E-ring isoprostane augments cholinergic neurotransmission in bovine trachealis via FP prostanoid receptors.
ABSTRACT 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-E2t-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 F2alpha-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-E2t-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-E2t-IsoP was mimicked by submicromolar concentrations of the FP-selective agonists PGF2alpha 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-E2t-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-E2t-IsoP, finding EFS-evoked relaxations to be unaffected by the isoprostane. We conclude that 15-E2t-IsoP acts upon an FP receptor on the cholinergic nerve endings, leading to enhanced neurotransmission.
- Gastroenterology 01/2011; 140(5). · 12.82 Impact Factor
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ABSTRACT: Recently we demonstrated that centrally administrated melittin, a phospholipase A(2) (PLA(2)) activator, caused the pressor effect in normotensive, conscious rats. In the present study, we aimed to determine the cardiovascular effect of peripherally injected melittin and the involvement of the central cholinergic system on these effects in the normotensive conscious rats. For this reason, 250, 500 or 1000microg/kg doses of melittin were injected intraperitoneally to normotensive male Sprague Dawley rats. Melittin produced dose- and time-dependent increases in mean arterial pressure (MAP) and heart rate (HR). Both peripheral (5mg/kg; i.p.) and central (500microg; i.c.v.) pretreatment with indomethacin, nonselective inhibitor of cyclooxygenase (COX) 1 and 2, totally abolished cardiovascular effect of melittin. Intraperitoneal (i.p.) pretreatment with propranolol, a nonselective beta-adrenergic receptor blocker, completely abolished the tachycardic response to melittin. Also, the pressor effect of melittin was partially attenuated in these rats. In order to test the mediation of the central cholinergic system on the pressor and tachycardic effects of melittin, the rats were pretreated with atropine sulfate (10microg; i.c.v.), a cholinergic nonselective muscarinic receptor antagonist, mecamylamine (50microg; i.c.v.), a cholinergic nonselective nicotinic receptor antagonist, methyllycaconitine (10microg; i.c.v.) or alpha-bungarotoxin (10microg; i.c.v.), selective antagonists of alpha7 subtype nicotinic acetylcholine receptors (alpha7nAChRs) 15min prior to melittin (500microg/kg; i.p.) injection. Pretreatment with mecamylamine, methyllycaconitine or alpha-bungarotoxin partially diminished the pressor and tachycardic response to melittin in the normotensive conscious rats whereas pretreatment with atropine sulfate had no effect. In conclusion, our data demonstrate that peripherally administered melittin exerts a clear pressor and tachycardic effect by activating COX pathway. The activation of central cholinergic nicotinic receptors, predominantly alpha7nAChRs, appears to be involved in the pressor and tachycardic effects of the drug.Prostaglandins Leukotrienes and Essential Fatty Acids 11/2009; 81(5-6):341-7. · 2.73 Impact Factor
Article: Isoprostanes and asthma.[Show abstract] [Hide abstract]
ABSTRACT: Isoprostanes are prostaglandin (PG)-like compounds generated in vivo following oxidative stress by non-enzymatic peroxidation of polyunsaturated fatty acids, including arachidonic acid. They are named based on their prostane ring structure and by the localization of hydroxyl groups on the carbon side chain; these structural differences result in a broad array of isoprostane molecules with varying biological properties. Generation of specific isoprostanes is also regulated by host cell redox conditions; reducing conditions favor F₂-isoprostane production while under conditions with deficient antioxidant capacity, D₂- and E₂-isoprostanes are formed. F₂-isoprostanes (F₂-isoP) are considered reliable markers of oxidative stress in pulmonary diseases including asthma. Importantly, F₂-isoP and other isoprostanes function as ligands for PG receptors, and potentially other receptors that have not yet been identified. They have been reported to have important biological properties in many organs. In the lung, isoprostanes regulate cellular processes affecting airway smooth muscle tone, neural secretion, epithelial ion flux, endothelial cell adhesion and permeability, and macrophage adhesion and function. In this review, we will summarize the evidence that F₂-isoP functions as a marker of oxidative stress in asthma, and that F₂-isoP and other isoprostanes exert biological effects that contribute to the pathogenesis of asthma. This article is part of a Special Issue entitled Biochemistry of Asthma.Biochimica et Biophysica Acta 05/2011; 1810(11):1091-5. · 4.66 Impact Factor