上皮对钾通道开放剂NIP - 121抑制蜂毒肽诱导的豚鼠离体气管收缩的影响。

Influence of epithelium on the inhibition of melittin-induced contraction of guinea-pig isolated trachea by the potassium channel opener NIP-121.

作者信息

Shikada K, Tanaka S

机构信息

Shiraoka Research Station of Biological Science, Nissan Chemical Industries, Ltd., Saitama, Japan.

出版信息

Br J Pharmacol. 1993 Aug;109(4):1091-6. doi: 10.1111/j.1476-5381.1993.tb13734.x.

DOI:10.1111/j.1476-5381.1993.tb13734.x

PMID:8401920

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2175738/

Abstract

We have investigated the effect of the potassium channel opener, NIP-121, on contraction elicited by melittin (a phospholipase A2 activator) in epithelium-intact and epithelium-denuded trachea isolated from guinea-pigs. The effects of NIP-121 were compared with those of isoprenaline, aminophylline and hydrocortisone. 2. In the presence of the cyclo-oxygenase inhibitor, indomethacin (5 microM), melittin (3 micrograms ml-1) caused time-dependent contraction. The melittin-induced contractile response was significantly augmented by removal of the epithelium and was concentration-dependently and completely inhibited by the phospholipase A2 (PLA2) inhibitor, p-bromophenacyl bromide (BPB 10-100 microM), and the lipoxygenase inhibitor, phenidone (10-300 microM). Similar inhibition of the melittin response by BPB (10 microM) and phenidone (10 microM) was observed in the epithelium-denuded trachea. 3. Concentration-dependent inhibition of the melittin response was induced by preincubation with NIP-121 (0.03 and 0.1 microM), isoprenaline (0.001 and 0.01 microM), aminophylline (30 and 100 microM) and hydrocortisone (100 and 300 microM). The effect of NIP-121 was abolished by glibenclamide (1 microM). 4. The inhibitory effect of NIP-121 on the melittin response was greatly reduced by removing the epithelium while that of the isoprenaline, aminophylline or hydrocortisone was not changed. 5. The inhibition of the melittin response by these drugs was similar to their inhibition of the contraction elicited by a low concentration (3 nM) of leukotriene D4 (LTD4) in the epithelium-intact trachea. Inhibition of the LTD4 response by NIP-121 was not observed in the epithelium-denuded trachea. However, higher concentrations of NIP-121 (0.3 and 1 microM) did inhibit LTD4-induced contractions of epithelium-denuded trachea.6. These findings suggest that melittin causes epithelium-dependent contraction of the guinea-pig isolated trachea which is mediated by products of lipoxygenase activity. NIP-121 may inhibit the melittin response by activating glibenclamide-sensitive potassium channels, which appear to be epithelium-dependent (an indirect effect of NIP-121 apart from its direct effect on the airway smooth muscle) while isoprenaline, aminophylline and hydrocortisone act directly to relax the trachealis smooth muscle.

摘要

我们研究了钾通道开放剂NIP - 121对豚鼠离体完整上皮和去上皮气管中蜂毒肽（一种磷脂酶A2激活剂）引发的收缩作用。将NIP - 121的作用与异丙肾上腺素、氨茶碱和氢化可的松的作用进行了比较。2. 在环氧化酶抑制剂吲哚美辛（5微摩尔）存在的情况下，蜂毒肽（3微克/毫升）引起时间依赖性收缩。去除上皮后，蜂毒肽诱导的收缩反应显著增强，并且磷脂酶A2（PLA2）抑制剂对溴苯甲酰溴（BPB 10 - 100微摩尔）和脂氧合酶抑制剂非那吡啶（10 - 300微摩尔）可浓度依赖性且完全抑制该反应。在去上皮气管中也观察到BPB（10微摩尔）和非那吡啶（10微摩尔）对蜂毒肽反应的类似抑制作用。3. 预先用NIP - 121（0.03和0.1微摩尔）、异丙肾上腺素（0.001和0.01微摩尔）、氨茶碱（30和100微摩尔）和氢化可的松（100和300微摩尔）孵育可诱导对蜂毒肽反应的浓度依赖性抑制。格列本脲（1微摩尔）可消除NIP - 121的作用。4. 去除上皮后，NIP - 121对蜂毒肽反应的抑制作用大大降低，而异丙肾上腺素、氨茶碱或氢化可的松的抑制作用未改变。5. 这些药物对蜂毒肽反应的抑制作用与其对完整上皮气管中低浓度（3纳摩尔）白三烯D4（LTD4）引发的收缩作用的抑制作用相似。在去上皮气管中未观察到NIP - 121对LTD4反应的抑制作用。然而，较高浓度的NIP - 121（0.3和1微摩尔）确实可抑制去上皮气管中LTD4诱导的收缩。6. 这些发现表明，蜂毒肽可引起豚鼠离体气管的上皮依赖性收缩，该收缩由脂氧合酶活性产物介导。NIP - 121可能通过激活格列本脲敏感的钾通道来抑制蜂毒肽反应，这些钾通道似乎是上皮依赖性的（这是NIP - 121除了对气道平滑肌的直接作用之外的间接作用），而异丙肾上腺素、氨茶碱和氢化可的松直接作用于松弛气管平滑肌。