Comparison of Electrophysiological Effects and Cardioprotective Activities of TwoThaliporphine Derivatives

• Main Authors: Yan-Ting Wang, 王彥婷
• Other Authors: Ming-Jai Su
• Format: Others
• Language: zh-TW
• Published: 2000
• Online Access: http://ndltd.ncl.edu.tw/handle/15531991086487237660

碩士 === 國立臺灣大學 === 藥理學研究所 === 88 === 1. (+)-Thaliporphine isolated from the plants of Neolitsea Konishii K is a phenolic aporphine alkaloid. (+)-Thaliporphine has been reported to be a positive inotropic agent associated with negative chronotropic effect. (+)-Thaliporphine was also reported to inhibit sodium current, potassium transient outward current and to increase calcium current. In addition, (+)-thaliporphine prolonged the action potential duration in rat isolated ventricular myocytes. Recently some data report that (+)-thaliporphine inhibited low density lipoprotein (LDL) peroxidation, and exerted the scavenging activities of diphenyl-2-picrylhydrazyl (DPPH) and superoxide anion. In animal study, (+)-thaliporphine had great efficacy against ischemia and ischemia-reperfusion induced arrhythmias. Besides, (+)-thaliporphine also reduced the mortality after ischemia or ischemia-reperfusion and the cardiac infarct zone after long term ischemia. 2. On literature, during ischemia-reperfusion, the free radical production and the calcium overload were the major causes of myocardial injury. To exclude the calcium channel excitation of (+)-thaliporphine and delineate the role of antioxidant activity and ion channels activities in cardioprotective effects of (+)-thaliporphine, TM-1 and Thali II , two (+)-thaliporphine derivatives, were synthesized. In this study, we characterized and compared the mechanical effects on isolated cardiac tissues, electrophysiological effects, free radical scavenging activities and the antiarrhythmic efficacies of these two compounds in isolated cardiac tissues or in ischemia-reperfusion animals. 3. In isolated rat right atria, TM-1 and Thali II both could decrease spontaneously beating rate and enhance the contractility dose-dependently. The relative heart rate was reduced by TM-1 (30 umM) and Thali II (30 uM) to 69.0±2.8% and 44.7±11.9% of control. The relative contractility was enhanced by TM-1 (30 uM) and Thali II (30 uM) to 130.4±10.7% and 118.4±23.7% of control (n=7). 4. Both TM-1 and Thali II could increase the contractile force of driven left atria slightly, but there were no significant differences. 5. TM-1 and Thali II possessed antiarrhythmic effects against ouabain-induced arrhythmia in driven right ventricular strips of guinea pig hearts. Both of them at 10 uM had the same conversion proportion (73.3 %). 6. In the Langendorff perfused rat heart, TM-1 and Thali II had the same ability at 30 uM to convert ventricular arrhythmias induced by ischemia-reperfusion (54.6 %). 7. TM-1 (1x10-7 mole/kg) and Thali II (2x10-7 mole/kg) could effectively reduce the mortality of ischemia-reperfusion rats. 8. Thali II (30 uM) exerted the DPPH , stable free radical, scavenging activity, but TM-1 didn't. Both TM-1 and Thali II couldn't scavenge the superoxide anion. 9. Whole cell voltage clamp study revealed that both TM-1 and Thali II (30 uM) blocked the sodium channel (INa), but only Thali II caused a leftward shift of steady-state inactivation curve of INa. When the prepulse duration was 200 ms, both TM-1 and Thali II (30 uM) prolonged the recovery time constant of INa from inactivation. 10. The L-type calcium currents were decreased by both TM-1 and Thali II (30 uM), but to a lesser degree. Only TM-1 could shift the steady-state inactivation curve of ICa, L to more negative potential direction. 11. Both TM-1 and Thali II (30 uM) inhibited the peak (Ipeak) and the steady state current (Iss) of potassium transient outward current (Ito) with a slightly left shift of its steady-state inactivation curve. Both TM-1 and Thali II (30 uM) prolonged the recovery time constant of Ito from inactivation. There were no difference between TM-1 and Thali II on Ito. 12. We concluded that both TM-1 and Thali II could inhibit sodium current, calcium current and potassium transient outward current. Only Thali II could exert DPPH scavenging activity, but both of TM-1 and Thali II couldn't scavenge the superoxide anion. In vitro study, TM-1 and Thali II could reverse the ouabain-induced or ischemia-reperfusion-induced ventricular arrhythmias to normal rhythm. These antiarrhythmic effects were probably related to their ionic channel inhibitory actions, but unrelated to the free radical scavenging actions. As for the decrease of the mortality rate in ischemia-reperfusion animals pretreated with TM-1 and Thali II, the mechanisms remain to be clarified.