarinic receptor is twenty-fourfold less than that of disopyramide (2 -4).Bidisomide has been shown to be effective on both supraventricular (5 -7) and ventricular arrhythmias (1, 6, 8 -10). Although the CAST study revealed the danger of continuous use of class I antiarrhythmic drugs for patients with post-myocardial infarction with or without pumping dysfunction (11), class I drugs are still useful in eliminating ventricular and other serious arrhythmias, so the development of some sodium channel blockers without side effects is of pharmaceutical interest.A previous experiment using guinea pig papillary muscles revealed that bidisomide decreased the maximum upstroke veloci...

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