title: Signal transduction and modulating pathways in tryptamine-evoked vasopressor responses of the rat isolated perfused mesenteric bed.
abstract: Tryptamine is an endogenous and dietary indoleamine-based trace amine implicated in cardiovascular pathologies, including hypertension, migraine and myocardial infarction. This study aimed at identifying the signalling pathways for the vasoconstrictor response to tryptamine in rat isolated perfused mesenteric arterial beds and co-released vasodilator modulators of tryptamine-mediated vasoconstriction. Tryptamine caused concentration-dependent vasoconstriction of the mesenteric bed, measured as increases in perfusion pressure. These were inhibited by the 5-HT(2A) receptor antagonist, ritanserin, indicating mediation via 5-HT(2A) receptors. The response was inhibited by the phospholipase C (PLC) and phospholipase A(2) (iPLA(2)) inhibitors, U-73122 and PACOCF(3), suggesting involvement of phospholipase pathways. Activation of these pathways by tryptamine releases cyclooxygenase (COX) products since indomethacin (non-selective inhibitor of COX-1/2) and nimesulide (selective COX-2 inhibitor) reduced the vasoconstriction. The most likely COX vasoconstrictor product was prostaglandin PGE(2) since the responses to tryptamine were reduced by AH-6809, a non-selective EP(1) receptor antagonist. Involvement of the Rho-kinase pathway in the tryptamine-evoked vasoconstriction was also indicated by its reduction by the Rho-kinase inhibitors, Y-27,632 and fasudil. The tryptamine vasoconstriction is modulated by the co-released endothelial vasodilator, nitric oxide. Thus, circulating tryptamine can regulate mesenteric blood flow through a cascade of signalling pathways secondary to stimulation of 5-HT(2A) receptors.
authors.affiliation: Division of Pharmacology, Cardiff School of Pharmacy & Pharmaceutical Sciences, Cardiff University, Cathays Park, Cardiff CF10 3NB, UK.
authors.forename: M Akhtar
authors.initials: MA
authors.lastname: Anwar
authors.forename: William R
authors.initials: WR
authors.lastname: Ford
authors.forename: Amy A
authors.initials: AA
authors.lastname: Herbert
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Broadley
mesh_terms: D000818:Animals; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000378:metabolism; D016713:Ritanserin / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D014363:Tryptamines / Q000008:administration & dosage / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; D014363:Tryptamines; D016713:Ritanserin; D009569:Nitric Oxide; C030820:tryptamine; D054460:rho-Associated Kinases; D015232:Dinoprostone