Porcine left atrial and sinoatrial 5-HT(4) receptor-induced responses: fading of the response and influence of development.
1.--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. 2.--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. 3.--Phosphodiesterase (PDE) enzyme inhibition with 3-isobutyl-1-methylxanthine (IBMX; 20 microM) 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. 4.--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). 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. 6.--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.
De Maeyer
Joris H
JH
Heymans Institute of Pharmacology, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium. jdmaeyer@prdbe.jnj.com
Straetemans
Roel
R
Schuurkes
Jan A J
JA
Lefebvre
Romain A
RA
D000818:Animals; D000831:Animals, Newborn; D001549:Benzamides / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D006325:Heart Atria / Q000254:growth & development / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000502:physiology; D044422:Receptors, Serotonin, 5-HT4 / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D058828:Serotonin 5-HT4 Receptor Agonists; D012849:Sinoatrial Node / Q000254:growth & development / Q000378:metabolism / Q000502:physiology; D013268:Stimulation, Chemical; D013552:Swine
D001549:Benzamides; D001572:Benzofurans; D007211:Indoles; D010726:Phosphodiesterase Inhibitors; D058828:Serotonin 5-HT4 Receptor Agonists; C406662:prucalopride; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; C105050:tegaserod; D010727:Phosphoric Diester Hydrolases