Janssen L J, Premji M, Netherton S, Catalli A, Cox G, Keshavjee S, Crankshaw D J
Asthma Research Group, Father Sean O'Sullivan Research Centre, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
J Pharmacol Exp Ther. 2000 Nov;295(2):506-11.
Isoprostanes are generated nonenzymatically during free radical-mediated lipid peroxidation, and are used clinically and experimentally as markers of oxidative stress. However, their biological effects are poorly understood. We examined the effects of seven different 8-isoprostanes in human and canine airway smooth muscles. In large order airways (carina) of the human, several isoprostanes evoked powerful contractions, with 8-iso-prostaglandin (PG) E(2), 8-iso-PGF(1 alpha), and 8-iso-PGF(2 alpha) being the most efficacious (and with logEC(50) values of 7.0, 5.9, and 6.2 microM, respectively). These contractions were sensitive to the prostanoid TP receptor antagonist ICI 192,605 (0.1-1 microM), but not the EP prostanoid receptor antagonist AH-6809 (50 microM), or the leukotriene receptor antagonists monteleukast or ICI 198,615 (both 1 microM). Qualitatively similar results were obtained in small order human airways (<2 mm o.d.), except that the isoprostanes were generally slightly less potent. None of the isoprostanes had any marked excitatory effect in canine airways. In carbachol-preconstricted tissues (pretreated with ICI 192,605 to block any potential contraction), several isoprostanes completely relaxed canine airways: 8-iso-PGE(1), 8-iso-PGE(2), and 8-iso-PGF(3 alpha) were the most potent, with logIC(50) values of 6.9, 6.9, and 5.7, respectively. Only 8-iso-PGF(3 alpha) relaxed human airways (logIC(50) = 4.9). Our results show that several 8-isoprostanes are highly biologically active in human and canine airways, evoking both excitatory and/or inhibitory effects, and that these effects are compound, species, and tissue dependent.
异前列腺素是在自由基介导的脂质过氧化过程中通过非酶促反应生成的，在临床和实验中用作氧化应激的标志物。然而，对其生物学效应的了解却很少。我们研究了七种不同的8-异前列腺素对人和犬气道平滑肌的影响。在人的大气道（隆突）中，几种异前列腺素可引起强烈收缩，其中8-异前列腺素（PG）E2、8-异前列腺素F1α和8-异前列腺素F2α最为有效（其半数有效浓度的对数logEC50值分别为7.0、5.9和6.2微摩尔）。这些收缩对前列腺素TP受体拮抗剂ICI 192,605（0.1 - 1微摩尔）敏感，但对EP前列腺素受体拮抗剂AH - 6809（50微摩尔）、白三烯受体拮抗剂孟鲁司特或ICI 198,615（均为1微摩尔）不敏感。在人的小气道（外径<2毫米）中获得了定性相似的结果，只是异前列腺素的效力通常略低。在犬气道中，没有一种异前列腺素具有明显的兴奋作用。在卡巴胆碱预收缩的组织中（用ICI 192,605预处理以阻断任何潜在的收缩），几种异前列腺素可使犬气道完全舒张：8-异前列腺素E1、8-异前列腺素E2和8-异前列腺素F3α最为有效，其半数抑制浓度的对数logIC50值分别为6.9、6.9和5.7。只有8-异前列腺素F3α可使人气道舒张（logIC50 = 4.9）。我们的结果表明，几种8-异前列腺素在人和犬气道中具有高度生物活性，可引起兴奋和/或抑制作用，并且这些作用因化合物、物种和组织而异。
