Pharmacology of vascular responses to trace amines

Trace amines including β-Phenylethylamine (β-PEA) and tyramine are vasoactive monoamines closely related to the classical neurotransmitters, noradrenaline, serotonin (5-HT) and dopamine. As vasoactive substances, the trace amines are considered sympathomimetic, eliciting vasoconstrictor responses through noradrenaline release, although they can also induce vasodilator responses. The trace amines are well-known agonists of trace amine-associated receptors (TAARs), of which TAAR1 is expressed in rat aorta. Pharmacological characterisation of TAAR1 has proven difficult as TAAR1 is located in intracellular compartments and is poorly expressed at the cell surface. Previous studies have attributed both trace amine-induced vasoconstrictor and vasodilator responses to TAAR1. The aim of the current thesis was to pharmacologically characterise both the vasoconstrictor and vasodilator actions of the trace amines. β-PEA- and tyramine -induced vasoconstrictor response in rat aortic rings were both significantly potentiated by endothelium removal or inhibition of endothelial nitric oxide synthase (eNOS). Vasoconstrictor responses to β-PEA were found to be resistant to blockade of post-synaptic uptake-2 transporters, antagonists of 5-HT2 receptors, α1-adrenoceptors, D1 and D2-class dopamine receptors and the mouse-specific TAAR1 antagonist, EPPTB. This indicates that β-PEA-induced contractile responses are likely mediated by a currently unidentified cell surface receptor or receptors. As EPPTB, is a poor tool for the study of rat TAAR1, it is possible that TAAR1 located at the plasma membrane mediates these responses. β-PEA-induced vasodilator responses in rat aortic rings were partially attenuated by endothelium removal or inhibition of eNOS. Vasodilator responses to β-PEA were resistant to antagonists of muscarinic M3 receptors, β2-adrenoceptors and EPPTB. β-PEA-induced vasodilator responses were completely abolished by inhibition of uptake-2 transporters indicating that vasodilation is mediated by an intracellular receptor such as TAAR1.