Effects Of Dipfluzine On Delayed Afterdepolarizations And Triggered Activity Of Cardiomyocytes

Dipfluzine (Dip), a novel calcium antagonist of diphenylpiperazines with similar structure to flunarizine, was first synthesized by Department of Chemistry, Beijing University. Dip, as other calcium antagonists, dilated various vascular smooth muscles. It could shorten action potential duration (APD) in guinea pig papillary muscles, reduce action potential amplitude (APA), maximal rate of depolarization in phase 0 (Vmax), velocity of diastolic (phase 4) depolarization (VDD) and rate of pacemaker firing (RPF) in sinoatrial node dominant pacemaker cells. It seems that this kind of calcium channel blockers has wide and profound effects on cardiovascular system. Moreover, the antiarrhythmic effects of this kind of calcium channel blockers have been reported in vivo or in vitro. Thus, some investigators hypothesized that this kind of calcium channel blocker might be a useful antiarrhythmic drug. Our present study was to investigate the effects of Dip on arrhythmias triggered by delayed afterdepolarizations (DADs) and triggered activity (TA). In this study, we used ouabain in guinea papillary muscles and isoprenaline (Iso) in human atrial fibers to induce DADs and TA. Then we investigatedthe antiarrhythmic effects of Dip with intracellular microelectrode techniques. The experimental projects and results were as follows.1. Effects of dipfluzine on delayed afterdepolarizations and triggered activity induced by ouabain in guinea pig papillary muscles.Aim: To investigate the effects of dipfluzine (Dip) on delayed afterdepolarizations (DADs) and triggered activity (TA) induced by ouabain and high Ca2+ in guinea pig papillary muscles.Methods: Stable and reproducible DADs and TA in guinea pig papillary muscles were induced by ouabain (1 umol-L-1) and high Ca2+ (5.4 mmol-L-1). DADs and TA were recorded using intracellular glass microelectrode technique.Results: (1) DADs and TA were markedly inhibited by pretreatment with Dip (10, 30 umol-L-1) . The amplitude and duration of DADs were reduced by Dip (30 umol-L-1) from 10.5 mV+2.2 mV and 230 ms+19 ms to 3.6 mV+0.3 mV and 152 ms+14 ms, respectively; and the induced time of DADs was prolonged from 21+5 to 66 min+11 min . TA was not observed. (2) Dip (10, 30 umol-L-1) had significant therapeutic effects on DADs and TA. The amplitude and duration of DADs were reduced by Dip (30 umol-L-1) from 10.4 mV+1.2 mV and 218 ms+22 ms to 3.3mV+0.6 mV and 159 ms+26 ms. The occurrence of TA was also abolished.Conclusion: Dip has inhibitory effects on DADs and TA induced by ouabain and high Ca2+ in guinea pig papillary muscles, which might be related to alleviation of intracellular calcium overload through inhibiting calcium channel and/or calcium release from sarcoplasmic reticulum. The effects of Dip on DADs and TA might produce antiarrhythmic effects.