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.