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

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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, β-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 [3H]-p-tyramine and [125I]-3-iodothyronamine were performed in rat ventricular tissue. Octopamine, β-phenylethylamine, and tryptamine produced a dose-dependent negative inotropic effect as shown by reduced cardiac output (IC50 = 109 μM, 159 μM, and 242 μM, respectively). In the same preparation a similar effect was produced by thyronamine and 3-iodothyronamine, with IC50 = 94 μM and 27 μM, 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 [3H]-p-tyramine and [125I]-3-iodothyronamine was observed in ventricular tissue. While [3H]-p-tyramine was displaced by 3-iodothyronamine, [125I]-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 = β-phenylethylamine, while tryptamine and p-tyramine are significantly less active.

Introduction

We have recently reported that 3-iodotyhyronamine (T1AM), a novel endogenous metabolite of thyroid hormone, produces negative inotropic and chronotropic actions in the isolated rat heart (Scanlan et al., 2004, Chiellini et al., 2007). T1AM can activate trace amine-associated receptor 1 (TAAR1) (Scanlan et al., 2004), one member of a novel family of G-protein coupled receptors, whose name reflects the fact that it interacts with trace amines (i.e. p-tyramine, β-phenylethylamine, octopamine, and tryptamine), but not with classical biogenic amines.

After TAAR1 was identified (Borowsky et al., 2001, Bunzow et al., 2001) a comprehensive search for TAAR1-like sequences in several nucleotide sequence databases led to the identification of several additional mammalian TAAR genes (Lindemann et al., 2005, Zucchi et al., 2006, Grandy, 2007). Due to the lack of selective ligands or antibodies, subtype differentiation has been achieved on the basis of the pharmacological effects produced in cells expressing mRNAs that code for specific TAARs. Since we have recently reported at least 5 TAAR subtypes to be expressed in rat heart (Chiellini et al., 2007), in the present work we compare the response to T1AM and to trace amines in order to obtain a pharmacological characterization of cardiac TAAR-mediated effects.

Section snippets

Chemicals and radionuclides

T1AM and thyronamine (T0AM) were synthesized as described elsewhere (Hart et al., 2006). All other reagents were from Sigma-Aldrich (St. Louis, MO), or by Invitrogen Life Technologies (Paisley, UK). [3H]-p-tyramine was obtained from Biotrend (Cologne, Germany), [125I]-T1AM was synthesized as described elsewhere (Chiellini et al., 2007), using [125I]-NaCl obtained from New England Nuclear (Milan, Italy).

Animals and perfusion technique

This investigation conforms to the Declaration of Helsinki and the Guiding Principles in the

Results

Baseline values of the hemodynamic variables averaged as follows, without any significant difference between groups: cardiac output 62.6 ± 1.2 ml/min, aortic flow 43.0 ± 0.8 ml/min coronary flow 19.6 ± 0.7 ml/min, peak systolic aortic pressure 177 ± 7 mm Hg, heart rate 274 ± 9 bpm. The effects of p-tyramine, β-phenylethylamine, octopamine and tryptamine, each used at 100 μM concentration, are reported in Table 1. The time course of the effects on cardiac output is shown in Fig. 1. A significant reduction

Discussion

TAARs are a family of G-protein coupled receptors that respond to trace amines, i.e. p-tyramine, β-phenylethylamine, octopamine, and tryptamine, but not to classical biogenic amines, e.g. adrenaline, dopamine or serotonin (Borowsky et al., 2001, Bunzow et al., 2001). Several TAAR genes have been identified, e.g. 17 different genes in rat, and they are expressed in several tissues, but their functional role is still largely unknown (Lindemann et al., 2005, Zucchi et al., 2006). Based on in vitro

Acknowledgement

This work was supported by Ministero dell'Università, dell'Istruzione e della Ricerca Scientifica e Tecnologica (MIUR, PRIN 2005).

References (21)

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