Fedorak R N, Empey L R, Walker K
Department of Medicine, University of Alberta, Edmonton, Canada.
Gastroenterology. 1992 Apr;102(4 Pt 1):1229-35.
In inflammatory bowel disease, prostaglandins are mucosal protective whereas leukotrienes are proinflammatory. Recent evidence suggests that the formation and action of leukotrienes are calcium-dependent, whereas the formation and action of prostaglandins are not. To examine the possibility that, because of differential regulation of arachidonic acid metabolism, calcium channel blockade might alter mucosal eicosanoid synthesis and accelerate healing during inflammatory bowel disease, we treated a 4% acetic acid-induced colitis model with verapamil and/or misoprostol and determined the effects on colonic macroscopic injury, mucosal inflammation as measured by myeloperoxidase activity, in vivo intestinal fluid absorption, and mucosal prostaglandin E2 and leukotriene B4 (LTB4) levels as measured by in vivo rectal dialysis. In colitic animals, verapamil treatment significantly improved colonic fluid absorption and macroscopic ulceration. This mucosal-protective effect of verapamil occurred in the presence of a twofold reduction in mucosal LTB4 synthesis. In noncolitic animals, verapamil alone had no effect on in vivo fluid absorption, macroscopic ulceration, or myeloperoxidase activity but did induce a threefold reduction in LTB4 synthesis in addition to shifting arachidonic acid metabolism towards a sixfold stimulation of prostaglandin E2 synthesis. Our results show that, when administered before the experimental induction of colitis, the calcium channel blocker, verapamil, has a mucosal-protective effect that occurs as a consequence of reduced mucosal leukotriene synthesis and increased prostaglandin synthesis. This differential regulation of arachidonic acid metabolism may play an important role in the development of novel therapeutic agents for inflammatory bowel disease.
在炎症性肠病中，前列腺素具有黏膜保护作用，而白三烯则具有促炎作用。最近的证据表明，白三烯的形成和作用依赖于钙，而前列腺素的形成和作用则不依赖于钙。为了研究由于花生四烯酸代谢的差异调节，钙通道阻滞剂可能会改变炎症性肠病期间黏膜类花生酸的合成并加速愈合，我们用维拉帕米和/或米索前列醇治疗了4%乙酸诱导的结肠炎模型，并确定了其对结肠宏观损伤、通过髓过氧化物酶活性测量的黏膜炎症、体内肠液吸收以及通过体内直肠透析测量的黏膜前列腺素E2和白三烯B4（LTB4）水平的影响。在结肠炎动物中，维拉帕米治疗显著改善了结肠液吸收和宏观溃疡。维拉帕米的这种黏膜保护作用发生在黏膜LTB4合成减少两倍的情况下。在非结肠炎动物中，单独使用维拉帕米对体内液体吸收、宏观溃疡或髓过氧化物酶活性没有影响，但除了使花生四烯酸代谢向前列腺素E2合成的六倍刺激转变外，还导致LTB4合成减少三倍。我们的结果表明，在实验性诱导结肠炎之前给予钙通道阻滞剂维拉帕米，会产生黏膜保护作用，这是由于黏膜白三烯合成减少和前列腺素合成增加所致。花生四烯酸代谢的这种差异调节可能在炎症性肠病新型治疗药物的开发中起重要作用。
