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Essential role of rho kinase in the Ca²⁺ sensitization of prostaglandin F₂-induced contraction of rabbit aortae

Katsuaki Ito, Erika Shimomura, Takahiro Iwanaga, Mitsuya Shiraishi, Kazutoshi Shindo, Junji Nakamura*, Hiromitsu Nagumo*, Minoru Seto*, Yasuharu Sasaki† and Yoh Takuwa ‡

Inhibition of dephosphorylation of the 20 kDa myosin light chain (MLC₂₀) is an important mechanism for the Ca²⁺-induced sensitization of vascular smooth muscle contraction. We investigated whether this mechanism operates in prostaglandin F₂ (PGF₂)-induced contraction of rabbit aortic smooth muscle and, if so, whether protein kinase C (PKC) or rho-associated kinase (rho kinase) contribute to the inhibition of dephosphorylation. In normal medium, PGF₂ (10 µM) increased the phosphorylation of MLC₂₀ and developed tension. The rho-kinase inhibitors fasudil and hydroxyfasudil inhibited these changes, despite having no effect on a phorbol-ester-induced MLC₂₀ phosphorylation. After treatment with verapamil or chelation of external Ca²⁺ with EGTA, PGF₂ increased the MLC₂₀ phosphorylation and tension without an increase in [Ca²⁺]_i, all of which were sensitive to fasudil and hydroxyfasudil. ML-9, a MLC kinase inhibitor, quickly reversed the KCl-induced MLC₂₀ phosphorylation and contraction to the resting level. However, fractions of PGF₂-induced contraction and MLC₂₀ phosphorylation were resistant to ML-9 but were sensitive to fasudil. Ro31-8220 (10 µM), a PKC inhibitor, did not affect the phosphorylation of MLC₂₀ and the tension caused by PGF₂, thus excluding the possibility of the involvement of PKC in the PGF₂-induced MLC₂₀ phosphorylation. PGF₂ increased phosphorylation at Thr654 of the myosin binding subunit (MBS) of myosin phosphatase, which is a target of rho kinase, and fasudil decreased the phosphorylation. These data suggest that the PGF₂-induced contraction is accompanied by the inhibition of MLC₂₀ dephosphorylation through rho kinase-induced MBS phosphorylation, leading to Ca²⁺ sensitization of contraction. An actin-associated mechanism may also be involved in the PGF₂-induced sensitization.

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