Gardiner P J, Norman P, Cuthbert N J, Tudhope S R, Abram T S
Bayer plc, Pharma Research, Stoke Court, Stoke Poges, UK.
Eur J Pharmacol. 1993 Jul 6;238(1):19-26. doi: 10.1016/0014-2999(93)90500-h.
The peptido-leukotriene receptor(s) (PL) on the ferret isolated spleen strip have been characterised by functional studies using the naturally occurring leukotrienes (LTs), a range of structurally distinct PL antagonists, and by ligand binding studies. LTB4 (0.01-10 microM) was inactive on ferret spleen whereas LTC4, LTD4 and LTE4 produced concentration-related contractions with maximal responses, relative to noradrenaline, of 57% (EC50 0.28 microM), 60% (EC50 0.5 microM) and 7% respectively. The leukotriene responses were unaltered by L-serine borate, L-cysteine, indomethacin, phentolamine, propranolol, mepyramine, methysergide or atropine, suggesting that the peptido-leukotrienes were acting through distinct PL receptors. The PL1 antagonists, FPL 55712 (0.01-10 microM), ICI 198615 (10 microM), SK&F 104353 (10 microM) and MK541 (10 microM) were all inactive against LTC4- or LTD4-induced contractile responses. LTE4 was a partial agonist with respect to LTC4 and LTD4 with pKB values of 5.8 and 5.5 respectively. Nifedipine (0.1 microM) produced a rightward shift of the concentration-response curves to both LTC4 and LTD4 and depressed their maximal responses. An unacceptably high level of non-specific binding of [3H]LTD4 to membrane preparations of ferret spleen prevented characterisation of this receptor by ligand binding. These results suggest that the ferret spleen has a homogeneous population of a PL receptor type which is insensitive to existing PL1 receptor antagonists. The functional characteristics of this PL receptor type are similar to those of the PL2 receptor on other tissues. The absence of PL1 receptors on this tissue makes it particularly useful in identifying new and selective drug tools for the PL2 receptor.
通过使用天然存在的白三烯（LTs）、一系列结构不同的肽白三烯受体拮抗剂进行功能研究，并结合配体结合研究，对雪貂离体脾条上的肽白三烯受体（PL）进行了表征。白三烯B4（LTB4，0.01 - 10微摩尔）对雪貂脾脏无活性，而白三烯C4（LTC4）、白三烯D4（LTD4）和白三烯E4（LTE4）产生浓度相关的收缩反应，相对于去甲肾上腺素，最大反应分别为57%（半数有效浓度[EC50] 0.28微摩尔）、60%（EC50 0.5微摩尔）和7%。白三烯反应不受L - 丝氨酸硼酸盐、L - 半胱氨酸、吲哚美辛、酚妥拉明、普萘洛尔、美吡拉敏、甲基麦角新碱或阿托品的影响，这表明肽白三烯是通过不同的PL受体起作用的。PL1拮抗剂FPL 55712（0.01 - 10微摩尔）、ICI 198615（10微摩尔）、SK&F 104353（10微摩尔）和MK541（10微摩尔）对LTC4或LTD4诱导的收缩反应均无活性。LTE4相对于LTC4和LTD4是部分激动剂，其平衡解离常数（pKB）值分别为5.8和5.5。硝苯地平（0.1微摩尔）使LTC4和LTD4的浓度 - 反应曲线右移，并降低其最大反应。[3H]LTD4与雪貂脾脏膜制剂的非特异性结合水平过高，无法通过配体结合来表征该受体。这些结果表明，雪貂脾脏具有一群对现有PL1受体拮抗剂不敏感的同质PL受体类型。这种PL受体类型的功能特征与其他组织上的PL2受体相似。该组织上不存在PL1受体，这使其在鉴定用于PL2受体的新型选择性药物工具方面特别有用。
