Effects of dietary amines on the gut and its vasculature.

Trace amines, including tyramine and beta-phenylethylamine (beta-PEA), are constituents of many foods including chocolate, cheeses and wines and are generated by so-called 'friendly' bacteria such as Lactobacillus, Lactococcus and Enterococcus species, which are found in probiotics. We therefore examined whether these dietary amines could exert pharmacological effects on the gut and its vasculature. In the present study we examined the effects of tyramine and beta-PEA on the contractile activity of guinea-pig and rat ileum and upon the isolated mesenteric vasculature and other blood vessels. Traditionally, these amines are regarded as sympathomimetic amines, exerting effects through the release of noradrenaline from sympathetic nerve endings, which should relax the gut. A secondary aim was therefore to confirm this mechanism of action. However, contractile effects were observed in the gut and these were independent of noradrenaline, acetylcholine, histamine and serotonin receptors. They were therefore probably due to the recently described trace amine-associated receptors. These amines relaxed the mesenteric vasculature. In contrast, the aorta and coronary arteries were constricted, a response that was also independent of a sympathomimetic action. From these results, we propose that after ingestion, trace amines could stimulate the gut and improve intestinal blood flow. Restriction of blood flow elsewhere diverts blood to the gut to aid digestion. Thus, trace amines in the diet may promote the digestive process through stimulation of the gut and improved gastrointestinal circulation.

Vasoconstriction of porcine left anterior descending coronary artery by ecstasy and cathinone is not an indirect sympathomimetic effect.

3,4-methylenedioxymethamphetamine ('Ecstasy', MDMA) and cathinone, the active constituent of khat leaves, were examined on pig isolated left anterior descending coronary arteries to determine whether they cause vasoconstriction and whether this was an indirect sympathomimetic action. Coronary artery rings were set up in Krebs solution (37 degrees C) gassed with 5% CO2 in O2. Endothelium remained intact as indicated by relaxation by bradykinin. Isometric tension was recorded and cumulative concentration-response curves (CRCs) for noradrenaline, ecstasy or cathinone plotted as a percent of the constriction to KCl (60 mM). Noradrenaline-induced contractions of the coronary artery were enhanced by propranolol (1 microM) indicating beta-adrenoceptor-mediated opposing vasodilatation. Cocaine (10 microM) further potentiated, while prazosin (1 microM) virtually abolished the contractions to noradrenaline. Cathinone and ecstasy constricted the coronary artery rings, the peak contractions being 56.5+/-4.2% (n=4) and 37.3+/-2.4% (n=4), respectively. Higher concentrations relaxed. The vasoconstriction was not affected by cocaine (10 microM), prazosin (1 microM, in the presence of cocaine) or removal of the endothelium. There was no tachyphylaxis or desensitisation on repeated administration of single doses. Ecstasy- and cathinone-induced coronary vasoconstriction is therefore via mechanisms other than indirect sympathomimetic activity or alpha1 -adrenoceptors. This activity could explain the cardiac adverse effects following their excessive use.

Signal transduction and modulating pathways in tryptamine-evoked vasopressor responses of the rat isolated perfused mesenteric bed.

Tryptamine is an endogenous and dietary indoleamine-based trace amine implicated in cardiovascular pathologies, including hypertension, migraine and myocardial infarction. This study aimed at identifying the signalling pathways for the vasoconstrictor response to tryptamine in rat isolated perfused mesenteric arterial beds and co-released vasodilator modulators of tryptamine-mediated vasoconstriction. Tryptamine caused concentration-dependent vasoconstriction of the mesenteric bed, measured as increases in perfusion pressure. These were inhibited by the 5-HT(2A) receptor antagonist, ritanserin, indicating mediation via 5-HT(2A) receptors. The response was inhibited by the phospholipase C (PLC) and phospholipase A(2) (iPLA(2)) inhibitors, U-73122 and PACOCF(3), suggesting involvement of phospholipase pathways. Activation of these pathways by tryptamine releases cyclooxygenase (COX) products since indomethacin (non-selective inhibitor of COX-1/2) and nimesulide (selective COX-2 inhibitor) reduced the vasoconstriction. The most likely COX vasoconstrictor product was prostaglandin PGE(2) since the responses to tryptamine were reduced by AH-6809, a non-selective EP(1) receptor antagonist. Involvement of the Rho-kinase pathway in the tryptamine-evoked vasoconstriction was also indicated by its reduction by the Rho-kinase inhibitors, Y-27,632 and fasudil. The tryptamine vasoconstriction is modulated by the co-released endothelial vasodilator, nitric oxide. Thus, circulating tryptamine can regulate mesenteric blood flow through a cascade of signalling pathways secondary to stimulation of 5-HT(2A) receptors.