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[摘要]：The monoamine, 5-hydroxytryptamine (5-HT), stimulates contraction of human uterine smooth muscle (myometrium), but the receptor subtypes involved have not been characterized. We studied the effects of a range of 5-HT receptor subtype-selective agonists and antagonists in isolated strips of myometrium obtained at the time of caesarean section. The 5-HT1A receptor agonist, 8-hydroxy-2-dipropylaminotetralin, produced an increase in contractions that was highly variable, of low potency, and was not significantly inhibited by the 5-HT1A antagonist WAY100635 [[O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl) ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide]. The 5-HT2 receptor agonist, alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT), produced a strong, consistent, and concentration-dependent stimulation of contractions (pEC(50) = 7.60 +/- 0.10, n = 5). The 5-HT2A receptor antagonist, ketanserin [3-[2-[4-(4-fluoro benzoyl)-piperidin-1-yl] ethyl]-1H-quinazoline-2,4-dione], caused a parallel shift in the response to alpha-Me-5-HT, with a pK(B) value consistent with its known affinity for the 5-HT2A receptor (pK(B) = 8.47 +/- 0.16, n = 5), but it had no effect on the response to oxytocin. The 5-HT2B and 5-HT2C receptor agonists, BW723C86 [(alpha-methyl-5-(2-thienylmethoxy)-1H-indole-3-ethanamine)] and Ro-60-01-75 [(S)-2-(6-chloro-5-fluoro-indol-1-yl)-1-methyl-ethylamine fumarate], produced inconsistent responses at potencies that were lower than expected for activation of their cognate receptors. The response to alpha-Me-5-HT was unaffected by the 5-HT2B and 5-HT2C receptor antagonists, SB204741 [(N-(1-methyl-1H-indolyl-5yl)-N-(3-methyl-5-isothiazolyl) urea)] and RS102221 [8-[5-(2,4dimethoxy-5-(4-trifluoromethyl phenylsulphonamido) phenyl-5-oxopentyl]-1,3,8-triazaspiro[4.5] decane-2,4-dione]. The 5-HT1B/1D receptor agonist, sumatriptan [1-[3-(2-dimethylaminoethyl)-1H-indol5-yl]-N-methyl-methanesulfonamide], the 5-HT4 agonist, cisapride [4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy) propyl]-3-methoxy-4-piperidyl]-2-methoxy-benzamide], and the 5-HT7 agonist, AS19 [(2S)-(+)-5-(1,3,5-trimethylpyrazol-4-yl)- 2-(dimethylamino) tetralin], all had no effect on myometrial contractility. 5-HT2A receptor mRNA and immunoreactivity were identified using reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemistry. Specific binding of [H-3] ketanserin was demonstrated. This study provides strong evidence for the expression of contractile 5-HT2A receptors in pregnant human myometrium, and this receptor is a potential target for novel uterotonic therapies. |
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