Functional study for physiological role of 5-hydroxytryptamine7 receptors in porcine myometrium

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5-Hydroxytryptamine (5-HT) inhibits the spontaneous contraction in longitudinal (LM) and circular muscles (CM) of the porcine uterus but CM is more sensitive to 5-HT than LM.The present experiments were designed to clarify the 5-HT receptor subtype mediating the inhibition, subcellular mechanisms of the inhibition and mechanisms underlying the muscle layer-dependent inhibition by 5-HTReceptor subtype : On the basis of ranking order of 5-HT receptor agonists (5-carboxamidotryptamine>5-HT>5-methoxytryptamine>8-hydroxy-2-(di-n-propylamino) tetralin) and 5-HT receptor antagonists (methiothepin>methysergide>metergoline>mianserin>clozapine>spiperone), it was demonstrated that the 5-HT_7 receptor mediated the inhibition of myometrial contractility by 5-HT.Inhibitory mechanism : Analysis of the 5-HT-induced inhibition suggested a following cascade of events in the porcine myometrium : 5-HT_7 receptor activation→activation of Gs→activation of adenylate cyclase→increase in cAMP→decrease in [Ca^< … More 2+>]i and Ca^<2+>-sensitivity of the contractile elements→inhibition of muscle contractility.5-HT_7receptor distribution : LM and CM layers contained a single class of [^3H]5-carboxamidotryptamine binding sites with a similar Kd value. However, Bmax in the CM was 4-times higher than that in the LM.The molecular study (reverse transcription polymerase chain reaction) demonstrated that the expression of 5-HT_7 receptor mRNA in the CM was higher than that in the LM.5-HT increased the cAMP in both muscle layers, but the increment in the CM was higher than that in the LM.Therefore, it was suggested that the different inhibition of the contractility by 5-HT was caused by muscle layer-related accumulation of cAMP (CM>LM), due to muscle-layer dependent distribution (CM>LM) of 5-HT_7 receptors. This heterogeneous distribution of 5-HT_7 receptor is quite unique and different from that of other receptors (muscarinc M_3 receptor, histamine H_1 receptor , endothelin A receptor, β and α2-adrenaline receptors, LM>CM) present in the porcine uterus.Muscle layer-dependent inhibition : 5-HT_7 and β_2-adrenaline receptor-mediatd pathways were the main inhibitory mechanisms in the porcine myometrium and shared in the inhibition of contractility in a smooth muscle layer-dependent manner (LM : β_2-adrenoceptors, CM : 5-HT_7 receptors). The responses of 5-HT and isoproterenol differ from region to region, probably because of differences in the dominant subtype of 5-HT receptors and density of β_2-adrenaline receptors. Bioactive peptides and nitric oxide do not play a significant physiological role (as inhibitory agents) in the regulation of porcine uterine contractility. Less