Modulation of Resistance Artery Tone by the Trace Amine b-Phenylethylamine: Dual Indirect Sympathomimetic and a1-Adrenoceptor Blocking Actions

The trace amine b-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 mM) enhanced nerve-evoked vasoconstriction in the perfused rat mesenteric bed but at a higher concentration (100 mM) significantly inhibited these responses. The a2-adrenoceptor antagonist rauwolscine (1 mM) also enhanced nerve-mediated vasoconstriction, but in the presence of both rauwolscine (1 mM) and PEA (30 mM) together, nerveevoked responses were initially potentiated and then showed time-dependent rundown. PEA (10 and 100 mM) 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 mM to 1 mM) caused concentrationdependent reversal of tone elicited by the a1-adrenoceptor agonists noradrenaline (EC50 51.69 6 10.8 mM; n 5 5), methoxamine (EC50 68.216 1.70 mM; n5 5), and phenylephrine (EC50 67.746 16.72 mM; n5 5) but was ineffective against tone induced by prostaglandin F2a or U46619 (9,11-dideoxy-9a,11amethanoepoxyprostaglandin F2a). In rat brain homogenates, PEA displaced binding of both [H]prazosin (Ki 25 mM) and [H]rauwolscine (Ki 1.2mM), ligands fora1anda2-adrenoceptors, respectively. These data provide the first demonstration that dual indirect sympathomimetic and a1-adrenoceptor blocking actions underlie the vascular effects of PEA in resistance arteries.