ABSTRACT
Under physiological conditions, the endothelium is inert for platelet activation and for the activation of the enzymatic components of the coagulation cascade. Endothelial thromboresistance is mainly derived from the coexistence of the following endotheliumrelated properties: (i) both platelets and endothelial cells are negatively charged, a characteristic that induces platelet cell repulsion; (ii) endothelial cells synthesize nitric oxide (NO), endothelial hyperpolarization factor (EHPF), and prostacyclin (PGI2), all of which are platelet inhibitors; (iii) endothelial cells constitutively express on their surface CD39 (an ecto-ADPase), thrombomodulin (disables thrombin action), and heparin sulfate (a glycosaminoglycan that activates antithrombin III); and (iv) healthy endothelium releases plasminogen activator, which in the presence of fibrin promotes fibrinolysis and resultant clot dissolution. Nevertheless, the presence and/or clustering of cardiovascular risk factors results in a breakdown of the endothelium’s cardioprotective properties, resulting in endothelial activation/dysfunction (1). The hallmark of endothelial dysfunction is a decrease in NO bioavailability. Indeed, the NO pathway has multiple synergistic interactions with respect to cyclic nucleotide generation/degradation and protein phosphorylation in platelets and smooth muscle cells, which regulates several cardiovascular functions, including vascular tone, leukocyte adhesion and migration, prevention of smooth muscle cell proliferation, and inhibition of platelet activation and thrombus formation. In fact, it has been described that acute inhibition of endogenous NO production in humans causes rapid platelet activation in vivo, which can be reversed by the administration of an NO donor, thereby demonstrating that platelet function in vivo is rapidly regulated by NO bioavailability (2). In consideration of the physiological regulation of NO and the well-established pathological implications of decreased NO bioavailability, delivery of supplemental NO is an attractive therapeutic option to help prevent disease progression. Indeed, NO donor drugs represent a useful pathway for systemic NO delivery (3), and organic nitrates have been used for more than a century as
effective therapies for symptomatic relief of cardiac ischemia. However, nitrates have limitations (4), and a number of alternative NO donor classes have emerged since the discovery that NO is an essential biological mediator (Table 1).
