Desensitization of the human 5-HT4 receptor in isolated atria of transgenic mice.

In the human cardiovascular system, serotonin (5-HT) exerts positive inotropic and chronotropic effects mediated by 5-HT4 receptors. Moreover, 5-HT4 receptor stimulation can cause arrhythmias in the human heart. Response to 5-HT can fade due to desensitization of the receptor system and/or activation of phosphodiesterases. In this study, we investigated a potential desensitization of the human 5-HT4(a) receptor expressed in the mouse heart. Therefore, we have used atrial preparations of transgenic (TG) mice with cardiac myocyte-specific overexpression of the human 5-HT4(a) receptor and their non-transgenic littermates (WT). Homologous (by 5-HT) and potentially heterologous (by isoprenaline) desensitization of the 5-HT4 receptor was investigated in atria of TG mice. 5-HT increased force of contraction in isolated electrically paced left atria and beating rate in spontaneously beating right atria only in preparations from TG but not from WT. Pre-treatment of isolated atria with high concentrations (10-600 μM) of 5-HT for 60 min attenuated the positive inotropic effects and the positive chronotropic effects of 5-HT in TG atria. Several inhibitors of desensitization including Zn2+, sucrose, and paroxetine were tested. Whereas sucrose was without any effect and Zn2+ only was partially effective, paroxetine was able to inhibit desensitization favoring at least in part a G-protein receptor-coupled kinase-mediated mechanism of 5-HT4 receptor desensitization in the TG mouse heart. In addition, desensitization of ventricular 5-HT4 receptors was noted in isolated perfused hearts (Langendorff preparations) from TG mice. In summary, we show homologous desensitization of the 5-HT4 receptor in the heart of a transgenic mouse model possibly dependent on active G-protein receptor-coupled kinase. The exact mechanism and a potentially heterologous desensitization have to be elucidated by further investigations.