E-Ring Isoprostane Augments Cholinergic Neurotransmission in Bovine Trachealis via FP Prostanoid Receptors
Firestone Institute for Respiratory Health, St. Joseph's Healthcare, and Department of Medicine, McMaster University, Hamilton, Ontario, Canada.American Journal of Respiratory Cell and Molecular Biology (Impact Factor: 3.99). 01/2008; 37(6):739-47. DOI: 10.1165/rcmb.2007-0022OC
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.
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ABSTRACT: Isoprostanes are products of peroxidative attack of membrane lipids. As such, they accumulate to substantial levels in conditions of oxidative stress, including many pulmonary vascular diseases such as acute lung injury and pulmonary hypertension, and are increasingly being used as indicators of disease state and severity. However, our group and others have hypothesized that they are more than inert markers, but may also act as signal transduction molecules. As isomers of prostaglandins, they can exert powerful biological effects on many lung cell types through actions on prostanoid receptors. In this review, we collect many lines of evidence that point to causal roles for the isoprostanes in those disease states.American Journal of Respiratory Cell and Molecular Biology 05/2008; 39(4):383-9. DOI:10.1165/rcmb.2008-0109TR · 3.99 Impact Factor
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ABSTRACT: Our purposes were to perform the pharmacological characterization of PGF(2alpha) receptor (prostanoid FP-receptor) involved in human umbilical vein contraction and confirm its expression in this tissue. Umbilical cords from healthy patients after full-term deliveries were employed. The vein was dissected out of cords and used for either isolated organ bath or reverse transcription-polymerase chain reaction (RT-PCR) and Western blot assays. The natural prostanoid FP-receptor agonist, PGF(2alpha), and its selective analogues, latanoprost and bimatoprost free acids are full agonists (produce more than 80% of the maximal contractile response to 5-HT) in human umbilical vein. The agonist potency (pEC(50)) order was PGF(2alpha) (6.01+/-0.05)>latanoprost free acid (5.65+/-0.07)=bimatoprost free acid (5.59+/-0.08). The contractile effects of PGF(2alpha) and latanoprost free acid were blocked competitively by the prostanoid FP-receptor antagonist, AL-8810. The antagonist potencies (pK(B)) of AL-8810 vs. PGF(2alpha) (5.93+/-0.05) and vs. latanoprost free acid (6.40+/-0.08) in human umbilical vein are in good agreement with its ability to antagonize prostanoid FP receptors of rat, mouse and human cells. In all samples, clear signal was detected for cDNA amplification of prostanoid FP receptor and the specific prostanoid FP-receptor antibody recognized a protein of approximately 64 kDa. In conclusion, taking into account the obtained functional and biochemical data, we propose for the first time that human umbilical vein express prostanoid FP-receptors and these receptors could be involved in the vasoconstriction action of PGF(2alpha) in this tissue.European journal of pharmacology 04/2009; 610(1-3):68-74. DOI:10.1016/j.ejphar.2009.03.022 · 2.53 Impact Factor
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ABSTRACT: Compelling evidence identifies airway smooth muscle (ASM) not only as a target but also a cellular source for a diverse range of mediators underlying the processes of airway narrowing and airway hyperresponsiveness in diseases such as asthma. These include the growing family of plasma membrane phospholipid-derived polyunsaturated fatty acids broadly characterised by the prostaglandins, leukotrienes, lipoxins, isoprostanes and lysophospholipids. In this review, we describe the enzymatic and non-enzymatic biosynthetic pathways of these lipid mediators and how these are influenced by drug treatment, oxidative stress and airways disease. Additionally, we outline their cognate receptors, many of which are expressed by ASM. We describe potential deleterious and protective roles for these lipid mediators in airway inflammatory and remodelling processes by describing their effects on diverse functions of ASM in asthma that have the potential to contribute to asthma pathogenesis and symptoms. These functions include contractile tone development, cytokine and extracellular matrix production, and cellular proliferation and migration.Pulmonary Pharmacology & Therapeutics 10/2009; 22(5):426-35. DOI:10.1016/j.pupt.2008.12.003 · 2.94 Impact Factor
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