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目的无义突变产生提早出现的终止密码子(Premature termination codon,PTC),其主要致病机制是突变基因单倍体表达不足,见于心脏钠通道SCN5A基因。SCN5A无义突变导致心脏传导功能障碍、扩张性心肌病和Brugada综合征(BrS)等疾病,目前尚无有效方法根治这类疾病,但药物将是治疗这类突变相关性疾病的最佳选择。近年来开发的口服药物PTC124,能够选择地抑制过早出现的终止密码子,诱导核糖体通读,不影响正常的终止密码子。为了评价该药物的安全性,本研究检测了PTC124对豚鼠心室肌细胞动作电位特性的急性效应。方法应用膜片钳方法研究PTC124对豚鼠心肌细胞动作电位的影响。采用酶法分离豚鼠心肌细胞,测定PTC124对心肌细胞的急性毒性作用。结果 PTC124对豚鼠心肌细胞静息膜电位、最大上升速率、动作电位幅度和动作电位持续时间在50和90%的复极期均没有受到影响。结论 PTC124不影响豚鼠心室肌细胞动作电位。该研究为今后评估这种疗法的使用价值,治疗具有潜在的致命性心律失常的BrS和/或传导障碍性疾病患者的安全性提供依据。
Purpose Nonsense mutations produce premature termination codon (PTC), the main pathogenic mechanism is the lack of haploid mutant gene expression found in the cardiac sodium channel SCN5A gene. SCN5A nonsense mutations lead to heart conduction disorders, dilated cardiomyopathy and Brugada syndrome (BrS) and other diseases, there is no effective way to cure these diseases, but the drug will be the treatment of such mutations associated disease the best choice. The oral drug PTC124, developed in recent years, selectively inhibits premature stop codons and induces ribosome readthrough without affecting the normal stop codon. In order to evaluate the safety of this drug, this study examined the acute effect of PTC124 on the action potential profile of guinea pig ventricular myocytes. Methods Patch-clamp method was used to study the effect of PTC124 on action potential of guinea pig cardiomyocytes. Guinea pig cardiomyocytes were isolated by enzymatic method and the acute toxicity of PTC124 to cardiomyocytes was determined. Results The resting membrane potential, the maximum rate of increase, the amplitude of action potential and the duration of action potential of PTC124 on guinea pig cardiomyocytes were not affected in 50 and 90% of repolarization periods. Conclusion PTC124 does not affect the action potential of guinea pig ventricular myocytes. This study provides the basis for future evaluations of the value of this therapy for treating patients with BrS and / or conductive disorders with potentially fatal arrhythmias.