Anti-arrhythmic Effects Of Taurine-magnesium Coordination Compound (TMCC) On Models Of Long QT Syndrome And Short QT Syndrome

Aim: In this study,the anti-arrhythmic effects of Taurine-Magnesium Coordination Compound(TMCC)were assessed on different models of Type 2 short QT syndrome(SQT2)and long QT syndrome(LQTS).From the levels of isolated heart,cell channel current and channel protein,respectively,to explore its mechanisms of anti-arrhythmic.Methods: Pinacidil(20 μM)/chromanol 293B(5 μM)+ low K+ was used to mimic the SQT2/LQTS model respectively in Langendorff guinea pig-perfused heart.Trapidil(1 m M)/chromanol 293B(5 μM)was used to establish the SQT2/LQTS model in guinea pig ventricular myocytes and to stimulate/inhibit HEK293 cells stably expressing IKs channels.All cells were incubated for 24 h in the absence and presence of drugs.The IKs current and action potentials were recorded by using the whole-cell patch-clamp technique.The western blot analysis was used to study the effects of TMCC on the KCNQ1/KCNE1 protein expression.Results: 1.TMCC(1,2,4,and 8 m M)significantly increased the RR interval,slowed the heart rate,and showed a concentration-dependent(P <0.01 vs.control);significantly prolonged QT interval(P <0.01 vs.control).TMCC had no effect on Tp-Te and r Tp-Te,and increased in i CEB(P <0.05 vs.control)in a concentration-dependent manner.2.TMCC(0.01,0.1,and 1 m M)could increase the RMP value,and significantly reduce the action potential repolarization 50% and 90% of the time(APD50,APD90)(all P <0.05 vs.control).3.The IKs I-V curve was shifted-down by TMCC(0.01,0.1,and 1 m M).TMCC decreased the peak of IKs by 27.99%,48.18% and 60.13%,respectively,(n = 7,P <0.05 vs.control),which was dose-dependent(IC50 = 201.1 μM).4.TMCC(0.01,0.1 m M)turned the IKs steady-state activation curve to left.5.24 h was the best incubation time.6.TMCC(0.1 mM)could increase KCNQ1/KCNE1 protein trafficking significantly.7.Pinacidil significantly shortened the QT interval and QTpeak,and increased r Tp-Te(P < 0.05 vs.control).Subsequently,TMCC perfusion significantly increased QT interval and QTpeak(P < 0.01 vs.pinacidil).TMCC also reversed the r Tp-Te value to the normal range.8.Pinacidil significantly increased total instability of RR interval(TIRR),short-term instability of RR interval(STIRR),total instability of QT interval(TIQT),and short-term instability of QT interval(STIQT)(all P < 0.05 vs.control).All of these could be reversed to the normal range by TMCC(1,2,and 4 m M)(P < 0.05 vs.pinacidil),except that TMCC(1 m M)did not affect STIRR and TIQT(P > 0.05).9.Trapidil shortened the action potential duration at 50%(APD50)and 90% repolarization(APD90),which could be extended by TMCC(P < 0.05 vs.trapidil).The increasing effect of trapidil on IKs expression was inhibited by TMCC.10.Chromanol 293B(5 μM)+ low K+ solution significantly increased Tp-Te and r Tp-Te by 72.09% and 69.20%,respectively(all P < 0.01 vs.control).Tp-Te was increased by 14.60%,48.85% and 54.20% respectively after TMCC(1,2,and 4 m M)perfused,and the medium and high concentration group and normal perfusion KH solution(P < 0.05 vs.control).The r Tp-Te was increased by 8.05%,28.47% and 26.36%,respectively,and there was no statistically significant difference(P < 0.05 vs.control)with normal perfusion of K-H solution.11.The incidence of Td P in the LQTS model group was 85.71%,TMCC(1,2,and 4 m M)decreased the probability to 71.42%,14.28%,and 0%,respectively.12.TIRR,STIRR,LTIRR,TIQT,STIQT,and LTIQT could be significantly increased by chromanol 293B(5 μM)+ Low K+(all P <0.05 vs.control).After co-infusion of 1,2,and 4 m M TMCC,although the above indexes were different from normal perfusion before administration,TMCC(1,2,and 4 m M)could significantly reduce RR and QT instability.13.Chromanol 293 B significantly prolonged APD50 and APD90(P <0.01 vs.pre-chromanol 293 B,n = 6).TMCC could attenuate the effect of chromanol 293 B on prolongation APD50 and APD90,which could be reversed to the normal range by TMCC(100,1 m M).14.TMCC(0.01,0.1,and 1 m M)were concentration-dependently against the effect of chromanol 293 B on IKs current inhibition,respectively weakened by 5.56 ± 2.54%,9.22 ± 1.07%,and 10.48 ± 2.31%.15.The IKs I-V curve was shifted downwards by chromanol 293B(5 μM),while upwards by TMCC.to move down to show the effect of inhibiting IKs.After incubation with TMCC(0.01,0.1,and 1 m M)could restore the decrease of peak IKs due to chromanol 293 B.Conclusion: 1.TMCC can slow down heart rate,prolong the QT/QTc duration and effective refractory period,and inhibit IKs current.It was suggested that TMCC may influence ventricular repolarization,and have a certain anti-arrhythmic effect.2.TMCC treatment may have beneficial effects by reducing the repolarization period and inhibiting repolarizing current-IKs.These results suggested TMCC as a reasonable therapeutic option for ventricular arrhythmia in SQT2.3.TMCC reduced the incidence of Td P by reducing the instabilition of RR and QT interval,shortening the action potential duration,and increasing the inhibited IKs current.It was suggested that TMCC have anti-arrhythmic effect on LQTS.4.TMCC could increase the expression of KCNQ1/KCNE1 protein.