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1 Department of Medicine, McMaster University, Hamilton, ON, Canada
* To whom correspondence should be addressed. E-mail: janssenl{at}mcmaster.ca.
Isoprostanes 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-iso PGE2 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 PGE2 (10 µM) 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 prostaglandin E2 (0.1 µM) and by the FP agonists prostaglandin F2 (0.1 µM) and fluprostenol (0.1 µM), but not by the EP3 agonist sulprostone (0.1 µM), or the TP agonist U46619 (0.1 µM). Antagonists of EP1- receptors (AH6809 and SC 19920; 10 µM) and TP receptors (ICI 192605; 1µM) had no effect on 8- iso PGE2-induced augmentation of cholinergic responsiveness. We conclude that 8-iso PGE2 induces non-specific airway smooth muscle hyperresponsiveness through a non-TP non-EP prostanoid receptor.
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