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E-Ring Isoprostane Augments Cholinergic Neurotransmission in Bovine Trachealis via FP Prostanoid Receptors

¹ Firestone Institute for Respiratory Health, St. Joseph's Healthcare, and Department of Medicine, McMaster University, Hamilton, Ontario, Canada

Correspondence and requests for reprints should be addressed to Dr. L. J. Janssen, L-314, St. Joseph's Hospital, 50 Charlton Ave. East, Hamilton, ON, L8N 4A6 Canada. E-mail: janssenl{at}mcmaster.ca

Isoprostanes are prostaglandin-like molecules that accumulate in oxidative stress and also exert powerful biological effects on a wide variety of tissues. We investigated the effects of several different isoprostanes on contractions evoked by electrical field stimulation (EFS) in bovine trachealis, finding only 15-E_2t-IsoP to augment those responses. Many others have shown that isoprostanes act on prostanoid receptors, usually those of the thromboxane-selective prostanoid receptor (TP) subtype, although some describe actions through prostaglandin E₂-selective prostanoid receptor (EP) or less frequently through prostaglandin F₂-selective prostanoid receptors (FP). We used an extensive panel of highly selective agonists and antagonists of prostanoid receptors to characterize the ones through which 15-E_2t-IsoP was acting here. Pretreatment with the FP-selective AL-8810 significantly inhibited the augmentation, whereas TP- and EP-selective blockers did not. On the other hand, the augmentation exerted by 15-E_2t-IsoP was mimicked by submicromolar concentrations of the FP-selective agonists PGF₂ and fluprostenol, as well as by micromolar concentrations of the TP-selective agonist U46619. The concentration–response relationship for exogenously added acetylcholine was not significantly affected by 15-E_2t-IsoP, confirming that the effect of the latter on EFS-evoked responses was exerted prejunctionally (i.e., to enhance release of Ach from nerve endings), rather than a direct postjunctional effect via a receptor on the smooth muscle. Finally, we investigated whether the inhibitory (adrenergic) innervation was also modulated by 15-E_2t-IsoP, finding EFS-evoked relaxations to be unaffected by the isoprostane. We conclude that 15-E_2t-IsoP acts upon an FP receptor on the cholinergic nerve endings, leading to enhanced neurotransmission.

Key Words: isoprostane • oxidative stress • prostanoid receptor • cholinergic neurotransmission

CLINICAL RELEVANCE This study describes a novel effect of an isoprostane upon neurotransmission in airways, an effect that has been largely unexplored. Also, very few studies have described such an action through the family of receptor that is employed by this agent.

 

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