Candura S M, Marraccini P, Costa L G, Manzo L, Rossi A, Coccini T, Tonini M
Department of Internal Medicine and Therapeutics, University of Pavia, Italy.
Pharmacol Toxicol. 1992 Dec;71(6):426-33. doi: 10.1111/j.1600-0773.1992.tb00573.x.
Central and peripheral alpha 2-adrenoceptors, including those of the gastrointestinal tract, have been indicated as a toxicity target of formamidine pesticides in mammals. In this study, the inhibitory effect of chlordimeform on twitch contractions from electrically-stimulated longitudinal muscle-myenteric plexus preparations (LMMPs) of the guinea-pig ileum was found to be resistant to the action of the alpha 2-adrenoceptor antagonist idazoxan. This drug was also ineffective on chlordimeform-induced inhibition of peristalsis recorded in whole ileal segments. As expected, idazoxan antagonized the inhibitory effect of the alpha 2-adrenoceptor agonist clonidine on twitch contractions and peristaltic activity. Chlordimeform reduced the amplitude of direct mechanical responses to a variety of spasmogens such as acetylcholine, histamine and substance P, suggesting a muscular site of action. Moreover, Ca(2+)-free, K(+)-depolarized LMMPs, chlordimeform inhibited submaximal contractions caused by addition of exogenous calcium, through an action apparently similar to that of the Ca2+ entry blocker nifedipine. Both chlordimeform- and nifedipine-induced inhibition of calcium contractions were reversed by the calcium channel activator BAY K 8644. This compound also partially prevented the inhibitory action of chlordimeform on peristaltic activity. On the whole, these results indicate that chlordimeform-induced depression of motor activity in the guinea-pig ileum is, at least in part, related to inhibition of transmembrane Ca2+ fluxes responsible for smooth muscle contraction.
包括胃肠道α2 -肾上腺素能受体在内的中枢和外周α2 -肾上腺素能受体，已被指出是甲脒类农药在哺乳动物体内的毒性作用靶点。在本研究中，发现杀虫脒对豚鼠回肠电刺激纵肌-肠肌丛标本（LMMPs）的抽搐收缩的抑制作用对α2 -肾上腺素能受体拮抗剂咪唑克生的作用具有抗性。该药物对杀虫脒诱导的全回肠段蠕动抑制也无效。正如预期的那样，咪唑克生拮抗了α2 -肾上腺素能受体激动剂可乐定对抽搐收缩和蠕动活动的抑制作用。杀虫脒降低了对多种痉挛剂如乙酰胆碱、组胺和P物质的直接机械反应的幅度，提示其作用位点在肌肉。此外，在无钙、钾去极化的LMMPs中，杀虫脒通过一种明显类似于钙通道阻滞剂硝苯地平的作用，抑制了添加外源钙引起的次最大收缩。杀虫脒和硝苯地平诱导的钙收缩抑制均被钙通道激活剂BAY K 8644逆转。该化合物也部分地阻止了杀虫脒对蠕动活动的抑制作用。总体而言，这些结果表明，杀虫脒诱导的豚鼠回肠运动活性抑制至少部分与抑制负责平滑肌收缩的跨膜Ca2 +通量有关。
