Nitric oxide-enhancing or -releasing agents as antithrombotic drugs

Nitric oxide (NO) is a powerful biological mediator provided with a number of activities of relevance for the prevention of thrombosis, like vasodilation, inhibition of platelet adhesion and aggregation, prevention of smooth muscle cell proliferation. Several cells in the circulation release NO, like endothelial cells which are the largest source, red blood cells, platelets and white blood cells, and conditions associated with an impaired production or bioavailability of NO predispose to arterial and venous thrombosis. It seems thus logical to use NO as an antithrombotic agent. However, given the extremely short half-life, limited water solubility and radical nature of this mediator, several chemical strategies to generate drugs releasing NO and/or favouring its endogenous production/bioavailability have been developed. Here we review the pharmacologic approaches to enhance endogenous NO or to induce NO-release developed over the last decades for their effects on platelet activation in vitro and in vivo and on thrombosis, in animal models and in humans. One limitation to the development of NO-releasing agents as antithrombotic drugs is represented by their concomitant vasodilatory action which, by inducing hypotension, limits their applicability. Further pharmacologic and clinical research of novel NO-enhancing and/or -releasing molecules is highly warranted in order to fully exploit the great antithrombotic potential of NO.