Department of Pharmacology, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, China.
The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province, Shijiazhuang, 050017, China.
Sci Rep. 2024 Aug 27;14(1):19839. doi: 10.1038/s41598-024-70962-x.
The compound NS5806 is a Kv4 channel modulator. This study investigated the chronic effects of NS5806 on cardiac hypertrophy induced by transverse aortic constriction (TAC) in mice in vivo and on neonatal rat ventricular cardiomyocyte hypertrophy induced by endothelin-1 (ET-1) in vitro. Four weeks after TAC, NS5806 was administered by gavage for 4 weeks. Echocardiograms revealed pronounced left ventricular (LV) hypertrophy in TAC-treated mice compared with sham mice. NS5806 attenuated LV hypertrophy, as manifested by the restoration of LV wall thickness and weight and the reversal of contractile dysfunction in TAC-treated mice. NS5806 also blunted the TAC-induced increases in the expression of cardiac hypertrophic and fibrotic genes, including ANP, BNP and TGF-β. Electrophysiological recordings revealed a significant prolongation of action potential duration and QT intervals, accompanied by an increase in susceptibility to ventricular arrhythmias in mice with cardiac hypertrophy. However, NS5806 restored these alterations in electrical parameters and thus reduced the incidence of mouse sudden death. Furthermore, NS5806 abrogated the downregulation of the Kv4 protein in the hypertrophic myocardium but did not influence the reduction in Kv4 mRNA expression. In addition, NS5806 suppressed in vitro cardiomyocyte hypertrophy. The results provide novel insight for further ion channel modulator development as a potential treatment option for cardiac hypertrophy.
化合物 NS5806 是一种 Kv4 通道调节剂。本研究探讨了 NS5806 对体内腹主动脉缩窄（TAC）诱导的小鼠心肌肥厚和体外内皮素-1（ET-1）诱导的新生大鼠心室肌细胞肥厚的慢性作用。TAC 后 4 周，通过灌胃给予 NS5806 4 周。超声心动图显示 TAC 处理的小鼠与假手术小鼠相比，左心室（LV）肥厚明显。NS5806 减轻了 LV 肥厚，表现为 LV 壁厚度和重量的恢复以及 TAC 处理小鼠收缩功能障碍的逆转。NS5806 还减弱了 TAC 诱导的心脏肥厚和纤维化基因表达的增加，包括 ANP、BNP 和 TGF-β。电生理记录显示动作电位持续时间和 QT 间期明显延长，伴有心脏肥厚小鼠室性心律失常易感性增加。然而，NS5806 恢复了这些电参数的改变，从而降低了小鼠猝死的发生率。此外，NS5806 阻断了肥厚心肌中 Kv4 蛋白的下调，但不影响 Kv4 mRNA 表达的减少。此外，NS5806 抑制了体外心肌细胞肥厚。这些结果为进一步开发离子通道调节剂作为心脏肥厚的潜在治疗选择提供了新的见解。
