Briejer M R, Akkermans L M, Meulemans A L, Lefebvre R A, Schuurkes J A
Department of Human and Animal Physiology, Wageningen Agricultural University, The Netherlands.
Naunyn Schmiedebergs Arch Pharmacol. 1993 May;347(5):464-70. doi: 10.1007/BF00166736.
The purpose of this study was to investigate whether the effects of cisapride and its close structural analogue R 76,186 on the isolated guinea-pig colon ascendens, are mediated through 5-HT4 receptors. Both cisapride and R 76,186 induced contractions in a concentration-dependent fashion, giving monophasic concentration-response curves (cisapride: EC50 = 1.1 x 10(-7) M, maximum effect = 40.3% of methacholine-induced (3 x 10(-7) M) contractions; R 76,186: EC50 = 2.4 x 10(-8) M, maximum effect = 52.1%). Blockade of either 5-HT2 or 5-HT3 receptors did not affect the responses to cisapride. However, tropisetron (in 5-HT4 receptor-blocking concentrations), and DAU 6285 and SDZ 205-557, two novel selective 5-HT4 receptor antagonists, depressed the concentration-response curve to cisapride (to about 50%), and the curve to R 76,186 was shifted to the right. The apparent pA2 values were 6.6 (tropisetron), 6.3 (DAU 6285), and 7.5 (SDZ 205-557). However, none of these antagonisms was purely competitive as higher concentrations of these antagonists depressed the curve to R 76,186. Desensitization of the 5-HT4 receptor with 5-methoxytryptamine (5-MeOT) inhibited the responses to cisapride, and abolished those to R 76,186. The contractions to cisapride and R 76,186 were sensitive to mutual antagonism, depressing their concentration-response curves.
Both cisapride and R 76,186 mediate their contractile effects in the guinea-pig colon ascendens through agonism at the 5-HT4 receptor, though cisapride also uses a non-5-HT mechanism. R 76,186 is a selective and potent 5-HT4 receptor agonist.
本研究的目的是调查西沙必利及其结构类似物R 76,186对离体豚鼠升结肠的作用是否通过5-羟色胺4（5-HT4）受体介导。西沙必利和R 76,186均以浓度依赖性方式诱导收缩，呈现单相浓度-反应曲线（西沙必利：半数有效浓度（EC50）= 1.1×10⁻⁷ M，最大效应 = 乙酰甲胆碱诱导的（3×10⁻⁷ M）收缩的40.3%；R 76,186：EC50 = 2.4×10⁻⁸ M，最大效应 = 52.1%）。阻断5-HT2或5-HT3受体均不影响对西沙必利的反应。然而，托烷司琼（处于5-HT4受体阻断浓度）以及两种新型选择性5-HT4受体拮抗剂DAU 6285和SDZ 205-557使西沙必利的浓度-反应曲线降低（至约50%），且R 76,186的曲线右移。表观拮抗常数（pA2）值分别为6.6（托烷司琼）、6.3（DAU 6285）和7.5（SDZ 205-557）。然而，这些拮抗作用均非纯粹竞争性的，因为这些拮抗剂的更高浓度会使R 76,186的曲线降低。用5-甲氧基色胺（5-MeOT）使5-HT4受体脱敏可抑制对西沙必利的反应，并消除对R 76,186的反应。对西沙必利和R 76,186的收缩反应对相互拮抗敏感，使它们的浓度-反应曲线降低。
西沙必利和R 76,186均通过激动5-HT4受体介导其在豚鼠升结肠的收缩作用，不过西沙必利也利用了一种非5-HT机制。R 76,186是一种选择性强效5-HT4受体激动剂。
