Galligan J J
Department of Pharmacology and Toxicology, Michigan State University, East Lansing.
J Pharmacol Exp Ther. 1993 Jan;264(1):375-83.
The actions of clonidine, 5-bromo-N-(4,5-dihydro-1H-imidazole-2-yl)-6-quinoxalinamine (UK 14304), D-Ala2, N-MePhe4, Gly-ol5 enkephalin (DAGOL), and morphine on neurogenic contractions were studied in guinea pig ileum longitudinal muscle myenteric plexus in vitro. Cholinergic contractions were evoked by 0.1 and 10 Hz transmural electrical stimuli; noncholinergic contractions (1 microM scopolamine present) were evoked only by trains of stimuli. Noncholinergic contractions were mediated largely by substance P (SP). DAGOL and morphine inhibited 0.1 Hz contractions; pD2 values were 8.0 and 6.0, respectively. DAGOL also inhibited 10-Hz cholinergic contractions (pD2 = 7.5). The actions of DAGOL were blocked by naloxone (Kb approximately 5 nM) indicative of an action at mu opioid receptors. DAGOL (1 microM) reduced by 50% noncholinergic responses evoked by 5 Hz but not 10- or 20-Hz stimulation. Morphine did not inhibit noncholinergic contractions. Clonidine and UK 14304 inhibited 0.1 Hz contractions with pD2 values of 8.1 and 7.4, respectively. Clonidine and UK 14304 also inhibited 10-Hz cholinergic contractions. UK 14304 inhibited equally well noncholinergic contractions evoked by 5-, 10- and 20-Hz stimuli. The actions of UK 14304 were blocked by idazoxan (Kb approximately 5 nM). UK 14304 and DAGOL Ka values were determined using null methods and were used to construct occupancy-response curves to measure coupling efficiency (efficacy) between agonist-occupied receptor and response. The relative efficacy of UK 14304 was: 10 Hz noncholinergic > or = 0.1 Hz cholinergic > 10 Hz cholinergic. The relative efficacy for DAGOL was: 0.1 Hz cholinergic > 10 Hz cholinergic >>> 10 Hz noncholinergic.(ABSTRACT TRUNCATED AT 250 WORDS)
在体外豚鼠回肠纵行肌肌间神经丛中,研究了可乐定、5-溴-N-(4,5-二氢-1H-咪唑-2-基)-6-喹喔啉胺(UK 14304)、D-丙氨酸2、N-甲基苯丙氨酸4、甘氨酰-醇5脑啡肽(DAGOL)和吗啡对神经源性收缩的作用。通过0.1和10Hz的跨壁电刺激诱发胆碱能收缩;非胆碱能收缩(存在1μM东莨菪碱)仅由刺激串诱发。非胆碱能收缩主要由P物质(SP)介导。DAGOL和吗啡抑制0.1Hz收缩;pD2值分别为8.0和6.0。DAGOL也抑制10Hz胆碱能收缩(pD2 = 7.5)。DAGOL的作用被纳洛酮阻断(Kb约为5nM),表明其作用于μ阿片受体。DAGOL(1μM)使5Hz刺激诱发的非胆碱能反应降低50%,但对10Hz或20Hz刺激诱发的反应无影响。吗啡不抑制非胆碱能收缩。可乐定和UK 14304抑制0.1Hz收缩,pD2值分别为8.1和7.4。可乐定和UK 14304也抑制10Hz胆碱能收缩。UK 14304对5Hz、10Hz和20Hz刺激诱发的非胆碱能收缩抑制效果相同。UK 14304的作用被咪唑克生阻断(Kb约为5nM)。使用无效方法测定UK 14304和DAGOL的Ka值,并用于构建占有率-反应曲线,以测量激动剂占据受体与反应之间的偶联效率(效能)。UK 14304的相对效能为:10Hz非胆碱能≥0.1Hz胆碱能>10Hz胆碱能。DAGOL的相对效能为:0.1Hz胆碱能>10Hz胆碱能>>>10Hz非胆碱能。(摘要截短于250字)