Nitric oxide insufficiency, platelet activation, and arterial thrombosis

Nitric oxide (NO) was originally discovered as a vasodilator product of the endothelium. Over the last 15 years, this vascular mediator has been shown to have important antiplatelet actions as well. By activating guanylyl cyc lase, inhibiting phosphoinositide 3-kinase, impairing capacitative calcium influx, and inhibiting cyclooxygenase-l, endothelial NO limits platelet act ivation, adhesion, and aggregation. Platelets are also an important source of NO, and this platelet-derived NO pool limits recruitment of platelets to the platelet-rich thrombus. A deficiency of bioactive NO is associated wit h arterial thrombosis in animal models, individuals with endothelial dysfun ction, and patients with a deficiency of the extracellular antioxidant enzy me glutathione peroxidase-3, This enzyme catalyzes the reduction of hydroge n and lipid peroxides, which limits the availability of these reactive oxyg en species to react with and inactivate NO. The complex biochemical reactio ns that underlie the function and inactivation of NO in the vasculature rep resent an important set of targets for therapeutic intervention for the pre vention and treatment of arterial thrombotic disorders.