title: Biochemical characterization of the mechanisms involved in the 5-hydroxytryptamine-induced increase in rat atrial rate.
abstract: Several possible mechanisms for 5-hydroxytryptamine (5-HT)-induced tachycardia in rat have been suggested: an activation of 5-HT1C or 5-HT2 receptors, an indirect sympathomimetic effect or a mechanism independent of 5-HT2 receptor stimulation. The aim of this study was to investigate the involvement of these mechanisms in the 5-HT-induced increase in rat atrial rate using biochemical methods. Indeed, the 5-HT1C and 5-HT2 receptors are linked to phosphoinositide hydrolysis and the noradrenaline (NA) released by 5-HT can stimulate the beta 1-adrenergic receptors linked to adenylate cyclase stimulation. The effect of varying concentrations of 5-HT on inositol phospholipid hydrolysis and adenylate cyclase activity of the rat isolated atria were measured. 5-HT (2 microM) did not modify total inositol phosphate (IP) production, while 5-HT 10 and 50 microM increased it 2-fold. The 5-HT2 antagonist ketanserin (1 microM) abolished IP accumulation induced by 5-HT microM), which indicates that this accumulation is 5-HT2 and not 5-HT1C receptor-mediated. Moreover, cyclic AMP (cAMP) formation was enhanced by 5-HT (5, 10, 20 and 50 microM). When atria were incubated 10 min with the beta-adrenergic receptor antagonist nadolol (1 microM), the increase in the cAMP level induced by 5-HT, whatever its concentration (10, 20 or 50 microM), was inhibited. Treating rats with reserpine (2.5 mg/kg, i.p., 48 and 24 hr before experimentation), which caused NA depletion in the heart, seemed to reduce the stimulating effect of 5-HT 10 and 50 microM on adenylate cyclase activity. Thus, the 5-HT-induced increase in cAMP is indirectly due to the activation of the beta-adrenergic receptors by the NA released by 5-HT. It is concluded that 5-HT stimulates both phosphoinositide turnover and adenylate cyclase activity in the rat isolated atria by activation of 5-HT2 receptors and by an indirect sympathomimetic effect.
authors.affiliation: Laboratoire de Pharmacologie, Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry, France.
authors.forename: C
authors.initials: C
authors.lastname: el Rawadi
authors.forename: M
authors.initials: M
authors.lastname: Davy
authors.forename: M
authors.initials: M
authors.lastname: Midol-Monnet
authors.forename: Y
authors.initials: Y
authors.lastname: Cohen
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006325:Heart Atria / Q000187:drug effects*; D007295:Inositol Phosphates / Q000378:metabolism; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D009248:Nadolol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology
chemical_list: D000319:Adrenergic beta-Antagonists; D007295:Inositol Phosphates; D012702:Serotonin Antagonists; D012701:Serotonin; D009248:Nadolol; D012110:Reserpine; D007650:Ketanserin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases