Effects Of Ibutilide On IKr Of Human Atrial Myocytes In Atrial Fibrillation

ObjectiveAtrial fibrillation(AF)is one of the most common arrhythmia encountered in clinical practice,while its prevalence is continuously increasing during the past few decades mainly due to aging of the population and improved survival of patients with other cardiovascular diseases.Since AF is independently associated with increased cardiovascular morbidity and mortality,it unequivocally represents a major public health problem.Actively exploring the mechanism of the AF,searching for the safe and effective medicine have become hot spots in today's research.It has long been known that AF has a propensity to become sustained over time.Compelling evidence is accumulating that AF's development and perpetuation depend on the change of the electrophysiology and structure in the atrium.The change of structure refers to abnormalities in atrial architecture such as atrial dilatation,fibrosis,apoptotic phenomena and others.The change of electrophysiology refers to changes such as effective refractory period(ERP)shortening,prolongation of conduction and so on.In their seminal study,Wijffels et al.were the first to demonstrate in animal experimental that AF provokes structural and functional alterations in atria that favour perpetuation of the arrhythmia.The underlying pathophysiological mechanism was named 'remodeling' indicating the development of the electrophysiology and structure change that promotes the maintenance and reoccurrence of AF.Rapidly activiting delayed rectifier potassium current(IKr)plays a dominant role in the repolarization of cardiac action potential,it has close relation to the cardiac action potential duration(APD)and ERP.The molecular biology of IKr contribute to cardiac electrophysiological properties, its electrical remodeling influences the APD and ERP which the occurrence and development of AF probability depends on.The blockers of IKr(III antiarrythmic agents)have recently been the focus of the clinical study and treatment of AF.Ibutilide, as a newer classⅢantiarrythmic agent,is effective in the atrial and ventricular arrhythmias.Because of species differences,it plays an important role in clinic works to study on ionic channel currents in human cells directly.The purpose of this study was to investigate the characterizations of IKr in single human atrial myocyte with AF and to observe the regulations of Ibutilide on this current by using the patch clamp whole cell recording techniques.Thus,it leads to the understanding of the underlying mechanisms of AF's occurrence and development,which provide experimental basis for development and application of new antiarrhythmic drugs and theoretical foundation for clinical doctors.MethodsSpecimens of human right atrial appendage were obtained from patients undergoing cardiopulmonary bypass.We used the method of enzymatic dispersion to get single rod-shaped,calcium-tolerant atrial cells for electrophysiology study.The specimen was divided into normal group and the atrial fibrillation group.Whole-cell pacth-clamp recording,voltage-clamp record the IKr current,current-clamp record the APD.Observe the effects of the different concentration of Ibutilide on the the IKr and APD in AF.Single cell as the statistical element,the data were assessed with t test and expressed as means±standard deviation(X~－±SD)with SPSS 13.0 software package.A value of P＜0.05 was considered significant.ResultsCompared with normal sinus rhythm group,atrial fibrillation group in patients with smaller IKr-channel current density and shorter APD.Ibutilide reduced IKr current density and the tail current density concentration-dependent in both normal group and AF group,Ibutilide prolonged the atrial APD concentration-dependent in both normal group and AF group.ConclusionElectrical remodeling after AF shorten the APD and ERP,which increased the susceptibility to AF and promoted the maintenance of AF.Electrical remodeling of IKr after AF extended APD and ERP in human atrial myocytes,which are probably a self-regulation and protection mechanisms after AF.Ibutilide can effectively block the IKr channel to improve the APD and ERP in human atrial myocytes,so as to get a effectively reversal and treatment of AF.