| Background and objectiveIonic channel currents in cardiomyocytes are important basis of action potential. The ionic events underlying abnormal automaticity, excitability, conduction, and refractoriness are fundamental mechanisms of cardiac arrhythmias. Meanwhile, most of the antiarrhythmic drugs act on one or more cardiac myocytes ionic channels. The last two decades have seen a rapid growth in our understanding of cardiac electrophysiological events with the development of patch-clamp technique. The studies of the mechanisms of arrhythmogenesis and the action of antiarrhythmic drugs have already focused on the events of ionic channel currents in isolated single heart cells.Carvedilol is a multiple action cardiovascular drug with blocking effects on a 1 and β1,22 receptors.In a number of clinical trials with patients sufferingfrom congestive heart failure, hypertention, and angina pectoris, carvedilol seems to be superior to other β -blocking agents. But the antiarrhythmic effects of carvedilol and its mechanisms remain unclear. Magnesium sulfate is belong to none of the four categery antiarrhythmic drugs. But it has been shown to be effective in various arrhythmias. The mechanisms of its antiarrhythmic effect also remain unclear.In this study, two arrhythmic animal models were set: inhalation of chloroform to induce ventricular fibrillation(VF) in mice; aconitine-induced arrhythmias in rats. The aim was to evaluate the antiarrhythmic effects of carvedilol and magnesium sulfate. In addition, the influences of different concentrations of carvedilol and magnesium sulfate on transmembrane ionic channel currents in isolated ventricular myocytes, including sodium current(lNa), L-type calcium current(Ica,L), transient outward potassium cerrent(Ito), and inward rectifier potasium current(IK1), were observed. Thereby the antiarrhythmic mechanisms of carvedilol and magnesium sulfate related to ionic channel currents may be disclosed. This can provide theoretical testimony for clinical prevention of cardiac arrhythmias of carvedilol and magnesium sulfate.Methods and results:Part I : 1 .Antiarrhythmic effects of carvedilol and magnesium sulfate on chloroform induced VF in mice: To inject equivalent saline (control group), carvedilol 1mg/kg (carvedilol group), magnesium sulfate 0.1g/kg (magnesium sulfate group) from mice caudal vein. The mice inhalated chloroform to induce VF. Carvedilol significantly reduced the incidence of VF in mice [22.22%(4/18) vs 88.89%(16/18),P<0.05]; Magnesium sulfate also significantly reduced theincidence of VF in mice [38.89%(7/18) vs 88.89%(16/18),P<0.05]. 2. Antiarrhythmic effects of carvedilol and magnesium sulfate on aconitine-induced arrhythmias in rats: To inject equivalent saline (control group), carvedilol 1mg/kg (carvedilol group), magnesium sulfate 0.1g/kg (magnesium sulfate group) from rats caudal vein. To inject aconitine, concentration of 0.001%, at speed of 5 μ g/min, from rat caudal vein. The doses of aconitine to produce premature ventricular contractions (PVCs), ventricular tachycardia (VT), ventricular fibrillation(VF),and cardiac arrest(CA) were(μg): 31.81 ± 2.04,36.06±3.79,64.13±1,40,84.65±5.25, respectively, in carvedilol group; and 33.23±1.56,45.00±3.01,72.40±1.39,90.73±0.31, respectively, in magnesium sulfate group. The doses of aconitine to produce various arrhythmias were significantly increased in carvedilol group and magnesium sulfate group vs control group(P<0.05 or P<0.01).Part II: Single ventricular myocytes of rats were isolated by perfusing the hearts with collagenase on a Langendorff perfusion apparatus. The effects of carvedilol on ionic channel currents of ventricular cardiomyocytes were investigated by using whole-cell patch-clamp technique. Results: 1.Different concentrations of carvedilol significantly reduced the maximum current peak and current density of INa, ICa,L, and Ito (P<0.05 or P<0.01 vs control group). Carvedilol also reduced the current peak at different depolarizing potentials, and voltage-current (I-...
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