The pharmacological characterization of 5‐HT 3 receptors in three isolated preparations derived from guinea‐pig tissues

• Published in: British journal of pharmacology Vol. 101; no. 3; pp. 591 - 598
• Main Authors: Butler, A., Elswood, C.J., Burridge, J., Ireland, S.J., Bunce, K.T., Kilpatrick, G.J., Tyers, M.B.
• Format: Journal Article
• Language: English
• Published: 01.11.1990
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1990.tb14126.x

The pharmacological characterization of the 5‐HT 3 receptors in guinea‐pig isolated tissues is described. The tissues used were ileum (longitudinal muscle‐myenteric plexus), colon and vagus nerve. The guinea‐pig isolated colon is a novel preparation. In the guinea‐pig isolated ileum, 5‐hydroxytryptamine (5‐HT, 1 × 10 −8 −3 × 10 −5 m ) and the selective 5‐HT 3 receptor agonist 2‐methyl‐5‐HT (3 × 10 −7 −1 × 10 −4 m ) caused concentration‐related contractions. The 5‐HT concentration‐response curve was biphasic whilst the 2‐methyl‐5‐HT curve was monophasic. The EC 50 value for the low potency portion of the 5‐HT curve was 4.1 × 10 −6 m . The EC 50 for 2‐methyl‐5‐HT was 1.23 × 10 −5 m . Selective 5‐HT 3 receptor antagonists caused rightward shifts of the 2‐methyl‐5‐HT curve and the lower potency portion of the 5‐HT curve. Neither ketanserin (1 × 10 −6 m ) nor methysergide (1 × 10 −5 m ) antagonized the responses to 5‐HT or 2‐methyl‐5‐HT. In the guinea‐pig isolated colon, 5‐HT (3 × 10 −7 −3 × 10 −5 m ; EC 50 2.4 × 10 −6 m ) caused contractions which were mimicked by 2‐methyl‐5‐HT (1 × 10 −6 −1 × 10 −4 m ; EC 50 7.2 × 10 −6 m ). Selective 5‐HT 3 receptor antagonists caused rightward displacements of the 5‐HT concentration‐response curves. Neither ketanserin (1 × 10 −6 m ) nor methysergide (1 × 10 −5 m ) had any effect on responses to 5‐HT or 2‐methyl‐5‐HT. In the guinea‐pig isolated vagus nerve, 5‐HT (1 × 10 −6 −3 × 10 −4 m ) and 2‐methyl‐5‐HT (1 × 10 −5 −1 × 10 −3 m ; EC 50 7.6 × 10 −5 m ) caused depolarizations; at higher concentrations there were afterhyperpolarizations. The maximum response to 2‐methyl‐5‐HT was less than half that to 5‐HT. Selective 5‐HT 3 receptor antagonists caused rightward displacements of the 5‐HT concentration‐response curves. Antagonists at other 5‐HT receptors (ketanserin, 1 × 10 −5 m and methysergide, 1 × 10 −6 m ) had no effect. The estimated affinity values of 5‐HT 3 receptor antagonists correlated well between the three models. Phenylbiguanide was inactive as an agonist or antagonist (up to 1 × 10 −4 m ) in each preparation. Comparisons with antagonist affinity values obtained in the rat isolated vagus nerve revealed marked differences. Antagonists were generally more potent on the rat isolated vagus nerve, although the differences varied considerably between antagonists. The results are discussed in terms of species‐related receptor differences.