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Background: 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 β-phenylethylamine and the TAAR-1 selective agonist RO5256390-induced vasoconstriction., Methods: 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., 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. The murine-selective TAAR1 antagonist, EPPTB, had no effect on either β-PEA or RO5256390-induced vasoconstriction. The α 1 -adrenoceptor antagonist, prazosin, and the α 2 -adrenoceptor antagonist, yohimbine, induced a shift of the β-PEA concentration response curve too small to be ascribed to antagonism of α 1 -or α 2 -adrenoceptors, respectively. The α 2 -adrenoceptor antagonist atipamezole had no effect on β-PEA or RO5256390-induced vasoconstriction., Conclusion: Vasoconstrictor responses to trace amines are not mediated by classical biogenic amine neurotransmitter receptors. Insensitivity of β-PEA vasoconstrictor responses to EPPTB, may be explained by its low affinity for rat rather than murine TAAR1. Therefore, TAAR1 remains the most likely candidate receptor mediating vasoconstrictor responses to trace amines and that prazosin and yohimbine have low affinity for TAAR1., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Acetylcholine (Ach) causes vasodilatation by nitric oxide (NO) release from the vascular endothelium. Vasoconstrictors such as α-adrenoceptor agonists (phenylephrine) or thromboxane TxA 2 mimetics (U46619) also release endothelial NO. Inhibition of nitric oxide synthase (NOS) with N ω -nitro-L-arginine (L-NAME) potentiates vasoconstriction by phenylephrine and the trace amine, β-phenylethylamine (PEA), indicating underlying opposing vasodilatation. However, the roles of the endothelium and NO in vasodilator and constrictor responses of guinea-pig aorta have not been examined and are the subject of this study. Guinea-pig thoracic aorta rings were set up in aerated Krebs solution (37 °C) and isometric tension recorded. Contractions to phenylephrine were fast onset, rapidly waned and antagonised by prazosin. PEA contractions were slow onset, sustained and not antagonised by prazosin and therefore not α 1 -adrenoceptor-mediated. PEA and phenylephrine contractions were enhanced by L-NAME whether endothelium was present or not. Ach produced only weak relaxation in a small proportion of endothelium intact U46619-constricted aortae, which were abolished by endothelium removal. In uncontracted aortae Ach caused small contractions, which like PEA contractions were potentiated by endothelium removal. α-Adrenoceptor agonists and trace amines release NO from non-endothelial sites causing underlying opposing vasodilatation. The endothelium plays only a minor role in vasodilator and vasoconstrictor responses of guinea-pigs aorta., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Sympathomimetic and trace amines, including β-phenylethylamine (PEA) and amphetamine, increase blood pressure and constrict isolated blood vessels. By convention this is regarded as a sympathomimetic response, however, recent studies suggest trace amine-associated receptor (TAAR) involvement. There is also uncertainty whether these amines also release nitric oxide (NO) causing opposing vasodilatation. These questions were addressed in guinea-pig isolated aorta, a species not previously examined. Guinea-pig aortic rings were set up to measure contractile tension. Cumulative concentration-response curves were constructed for the reference α-adrenoceptor agonist, phenylephrine, PEA or d-amphetamine before and in the presence of vehicles, the α 1 -adrenoceptor antagonist, prazosin (1µM), the nitric oxide synthase inhibitor, N ω -nitro-L-arginine (L-NAME), or NO scavengers, curcumin and astaxanthin. Prazosin inhibited phenylephrine contractions with low affinity consistent with α 1L -adrenoceptors. However, PEA and amphetamine were not antagonised, indicating non-adrenergic responses probably via TAARs. L-NAME potentiated contractions to PEA both in the absence and presence of prazosin, indicating that PEA releases NO to cause underlying opposing vasodilatation, independent of α 1 -adrenoceptors. L-NAME also potentiated amphetamine and phenylephrine. PEA was potentiated by the NO scavenger astaxanthin but less effectively. Curcumin, an active component of turmeric, however, inhibited PEA. Trace amines therefore constrict blood vessels non-adrenergically with an underlying NO-mediated non-adrenergic vasodilatation. This has implications in the pressor actions of these amines when NO is compromised., (Copyright © 2017 Elsevier B.V. All rights reserved.)