Characterization of 5‐HT3 and ‘atypical’ 5‐HT receptors mediating guinea‐pig ileal contractions in vitro

• Published in: British journal of pharmacology 1990-11, Vol.101 (3), p.513-520
• Main Authors: Eglen, R.M., Swank, S.R., Walsh, L.K.M., Whiting, R.L.
• Format: Article
• Language: English
• Subjects: Animals; Guinea Pigs; Ileum - drug effects; Ileum - physiology; In Vitro Techniques; Male; Muscle Contraction - drug effects; Muscle Contraction - physiology; Phenoxybenzamine - pharmacology; Receptors, Serotonin - classification; Receptors, Serotonin - drug effects; Receptors, Serotonin - physiology; Serotonin - pharmacology; Serotonin Antagonists - pharmacology; Tetrodotoxin - pharmacology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1990.tb14113.x

1 Neuronal 5‐hydroxytryptamine (5‐HT) receptors mediating contraction of guinea‐pig ileal segments have been characterized in vitro by the use of methysergide to block 5‐HT1‐like and 5‐HT2 receptors. Concentration‐response curves to 5‐HT were biphasic (first phase, defined as those responses occurring between 1 nm and 0.32 μm 5‐HT, –log EC50 = 7.15 ± 0.08; second phase, defined as these responses occurring between 0.32 μm and 32 μm 5‐HT, –log EC50 = 5.32 ± 0.03) but monophasic to 5‐methoxytryptamine (−log EC50 = 7.0 ± 0.08) and 2 methyl 5‐HT (−log EC50 = 5.2 ± 0.13). The maximal response of the first phase to 5‐HT and the maximal response to 5‐methoxytryptamine were 30 ± 4% and 35 ± 5% respectively of the maximum response to the second phase of the 5‐HT concentration‐effect curve (set at 100%). In contrast, the maximal response to 2‐methyl‐5‐HT equalled that obtained with 5‐HT (second phase). 2 The responses comprising the second phase of the concentration‐effect curve to 5‐HT were antagonized by 1 μm ICS 205–930, ondansetron, granisetron, quipazine, N‐methyl‐quipazine and (R,S)‐zacopride and the following pKB values, with 5‐HT as the agonist, were obtained at the 5‐HT3 receptor: ICS 205–930 7.61 ± 0.05, ondansetron 6.90 ± 0.04, granisetron 7.90 ± 0.04, (S)‐zacopride 8.11 ± 0.06, (R,S)‐zacopride 7.64 ± 0.11, and (R)‐zacopride 7.27 ± 0.06. 3 Under conditions of 5‐HT1‐like, 5‐HT2 and 5‐HT3 receptor blockade, the following rank order of agonism was observed: 5‐HT > 5‐methoxytryptamine = renzapride > (S)‐zacopride > (R,S)‐zacopride > 5‐carboxamidotryptamine > BRL 24682 > (R)‐zacopride > metoclopramide > 2‐methyl‐5‐HT ≫ sulpiride. 8‐Dihydroxydiphenylaminotetralin (8‐OHDPAT), GR 43175, N,N‐dipropyl‐5‐carboxamidotryptamine, ondansetron, ICS 205–930, granisetron, quipazine and N‐methyl‐quipazine were inactive as agonists and antagonists. Relative to 5‐HT, (R,S)‐zacopride acted as a partial agonist (intrinsic activity, α = 0.80; –log EC50 = 6.3 ± 0.12; –log KA = 6.1 ± 0.03) as did (R)‐zacopride (α = 0.4, –log EC50 5.7 ± 0.08, –log KA = 5.5 ± 0.11). (S)‐zacopride acted as a full agonist (−log EC50 = 6.9 ± 0.03). ICS 205–930 (3 μm) antagonized competitively responses to 5‐HT, 5 methoxytryptamine, (R,S)‐ and (S)‐zacopride and 5‐carboxamidotryptamine yielding –log KB estimates ranging from 6.1–6.5. 4 It is concluded that two different 5‐HT receptors mediate excitatory neuronal responses in the guinea‐pig ileum. 5‐HT3 receptors mediate the second phase of the biphasic c