Blocking NO synthesis: how, where and why?

Key Points Nitric oxide (NO) is an intracellular and intercellular messenger molecule that has been implicated in a wide range of physiological processes. Overproduction of NO can cause tissue damage and dysregulated cellular signalling, and seems to be a key feature of pathogenesis in several inflammatory and degenerative disorders. Three isoforms of nitric oxide synthase (NOS) have been identified: endothelial (eNOS), neuronal (nNOS) and inducible (iNOS). Although all three have important physiological roles, it is overproduction of NO from iNOS and nNOS that is important in certain disease states. These isoforms are therefore potential targets for new treatments. NO donation or boosting NO effects is also a target for treatments, but this article focuses solely on inhibition. Studies with pharmacological inhibitors of NOS isozymes, and NOS-isoform knockout mice, indicate that blockade of individual NOS isozymes might produce therapeutic benefit, but will also be associated with harmful effects. For long-term treatment, a drug must not inhibit eNOS, as this would cause atherosclerosis and have significant adverse cardiovascular effects. The active site of NOS isozymes is significantly conserved, so that isoform selectivity has not been easy to achieve. Nonetheless, compounds are now available that show specificity for inhibition of iNOS or nNOS over eNOS. Furthermore, compounds have been identified that inhibit activity through inhibition of dimerization or inhibition of cofactor binding. Compounds that block NO generation have therapeutic potential, and some are close to entering clinical trials. Potential targets include asthma, arthritis, neurodegenerative disorders, cancer, gastrointestinal inflammation and pain. Even isoform-selective inhibition of NOS is likely to be associated with significant unwanted side effects. Partial inhibition of NOS isozymes might be a better option than complete or near complete inhibition. Even then, it seems that the role of NO might change from harmful to helpful during the course of a single process. For example, iNOS activity can be involved in tissue destruction, and in wound repair and resolution of inflammation. Alternative approaches to decreasing harmful generation of NO while leaving physiological NO unaffected include inhibition of enzymes that regulate cofactors for NOS, manipulation of substrate levels or inhibition of enzymes that metabolize endogenous inhibitors of NOS. Drugs that affect the activity of s