Effects of leukotrienes on ion transport in human calonic mucosa

白三烯在炎症性肠病中起重要作用。以往的研究揭示了多肽脑三烯对平滑肌收缩和跨粘膜离子转运的影响，这可能导致肠运动亢进和电解质和水分的丢失，即腹泻。本研究的目的是评价多肽脑三烯拮抗剂ONO-1078的作用，并评估其未来的临床应用。我们用Ussing和Mugnus技术研究了ONO-1078对肽类化合物引起的大鼠结肠电解质转运和肌肉收缩的影响。在结肠镜检查中获得的人体活检标本也被用于离子转运研究。在估计的间质浓度(1 nm-100 nm)下，相同剂量的多肽优三烯可引起大鼠和人的跨粘膜离子转运和大鼠结肠的平滑肌收缩。短路电流变化的时间过程有两个阶段，即快速和一过性降低和随后的一过性增加，这似乎主要是由于钠离子和氯离子引起的。大鼠结肠平滑肌在加入多肽后短暂收缩，这种作用可能与炎症性肠病的腹泻有关。ONO-1078有望在临床上有效地用于治疗轻至中度炎症性肠病中与肽多优三烯相关的腹泻。

Leukotrienes play important roles in inflammatory bowel diseases. Previous studies have revealed the effects of peptidoleukotrienes on smooth muscle contraction and transmucosal ion transport, which may cause hyperactive bowel movement and the loss of electrolytes and water, i.e., diarrhea.The purpose of the present study was to evaluate the effects of the peptidoleukotrienes antagonist ONO-1078 and to assess its possible future clinical use. We examined the effects of ONO-1078 on peptidoleukotrienes-induced changes in electrolyte transport and muscle contraction in the rat colon, with the Ussing and Mugnus techniques. Human biopsy specimens obtained at colonoscopy were also used for ion transport studies. Transmucosal ion transport in both rats and humans, and smooth muscle contractions in the rat colon, were induced by similar doses of peptidoleukotrienes at estimated interstitial concentration (1nM-100nM). The time course of changes in short circuit current had two phases, a rapid and transient decrease and a subsequent transient increase, which seemed to be due mainly to Na^+ and Cl_-, respectively.Rat colon smooth muscle contracted transiently after the addition of peptidoleukotorienes.These effects of peptidoleukotrienes, which could be related to the diarrhea in inflammatory bowel diseases, were inhibited by ONO-1078. ONO-1078 is expected to be effective in clinical use against peptidoleukotrienes-related diarrhea in mild to moderate inflammatory bowel diseases.