INVOLVEMENT OF 5-HYDROXYTRYPTAMINE(7) RECEPTORS IN INHIBITION OF PORCINE MYOMETRIAL CONTRACTILITY BY 5-HYDROXYTRYPTAMINE

1 5-Hydroxytryptamine (5-HT; 1 nM-100 mu M) concentration-dependently inhibited the amplitude and frequency of spontaneous contractions in l ongitudinal and circular muscles of the porcine myometrium. The circul ar muscle (EC50; 68-84 nM) was more sensitive than the longitudinal mu scle (EC50; 1.3-1.44 mu M) to 5-HT. To characterize the 5-HT receptor subtype responsible for inhibition of myometrial contractility, the ef fects of 5-HT receptor agonists on spontaneous contractions and of 5-H T receptor antagonists on inhibition by 5-HT were examined in circular muscle preparations. 2 Pretreatment with tetrodotoxin (1 mu M), propr anolol (1 mu M), atropine (1 mu M), guanethidine (10 mu M) or L-NAME ( 100 mu 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 ce lls. 3 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-O H-DPAT. On the other hand, oxymethazoline, alpha-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 mu M. 4 Inhibition by 5-HT was not decreased by either pindolol (1 mu M), keta nserin (1 mu M), tropisetron (10 mu M), MDL72222 (1 mu M) Or GR113808 (10 mu M), but was antagonized by the following compounds in a competi tive manner (with pA(2) values in parentheses): methiothepin (8.05), m ethysergide (7.92), metergoline (7.4), mianserin (7.08), clozapine (7. 06) and spiperone (6.86). 5 Ro 20-1724 (20 mu M) and rolipram (10 mu M ) significantly enhanced the inhibitory response of 5-HT, but neither zaprinast (10 mu M) nor dipyridamole (10 mu M) altered the response of 5-HT. 6 5-HT (1 nM-1 mu M) caused a concentration-dependent accumulat ion of intracellular cyclic AMP in the circular muscle. 7 From the pre sent 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 ade nylate cyclase that is positively coupled to 5-HT7 receptors.