Takata Marina, Nishikawa Mika, Hayashi Hisaki, Yamamura Aya, Saku Keita, Kawada Toru, Sato Motohiko, Kawahito Shinji, Kinoshita Hiroyuki
Department of Dental Anesthesiology, Tokushima University Hospital, Tokushima, JPN.
Department of Physiology, Aichi Medical University, Nagakute, JPN.
Cureus. 2025 Jul 13;17(7):e87854. doi: 10.7759/cureus.87854. eCollection 2025 Jul.
Background It remains unclear whether omecamtiv mecarbil, a cardiac myosin direct activator, enhances vascular smooth muscle myosin function at clinical and supra-clinical doses. Aims The current study evaluated the effect of omecamtiv mecarbil, a cardiac myosin activator, on vascular smooth muscle contraction mediated by myosin phosphatase target subunit-1 (MYPT1) phosphorylation in rats. Methods Endothelium-denuded rat aortic rings underwent isometric force recordings (n = 7-9) and western immunoblotting (n = 5) to assess vascular smooth muscle MYPT1 phosphorylation. Aortic rings were incubated with phenylephrine, omecamtiv mecarbil (10 or 10 mol/L), or both. Mean arterial pressure and heart rate in rats were measured with (n = 5) or without (n = 5) intravenous administration of omecamtiv mecarbil (10 mol/L) under general anesthesia. Results The clinical (10 mol/L) and supra-clinical (10 mol/L) doses of omecamtiv mecarbil did not alter the phenylephrine-induced concentration-response curves (10 to 10 mol/L). Omecamtiv mecarbil (10 mol/L) did not affect vascular smooth muscle MYPT1 phosphorylation induced by phenylephrine (10 mol/L). Intravenous omecamtiv mecarbil (10 mol/L) did not change either mean arterial pressure or heart rate under general anesthesia. Conclusion At clinical and supra-clinical doses, omecamtiv mecarbil did not alter phenylephrine-induced vascular smooth muscle contraction via MYPT1 phosphorylation or hemodynamic parameters under anesthesia in rats. These findings suggest that omecamtiv mecarbil, even at high doses, does not appear to influence vascular smooth muscle function, supporting its preclinical evidence of vascular safety as a cardiac myosin direct activator.
心脏肌球蛋白直接激活剂奥米卡替麦卡比在临床及超临床剂量下是否能增强血管平滑肌肌球蛋白功能仍不清楚。目的：本研究评估心脏肌球蛋白激活剂奥米卡替麦卡比对大鼠中由肌球蛋白磷酸酶靶向亚基-1（MYPT1）磷酸化介导的血管平滑肌收缩的影响。方法：对去内皮的大鼠主动脉环进行等长张力记录（n = 7 - 9）和蛋白质免疫印迹分析（n = 5），以评估血管平滑肌MYPT1磷酸化情况。主动脉环与去氧肾上腺素、奥米卡替麦卡比（10或10 μmol/L）或两者一起孵育。在全身麻醉下，对大鼠静脉注射（n = 5）或不注射（n = 5）奥米卡替麦卡比（10 μmol/L），测量平均动脉压和心率。结果：奥米卡替麦卡比的临床剂量（10 μmol/L）和超临床剂量（10 μmol/L）均未改变去氧肾上腺素诱导的浓度-反应曲线（10至10 μmol/L）。奥米卡替麦卡比（10 μmol/L）不影响去氧肾上腺素（10 μmol/L）诱导的血管平滑肌MYPT1磷酸化。在全身麻醉下，静脉注射奥米卡替麦卡比（10 μmol/L）既不改变平均动脉压也不改变心率。结论：在临床及超临床剂量下，奥米卡替麦卡比不会通过MYPT1磷酸化改变去氧肾上腺素诱导的大鼠血管平滑肌收缩或麻醉状态下的血流动力学参数。这些发现表明，奥米卡替麦卡比即使在高剂量下似乎也不会影响血管平滑肌功能，支持了其作为心脏肌球蛋白直接激活剂的血管安全性的临床前证据。
