Study of the contractile effect of 5-hydroxytryptamine (5-HT) in the isolated longitudinal muscle strip from guinea-pig ileum

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Abstract
1. The contractile effect of 5-HT in the isolated longitudinal ileal muscle of adult guinea-pigs was studied over a large concentration range. 2. 5-HT produced a biphasic concentration-response curve indicative of an interaction with at least two indenpendent populations of receptors. The concentrations which elicited half-maximal effects for the first and the second phases of the concentration-response curve were estimated as 1.5±1.2×10−8 mol/l and 1.3±0.4×10−6 mol/l respectively. The maximal response produced by the interaction of 5-HT with the high affinity receptor (i. e. first phase) was calculated as 27±9.3% of the total response. 3. The biphasic concentration-response was not influenced by methysergide (10−6 mol/l). 4. The effect of low concentrations of 5-HT (−7 mol/l) was antagonised by atropine (10−7 mol/l), tetrodotoxin (TTX) (10−6 mol/l), morphine (10−5 mol/l), the substance P antagonist,d-Pro4,d-Trp7,9-SP4–11 (3×10−5 mol/l) and capsaicin (10−5 mol/l). Physostigmine (10−7 mol/l) augmented the effect. 5. The response to high concentrations of 5-HT (3×10−7–3×10−6 mol/l) was antagonised by ICS 205-930 andd-Pro4,d-Trp7,9-SP4–11 in a competitive manner and was inhibited by TTX, morphine and capsaicin in an insurmountable way. 6. The effect of very high concentrations of 5-HT (>10−5 mol/l) could be partially antagonised by methysergide (10−7 mol/l) in the presence of ICS 205-930 (10−7 mol/l) and totally by a combination of methysergide and TTX. 7. We conclude that in longitudinal muscle strips from the ileum of adult guinea-pigs a contractile action of 5-HT can be mediated by the activation of three independent receptors. At concentrations below 3×10−7 mol/l 5-HT causes the release of substance P which subsequently releases acetylcholine. At concentrations higher than 3×10−7 mol/l 5-HT releases substance P which then directly activates SP-receptors on the smooth muscle cells. The stimulation of postjunctional 5-HT D-receptors only occurs at concentrations of 5-HT greater than 10−5 mol/l, and thus appears to be of minor importance.