Catalli, Adriana, and Luke J. Janssen. Augmentation of bovine airway smooth muscle responsiveness to carbachol, KCl, and histamine by the isoprostane 8-iso-PGE 2. Am J Physiol Lung Cell Mol Physiol 287: L1035-L1041, 2004. First published July 16, 2004 doi:10.1152/ajplung.00138.2004Isoprostanes are generated during periods of oxidative stress, which characterize diseases such as asthma and cystic fibrosis. They also elicit functional responses and may therefore contribute to the pathology of these diseases. We set out to examine the effects of isoprostanes on airway responsiveness to cholinergic stimulation. Muscle bath techniques were employed using isolated bovine tracheal smooth muscle. 8-Isoprostaglandin E 2 (8-iso-PGE 2) increased tone directly on its own, although the magnitude of this response, even at the highest concentration tested, was only a fraction of that evoked by KCl or carbachol. More importantly, though, pretreatment of the tissues with 8-iso-PGE 2 (10 M) markedly augmented responses to submaximal and even subthreshold concentrations of KCl, carbachol, or histamine, whereas maximal responses to these agents were unaffected by the isoprostane. The augmentative effect on cholinergic responsiveness was mimicked by PGE 2 (0.1 M) and by the FP agonists PGF2 (0.1 M) and fluprostenol (0.1 M), but not by the EP3 agonist sulprostone (0.1 M) or the TP agonist U-46619 (0.1 M). Antagonists of EP1 receptors (AH-6809 and SC-19920, 10 M) and TP receptors (ICI-192605, 1 M) had no effect on 8-iso-PGE2-induced augmentation of cholinergic responsiveness. We conclude that 8-iso-PGE2 induces nonspecific airway smooth muscle hyperresponsiveness through a non-TP non-EP prostanoid receptor. prostanoid receptors; contraction; asthma; oxidative stress; 8-isoprostaglandin E2 ISOPROSTANES ARE A LARGE GROUP of free radical-generated, prostaglandin-like molecules that have proven useful as markers of oxidative stress. Only recently have researchers begun to recognize these molecules as having their own potent biological activity. Most research to date has focused solely on the excitatory actions of isoprostane 8-iso-PGF 2␣ , which is responsible for such physiological responses as vasoconstriction, bronchoconstriction (22,25,27), and modulation of platelet aggregation (28,38).Isoprostanes are detected in normal human plasma, urine, bronchoalveolar lavage fluid (33-35), and exhaled breath condensates (31). More importantly, their concentrations are significantly elevated during periods of oxidative stress, which characterizes such diseases as asthma (2,3,31,45), chronic obstructive pulmonary disorder (30, 37), interstitial lung disease (29), and cystic fibrosis (9,11,32) and as such may contribute to the pathology underlying these conditions.There are a number of reports indicating that isoprostanes exert their biological effects through classic prostanoid receptors. This is not surprising considering the strong structural similarities between isoprostanes and prostaglandins; both groups of molecules possess a cyclopentane ...