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 F_2α or U46619 (9,11-dideoxy-9α,11α-methanoepoxyprostaglandin F_2α). In rat brain homogenates, PEA displaced binding of both [³H]prazosin (K_i ≈ 25 μM) and [³H]rauwolscine (K_i ≈ 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.