James F. Kerwin Jr.* Pages 507 - 532 ( 26 )
Recent advances in the regulation and pharmacology of nitric oxide synthase (NOS) have enabled the discovery of novel NOS inhibitors as well as a better understanding of the mechanism of action of NOS. NO is an essential second messenger and autacoid. A critical balance of NO production is maintained between normal physiologically processes and those levels potentially associated with pathophysiology. Several approaches have been explored to reduce NO levels and to inhibit NOS, inclusive of direct NOS inhibition, inhibition of NOS cofactors and cofactor biosynthesis, regulation of NOS enzyme levels and direct trapping of NO and its by-products. The advent of more selective inhibitors and transgenic models has allowed pharmacological advances which point to potential therapeutic possibilities. Therapeutically, NOS inhibitors are currently being evaluated in endotoxemia and sepsis but also may have roles in immunomodulation and neuroprotection. In addition the advances in understanding of the physiological role of NO has renewed interest in NO-donating approaches to therapy. One of the more interesting clinical developments has been the use of NO itself in pulmonary hypertension. This review will address recent advances in the pharmacology of NOS, the design and discovery of NOS inhibitors and the therapeutic regulation of NO.