Electromechanical characterization of cinnamophilin, a natural thromboxane A2 receptor antagonist with anti-arrhythmic activity, in guinea-pig heart
Electromechanical characterization of cinnamophilin, a natural thromboxane A2 receptor antagonist with anti-arrhythmic activity, in guinea-pig heart
复制标题
DOI：
10.1038/sj.bjp.0707541
复制
发表时间：
2008-01-01
影响因子：
7.3
通讯作者：
Kuo, C-M
中科院分区：
文献类型：
--
作者：
Chang, G-J;Su, M-J;Kuo, C-M
背景与目的：肉桂酚是一种血栓素A（2）受体拮抗剂，在大鼠心脏中具有显著的抗心律失常作用。本研究的目的是确定其在豚鼠心脏的机电和抗心律失常的作用。实验方法：采用微电极研究心室乳头肌动作电位。采用Fluo-3荧光比率法和全细胞电压钳技术分别记录单个心室肌细胞的钙瞬变和膜电流。心内心电图，并从离体灌流hearts.Key结果：在乳头肌，肉桂酚降低最大上升速率（V-最大值）和动作电位的持续时间，并减少收缩力的抗心律失常的疗效进行了测定。在单个心室肌细胞中，肉桂酚降低Ca 2+瞬时振幅。肉桂酚降低L-型钙电流（I-Ca，I-L）（IC_（50）=7.5 μ M）与使用依赖性，诱导电压依赖性失活的负移和延迟恢复失活。肉桂酚还降低Na+电流（I-Na）（IC_（50）=2.7 μ M），并在较小程度上，延迟外向（I-K），内向整流（I-K_1），和ATP敏感（I-K，I-ATP）的K+电流。在离体灌流心脏，肉桂酚延长房室结传导间期、文氏周期长度、房室结、希氏-浦肯野系统和心室的不应期，缩短心室复极时间。结论和意义：这些结果表明，有希望的抗心肌缺血作用和肉桂酚引起的豚鼠心脏的电机械功能的变化，可以主要解释通过抑制I-Ca，I-L和I-Na。
Background and purpose: Cinnamophilin, a thromboxane A(2) receptor antagonist, has been identified as a prominent antiarrhythmic agent in rat heart. This study aimed to determine its electromechanical and anti-arrhythmic effects in guinea-pig hearts.Experimental approach: Microelectrodes were used to study action potentials in ventricular papillary muscles. Fluo-3 fluorimetric ratio and whole-cell voltage-clamp techniques were used to record calcium transients and membrane currents in single ventricular myocytes, respectively. Intracardiac electrocardiograms were obtained and the anti-arrhythmic efficacy was determined from isolated perfused hearts.Key results: In papillary muscles, cinnamophilin decreased the maximal rate of upstroke (V-max) and duration of action potential, and reduced the contractile force. In single ventricular myocytes, cinnamophilin reduced Ca2+ transient amplitude. Cinnamophilin decreased the L-type Ca2+ current (I-Ca,I-L)(IC50=7.5 mu M) with use-dependency, induced a negative shift of the voltage-dependent inactivation and retarded recovery from inactivation. Cinnamophilin also decreased the Na+ current (I-Na) (IC50=2.7 mu M) and to a lesser extent, the delayed outward (I-K), inward rectifier (I-K1), and ATP-sensitive (I-K,I-ATP) K+ currents. In isolated perfused hearts, cinnamophilin prolonged the AV nodal conduction interval and Wenckebach cycle length and the refractory periods of the AV node, His-Purkinje system and ventricle, while shortening the ventricular repolarization time. Additionally, cinnamophilin reduced the occurrence of reperfusion-induced ventricular fibrillation.Conclusions and implications: These results suggest that the promising anti-arrhythmic effect and the changes in the electromechanical function induced by cinnamophilin in guinea-pig heart can be chiefly accounted for by inhibition of I-Ca,I-L and I-Na.