CHARACTERIZATION OF THE 5-HT(4) RECEPTOR MEDIATING TACHYCARDIA IN PIGLET ISOLATED RIGHT ATRIUM

1 In order to explore whether 5-HT4 receptor subtypes exist, we have c haracterized further the 5-HT4 receptor that mediates tachycardia in t he piglet isolated right atrium. All experiments were carried out in t he presence of propranolol (400 nm) and cocaine (6 muM). We used trypt amine derivatives, substituted benzamides and benzimidazolone derivati ves as pharmacological tools. 2 Tachycardia responses to 5-hydroxytryp tamine (5-HT) were mimicked by other tryptamine derivatives with the f ollowing order of potency: 5-HT > 5-methoxytryptamine > alpha-methyl-5 -HT = bufotenine > 5-carboxamidotryptamine = tryptamine (after treatme nt 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 potenc y order was renzapride > cisapride = (-)-zacopride > metoclopramide > (+)-zacopride. 4 The benzimidazolone derivatives had contrasting effec ts. BIMU 8 -methyl(ethyl-2-oxo-1H-benzimidazole-1-carboxamide hydrochl oride) was a full agonist relative to 5-HT whilst BIMU 1 hydro-3-ethyl -2-oxo-1H-benzimidazole-1-carboxamide hydrochloride) was a partial ago nist with low intrinsic activity compared to 5-HT but had similar pote ncy. We estimated a pK(B) of 7.9 for BIMU 1 antagonism of 5-HT-induced tachycardia. DAU 6215 -2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxami de, hydrochloride) had no chronotropic activity and was found to be a simple competitive antagonist with a pK(B) of 7.1 5 SB 203186 (1-piper idinyl)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 high er than that of tropisetron (ICS 205-930; pK(B) = 6.9) and DAU 6215 (p K(B) = 7.0). GR113808 (([1-[2-[methylsulphonyl amino]ethyl]-4-piperidi nyl] methyl 1-methyl-1H-indole-3-carboxylate) and SDZ 205-557 hylamino ethyl)2-methoxy-4-amino-5-chloro-benzoate) also antagonized 5-HT-induc ed tachycardia but not by simple competitive blockade. 6 The sinoatria l 5-HT4 receptor in the piglet has a pharmacological profile that corr elates well with 5-HT4 receptors characterized in rat oesophagus, guin ea-pig ileum and colon, mouse embryonic colliculi neurones and human a trium.