| Objective: Atrial fibrillation is the most common sustained arrhythmia encountered in primary clinical practice. According to the Framingham Heart Study, atrial fibrillation has a prevalence of 4 percent in the adult population. As the patient population continues to age, the prevalence of this arrhythmia rises as well, from less than 0.05 percent in patients 25 to 35 years of age to more than 5 percent in patients over 69 years of age. Atrial fibrillation is associated with significant morbidity, including an increased susceptibility to embolic stroke. It is estimated that the annual risk of stroke in patients with atrial fibrillation is as high as 4.5 percent. Atrial fibrillation also can decrease exercise tolerance and has been associated with tachycardia-induced cardiomyopathy. Electrical cardioversion of atrial fibrillation can be ineffective in several cases (long-lasting atrial fibrillation, large atria, advanced age, underlying diseased, high transthoracic impedance). Electrial cardioversion of atrial fibrillation will unsucceed in 20 percent patients, atrial fibrillation will recur in a few minutes after restoration sinus rhythm. It is important for pharmacological cardioversion of atrial fibrillation because it can improve exercise tolerance and decrease morbidity of embolic stroke. The CAST Test has documented that certain Class I drugs may increase mortality in postinfarction patients, during the past 10 years there has been a major shift in antiarrhythmic drug development from class I to III antiarrhythmic agents. Ibutilide fumarate is a new class III intravenous antiarrhythmic agent indicated for the acute termination of atrial fibrillation and flutter and is the most important antiarrhythmic drug. The studies demonstrated ibutilide can block the outward K+ current of repolarization, enhance the inward current of plateau duration(including the slow Na+ current and the calcium current), prolong APD and ERP and terminate excitable reentry. The study of ibutilide focus on the potassium current, the calcium current and the slow Na+ current. there is no study about the fast Na+ current. Though the test has demonstrated that after the addition of TTX there was no shortening of APD or ERP compared to treatment with ibutilide alone, it can not explain ibutilide has no effect on the fast Na+ current . To explore the cellular basis of the ibutilide's effect on atrial fibrillation and atrial flutter, the fast Na+ current from rabbit atrial cells was recorded by using patch clamp techniques in the whole-cell configuration with or without ibutilide.Material and methods1 Experimental animals: Forty healthy rabbits (Newsland pure white, come from Hebei medical university) of either sex weighing 1.5 to 2 kg were used in the study. The rabbits were divided into four groups: (1)Ten rabbits that had not underwent ibutilide were defined as control group(Con). (2) Ten rabbits were used in 10-7mol/L concentration of ibutilide(10-7). (3) Ten rabbits were used in 10-6mol/L concentration of ibutilide(10-6).(4) Ten rabbits were used in 10-5mol/L concentration of ibutilide(10-5).2 Cell isolation: Single atrial myocytes from atrial tissue were enzymatically dissociated and isolated.3 Current recording and data analysis: The INa was recorded by means of patch clamp whole-cell recording techniques under voltage clamp. The INa currents in cells from the group of undergone ibutilide in the different concentration were compared with cells in the control group. The experiments were performed at room temperature(20~25℃). The data were expressed as means±SD, statistical analysis was performed using one-way analysis of variance(ANOVA)with SPSS 10.0 software package to test for the significance of the effects of ibutilide on the sodium ion channel activity and kinetics. A value of p<0.05 was considered significant.Results1 The INa current density-voltage relationship (I-V) curves and activation curves were voltage-dependent and showed as"V"type current properties. They were activated at–70mV, reached the maximum at–20mV and reversed at +50mV. Peak INa current density (at–20mV) was significantly reduced in ibutilide(10-7)(–68.82±4.43pA/pF, n=14 cells) , ibutilide(10-6) (–45.26±3.46pA/pF, n=11 cells) and ibutilide(10-5) (–33.46±3.11pA/pF, n=11 cells) , the three concentration ibutilide groups compared with that in Con (–87.12±4.67pA/pF,n=12 cells) , P<0.05. This was not accompanied by a shift in the current density-voltage relationship configuration and did not change their active, peak and reverse potentials.2 The steady-state inactivation curves INa were voltage-dependent and showed as"reversed S"type. The INa steady-state inactivation curves showed that the membrane potentials for half-maximal inactivation (V0.5) were shifted markedly in the hyperpolarizing direction (that is, to more negative potentials) in ibutilide(10-7) (–92.7±4.2mV, n=11 cells), ibutilide(10-6) (–103.3±4.5mV, n=10 cells) ,and ibutilide(10-5) (–115.1±4.6 mV, n=11 cells)compared with Con (–78.6±4.1mV, n=10 cells), P<0.01 , P<0.05 and P<0.05 ,respectively. 3 The rate of recovery from inactivation of INa were significant slower in three concentration of ibutilide(10-7,10-6,10-5) with that in Con, P<0.05 ,P<0.01, P<0.001,respectively.Conclusions1 The study indicated that INa in different concentration ibutilide groups were significant suppressed , which showed as reduction of INa current density, shift in hyperpolarization direction of steady-state INa inactivation curves , and slow INa recovery rate from inactivation. These changes may underlie the altered electrical activity (decrease in the velocity and amplitude of pase 0 of action potential) and abnormal transmembrane action potentials contributing to terminate atrial arrhythmias.2 The study indicated that the effect of ibutilide on the sodium ion channel activity and kinetics was concentration-dependent, which may underlie electrical activity.3 The usefulness of ibutilide to inhibit atrial arrhythmias may depend on the suppression the fast sodium ion channel in phase 0 of action potential.
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