Involvement of 5‐hydroxytryptamine 7 receptors in inhibition of porcine myometrial contractility by 5‐hydroxytryptamine

5‐Hydroxytryptamine (5‐HT; 1 n M –100 μ M ) concentration‐dependently inhibited the amplitude and frequency of spontaneous contractions in longitudinal and circular muscles of the porcine myometrium. The circular muscle (EC 50 ; 68–84 n M ) was more sensitive than the longitudinal muscle (EC 50 ; 1.3–1.44 μ M ) to 5‐HT. To characterize the 5‐HT receptor subtype responsible for inhibition of myometrial contractility, the effects of 5‐HT receptor agonists on spontaneous contractions and of 5‐HT receptor antagonists on inhibition by 5‐HT were examined in circular muscle preparations. Pretreatment with tetrodotoxin (1 μ M ), propranolol (1 μ M ), atropine (1 μ M ), guanethidine (10 μ M ) or L ‐NAME (100 μ M ) failed to change the inhibition by 5‐HT, indicating that the inhibition was due to a direct action of 5‐HT on the smooth muscle cells. 5‐CT, 5‐MeOT and 8‐OH‐DPAT mimicked the inhibitory response of 5‐HT, and the rank order of the potency was 5‐CT>5‐HT>5‐MeOT>8‐OH‐DPAT. On the other hand, oxymethazoline, α‐methyl‐5‐HT, 2‐methyl‐5‐HT, cisapride, BIMU‐1, BIMU‐8, ergotamine and dihydroergotamine had almost no effect on spontaneous contractions, even at 10–100 μ M . Inhibition by 5‐HT was not decreased by either pindolol (1 μ M ), ketanserin (1 μ M ), tropisetron (10 μ M ), MDL72222 (1 μ M ) or GR113808 (10 μ M ), but was antagonized by the following compounds in a competitive manner (with pA 2 values in parentheses): methiothepin (8.05), methysergide (7.92), metergoline (7.4), mianserin (7.08), clozapine (7.06) and spiperone (6.86). Ro 20‐1724 (20 μ M ) and rolipram (10 μ M ) significantly enhanced the inhibitory response of 5‐HT, but neither zaprinast (10 μ M ) nor dipyridamole (10 μ M ) altered the response of 5‐HT. 5‐HT (1 n M –1 μ M ) caused a concentration‐dependent accumulation of intracellular cyclic AMP in the circular muscle. From the present results, the 5‐HT receptor, which is functionally correlated with the 5‐HT 7 receptor, mediates the inhibitory effect of 5‐HT on porcine myometrial contractility. This inhibitory response is probably due to an increase in intracellular cyclic AMP through the activation of adenylate cyclase that is positively coupled to 5‐HT 7 receptors.British Journal of Pharmacology (1998) 123 , 173–182; doi: 10.1038/sj.bjp.0701583