Role of the extracellular signal-regulated kinase (Erk) signal transduction cascade in α2 adrenoceptor-mediated vasoconstriction in porcine palmer lateral vein

被引:32
作者
Roberts, RE [1 ]
机构
[1] Univ Nottingham, Sch Med, Queens Med Ctr, Inst Cell Signalling, Nottingham NG7 2UH, England
关键词
Erk; alpha(2) adrenoceptors; vasoconstriction; calcium influx; tyrosine kinase;
D O I
10.1038/sj.bjp.0704149
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1. The mechanism of alpha (2) adrenoceptor-mediated vasoconstriction is unknown, but may involve activation of voltage-sensitive calcium channels, and/or a protein tyrosine kinase. Recently the extracellular signal-regulated kinase (Erk) cascade, often an event downstream of tyrosine kinase activation, has been shown to mediate vasoconstriction to a variety of agents. The aim of this present study was to determine the involvement of the Erk signal transduction cascade in at adrenoceptor-mediated vasoconstriction, and to confirm the involvement of activation of voltage-sensitive calcium channels, and protein tyrosine kinase. 2 Contractions to the alpha (2) adrenoceptor agonist UK14304 in the porcine palmar lateral vein in vitro were reduced 70-80% by the MEK inhibitors PD98059 (10-50 muM) and U0126 (10-50 muM), indicating the involvement of the Erk signal transduction cascade. Immunoblots also demonstrated an increase in the phosphorylated (activated) form of Erk in palmar lateral vein segments after contraction with UK14304, which was inhibited by PD98059 and U0126. 3 The calcium channel blockers nifedipine and verapamil, or removal of extracellular calcium inhibited UK14304-induced contractions and phosphorylation of Erk, demonstrating the importance of an influx of extracellular calcium. UK14304-induced contractions were inhibited by PP2 (1-10 muM), a selective inhibitor of Src tyrosine kinases, but not by PP3, an inactive analogue. PP2 also prevented the phosphorylation of Erk by UK14304. 4 These data demonstrate that alpha (2) adrenoceptor-mediated vasoconstriction in the porcine palmar lateral vein is dependent upon activation of the Erk signal transduction cascade, which is downstream of an influx of extracellular calcium, and activation of Src tyrosine kinases.
引用
收藏
页码:859 / 866
页数:8
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