Rho‐kinase inhibitor inhibits both myosin phosphorylation‐dependent and ‐independent enhancement of myofilament Ca2+ sensitivity in the bovine middle cerebral artery

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Abstract
The role of Rho kinase in Ca2+ sensitization of the contractile apparatus in smooth muscle was investigated in the bovine middle cerebral artery. U46619, a thromboxane A2 analog, induced a greater sustained contraction with a smaller [Ca2+]i elevation than that seen with 118 mM K+. The level of myosin light chain (MLC) phosphorylation obtained in the initial phase of the contraction was higher than that seen with 118 mM K+; thereafter, it gradually declined to a comparable level in the late phase. During the steady state of the U46619‐induced contraction, Y27632 (10 μM), a Rho‐kinase inhibitor, partially inhibited [Ca2+]i, although it substantially inhibited tension and MLC phosphorylation. Wortmannin (10 μM), an MLC kinase inhibitor, had no significant effect on [Ca2+]i, but it completely inhibited MLC phosphorylation and partially inhibited tension. The wortmannin‐resistant tension development was thus not associated with MLC phosphorylation, and this component was completely inhibited by Y27632. In conclusion, U46619 enhanced Ca2+ sensitivity in a manner both dependent and independent of MLC phosphorylation in the bovine middle cerebral artery. Both mechanisms of Ca2+ sensitization can be inhibited by the Rho‐kinase inhibitor. British Journal of Pharmacology (2003) 140, 871–880. doi:10.1038/sj.bjp.0705487

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