Real And Potential Therapeutics

Broadly, there are three strategies: introducing NO (or amplifying its downstream effects, in the case of Viagra), blocking NO production via NOS inhibitors, and scavenging NO oxidation products.

Inhaled NO is utilized as a therapeutic agent in pathological states in which pulmonary arterial hypertension is present. Indeed, the use of NO in patients with severe adult respiratory distress syndrome (ARDS) is now commonplace. Inhaled NO (5-80 ppm) results in improved hemodynamics and oxygenation status in a variety of pathological states. In addition, inhaled NO extends far beyond the pulmonary site and affects peripheral microvascular beds, making it a potential means of treating reperfusion injury associated with trauma. Major potential toxicities of inhaled NO, such as pulmonary edema, are related to the formation of N02 (a strong oxidizer). There is also the risk of methemoglobinemia, but this is rarely a problem as NO delivery is confined to 0.5-4%.

With its vasoprotective properties, local NO delivery is a promising approach for the prevention of intimai hyperplasia associated with vascular injury and atheroscleosis. In addition, adequate rates of NO production are essential for normal wound healing as it promotes angiogenesis and endothelial and epithelial cell proliferation/migration. From animal studies, viral transfer of the NOS-2 gene appears to be an ideal strategy for restenosis and in the promotion of excisional wound healing.

Another potentially therapeutic application of NO lies in its ability to inhibit caspases and thus to block apoptosis. Programmed cell death contributes to dysfunction or failure in many organs, including the heart and liver, resulting in the need for radical therapies such as transplantation. The generation of molecules capable of delivering NO to a specific organ without causing widespread systemic effects is currently underway. On the other hand, chronic inflammation and infection are risk factors for cancer, situations in which the NOS-2 gene is persistently expressed. The inactivation of tumor suppressor genes and the activation of oncogenes involve damage to DNA, and NO can deaminate purines and pyrimidines and also cause oxidative damage to DNA.

Most of the current NOS inhibitors have no appreciable isoform selectivity. Recently, however, several compounds with selectivity have been reported, such as L-A^-Cl-iminoethyOlysine and A-(3-(aminomcth-yl)benzyl)acetamidinc for NOS-2, and also pteridine antagonists. The main indications for NOS-1 inhibitors would be disease states involving brain ischemia, but there is a much wider spectrum for NOS-2 inhibitors (septic shock, inflammatory and infectious diseases, transplantation). While their development is at an early stage, scavengers of ONOO" (more appropriately, with the intermediates derived from the reaction of 0N00~/C02) may prove useful in protecting tissues from the effects of reperfusion injury.

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