Vidarabine, an anti-herpesvirus agent, prevents catecholamine-induced arrhythmias without adverse effect on heart function in mice
Vidarabine, an anti-herpesvirus agent, prevents catecholamine-induced arrhythmias without adverse effect on heart function in mice
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阿糖腺苷是一种抗疱疹病毒药物，可预防儿茶酚胺引起的心律失常，且不会对小鼠的心脏功能产生不利影响
DOI：
10.1007/s00424-018-2121-4
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Ishikawa Yoshihiro
中科院分区：
文献类型：
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作者：
Suita Kenji;Fujita Takayuki;Cai Wenqian;Hidaka Yuko;Jin Huiling;Prajapati Rajesh;Umemura Masanari;Yokoyama Utako;Sato Motohiko;Knollmann Bj?rn C.;Okumura Satoshi;Ishikawa Yoshihiro
交感神经激活引起临床上重要的心律失常，包括心房颤动（AF）和室性快速性心律失常。尽管β-肾上腺素能受体阻滞剂治疗的有效性被广泛接受，但其多种严重副作用通常阻止其开始或继续。本研究的目的是确定阿糖腺苷，腺苷酸环化酶（AC）靶向抗交感神经药物，作为心律失常的替代治疗的优势。我们发现，阿糖腺苷，我们确定为心脏AC抑制剂，一贯缩短AF持续时间，减少交感神经激活诱导的室性心律失常的发生率。在心房和心室肌细胞中，阿糖腺苷抑制肾上腺素能受体刺激诱导的RyR 2磷酸化、肌浆网（SR）Ca 2+渗漏和SR的自发Ca 2+释放，后者被认为是潜在的促心律失常触发因素。此外，阿糖腺苷还抑制交感神经激活诱导的心肌细胞活性氧（ROS）的产生。阿糖腺苷的抗肿瘤特性对ROS产生的抑制作用的关键作用也已在动物研究中得到暗示。此外，正如预期的那样，阿糖腺苷对AC功能发挥抑制作用，这在心脏中比在其他地方更有效。心功能指标包括射血分数和心率不受剂量阿糖胞苷足以发挥抗心律失常作用的影响。这些结果表明，阿糖腺苷抑制儿茶酚胺诱导的AF或室性心律失常，而不恶化小鼠的心功能。
Sympathetic activation causes clinically important arrhythmias including atrial fibrillation (AF) and ventricular tachyarrhythmia. Although the usefulness of β-adrenergic receptor blockade therapy is widely accepted, its multiple critical side effects often prevent its initiation or continuation. The aim of this study is to determine the advantages of vidarabine, an adenylyl cyclase (AC)-targeted anti-sympathetic agent, as an alternative treatment for arrhythmia. We found that vidarabine, which we identified as a cardiac AC inhibitor, consistently shortens AF duration and reduces the incidence of sympathetic activation-induced ventricular arrhythmias. In atrial and ventricular myocytes, vidarabine inhibits adrenergic receptor stimulation-induced RyR2 phosphorylation, sarcoplasmic reticulum (SR) Ca2+leakage, and spontaneous Ca2+release from SR, the last of which has been considered as a potential arrhythmogenic trigger. Moreover, vidarabine also inhibits sympathetic activation-induced reactive oxygen species (ROS) production in cardiac myocytes. The pivotal role of vidarabine’s inhibitory effect on ROS production with regard to its anti-arrhythmic property has also been implied in animal studies. In addition, as expected, vidarabine exerts an inhibitory effect on AC function, which is more potent in the heart than elsewhere. Indexes of cardiac function including ejection fraction and heart rate were not affected by a dosage of vidarabine sufficient to exert an anti-arrhythmic effect. These findings suggest that vidarabine inhibits catecholamine-induced AF or ventricular arrhythmia without deteriorating cardiac function in mice.