Excitatory and inhibitory actions of isoprostanes in human and canine airway smooth muscle.
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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.
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