| Objective:To investigate the effect of mallotoxin(MTX) on action potential of isolated guinea pig ventricular myocytes, electrocardiogram and myocardial contractility of isolated guinea pig hearts in the absence and presence of hERG channel blocker E-4031, which hope to describe a primary research on its characteristic of anti-arrhythmia and proarrhythmia.Methods:1. Single ventricular myocyte was isolated from guinea pig heart by enzymatic dissociation. Effects of mallotoxin on action potential duration in the absence and presence of hERG channel blocker E-4031 were recorded by current clamp mode using whole patch clamp technique.2. The isolated guinea pig heart was retrograde perfused by using Langendorff technique. In order to derermine the effects of mallotoxin on heart rate, QT/QTc interval, transmural dispersion, instability of RR interval and instability of QT interval in the absence and presence of hERG channel blocker E-4031, INa, L channel activator DPI 201-106 as well as E-4031(under low K+ concentration), the electrocardiogram of isolated guinea pig hearts was recorded by using Biopac physiological recorder.3. The isolated guinea pig heart was retrograde perfused by using Langendorff technique. Effects of mallotoxin on left ventricular systolic pressure(LVSP), peak rate of rise of left ventricular pressure(+dp/dtmax) and left ventricular end diastolic pressure(LVEDP) of isolated guinea pig hearts in the absence and presence of INa, L channel activator DPI 201-106 were recorded by inserting the baroreceptor to left ventricular.Results:1. Results of the action potential measurement in single guinea pig ventricular myocyte show that, compared with the control group, 0.2, 0.4 and 0.6 ?mol·L-1mallotoxin shortened action potential duration in a concentration dependent way.With 0.2, 0.4 and 0.6 ?mol·L-1 mallotoxin, APD90 were decreased from 227.18±10.13ms to 210.82±8.31 ms(n=5, p>0.05), 189.29±9.52 ms(n=5, p<0.01) and 173.93±6.72ms(n=5, p<0.01); APD60 were decreased from 220.03±9.41 ms to 203.65±10.24 ms(n=5, p<0.05), 181.78±10.51 ms(n=5, p<0.05) and 166.15±7.35 ms(n=5, p<0.01);APD30 were decreased from 200.03±10.52 ms to 183.45±8.13 ms(n=5, p<0.05),156.12±9.21 ms(n=5, p<0.01) and 136.87±7.24 ms(n=5, p<0.01). In a given time,mallotoxin could induced triangulation of action potential, APD90-30 were increased from 27.19±10.13 ms to 27.37±8.25 ms(n=5, p>0.05), 33.17±9.31 ms(n=5, p<0.05)and 37.06±7.30 ms(n=5, p<0.05).2. Results of the action potential measurement in single guinea pig ventricular myocyte show that, compared with the control group, APD90 was increased from202.67±8.32 ms to 233.95±7.81 ms(n=5, p<0.01) by 10 nmol·L-1 E-4031, then the prolonged APD90 could be decreased to 218.07±9.23 ms(n=5, p<0.05), 204.73±9.51ms(n=5, p<0.01) and 187.31±8.82 ms(n=5, p<0.01) by 0.2, 0.4 and 0.6 ?mol·L-1mallotoxin; compared with the control group, APD90 was increased from 206.39±8.57 ms to 223.94±9.33 ms(n=5, p<0.05) by 0.5 ?mol·L-1 DPI 201-106, then the prolonged APD90 could be decreased to 196.74±7.92 ms(n=5, p<0.01) by 0.4?mol·L-1 mallotoxin. Compared with 10 nmol·L-1 E-4031, instability of repolarization was significant increased by 2 ?mol·L-1 E-4031, short-term instability of APD90 was increased from 8.02±1.26 ms to 130.07±20.61 ms(n=5, p<0.01), then the data could be decreased to 2.92±0.83 ms(n=5, p<0.01) by 0.4 ?mol·L-1 mallotoxin.3. Results of the electrocardiogram measurement in isolated guinea pig hearts show that, compared with the control group, with 0.2, 0.4 and 0.6 ?mol·L-1mallotoxin, QT interval were shortened from 175.47±13.99 ms to 160.23±17.33 ms(n=6, p<0.05), 140.97±12.75 ms(n=6, p<0.01) and 133.73±14.40 ms(n=6, p<0.01);heart rate which turned from 218.73±19.81 beats/min to 224.43±13.14 beats/min(n=6,p>0.05), 219.11±21.88 beats/min(n=6, p>0.05) and 214.35±13.97 beats/min(n=6,p>0.05) were not influenced; the transmural dispersion were decreased from45.39±9.61 ms to 39.43±6.38 ms(n=6, p>0.05), 26.53±7.63 ms(n=6, p<0.01) and35.27±10.44 ms(n=6, p<0.05); instability of RR and QT interval were increased by0.8 ?mol·L-1 mallotoxin.4. Results of the electrocardiogram measurement in isolated guinea