INVESTIGATION INTO THE 5-HYDROXYTRYPTAMINE RECEPTOR MEDIATING SMOOTH-MUSCLE RELAXATION IN THE RAT ESOPHAGUS

1 An investigation has been made into the 5-hydroxytryptamine (5-HT) receptor mediating relaxation of rat oesophagus in preparations precontracted with carbachol. 2 In tissues treated with pargyline (100-mu-M) and in the presence of corticosterone (30-mu-M) and cocaine (30-mu-M) the potency of 5-HT and 5-methoxytyramine (5-MeOT) was not changed but the maximum response to these agonists was reduced. Thus there was no evidence of metabolism and/or uptake through an amine depleting mechanism. 3 The relaxant concentration-effect curves to 5-HT were shifted to the left in a concentration-related manner by isobutylmethylxanthine (1 and 10-mu-M), suggesting the involvement of adenosine 3':5'-cyclic monophosphate in these responses. 4 5-HT produced concentration-related relaxations of rat oesophagus with an EC50 value of 0.24-mu-M. Several indole agonists were tested and the following rank order of potency of key agonists obtained: 5-HT > alpha-methyl-5-hydroxytryptamine = 5-carboxamidotryptamine (5-CT) > 5-MeOT. In contrast, 2-methyl-5-hydroxytryptamine, sumatriptan and 8-hydroxy-2-(di-n-propylamino) tetralin were weak or inactive. 5 The substituted benzamides, metoclopramide, cisapride, renzapride and R,S-zacopride acted as partial agonists, producing 60-70% of the 5-HT maximum. 6 The relaxation responses to 5-HT were neither inhibited by antagonists selective for 5-HT1 or 5-HT2 receptors nor by the 5-HT3 receptor antagonists, ondansetron, granisetron or MDL 72222. 7 The relaxation responses induced by 5-HT, 5-CT, 5-MeOT and renzapride were selectively inhibited by high concentrations of ICS 205-930 with pK(B) values of approximately 6. 8 The 5-HT receptor mediating relaxation in rat oesophagus cannot be designated 5-HT1, 5-HT2 or 5-HT3 under the current 5-HT classification, but the observed effects are consistent with stimulation of the putative 5-HT4 receptor.