Porcine left atrial and sinoatrial 5‐HT 4 receptor‐induced responses: fading of the response and influence of development

In this study, we aimed to characterize in vitro the effects of the benzofuran 5‐HT 4 receptor agonists prucalopride, R149402 and R199715 and the indolic agents tegaserod and 5‐HT in the atria of young pigs (10–11 weeks) and newborn piglets. In the paced left atrium of young pigs, only 5‐HT results in positive inotropic responses when administered cumulatively (maximal effect relative to isoprenaline=53%, pEC 50 =6.8); however, all agonists showed lusitropic effects. Noncumulative administration results in greater positive inotropic responses for 5‐HT and induces moderate positive inotropic responses for the other agonists; these responses fade. Phosphodiesterase (PDE) enzyme inhibition with 3‐isobutyl‐1‐methylxanthine (IBMX; 20  μ M ) enhances the responses to cumulatively administered 5‐HT (maximal effect=89%, pEC 50 =7.7) and reveals clear positive inotropic effects for prucalopride, tegaserod, R149402 and R199715; fading is abolished. The maximal effect of the benzofurans is less pronounced than that of the indoles. In the spontaneously beating right atrium of young pigs, all agonists show chronotropic activity when administered cumulatively in the absence of IBMX, without fade. Benzofurans behaved as partial agonists compared to 5‐HT (maximal effect=54%, pEC 50 =6.5). In newborns, the inotropic activity of the agonists in the IBMX‐treated left atrium was less pronounced than in the young pig; the same applied for the chronotropic response in the right atrium, except for 5‐HT. In conclusion, the atrial responses to 5‐HT 4 receptor activation increase in the first months of life; the inotropic response is regulated by PDEs. Prucalopride, R149402 and R199715 are partial agonists compared to 5‐HT.British Journal of Pharmacology (2006) 147 , 140–157. doi: 10.1038/sj.bjp.0706497