Alpha 2 adrenoceptor-mediated vasoconstriction in porcine palmar lateral vein: role of phosphatidylinositol 3-kinase and EGF receptor transactivation.
1 Alpha(2) adrenoceptors cause vasoconstriction in the porcine palmar lateral vein through a mechanism involving the ERK signal transduction cascade, calcium influx, and a Src tyrosine kinase. The aim of the present study was to determine if phosphatidylinositol 3-kinase (PI 3-kinase) and/or epidermal growth factor (EGF) receptor transactivation are also involved. 2 alpha(2) Adrenoceptor-mediated vasoconstriction and ERK2 activation in the porcine palmar lateral vein was inhibited in the presence of either the PI 3-kinase inhibitor LY294002, or the EGF receptor tyrosine kinase inhibitor AG1478 suggesting the involvement of both PI 3-kinase and EGF receptor transactivation. 3 Akt phosphorylation was increased in segments of porcine palmar lateral vein contracted with UK14304 indicating an increase in Akt activation. This is a further indication that PI 3-kinase is involved in alpha(2) adrenoceptor-mediated vasoconstriction. Akt activation was inhibited by the Src tyrosine kinase inhibitor PP2, and removal of extracellular calcium. 4 UK14304 (10 microM) stimulated an increase in intracellular calcium in segments of palmar lateral vein. This was inhibited by removal of extracellular calcium, but not by nifedipine suggesting the rise in calcium is due to influx of calcium through non-L type calcium channels. The increase in calcium was also inhibited by LY294002 indicating that PI 3-kinase is upstream of calcium influx. 5 These data indicate that alpha(2) adrenoceptor-mediated vasoconstriction in the porcine palmar lateral vein is dependent upon stimulation of PI 3-kinase, leading to an influx of calcium. This results in activation of the EGF receptor tyrosine kinase, and finally activation of ERK-MAP kinase.
Roberts
R E
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Institute of Cell Signalling, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH UK. richard.roberts@nottingham.ac.uk
D058647:Adrenergic alpha-2 Receptor Agonists; D000818:Animals; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005552:Forelimb / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology; D066298:In Vitro Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism*; D013552:Swine; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014680:Veins / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*
D058647:Adrenergic alpha-2 Receptor Agonists; D018341:Receptors, Adrenergic, alpha-2; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors