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Enhancement of α 2 ‐adrenoceptor‐mediated vasoconstriction by the thromboxane‐mimetic U46619 in the porcine isolated ear artery: role of the ERK–MAP kinase signal transduction cascade
Author(s) -
Bhattacharya B,
Roberts R E
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705208
Subject(s) - vasoconstriction , mapk/erk pathway , thromboxane a2 , thromboxane , phosphorylation , thromboxane receptor , endocrinology , rho associated protein kinase , medicine , protein kinase c , chemistry , extracellular , kinase , signal transduction , receptor , biochemistry , platelet
α 2 ‐Adrenoceptor‐mediated contractions in porcine blood vessels can be enhanced in the presence of the thromboxane‐mimetic U46619, and forskolin. The aim of this study was to determine the role of U46619 in the enhanced contractions, and to determine whether signalling through the ERK–MAP kinase pathway is involved. Responses to the α 2 ‐adrenoceptor agonist UK14304 (1 μ M ) were increased from 22±3% of the response to 60 m M KCl to 68±12% ( n =8, mean±s.e.m.) in the presence of a low concentration of U46619 (<20% of the 60 m M KCl response). Both the direct and the U46619‐enhanced UK14304 responses were inhibited by 50 μ M PD98059, an inhibitor of the ERK–MAP kinase pathway. UK14304‐induced contractions were associated with an increase in ERK2 phosphorylation, indicating an increased activity. In the presence of U46619, there was an enhanced phosphorylation of ERK2. U46619 on its own had no effect on ERK phosphorylation. Both the direct and enhanced UK14304 contractions were inhibited in the absence of extracellular calcium. These conditions also prevented the increase in ERK2 phosphorylation. This indicates a role for calcium influx in the enhanced contractions. In conclusion, this study demonstrates that precontraction with the thromboxane‐mimetic U46619 enhances α 2 ‐adrenoceptor‐mediated vasoconstriction through the enhancement of the ERK–MAP kinase pathway, and influx of extracellular calcium.British Journal of Pharmacology (2003) 139 , 156–162. doi: 10.1038/sj.bjp.0705208