OBJECTIVE To explore kinetic features and its underlying mechanism of the positive inotropic effect of liguzinediol(LZDO)in rats. METHODS ①An In vivo study was made to record the effect of LZDO 20 mg · kg-1 injected for 30 consecutive min from the left external jugular vein on pressure-volume relationships. ②Ex vivo study was used to record the antagonistic effect of LZDO on reduced contractility induced by caffeine. Caffeine and LZDO were perfused as follows:normal perfusion solution, caffeine 0.5 mmol · L-1,and then caffeine 0.5 mmol · L-1+LZDO 100 μmol · L-1. ③ Ca2+ transient from cardiomyocyte sarcoplasmic reticulum (SR) was measured to analyze the effect of LZDO on Ca2 +release blocked by thapsigargin. Thapsigargin and LZDO were perfused as follows:normal perfusion solution,thapsigargin 2 μmol · L-1,and then thapsigargin 2 μmol · L-1+LZDO 100 μmol · L-1.④The SR vesicles were prepared and the effect of LZDO(1,10 and 100μmol·L-1)on sarcoplasmic reticulum Ca2+ATPase(SERCA2a)activity was determined according to the ultramicro-Ca2+-ATP enzyme kit. RESULTS ① LZDO 20 mg · kg- 1 significantly reduced the end-systolic volume (Ves) and enhanced the end-systolic pressure (Pes),stroke volume (SV),ejection fraction (EF),cardiac output(CO),peak rate of rise of left ventricular pressure(+dp/dtmax)and stroke work(SW)(P<0.05). However,LZDO 20 mg · kg-1 did not significantly change the heart rate(HR )or the end-diastolic volume (Ved). ② Caffeine 0.5 mmol · L- 1 significantly enhanced HR,left ventricular developed pressure (LVDP ),and+dp∶dtmax at 5 min after caffeine and decreased at 30 min. However,LZDO 100μmol·L-1 restored the reduced HR,LVDP,and+dp/dtmax induced by caffeine at 30 min(P<0.05).③Thapsigargin 2μmol·L-1 significantly reduced the SR Ca2+transient from perfusion solution group(100±5)%to(51± 5)%(P<0.05) and LZDO 100 μmol · L-1 failed to restore the decreased Ca2+ transient〔(49 ± 4)%〕. Normalized Ca2+transients were reduced by thapsigargin 2μmol·L-1 and thapsigargin 2μmol·L-1+LZDO 100 μmol · L-1. ④ LZDO(10 and 100 μmol · L-1)significantly increased the activities of SERCA2a in perfusion solution group 0.98±0.10 to 1.17±0.20 and (1.43±0.09)μmol Pi·g-1·h-1,respectively(P<0.05). CONCLUSION LZDO can enhance SR Ca2+ gradient by activating the SERCA2a and might be developed to serve as a potential positive inotropic agent in clinical settings.

OBJECTIVE To explore the effect and underlying mechanism of promethazine(PMZ) on proarrhythmia in guinea pigs. METHODS ① InvivoECG recordings were made to analyze effects of jugular intravenous(iv)injection of PMZ on ECG in guinea pigs. PMZ was injected in this order:3.83→7.67→15.33→38.33 mg·kg-1 cumulatively. ② In vitroECG recordings were made to analyze effects of PMZ on ECG in isolated hearts of guinea pigs. PMZ was perfused in such order:0. 1 → 1 → 10 →50 μmol·L-1 . ③ L-type Ca2+ currents from ventricular myocytes in guinea pigs were recorded to investi-gate the PMZ's blocking effect. PMZ was perfused in such order:0.1→1→10→50 μmol·L-1→washout.④ hNav1.5 and hERG currents were recorded to investigate the PMZ's blocking effects. PMZ-perfused in such order:1→3→10→30 μmol·L-1 for hNav1.5 current analysis,and 0.3→1→3→10 μmol·L-1 for hERG current analysis. RESULTS ① PMZ(15.33 mg·kg-1 )significantly prolonged QRS intervals in guinea pigs invivoECG(P﹤0.05). PMZ(38.33 mg·kg-1 )prolonged QRS,QTc,and P-R intervals but reduced the heart rate( P﹤0.05). PMZ(10 μmol·L-1 )reduced the heart rate of isolated guinea pig hearts. PMZ 50 μmol·L-1 prolonged QRS and QTc intervals and further reduced the heart rate(P﹤0.05).③ PMZ inhibited the L-type Ca2+ current from ventricular myocytes in guinea pigs in a concentration-dependent manner with the lC50 of(8.9±1.0)μmol·L-1 . ④ PMZ inhibited the hNav1.5 and hERG currents in a concentration-dependent manner with the lC50 of 6.1±1.5 and(1.6±0.2)μmol·L-1 ,respectively. CONCLUSION PMZ might cause arrhythmia at overdoses and incombination with other drugs which have potential blocking effect on /Na ,Ca2+ and /kr currents. The proarrhythmic effect of PMZ might be mediated by the blocking effect on /Na ,Ca2+ and /kr currents.

