Abstract

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) E₂, 8-iso-PGF_1α, and 8-iso-PGF_2α being the most efficacious (and with logEC₅₀ values of 7.0, 5.9, and 6.2 μM, respectively). These contractions were sensitive to the prostanoid TP receptor antagonist ICI 192,605 (0.1–1 μM), but not the EP prostanoid receptor antagonist AH-6809 (50 μM), or the leukotriene receptor antagonists monteleukast or ICI 198,615 (both 1 μM). 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-PGE₁, 8-iso-PGE₂, and 8-iso-PGF_3α were the most potent, with logIC₅₀ values of 6.9, 6.9, and 5.7, respectively. Only 8-iso-PGF_3α relaxed human airways (logIC₅₀ = 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.