Inhibitory Effects Of Isoquinoline Alkaloids SIPI409 On Experimental Arrhythmias

The effects of SIPI409 on functional refractory period(FRP)in isolated guinea pig papillary muscles and left atrium were studied using paired stimulation technique. We also recorded the effect of SIPI409 on the contraction force and the contraction frequency of left atrium.FRP was extended by SIPI409 dose-dependently(1,3,10,30 to 100μM)(P<0.01) in isolated left ventricular papillary muscles and left atrium. In left atrium,SIPI4091μM extend FRP (P<0.05),and SIPI409 in 3,10,30and 100μM can significantly extend FRP (P<0.01) significantly.Left atrium contraction force, left ventricular papillary muscle contraction force and the heart rate were shortened by SIPI409 dose-dependently (P<0.01) significantly. The heart rate was shortened in 1μM (P<0.05),and significantly shortened in 3,10,30 and 100μM of SIPI409 (P<0.01). The effects of SIPI409 on myocardial ischemia-reperfusion induced arrhythmia in rats were studied using coronary artery ligation reperfusion technique.Arrhythmia occurrenced in normal saline group with arrhythmia score of 5.33±0.22 ten minutes after coronary artery ligation reperfusion. The scores of SIPI409 2.5mg/kg, 5mg/kg, 10mg/kg groups were 1±0.58, 2.2±0.96, 0, and amiodarone 2.5mg/kg group was 2±0.55.SIPI409 could reduce heart rate (HR) dose-dependently, the 5mg/kg and 10mg/kg group decreased HR (P<0.01) obviously in ligation and ligation 10min. That indicates that SIPI409 has antiarrhythmic effect.Constant speed syringe was used to constant infusion ouabain, and then SIPI409 was injected by intravenous. The effects of SIPI409 on cardiac rhythm were observed.The dosage of ouabain that could induce arrhythmia in guinea pigs for ventricular tachycardia(VT),ventricular fibrillation(VF)and ventricular premature(VP),for VP was 191.25±44.78μg/kg,for VF was 248.01±50.93μg/kg and for VT was 199.54±47.83μg/kg in SIPI409 group,was significantly different(P<0.01) in SIPI409 group compared with the control group. Significant difference(P<0.01) was also observed between saline group and SIPI409 group. The effects of SIPI409 on QTc and HR on guinea pigs papillary were studied using RM6240 system.QTc was extended and HR was shortened by SIPI409 concentration dependently in guinea pigs (P<0.01). With increasing concentration from 2.5mg/kg,5mg/kg to 10mg/kg,SIPI409 could significantly prolong FRP and shorten HR. The fact that the SIPI409 10mg/kg group and amiodarone 10mg/kg group, sotalol 10mg/kg group do not have significant differences indicates that the doses of SIPI409 at10mg/kg is safe.Conclusion:1. SIPI409 can prolong FRP in papillary muscle and atrium in vitro. In the left atrium contraction force,left ventricular papillary muscle contraction force and the heart rate were shortened by SIPI409.2. SIPI409 can reduce coronary artery ligation reperfusion in rat VE frequently, reduce the incidence of VT and VF; meanwhile SIPI409 can increase the dose of ouabain which can induced VE, VT, VF.3.In normal guinea pigs, SIPI409 can prolong its QTc and shorten HR.