de Ridder W J, Schuurkes J A
Department of Gastrointestinal Pharmacology, Janssen Research Foundation, Beerse, Belgium.
J Pharmacol Exp Ther. 1993 Jan;264(1):79-88.
Prokinetic benzamides (e.g., cisapride) enhance gastrointestinal motility and transit. In vitro studies on the guinea pig ileum suggest that their effect is mediated via serotonergic 5-hydroxytryptamine (5-HT4) receptors, resulting in a facilitation of cholinergic neurotransmission. However, most in vivo studies have been performed on the canine stomach. Therefore, our aim was to determine whether the findings obtained on the guinea pig ileum can be extrapolated to another species and another organ. Does a benzamide facilitate cholinergic neutrotransmission on strips of the canine stomach in vitro? If so, does the benzamide exert its effect via a serotonergic 5-HT4 mechanism? Longitudinal muscle strips with adhering myenteric plexus were isolated from the canine stomach and were electrically stimulated at submaximal frequencies resulting in a mean contractile response of 16 +/- 7% of the response to methacholine (10(-6) M). Atropine and tetrodotoxin (both 3 x 10(-7) M) abolished the contractile responses, whereas hexamethonium (10(-4) M) had no effect. Cisapride (3 x 10(-7) M) enhanced the contractile responses from 14 to 70% (59 +/- 5% increase). 5-HT (3 x 10(-7) M) similarly enhanced the responses from 12 to 72% (58 +/- 5% increase). Cisapride induced a sustained enhancement throughout the duration of the experiment; in contrast, the effect of 5-HT subsided in about 90 min. Single-concentration administration of cisapride (10(-8)-10(-6) M) and 5-HT (10(-9)-3 x 10(-7) M) resulted in EC50 values of 1.0 (0.8-1.4) x 10(-7) M for cisapride and 1.3 (0.8-2.1) x 10(-8) M for 5-HT. Methiothepin and methysergide (both 3 x 10(-7) M; 5-HT1-receptor antagonists), ketanserin and LY 53857 (both 3 x 10(-7) M; 5-HT2-receptor antagonists), granisetron (3 x 10(-7) M; 5-HT3-receptor antagonist) or ICS 205-930 (3 x 10(-7) M; 5-HT3-receptor antagonist and in addition 5-HT4-receptor antagonist at 3 x 10(-6) M) did not reduce the responses to both cisapride and 5-HT. 1-(1-Naphthalenyl)piperazine (10(-6) M; 5-HT-receptor antagonist in the rat gastric fundus) significantly reduced the increase by 5-HT (24 +/- 7%; 7-31%) but had no effect on the cisapride (3 x 10(-7) M)-induced increase (69 +/- 4%; 8-77%).(ABSTRACT TRUNCATED AT 400 WORDS)
促动力苯甲酰胺类药物（如西沙必利）可增强胃肠动力和转运。对豚鼠回肠的体外研究表明，其作用是通过5-羟色胺能5-羟色胺（5-HT4）受体介导的，从而促进胆碱能神经传递。然而，大多数体内研究是在犬胃上进行的。因此，我们的目的是确定在豚鼠回肠上获得的研究结果是否可以外推到另一个物种和另一个器官。苯甲酰胺类药物在体外是否能促进犬胃条带的胆碱能神经传递？如果是，苯甲酰胺类药物是否通过5-羟色胺能5-HT4机制发挥作用？从犬胃中分离出带有肌间神经丛的纵行肌条，以亚最大频率进行电刺激，产生的平均收缩反应为对乙酰甲胆碱（10(-6) M）反应的16±7%。阿托品和河豚毒素（均为3×10(-7) M）可消除收缩反应，而六甲铵（10(-4) M）则无作用。西沙必利（3×10(-7) M）可使收缩反应从14%增强至70%（增加59±5%）。5-羟色胺（3×10(-7) M）同样可使反应从12%增强至72%（增加58±5%）。在整个实验过程中，西沙必利可引起持续增强；相比之下，5-羟色胺的作用在约90分钟后消退。单次给予不同浓度的西沙必利（10(-8)-10(-6) M）和5-羟色胺（10(-9)-3×10(-7) M），西沙必利的半数有效浓度（EC50）值为1.0（0.8-1.4）×10(-7) M，5-羟色胺的EC50值为1.3（0.8-2.1）×10(-8) M。甲硫噻平与甲基麦角新碱（均为3×10(-7) M；5-HT1受体拮抗剂）、酮色林与LY 53857（均为3×10(-7) M；5-HT2受体拮抗剂）、格拉司琼（3×10(-7) M；5-HT3受体拮抗剂）或ICS 205-930（3×10(-7) M；5-HT3受体拮抗剂，另外在3×10(-6) M时为5-HT4受体拮抗剂）均未降低对西沙必利和5-羟色胺的反应。1-（1-萘基）哌嗪（10(-6) M；大鼠胃底的5-HT受体拮抗剂）可显著降低5-羟色胺引起的增加（24±7%；7-31%），但对西沙必利（3×10(-7) M）引起的增加无作用（69±4%；8-77%）。（摘要截选至400字）