OBJECTIVE Toexploretheantagonisticeffectofadrenaline(Adr)onproarrhythmiain-duced by Chinese herbal intravenous injection of Shuanghuanglian Injection (SHL).METHODS ① In vivo ECG recording was made to analyze effects of jugular intravenous (iv)injection of SHL alone and SHL plus adrenaline on ECG in guinea pigs.SHL and/or adrenaline were injected accumulatively in this order:SHL 276 mg·kg -1→2760 mg·kg -1→adrenaline 0.0078 mg·kg -1→adrenaline 0.039 mg·kg -1 .② In vitro ECG recording was made to analyze effects of SHL and SHL plus adrenaline on ECG in isola-ted hearts of guinea pigs.SHL and/or adrenaline were perfused in this order:SHL 0.3 g·L-1→SHL 1 .5 g·L-1→SHL 1 .5 g·L-1 +Adr 0.42 mg·L-1→SHL 1 .5 g·L-1→control perfusion solution.③ Single ventricular myocyte action potential was recorded to analyze the effect of SHL alone and SHL plus adren-aline on the action potential durations at 50% (APD50 )and 90% (APD90 )repolarization levels.SHL alone was perfused in such order:SHL 0.3 g·L-1 →SHL 1 .5 g·L-1 →SHL 3 g·L-1 +adrenaline 0.83 mg·L-1 .RESULTS ①SHL (2760 mg·kg -1 )significantly reduced heart rate and prolonged QRS and QTc intervals in vivo ECG.Adrenaline (0.0078 mg·kg -1 and 0.039 mg·kg -1 )significantly amelio-rated the proarrhyth mia of SHL by shortening QTc,P-R intervals and increasing heart rate.② SHL (1 .5 g·L-1 )remarkably reduced heart rate and prolonged P-R interval in isolated guinea pig hearts in vitro.Adrenaline (0.42 mg·L-1 )significantly increased heart rate and shortened the QTc interval.③ SHL (3 g·L-1 )remarkably prolonged the APD50 and APD90.Adrenaline abolished the prolonged effectofSHLonAPD50APD90.CONCLUSION Adrenalinemightbeclinicallyusedtotreatsevere adverse drug reactions induced by SHL based on its antagonistic effect on arrhythmia.

OBJECTIVE To explore potential proarrhythmic effect and underlying mechanism of azithromycin (AZM) and Shengmai injection (SM) used clinically.METHODS ① In vivo guinea pig ECG recordings were made to analyze effects of jugular intravenous(iv) injection of AZM [38.2 mg· kg-1,one time (clinically relevant dose,CRD)],or SM (4.6 mL· kg-1,one time CRD) or their combination.②In vitro ECG recordings were made to analyze effects of AZM,SM or AZM + SM on ECG in isolated hearts of guinea pigs.AZM [one,five and ten times (clinically relevant concentrations,CRC)] was perfused in this order:41.5 →207.5 → 415 mg· L-1 and SM (one,five and ten times CRC) in this order:5 →25 →50 mL· L-1.Also,AZM (41.5 mg· L-1,one time CRC) +SM (5 mL· L-1,one time CRC) was perfused to isolated hearts of guinea pigs.③ Enzymatically isolated cardiomyocytes from guinea pig left ventricles were perfused in this order:AZM 41.5 mg· L-1 →AZM 41.5 mg· L-1+SM 5 mL· L-1 for action potential,L-type Ca2+ and Na+ current recordings,respectively.RESULTS ① Neither AZM 38.2 mg· kg-1,nor SM 4.6 mL· kg-1 significantly changed the in vivo ECG.However,AZM 38.2 mg· kg-1 +SM 4.6 mL · kg-1 significantly reduced heart rate (P＜0.05) and prolonged the P-R (P＜0.05) and QRS (P＜0.05) intervals.②AZM 41.5,207.5 and 415 mg· L-1 reduced heart rate (P＜0.05) and prolonged the P-R (P＜0.05) and QRS (P＜0.05) intervals in a concentration-dependent manner.AZM 415 mg·L-1 also prolonged QTc (P＜0.05) interval.SM 5,25 and 50 mL· L-1 reduced heart rate (P＜0.05) and prolonged the P-R interval (P＜0.05) in a concentration-dependent manner.SM had no effect on QRS or QTc intervals.Washout partially recovered the above changes.Moreover,AZM 41.5 mg· L-1 + SM 5 mg·L-1 significantly reduced heart rate (P＜0.05) and prolonged the P-R (P＜0.05) and QRS intervals.③ AZM 41.5 mg·L-1 did not significantly change the action potential amplitude (APA),action potential durations at 50％ (APD50) and 90％ (APD90) repolarization levels,or L-type Ca2+ and Na+ currents.However,AZM+SM 5 mg· L-1 significantly reduced APA (P＜0.05),shortened APD50 (P＜0.05) and APD90 (P＜0.05) and inhibited the L-type Ca2+ (P＜0.05) and Na+ (P＜0.05) currents.CONCLUSION AZM and SM has potential prorrhythmic risks.The combined use might cause higher risk of arrhythmia.The underlying mechanism for proarrhythmia is mediated by inhibition of the L-type Ca2+ and Na+ currents.