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-HT 1C or 5-HT 2 receptors, an indirect sympathomimetic effect or a mechanism independent of 5-HT 2 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-HT 1C and 5-HT 2 receptors are linked to phosphoinositide hydrolysis and the noradrenaline (NA) released by 5-HT can stimulate the β 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 μM) did not modify total inositol phosphate (IP) production, while 5-HT 10 and 50 μM increased it 2-fold. The 5-HT 2 antagonist ketanserin (1 μM) abolished IP accumulation induced by 5-HT (50 μM), which indicates that this accumulation is 5-HT 2 and not 5-HT 1C receptor-mediated. Moreover, cyclic AMP (cAMP) formation was enhanced by 5-HT (5, 10, 20 and 50 μM). When atria were incubated 10 min with the β-adrenergic receptor antagonist nadolol (1 μM), the increase in the cAMP level induced by 5-HT, whatever its concentration (10, 20 or 50 μM), 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 μM on adenylate cyclase activity. Thus, the 5-HT-induced increase in cAMP is indirectly due to the activation of the β-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-HT 2 receptors and by an indirect sympathomimetic effect.