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CARDIOVASCULAR

The Role of Rho Kinase and Extracellular Regulated Kinase-Mitogen-Activated Protein Kinase in ₂-Adrenoceptor-Mediated Vasoconstriction in the Porcine Palmar Lateral Vein

Institute of Cell Signalling and Department of Obstetrics and Gynaecology, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, United Kingdom

₂-Adrenoceptor-mediated vasoconstriction in the porcine palmar lateral vein is dependent upon activation of the extracellular signal-regulated kinase-mitogen-activated protein (ERK-MAP) kinase signal transduction pathway. Recent studies have shown that ₂-adrenoceptor-mediated vasoconstriction in the rat aorta is also dependent upon activation of Rho kinase. The aim of this study was to determine whether Rho kinase and ERK-MAP kinase are part of the same signaling pathway. The Rho kinase inhibitor Y27632 (trans-4-[(1R)-1-aminoethyl]-N-4-pyridinylcyclohexanecarboxamide dihydrochloride) (10 µM) almost completely inhibited the contractile response to the ₂-adrenoceptor agonist UK14304 (5-bromo-6-[2-imidazolin-2-ylamine]-quinoxaline bitartrate) in segments of porcine palmar lateral vein [maximum response 2.9 ± 2.3% of 60 mM KCl response (mean ± S.E.M.) in the presence of Y27632, compared with 64.9 ± 7.1% in control tissues, n = 4]. However, Y27632 had no effect on ₂-adrenoceptor-mediated ERK activation, as measured by Western blotting. ₂-Adrenoceptor-mediated vasoconstriction was associated with an increase in phosphorylation of the myosin phosphatase-targeting subunit (MYPT) at Thr696 (the Rho kinase phosphorylation site). This phosphorylation was inhibited by 10 µM Y27632. In contrast, inhibition of ERK activation with the MAP kinase kinase inhibitor PD98059 (2-amino-3-methoxyflavone) (50 µM) had no effect on MYPT phosphorylation. Both Y27632 and PD98059 inhibited myosin light chain phosphorylation. These data indicate that ₂-adrenoceptor-mediated vasoconstriction in the porcine palmar lateral vein is dependent upon both Rho kinase and ERK activation, although these are separate pathways. Rho kinase causes vasoconstriction through inhibition of myosin phosphatase and an increase in myosin light chain phosphorylation, whereas ERK causes vasoconstriction through a myosin phosphatase-independent pathway.

Address correspondence to: Dr. Richard Roberts, Institute of Cell Signalling and Department of Obstetrics and Gynaecology, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK. E-mail: richard.roberts{at}nottingham.ac.uk

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