RT Journal Article SR Electronic T1 Modulation of Resistance Artery Tone by the Trace Amine β-Phenylethylamine: Dual Indirect Sympathomimetic and α1-Adrenoceptor Blocking Actions JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 164 OP 171 DO 10.1124/jpet.114.216523 VO 351 IS 1 A1 Deepak Narang A1 Paul M. Kerr A1 Stephanie E. Lunn A1 Rhys Beaudry A1 Julie Sigurdson A1 Margaret D. Lalies A1 Alan L. Hudson A1 Peter E. Light A1 Andrew Holt A1 Frances Plane YR 2014 UL http://jpet.aspetjournals.org/content/351/1/164.abstract AB 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 F2α or U46619 (9,11-dideoxy-9α,11α-methanoepoxyprostaglandin F2α). In rat brain homogenates, PEA displaced binding of both [3H]prazosin (Ki ≈ 25 μM) and [3H]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.