Lack of Effect of Omecamtiv Mecarbil on Smooth Muscle Myosin Phosphatase Target Subunit-1 (MYPT1) Phosphorylation and Hemodynamics in Rats

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^-6 or 10^-5 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^-5 mol/L) under general anesthesia. Results The clinical (10^-6 mol/L) and supra-clinical (10^-5 mol/L) doses of omecamtiv mecarbil did not alter the phenylephrine-induced concentration-response curves (10^-9 to 10^-5 mol/L). Omecamtiv mecarbil (10^-5 mol/L) did not affect vascular smooth muscle MYPT1 phosphorylation induced by phenylephrine (10^-5 mol/L). Intravenous omecamtiv mecarbil (10^-5 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.

blood pressure; blood vessel; contraction; myosin; omecamtiv mecarbil; vascular smooth muscle.