title: Modulation of resistance artery tone by the trace amine β-phenylethylamine: dual indirect sympathomimetic and α1-adrenoceptor blocking actions.
abstract: The trace amine β-phenylethylamine (PEA) is normally present in the body at low nanomolar concentrations but can reach micromolar levels after ingestion of drugs that inhibit monoamine oxidase and primary amine oxidase. In vivo, PEA elicits a robust pressor response, but there is no consensus regarding the underlying mechanism, with both vasodilation and constriction reported in isolated blood vessels. Using functional and biochemical approaches, we found that at low micromolar concentrations PEA (1-30 μM) enhanced nerve-evoked vasoconstriction in the perfused rat mesenteric bed but at a higher concentration (100 μM) significantly inhibited these responses. The α2-adrenoceptor antagonist rauwolscine (1 µM) also enhanced nerve-mediated vasoconstriction, but in the presence of both rauwolscine (1 µM) and PEA (30 µM) together, nerve-evoked responses were initially potentiated and then showed time-dependent rundown. PEA (10 and 100 μM) significantly increased noradrenaline outflow from the mesenteric bed as determined by high-pressure liquid chromatography coupled with electrochemical detection. In isolated endothelium-denuded arterial segments, PEA (1 µM to 1 mM) caused concentration-dependent reversal of tone elicited by the α1-adrenoceptor agonists noradrenaline (EC50 51.69 ± 10.8 μM; n = 5), methoxamine (EC50 68.21 ± 1.70 μM; n = 5), and phenylephrine (EC50 67.74 ± 16.72 μM; n = 5) but was ineffective against tone induced by prostaglandin F2 α or U46619 (9,11-dideoxy-9α,11α-methanoepoxyprostaglandin F2 α). In rat brain homogenates, PEA displaced binding of both [(3)H]prazosin (Ki ≈ 25 μM) and [(3)H]rauwolscine (Ki ≈ 1.2 μM), ligands for α1- and α2-adrenoceptors, respectively. These data provide the first demonstration that dual indirect sympathomimetic and α1-adrenoceptor blocking actions underlie the vascular effects of PEA in resistance arteries.
authors.affiliation: Department of Pharmacology (D.N., P.M.K., S.E.L., R.B., J.S., M.D.L., A.L.H., P.E.L., A.H., F.P.), and Cardiovascular Research Centre (P.E.L., F.P.), University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Deepak
authors.initials: D
authors.lastname: Narang
authors.affiliation: Department of Pharmacology (D.N., P.M.K., S.E.L., R.B., J.S., M.D.L., A.L.H., P.E.L., A.H., F.P.), and Cardiovascular Research Centre (P.E.L., F.P.), University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Kerr
authors.affiliation: Department of Pharmacology (D.N., P.M.K., S.E.L., R.B., J.S., M.D.L., A.L.H., P.E.L., A.H., F.P.), and Cardiovascular Research Centre (P.E.L., F.P.), University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Lunn
authors.affiliation: Department of Pharmacology (D.N., P.M.K., S.E.L., R.B., J.S., M.D.L., A.L.H., P.E.L., A.H., F.P.), and Cardiovascular Research Centre (P.E.L., F.P.), University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Rhys
authors.initials: R
authors.lastname: Beaudry
authors.affiliation: Department of Pharmacology (D.N., P.M.K., S.E.L., R.B., J.S., M.D.L., A.L.H., P.E.L., A.H., F.P.), and Cardiovascular Research Centre (P.E.L., F.P.), University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Sigurdson
authors.affiliation: Department of Pharmacology (D.N., P.M.K., S.E.L., R.B., J.S., M.D.L., A.L.H., P.E.L., A.H., F.P.), and Cardiovascular Research Centre (P.E.L., F.P.), University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Margaret D
authors.initials: MD
authors.lastname: Lalies
authors.affiliation: Department of Pharmacology (D.N., P.M.K., S.E.L., R.B., J.S., M.D.L., A.L.H., P.E.L., A.H., F.P.), and Cardiovascular Research Centre (P.E.L., F.P.), University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Hudson
authors.affiliation: Department of Pharmacology (D.N., P.M.K., S.E.L., R.B., J.S., M.D.L., A.L.H., P.E.L., A.H., F.P.), and Cardiovascular Research Centre (P.E.L., F.P.), University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Light
authors.affiliation: Department of Pharmacology (D.N., P.M.K., S.E.L., R.B., J.S., M.D.L., A.L.H., P.E.L., A.H., F.P.), and Cardiovascular Research Centre (P.E.L., F.P.), University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Holt
authors.affiliation: Department of Pharmacology (D.N., P.M.K., S.E.L., R.B., J.S., M.D.L., A.L.H., P.E.L., A.H., F.P.), and Cardiovascular Research Centre (P.E.L., F.P.), University of Alberta, Edmonton, Alberta, Canada fplane@ualberta.ca.
authors.forename: Frances
authors.initials: F
authors.lastname: Plane
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D010627:Phenethylamines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects*; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D010627:Phenethylamines; D018340:Receptors, Adrenergic, alpha-1; D015016:Yohimbine; C029261:phenethylamine