Potential protective properties of a stable, slow-releasing nitric oxide donor, GEA 3175, in the lung.
Nitric oxide (NO), is known to exert vasodilatory, bronchodilatory, and antiplatelet effects, and quantitative or functional NO deficiency has been implicated in various cardio-vascular and airway diseases. NO donors, which are drugs capable of releasing NO either spontaneously or tissue-dependently, represent a way of increasing NO. Here, we review our current understanding of the NO donor, GEA 3175, 1,2,3,4-oxatriazolium, 3-(3-chloro-2-methylphenyl)-5-[[(methylphenyl)sulphonyl]amino], hydroxide inner salt. GEA 3175 is a mesoionic 3-aryl substituted oxatriazole-5-imine derivative, which is a potent, stable, slow releasing NO donor with important actions in various organ systems. In isolated guinea pig trachea, rat bronchi and bovine and human small bronchioles, GEA 3175 induces potent, long-lasting relaxation. In vivo, in sensitized guinea pigs, GEA 3175 protects against antigen-induced bronchoconstriction. GEA 3175 also exerts potent vasodilatory properties. In isolated human pulmonary arteries, GEA 3175 induces relaxation which is long-lasting and more potent than in airways. In isolated systemic arteries, GEA 3175 is also a potent vasodilator. By intravenous infusion GEA 3175 reduces blood pressure similarly to nitroglycerin. Vascular and bronchiolar relaxations were shown to be mediated via NO dependent pathways. GEA 3175 is also a potent anti-inflammatory agent. Functions of polymorphnuclear cells (PMNs) such as leucotriene B(4) (LTB(4)) - synhesis, chemotaxis and superoxide (O(-) (2)) production are inhibited by GEA 3175. GEA3175 also inhibits upregulation of E-selectin in human umbilical vein endothelial cells (HUVECs) and hence adhesion of neutrophils. Another action of GEA 3175 on the endothelium is inhibition of prostacyclin release. Finally, GEA 3175 has been demonstrated to be an antiplatelet agent. Thrombin-induced platelet aggregation was inhibited by GEA 3175 in a cyclic GMP- and vasodilator-stimulated phosphoprotein (VASP)-phosphorylation-dependent manner. Thus, GEA 3175 has been demonstrated to exert bronchodilatory, pulmonary vasodilatory, antiplatelet as well as anti-inflammatory actions. Given these actions GEA 3175 may represent a potentially useful drug. The exact mechanism whereby GEA 3175 releases NO is, however, still unknown. In addition, most of the studies so far have been performed in isolated tissue preparations. Clearly, further in vivo studies involving animal models are required to clarify safety issues and whether GEA 3175 can be used in the treatment of pulmonary hypertension and/or airway diseases.
Laursen
Britt Elmedal
BE
Department of Pharmacology, University of Aarhus, Aarhus C, Denmark.
Stankevicius
Edgaras
E
Pilegaard
Hans
H
Mulvany
Michael
M
Simonsen
Ulf
U
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D001993:Bronchodilator Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000502:physiology; D020030:Nitric Oxide Donors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D014230:Triazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D014665:Vasodilator Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity
D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; C093084:GEA 3175; D020030:Nitric Oxide Donors; D010975:Platelet Aggregation Inhibitors; D014230:Triazoles; D014665:Vasodilator Agents