pig hearts show that, compared with the control group, with 10 nmol·L-1 E-4031, QT interval was prolonged from 184.46±13.19 ms to 223.22±22.53 ms(n=6, p<0.01); the transmural dispersion was increased from 50.80±8.26 ms to 68.61±13.62 ms(n=6,p<0.01). Then, with 0.2, 0.4 and 0.6 ?mol·L-1 mallotoxin, the prolonged QT interval could be shortened to 217.40±19.25 ms(n=6, p>0.05), 190.63±28.73 ms(n=6, p<0.01)and 157.77±11.57 ms(n=6, p<0.01); the increased transmural dispersion could be decreased to 53.67±11.31 ms(n=6, p<0.05), 55.50±17.38 ms(n=6, p<0.05) and33.97±9.10 ms(n=6, p<0.01).5. Results of the electrocardiogram measurement in isolated guinea pig hearts show that, compared with the control group, under low K+ concentration(2 mmol·L-1)and 10 nmol·L-1 E-4031, QT interval was much more prolonged, which changed from196.80±9.37 ms to 243.27±9.19 ms(n=5, p<0.01); the transmural dispersion was increased from 59.60±11.76 ms to 120.73±3.87 ms(n=5, p<0.01), which increased by nearly 103%; the short-term instability of RR interval(STIRR) was increased from0.98±0.41 ms to 45.63±15.31 ms(n=5, p<0.01), the long-term instability of RR interval(LTIRR) was increased from 3.69±1.62 ms to 38.29±12.73 ms(n=5, p<0.01),the total instability of RR interval(TIRR) was increased from 4.05±1.50 ms to64.73±20.31 ms(n=5, p<0.01); the short-term instability of QT interval(STIQT) was increased from 1.76±0.67 ms to 23.09±9.52 ms(n=5, p<0.01), the long-term instability of QT interval(LTIQT) was increased from 2.44±1.02 ms to 57.15±16.22ms(n=5, p<0.01), the total instability of QT interval(TIQT) was increased from3.53±1.41 ms to 65.30±17.42 ms(n=5, p<0.01). Then, with 0.4 ?mol·L-1 mallotoxin,the prolonged QT interval could be shortened to 206.89±14.35 ms(n=5, p<0.05), the increased transmural dispersion could be decreased to 75.07±7.53 ms(n=5, p<0.01);the increased STIRR could be decreased to 1.79±0.53 ms(n=5, p<0.01), LTIRR could be decreased to 1.55±0.40 ms(n=5, p<0.01), TIRR could be decreased to 2.66±0.65ms(n=5, p<0.01); STIQT could be decreased to 2.78±1.12 ms(n=5, p<0.01), LTIQT could be decreased to 4.32±1.22 ms(n=5, p<0.01), TIQT could be decreased to5.81±2.12 ms(n=5, p<0.01).6. Results of the electrocardiogram measurement in isolated guinea pig hearts show that, compared with the control group, with 0.5 ?mol·L-1 DPI 201-106, QTinterval was prolonged from 180.87±13.29 ms to 228.97±29.85 ms(n=6, p<0.01); the transmural dispersion was increased from 48.50±9.15 to 72.83±23.79 ms(n=6,p<0.05). Then, with 0.4 ?mol·L-1 mallotoxin, the prolonged QT interval could be decreased to 174.77±13.39 ms(n=6, p<0.01); the increased transmural dispersion could be decreased to 44.90±22.61 ms(n=6, p<0.01); besides, mallotoxin could also decreased the incidence of P-on-T like early afterdepolarization which was increased by DPI 201-106.7. Results of the measurement of ventricular pressure in isolated guinea pig hearts show that, compared with the control group, with 0.4 ?mol·L-1 mallotoxin, the left ventricular systolic pressure(LVSP) was decreased(n=6, p<0.01); +dp/dtmax was also decreased(n=6, p<0.05); the left ventricular end diastolic pressure(LVEDP) was increased(n=6, p<0.05). Compared with the control group, with 0.5 ?mol·L-1 DPI201-106, the LVSP and +dp/dtmax was increased(n=6, p<0.05). Then, with 0.4?mol·L-1 mallotoxin, the increased LVSP and +dp/dtmax could be decreased(n=6,p<0.01).Conclusion:1. Mallotoxin shortens the action potential duration and decreases the increased instability of action potential repolarization.2. By shortening the QT interval, especially by decreasing the transmural dispersion, mallotoxin could reverse LQT2 and LQT3. High concentration of mallotoxin could lead to certain arrhythmia.3. The increased instability of RR and QT interval which were induced by E-4031 under low K+ concentration could be decreased by mallotoxin, besides, the incidence of P-on-T like early afterdepolarization which were increased by E-4031(under low K+ concentration) and DPI 201-106 could be decreased, too.4. Mallotoxin decreases LVSP, and reverses the increased LVSP induced by DPI201-106. |
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