Barone F C, Bondinell W E, Labosh T J, White R F, Ormsbee H S
Department of Pharmacology, Smith Kline and French Laboratories, King of Prussia, PA 19406.
Life Sci. 1989;44(8):533-42. doi: 10.1016/0024-3205(89)90615-2.
The motor effects of cholecystokinin 26-33-amide (CCK octapeptide; CCK-OP) and several purported CCK receptor antagonists on canine colonic circular muscle were determined in pentobarbital anesthetized dogs. Intravenous injections of CCK-OP had no effect on colonic motility at doses that contracted the gallbladder, stomach and duodenum. CCK-OP delivered by intraarterial injection to a small segment of the proximal colon produced a dose related increase in colonic motility with one-half maximum response at 12 ng/Kg and maximum response at 50 ng/Kg. The effects of intraarterial injections of several established CCK-receptor antagonists on proximal colonic responses to intraarterial injections of CCK-OP were determined. Proglumide, 10 mg/Kg, did not produce colonic contractions itself, but antagonized CCK-OP-induced responses. Carbobenzyloxy (CBZ)-CCK27-32-amide antagonized CCK-OP-induced colonic responses and also had no effect on basal colonic motility (0.1-1 and 5 micrograms/Kg). Neither compound antagonized acetylcholine- induced colonic responses. Butoxycarbonyl (BOC)-CCK31-33-amide increased basal colonic motility, but did not alter CCK-OP-induced responses at doses of 0.1 and 0.2 mg/Kg. Dibutyryl-cGMP at a dose of 0.1 mg/Kg did not affect basal motility or CCK-OP-induced contractions. At a dose of 1.0 mg/kg it increased basal colonic motility but did not affect CCK-OP-induced contractions. Pentagastrin increased colonic motor activity only at a dose of 5 micrograms/Kg, i.a., a much higher dose than effective doses of CCK-OP. The mechanism of CCK-OP-induced colonic motor effects also was determined. Atropine sulfate, 100 micrograms/Kg, i.v. significantly reduced both intraarterial acetylcholine-and CCK-OP-induced maximum colonic contractions. Tetrodotoxin, at intravenous doses that completely block neuronal activity, did not affect maximum acetylcholine-induced contractions but practically eliminated maximum CCK-OP-induced maximum colonic responses. In conclusion, intraarterial CCK-OP produces circular muscle contraction of the canine proximal colon that is mediated by stimulation of specific CCK receptors which produce the release of acetylcholine from cholinergic enteric neurons. Proglumide and CBZ-CCK27-32-amide are effective CCK receptor antagonists at these colonic neuronal receptors.
在戊巴比妥麻醉的犬身上，测定了胆囊收缩素26 - 33 -酰胺（CCK八肽；CCK - OP）及几种所谓的CCK受体拮抗剂对犬结肠环行肌的运动效应。静脉注射CCK - OP在能使胆囊、胃和十二指肠收缩的剂量下，对结肠运动没有影响。经动脉注射CCK - OP至近端结肠的一小段，可使结肠运动呈剂量相关性增加，12 ng/Kg时产生半数最大反应，50 ng/Kg时产生最大反应。测定了经动脉注射几种已确定的CCK受体拮抗剂对近端结肠对经动脉注射CCK - OP反应的影响。10 mg/Kg的丙谷胺本身不引起结肠收缩，但可拮抗CCK - OP诱导的反应。苄氧羰基（CBZ）- CCK27 - 32 -酰胺可拮抗CCK - OP诱导的结肠反应，且对基础结肠运动也无影响（0.1 - 1和5微克/Kg）。这两种化合物均不拮抗乙酰胆碱诱导的结肠反应。丁氧羰基（BOC）- CCK31 - 33 -酰胺可增加基础结肠运动，但在0.1和0.2 mg/Kg剂量下不改变CCK - OP诱导的反应。0.1 mg/Kg剂量的二丁酰环磷鸟苷不影响基础运动或CCK - OP诱导的收缩。在1.0 mg/kg剂量时，它可增加基础结肠运动，但不影响CCK - OP诱导的收缩。五肽胃泌素仅在5微克/Kg的剂量下（经动脉注射）增加结肠运动活性，该剂量远高于CCK - OP的有效剂量。还确定了CCK - OP诱导结肠运动效应的机制。静脉注射100微克/Kg硫酸阿托品可显著降低经动脉注射乙酰胆碱和CCK - OP诱导的最大结肠收缩。河豚毒素在完全阻断神经元活动的静脉剂量下，不影响最大乙酰胆碱诱导的收缩，但几乎消除了最大CCK - OP诱导的最大结肠反应。总之，经动脉注射CCK - OP可使犬近端结肠环行肌收缩，这是通过刺激特定的CCK受体介导的，该受体可使胆碱能肠神经元释放乙酰胆碱。丙谷胺和CBZ - CCK27 - 32 -酰胺是这些结肠神经元受体有效的CCK受体拮抗剂。
