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Received August 12, 2002
Accepted after revision November 11, 2002
-induced contraction of rabbit aortae
1 Department of Veterinary Pharmacology, Faculty of Agriculture, Miyazaki University, Miyazaki 889-2192, Japan
2 Frontier 21 Project, Institute for Life Science Research, Asahi Kasei Corporation, Fuji, Shizuoka 416-8501, Japan
3 Department of Pharmacology, Faculty of Pharmacy, Kitasato University, Tokyo 108-8641, Japan
4 Department of Physiology, Kanazawa University School of Medicine, Kanazawa, Ishikawa 920-8640, Japan
* To whom correspondence should be addressed. E-mail: itokt{at}cc.miyazaki-u.ac.jp.
Inhibition of dephosphorylation of the 20 kDa myosin light chain (MLC20) is an important mechanism in 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 the enhanced myosin regulatory light chain (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 the developed 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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