5-HT7 receptor-mediated relaxation of the oviduct in nonpregnant proestrus pigs.

The effects of 5-hydroxytryptamine (5-HT) on the muscle tonus of the ampulla and isthmus of the oviduct isolated from nonpregnant proestrus pigs were investigated, and the 5-HT receptor subtype and mechanisms of the responses were analyzed. 5-HT (1 nM-10 microM) caused a relaxation of longitudinal and circular muscles of the isthmus in a concentration-dependent manner. Tetrodotoxin did not change the relaxation, indicating a direct action of 5-HT on smooth muscle cells. The EC(50) value in the longitudinal muscle was significantly lower than that in the circular muscle but the maximum relaxations were similar. 5-HT also caused a relaxation of both muscle layers in the ampulla but the maximum relaxation of both muscles was smaller than that of the isthmus. 5-Carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT) and (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) mimicked the relaxation of the isthmic longitudinal muscle by 5-HT, and the ranking order was 5-CT>5-HT>5-MeOT>8-OH-DPAT. On the other hand, oxymethazoline, 2-methyl-5-hydroxytryptamine (2-methyl-5-HT), alpha-methyl-5-hydroxytryptamine (alpha-methyl-5-HT), [endo-N-8-methyl-8-azabicyclo-(3,2,1) oct-3-yl]-2,3-dihydro-3-ethyl-2-oxo-1H-benzimidazol-1-carboxamide (BIMU-1), ergotamine and dihydroergotamine were less effective. The relaxation by 5-HT was not decreased by ketanserin, 2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino)ethyl ester (tropisetron) or [1[2-(methylsulphonyl) amino ethyl]-4-piperidinyl]methyl-1-methyl-1H-indole-3-carboxylate (GR113808) but was antagonized by the following compounds in a competitive manner (with pK(b) values in parentheses): 2a-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-2a,3,4,5-tetrahydro-benzo[cd]indol-2(1H)-one (DR4004, 9.31), methiothepin (8.91), methysergide (7.95), metergoline (7.98), mianserin (7.69), mesulergine (8.4), spiperone (6.86) and clozapine (7.4). The correlation of these pK(b) values with pK(i) values of cloned 5-HT(7) receptor or pA(2) values of porcine uterus was high and significant. 4-(3-Butoxy-4-methoxybenzyl)-imidazolidin-2-one (Ro20-1724) significantly enhanced the relaxation by 5-HT but zaprinast, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and L-nitroarginine methylester (L-NAME) did not change the responses to 5-HT. 5-HT increased cyclic AMP in the isthmic oviduct. Ampulla and isthmus contained a single class of [3H]5-CT binding sites with a similar K(d) value (0.4 nM), but the density of the receptors in the isthmus was 2.4 times higher than that in the ampulla. A significant correlation was found between the pK(i) values in the oviduct and those of the cloned 5-HT(7) receptors. Isoprenaline, sodium nitroprusside, vasoactive intestinal peptide and pituitary adenylate cyclase activating peptide were less effective in causing the relaxation of the oviduct. In conclusion, the 5-HT receptor, functionally correlated to the 5-HT(7) type, mediates the relaxation of the porcine oviduct by 5-HT through an increase in intracellular cyclic AMP. The degrees of 5-HT-induced relaxation in the isthmus and ampulla of the oviduct were different due to the heterogeneous distribution of 5-HT(7) receptors. The strongest relaxation through 5-HT(7) receptor activation suggests that 5-HT plays an important physiological role in the regulation of porcine oviduct contractility.