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Characterization of the 5‐HT 4 receptor mediating tachycardia in piglet isolated right atrium
Author(s) -
Medhurst Andrew D.,
Kaumann Alberto J.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13916.x
Subject(s) - agonist , pargyline , chemistry , partial agonist , potency , hydrochloride , pharmacology , stereochemistry , receptor , serotonin , biology , biochemistry , in vitro
1 In order to explore whether 5‐HT 4 receptor subtypes exist, we have characterized further the 5‐HT 4 receptor that mediates tachycardia in the piglet isolated right atrium. All experiments were carried out in the presence of propranolol (400 n m ) and cocaine (6 μ m ). We used tryptamine derivatives, substituted benzamides and benzimidazolone derivatives as pharmacological tools. 2 Tachycardia responses to 5‐hydroxytryptamine (5‐HT) were mimicked by other tryptamine derivatives with the following order of potency: 5‐HT > 5‐methoxytryptamine > α‐methyl‐5‐HT = bufotenine > 5‐carboxamidotryptamine = tryptamine (after treatment with pargyline) > 5‐methoxy‐ N , N ‐dimethyltryptamine > 2‐methyl‐5‐HT. 3 The substituted benzamides were all partial agonists relative to 5‐HT except (−)‐zacopride which was a full agonist. The stimulant potency order was renzapride > cisapride = (−)‐zacopride > metoclopramide > (+)‐zacopride. 4 The benzimidazolone derivatives had contrasting effects. BIMU 8 (endo‐N‐(8‐methyl‐8‐azabicyclo[3.2.1]oct‐3‐yl)‐2,3‐dihydro‐(1‐methyl(ethyl‐2‐oxo‐1H‐benzimidazole‐1‐carboxamide hydrochloride) was a full agonist relative to 5‐HT whilst BIMU 1 (endo‐N‐(8‐methyl‐8‐azabicyclo[3.2.1]oct‐3‐yl)‐2,3‐dihydro‐3‐ethyl‐2‐oxo‐1H‐benzimidazole‐1‐carboxamide hydrochloride) was a partial agonist with low intrinsic activity compared to 5‐HT but had similar potency. We estimated a p K B of 7.9 for BIMU 1 antagonism of 5‐HT‐induced tachycardia. DAU 6215 (N‐endo‐8‐methyl‐8‐azabicyclo[3.2.1]‐oct‐3‐yl)‐2,3‐dihydro‐2‐oxo‐1H‐benzimidazole‐1‐carboxamide, hydrochloride) had no chronotropic activity and was found to be a simple competitive antagonist with a p K B of 7.1 5 SB 203186 (1‐piperidinyl)ethyl 1H‐indole 3‐carboxylate) was a potent antagonist with a p K B of 8.3. The affinity of SB 203186 was approximately 20 times higher than that of tropisetron (ICS 205–930; p K B = 6.9) and DAU 6215 (p K B = 7.0). GR113808 (([1‐[2‐[methylsulphonyl amino]ethyl]‐4‐piperidinyl] methyl 1‐methyl‐1H‐indole‐3‐carboxylate) and SDZ 205–557 ((2‐diethylaminoethyl)2‐methoxy‐4‐amino‐5‐chloro‐benzoate) also antagonized 5‐HT‐induced tachycardia but not by simple competitive blockade. 6 The sinoatrial 5‐HT 4 receptor in the piglet has a pharmacological profile that correlates well with 5‐HT 4 receptors characterized in rat oesophagus, guinea‐pig ileum and colon, mouse embryonic colliculi neurones and human atrium.