Excess EDRF/NO, a potentially deleterious condition that may be involved in accelerated atherogenesis and other chronic disease states.
1. To date, no method exists for preventing the injury-induced, accelerated atherogenesis that can occur as a "late complication" after initially successful invasive cardiovascular therapy (e.g. coronary angioplasty, endarterectomy). The problems intrinsic to some of the therapeutic approaches that are presently being developed have been analyzed, and the need for an alternative approach is evident. 2. An hypothesis is advanced, providing a novel conceptual basis for developing preventive therapy for accelerated atherogenesis, as well as for other chronic (degenerative) disease states, using agents that selectively inhibit the actions and metabolic transformations of excessive amounts of endogenously-derived and/or exogenously-acquired nitric oxide (NO). 3. It is considered that excess NO can damage tissue by enhancing the formation of hydroxyl radicals (OH.) via the peroxynitrite pathway and alpha-hydroxynitrosamines via nitrosation processes, and that it can stimulate cell proliferation by activating guanyl cyclase. These actions would facilitate the process of accelerated atherogenesis. 4. Selectivity for opposing the effects and metabolic handling of excess NO, regardless of its origin (endogenous via the action of constitutive or inducible NO synthase, or exogenous), rather than selectivity for inhibiting the activity of inducible versus constitutive NO synthase, is considered to be the key element required of candidate therapeutic agents. 5. The vitamin C derivative, 2-O-octadecylascorbic acid, which could protect that part of the NO mechanism that is essential for normal function by scavenging superoxide anion-radicals (O2-., while preventing the formation of OH. and potentially toxic nitrosamines via metabolic reactions involving excess NO, represents a model compound for developing effective therapy.
DeFeudis
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Institute for BioScience, Grafton, MA 01519, USA.
D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism*; D002908:Chronic Disease; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*
D009569:Nitric Oxide