prostaglandin-d2 and ozagrel

COPD (Chronic Obstructive Pulmonary Disease) and bronchial asthma are two severe lung diseases which represent a major problem of world public health. Leukotrienes and prostanoids play an important role in the pathogenesis of pulmonary diseases. Prostanoids: prostaglandins (PGs) and thromboxane A2 (TXA2), the cyclooxygenase metabolites of arachidonic acid are implicated in the inflammatory cascade that occurs in asthmatic airways. Recently, the roles played by isoprostanes or prostaglandin-like compounds nonenzymatically generated via peroxidation of membrane phospholipids by reactive oxygen species, in particular F2-isoprostanes, in pulmonary pathophysiology have been highlighted. This article aims to provide an overview of the role of prostanoids and isoprostanes in the pathogenesis of COPD and asthma and to discuss the pharmacological strategies developed in prevention and/or treatment of these pathologies.

Topics: Animals; Asthma; Benzoquinones; Carbazoles; Enzyme Inhibitors; F2-Isoprostanes; Heptanoic Acids; Humans; Methacrylates; Prostaglandin Antagonists; Prostaglandin D2; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Receptors, Immunologic; Receptors, Prostaglandin; Receptors, Thromboxane A2, Prostaglandin H2; Sulfonamides; Thromboxane A2; Thromboxane-A Synthase

To better understand metabolites of arachidonic acid generated from human mast cells, the present study assessed the capacity of human mast cells to synthesize thromboxane B2 (TXB2). Anti-IgE challenge of human sinus mast cells resulted in the generation of TXB2 in a dose-dependent manner with a maximal generation of 8.2+/-4.4 ng/10(6) cells (n = 12), which is about 10-fold lower than the maximal generation of prostaglandin D2 (PGD2). Pretreatment of the cells with OKY-046, an inhibitor of TXA synthase, prevented formation of TXB2 in a dose-dependent manner without affecting the generation of PGD2 or leukotriene C4. Experiments using indomethacin or MK-591, a potent FLAP inhibitor, showed that shunting of arachidonic acid did not occur in a single-cell suspension of mast cells. Analysis by RT-PCR revealed that two species of TXA synthase, the full-length TXA synthase mRNA (TXAS-1, 570 BP) and a small quantity of the alternate-spliced form (400 BP), were present in mast cells. When cellular levels of TXAS-1 mRNA were normalized to those of G3PDH mRNA, the relative concentration of TXAS-1 was 2.06+/-0.60 (n = 7) in highly purified sinus mast cells (92.3+/-3.0% pure) and 3.66+/-0.98 (n = 5) in eosinophils.

Topics: 5-Lipoxygenase-Activating Proteins; Alternative Splicing; Antibodies, Anti-Idiotypic; Carrier Proteins; Cell Separation; Dose-Response Relationship, Drug; Histamine Release; Humans; Indoles; Mast Cells; Membrane Proteins; Methacrylates; Nasal Mucosa; Paranasal Sinuses; Prostaglandin D2; Quinolines; RNA, Messenger; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

We examined the effect of thromboxane A2 (TXA2) synthetase inhibitor, OKY-046, on bronchoconstriction induced by antigen and various spasmogenic mediators in guinea pigs in vivo. Further, inhibitory activities of OKY-046 on contractions of isolated tracheae and lung parenchymal strips induced by various contractile agents were also investigated in vitro. OKY-046, but not indomethacin, significantly inhibited antigen-induced bronchoconstriction in a dose-dependent manner. Moreover, OKY-046 attenuated bronchoconstrictions induced by peptide leukotrienes (LTs) and platelet activating factor (PAF), but not those by histamine, prostaglandin D2 (PGD2) and STA2 (a stable TXA2 mimetic agent). Although contractile responses induced by spasmogens such as peptide LTs, PAF and histamine were not influenced by OKY-046 in isolated tracheae, OKY-046 elicited significant and concentration-dependent inhibitions against contractile responses induced by peptide LTs and PAF in isolated lung parenchymal strips. These results suggest the possible involvement of TXA2 in the development of anaphylactic bronchoconstriction in sensitized guinea pigs.

Topics: Acrylates; Animals; Blood Pressure; Bordetella pertussis; Bronchi; Guinea Pigs; Histamine; In Vitro Techniques; Indomethacin; Leukotrienes; Lung; Male; Methacrylates; Muscle Contraction; Muscle, Smooth; Platelet Activating Factor; Prostaglandin D2; Thromboxane-A Synthase; Trachea

The purpose of this study was to characterize by pharmacological means the inotropic action of prostaglandin D2 (PGD2) in the guinea-pig heart. In the whole heart perfused at constant pressure, PGD2 (0.01-10 micrograms) reduced coronary flow rate and decreased left ventricular contractile force in a dose-dependent manner. When the coronary vasoconstricting effect of PGD2 was antagonized by the PG antagonist sodium p-benzyl-4[1-oxo-2-(4-chlorobenzyl)-3-phenyl propyl]phenyl phosphonate (N-0164), by the cyclooxygenase inhibitor indomethacin or by the thromboxane synthetase inhibitor sodium (E)-3-[4-(1-imidazolyl-methyl)phenyl]-2-propanoate (OKY 046), the negative inotropic response to PGD2 was attenuated or completely abolished and a positive inotropic effect was unmasked. In the isolated left atrium or right ventricular papillary muscle preparations, PGD2 induced only a positive inotropic response. The atrial response to PGD2 was unaffected by N-0164, indomethacin or propranolol but was markedly decreased by carbachol or adenosine. Conversely, the response of the papillary muscle to PGD2 was potentiated by papaverine. Thus, these data indicate that PGD2 has a primary positive inotropic effect, which may involve cyclic AMP metabolism. On the other hand, because PGD2 is also a potent coronary vasoconstrictor, the secondary negative inotropic effect of PGD2 predominates.

Topics: Animals; Coronary Circulation; Coronary Vessels; Cyclic AMP; Depression, Chemical; Dose-Response Relationship, Drug; Guinea Pigs; In Vitro Techniques; Indomethacin; Male; Methacrylates; Myocardial Contraction; Platelet Activating Factor; Prostaglandin D2; Prostaglandins D; SRS-A; Stimulation, Chemical; Vasoconstriction