Cardiac effects of trace amines: pharmacological characterization of trace amine-associated receptors

FRASCARELLI S;GHELARDONI S;CHIELLINI G;VARGIU, ROMINA;RONCA TESTONI S;SCANLAN TS;GRANDY DK;ZUCCHI R.

2008-01-01

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Abstract

Trace amine-associated receptors, a novel class of G-protein coupled receptors which respond to trace amines but not to classical biogenic amines, have been found to be expressed in heart. Therefore, we investigated the cardiac effects of the trace amines p-tyramine, beta-phenylethylamine, octopamine, and tryptamine. Isolated rat hearts were perfused in the presence of trace amines, monitoring the hemodynamic variables. In addition, radioligand binding experiments with [H-3]-p-tyramine and [I-125]-3-iodothyronamine were performed in rat ventricular tissue. Octopamine, beta-phenylethylamine, and tryptamine produced a dose-dependent negative inotropic effect as shown by reduced cardiac Output (IC50 = 109 mu M, 159 mu M and 242 mu M, respectively). In the same preparation a similar effect was produced by thyronamine and 3-iodothyronamine, with IC50=94 mu M and 27 mu M, respectively. The negative inotropic effect of octopamine was confirmed in a papillary muscle preparation. All trace amines except tryptamine increased the heart rate, but this action could be attributed to their sympathomimetic properties, since it was abolished by propranolol. The negative inotropic effect of trace amines was significantly increased by the tyrosine kinase inhibitor genistein. Specific and saturable binding of [H-3]-p-tyramine and [I-125]-3-iodothyronamine was observed in ventricular tissue. While [H-3]-p-tyramine was displaced by 3-iodothyronamine, [I-125]-3-iodothyronamine was not displaced by p-tyramine. In conclusion, trace amines and thyronamines are negative inotropic agents. Their effect appears to be mediated by a subtype of trace amine-associated receptor which is characterized by the rank of potency: 3-iodothyronamine > thyronamine = octopamine = beta-phenylethylamine, while tryptamine and p-tyramine are significantly less active.