title: Functional evaluation of the receptors mediating vasoconstriction of rat aorta by trace amines and amphetamines.
abstract: Trace amines including β-phenylethylamine (β-PEA) and amphetamines classically exert pharmacological actions via indirect sympathomimetic mechanisms. However, there is evidence for other mechanisms and this study explores the receptors mediating vasoconstriction in rat aorta. β-PEA, d-amphetamine, MDMA, cathinone and methylphenidate caused concentration-dependent contractions of rat isolated aortic rings which were unaffected by prazosin (1 μM), ICI-118,551 (1 μM), cocaine (10 μM) and pargyline (10 μM), to inhibit α1- and β2-adrenoceptors, neuronal transport and monoamine oxidase (MAO), respectively. Octopamine concentration-response curves, however, were shifted to the right. In the presence of the inhibitors, the rate of onset of octopamine contractions was slowed. Lineweaver-Burk analysis of the kinetics of the response generated different KM values for octopamine in the absence (2.35 × 10(-6)M) and presence (6.09 × 10(-5)M) of inhibitors, indicating mediation by different receptors. Tryptamine-induced vasoconstriction also resisted blockade by adrenergic inhibitors and the 5-HT1A, 1B, 1D and 5-HT2A receptor antagonists, methiothepin (50 nM) and ketanserin (30 nM), respectively. Trace amines and amphetamines therefore exert vasoconstriction independently of adrenoceptors, neuronal transport and 5-HT receptor activation. There was no evidence of tachyphylaxis or cross-tachyphylaxis of the vasoconstriction to these amines. Tyramine was a partial agonist and in its presence, β-PEA, d-amphetamine and octopamine were antagonised indicating that they all act through a common receptor for which tyramine serves as an antagonist. We conclude that the vasoconstriction is via TAAR-1, because of structural similarities between amines, ability to stimulate recombinant trace amine-associated receptor 1 (TAAR-1) and the presence of TAAR-1 in rat aorta.
authors.affiliation: Division of Pharmacology, Cardiff School of Pharmacy & Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cathays Park, Cardiff, Wales CF10 3NB, UK. BroadleyKJ@Cardiff.ac.uk
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Broadley
authors.forename: Martina
authors.initials: M
authors.lastname: Fehler
authors.forename: William R
authors.initials: WR
authors.lastname: Ford
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Kidd
mesh_terms: D018674:Adrenergic Antagonists / Q000494:pharmacology; D000588:Amines / Q000494:pharmacology*; D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D003000:Clonidine / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D018674:Adrenergic Antagonists; D000588:Amines; D043562:Receptors, G-Protein-Coupled; D012701:Serotonin; D000661:Amphetamine; D003000:Clonidine
keywords: Amphetamines; Octopamine; Rat aorta; Tryptamine; Tyramine; Vasoconstriction; β-Phenylethylamine