Frascarelli Sabina, Ghelardoni Sandra, Chiellini Grazia, Vargiu Romina, Ronca-Testoni Simonetta, Scanlan Thomas S, Grandy David K, Zucchi Riccardo
Dipartimento di Scienze dell'Uomo e dell'Ambiente, University of Pisa, Pisa, Italy.
Eur J Pharmacol. 2008 Jun 10;587(1-3):231-6. doi: 10.1016/j.ejphar.2008.03.055. Epub 2008 Apr 7.
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 [3H]-p-tyramine and [125I]-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 (IC(50)=109 microM, 159 microM, and 242 microM, respectively). In the same preparation a similar effect was produced by thyronamine and 3-iodothyronamine, with IC(50)=94 microM and 27 microM, 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 [(3)H]-p-tyramine and [125I]-3-iodothyronamine was observed in ventricular tissue. While [3H]-p-tyramine was displaced by 3-iodothyronamine, [(125)I]-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.
痕量胺相关受体是一类新型的G蛋白偶联受体，对痕量胺有反应，但对经典生物胺无反应，已发现其在心脏中表达。因此，我们研究了痕量胺对羟基苯乙胺、β-苯乙胺、章鱼胺和色胺对心脏的影响。在痕量胺存在的情况下对离体大鼠心脏进行灌注，监测血流动力学变量。此外，在大鼠心室组织中进行了用[3H]-对羟基苯乙胺和[125I]-3-碘甲腺原氨酸的放射性配体结合实验。章鱼胺、β-苯乙胺和色胺产生剂量依赖性负性肌力作用，表现为心输出量降低（IC(50)分别为109 microM、159 microM和242 microM）。在同一制备物中，甲腺原氨酸和3-碘甲腺原氨酸产生类似作用，IC(50)分别为94 microM和27 microM。章鱼胺的负性肌力作用在乳头肌制备物中得到证实。除色胺外的所有痕量胺均增加心率，但这种作用可归因于它们的拟交感神经特性，因为普萘洛尔可消除这种作用。酪氨酸激酶抑制剂染料木黄酮显著增强了痕量胺的负性肌力作用。在心室组织中观察到[(3)H]-对羟基苯乙胺和[125I]-3-碘甲腺原氨酸的特异性和饱和性结合。虽然[3H]-对羟基苯乙胺被3-碘甲腺原氨酸取代，但[(125)I]-3-碘甲腺原氨酸不被对羟基苯乙胺取代。总之，痕量胺和甲腺原胺是负性肌力药物。它们的作用似乎由痕量胺相关受体的一种亚型介导，其特征在于效力顺序：3-碘甲腺原氨酸>甲腺原氨酸 = 章鱼胺 = β-苯乙胺，而色胺和对羟基苯乙胺的活性明显较低。
