Abstract Background and Purposes: Although trace amines, including β-phenylethylamine (β-PEA), cause vasoconstriction, they also induce endothelial nitric oxide release via an unknown mechanism. This study evaluates the cellular site of action and receptors mediating β-PEA-induced vasodilation. Experimental Approach: In vitro vasodilator responses to β-PEA were assessed using aortic rings and third-order mesenteric arteries of male Sprague-Dawley rats. Key Results: β-PEA-induced concentration-dependent vasodilation of pre-constricted aortic rings and third-order mesenteric arteries were partially sensitive and insensitive to endothelium removal, respectively. In aortic rings vasodilator responses to β-PEA were unaffected by EPPTB, a selective antagonist of murine trace amine associated receptor 1 (TAAR1), or antagonists of β2-adrenoceptors and muscarinic acetylcholine M3 receptors. The inhibitor of uptake-2 transport, decynium-22, abolished β-PEA-induced vasodilation revealing a vasoconstrictor response. Conclusion and Implications: Vasodilator responses to β-PEA do not involve cell surface receptors. We propose that β-PEA utilises uptake-2 transporters to gain access to an intracellular site. Although the identify of the intracellular site is unknown, the mechanism is similar to that previously reported where intracellular TAAR1 medated responses in HEK293 cells. Vasodilatation is the dominant response to trace amines of mesenteric vessels whereas in the aorta, it opposes vasoconstriction.

Background and Purposes: Substantial evidence indicates trace amines can induce vasoconstriction independently of noradrenaline release. However, the mechanism underlying noradrenaline-independent vasoconstrictor responses to trace amines has not yet been established. This study evaluates the role of trace amine-associated receptor 1 (TAAR1) and other biogenic amine receptors in mediating trace amine-induced vasoconstriction. Experimental Approach: Vasoconstrictor responses to β-PEA and the TAAR1-selective agonist, RO5256390 were assessed in vitro in endothelium-denuded aortic rings and third-order mesenteric arteries of male Sprague Dawley rats. Key Results: β-PEA and RO5256390 induced concentration-dependent vasoconstriction of aortic rings but not third-order mesenteric arteries. Vasoconstrictor responses in aortic rings were insensitive to antagonists of 5-HT and dopamine. The murine-selective TAAR1 antagonist, EPPTB, had no effect on either β-PEA or RO5256390-induced vasoconstriction. The α1-adrenoceptor antagonist, prazosin, and the α2-adrenoceptor antagonist, yohimbine, induced a small but significant shift of the β-PEA concentration response curve that could not be ascribed to blockade of α1- or α2-adrenoceptors. Conclusion and Implications: Vasoconstrictor responses to trace amines are not mediated by classical biogenic amine neurotransmitter receptors. Although β-PEA vasoconstrictor responses were insensitive to ETTP, it has low affinity for rat TAAR1. Therefore, we propose that TAAR1 remains the most likely candidate receptor mediating vasoconstrictor responses to trace amines and that prazosin and yohimbine have some affinity for TAAR1.