Mechanisms of suppression of ischemiaa related arrhythmias for Na/H exchange inhibitors

选择性Na^+/H^+交换抑制剂在心肌缺血动物模型中显示出心脏保护作用。其中，cariporide、KB-R9032、SMP-300和FR168888对狗和大鼠冠状动脉结扎/再灌注诱导的VF有抑制作用，这可能是由于H^+挤压后Ca^<2+>过载所致。KB-R9032还能降低犬冠状动脉闭塞期间的室性早搏数。对狗和大鼠体内血流动力学参数无影响，对其他由洋地黄或肾上腺素引起的Ca^<2+>过载引起的心律失常无显著影响。在大鼠中，cariporide不抑制缺血预处理的抗心律失常作用。虽然几乎没有心电图变化来解释抗心律失常的作用，但在代谢方面的有利作用，如减弱大鼠心肌再灌注时磷酸肌酸过调。尽管有这些有利的动物数据，但初步临床试验并未显示出卡瑞波利对急性冠状动脉疾病的显著保护作用。一种新的选择性Na^+/Ca^+交换抑制剂KB-R7943对狗的再灌注VF和洋地黄心律失常没有显示出保护作用，尽管有有利的作用。

Selective Na^+/H^+ exchange inhibitors have been shown to have cardioprotective effects in animal models of myocardial ischemia. Among them, cariporide, KB-R9032, SMP-300 and FR168888 suppressed coronary ligation/reperfusion induced VF in dogs and rats, which might have been induced by Ca^<2+> overload after extrusion of H^+. KB-R9032 also decreased the number of PVCs during coronary occlusion in dogs. They had no effects on cardiohemodynamic parameters of in vivo dogs and rats, nor had no significant effects on other Ca^<2+> overload induced arrhythmias by digitalis or adrenaline. In rats, cariporide did not suppress antiarrhythmic effects of ischemic preconditioning. Though there were almost no ECG changes to explain antiarrhythmic effects, metabolically favorable effects, such as blunting creatine phosphate overshoot during reperfusion in rat myocardium were observed. Regardless of these favorable animal data, a preliminary clinical trial of cariporide did not show marked protective effect in acute coronary diseases. A new selective Na^+/Ca^+ exchange inhibitor, KB-R7943, did not show protective effect against against reperfusion VF and digitalis arrhythmias in dogs, though favorable effects have been reported in.