Characterisation of a postjunctional 5-ht(7)-like and a prejunctional 5-HT3 receptor mediating contraction of rat isolated jejunum

The 5-HT (5-hydroxytryptamine)-induced contractile biphasic concentration-effect curve in rat isolated jejunum was investigated. The PEC(50) values for the first and second phases were 8.0 and 6.1, respectively. The responses were insensitive to atropine (0.1 mu M), ketanserin(2 mu M),(-)pindolol(5 mu M), yohimbine (0.1 mu M) and GR 113808 ({1-[2-(methyl-sulphonylamino)ethyl]-4-piperidinyl}methyl 1-methyl-1H-indole-3-carboxylate, 1 mu M) but susceptible to cocaine (10 mu M) The low affinity phase was blocked by tetrodotoxin (1 mu M), ondansetron (1 mu M) and SR48968 (S)-N-methyl-N-[4-(4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl)butyl]benzamide, 0.1 mu M) The high affinity phase was antagonised non-surmountably by fluoxetine (1 mu M) methysergide(0.1 mu M), spiperone (0.1 mu M) and methiothepin (0.1 mu M) Ritanserin (0.01-0.1 mu M) and mesulergine (0.01-0.1 mu M) acted as surmountable, competitive antagonists with pA(2) values of 8,0 and 8.1, respectively. Clozapine (0.1 mu M) was a surmountable antagonist with an apparent pA(2) value of 8.0. The rank potency order of the 5-HT receptor agonists was 5-CT (5-carboxyamidotryptamine) greater than or equal to 5-HT = 5-methoxytryptamine greater than or equal to alpha-methyl-5-HT much greater than 8-OH-DPAT ((+/-)-2-dipropyl-amino-8-hydroxy-1,2,3,4-tetrahydronaphthalene) > dipropyl-5-CT > renzapride = sumatriptan. The responses to 5-HT and 5-CT were not potentiated by pargyline (10 and 100 mu M). It is suggested that rat jejunum contains a neuronal 5-HT3 receptor facilitating neurokinin release and a contractile smooth muscle 5-HT receptor with a pharmacological operational profile similar to the cloned 5-ht(7) receptor.