Article date: January 1998
By: Takio Kitazawa, Osamu Kubo, Masami Satoh, Tetsuro Taneike, in Volume 123, Issue 2, pages 173-182
5‐Hydroxytryptamine (5‐HT; 1 nM–100 μM) concentration‐dependently inhibited the amplitude and frequency of spontaneous contractions in longitudinal and circular muscles of the porcine myometrium. The circular muscle (EC50; 68–84 nM) was more sensitive than the longitudinal muscle (EC50; 1.3–1.44 μM) 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 μM), propranolol (1 μM), atropine (1 μM), guanethidine (10 μM) or L‐NAME (100 μM) 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 μM.
Inhibition by 5‐HT was not decreased by either pindolol (1 μM), ketanserin (1 μM), tropisetron (10 μM), MDL72222 (1 μM) or GR113808 (10 μM), but was antagonized by the following compounds in a competitive manner (with pA2 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 μM) and rolipram (10 μM) significantly enhanced the inhibitory response of 5‐HT, but neither zaprinast (10 μM) nor dipyridamole (10 μM) altered the response of 5‐HT.
5‐HT (1 nM–1 μM) 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‐HT7 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‐HT7 receptors.
5‐Hydroxytryptamine (5‐HT; 1 nM–100 μM) concentration‐dependently inhibited the amplitude and frequency of spontaneous contractions in longitudinal and circular muscles of the porcine myometrium. The circular muscle (EC50; 68–84 nM) was more sensitive than the longitudinal muscle (EC50; 1.3–1.44 μM) 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 μM), propranolol (1 μM), atropine (1 μM), guanethidine (10 μM) or L‐NAME (100 μM) 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 μM.
Inhibition by 5‐HT was not decreased by either pindolol (1 μM), ketanserin (1 μM), tropisetron (10 μM), MDL72222 (1 μM) or GR113808 (10 μM), but was antagonized by the following compounds in a competitive manner (with pA2 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 μM) and rolipram (10 μM) significantly enhanced the inhibitory response of 5‐HT, but neither zaprinast (10 μM) nor dipyridamole (10 μM) altered the response of 5‐HT.
5‐HT (1 nM–1 μM) 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‐HT7 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‐HT7 receptors.
British Journal of Pharmacology (1998) 123, 173–182; doi:10.1038/sj.bjp.0701583
DOI: 10.1038/sj.bjp.0701583
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