This proposal is directed at the development and optimization of an in vivo technique for quantifying the whole body production rate of nitric oxide. The method traces the conversion of an arginine analog into the corresponding analog of citrulline, a process that is mediated by nitric oxide synthase. Kinetic analysis affords an upper limit for the NO biosynthesis rate. The approach is innovative because it employs a non- proteinogenic arginine surrogate, whose metabolism is unaffected by the kinds of substrate cycling that confounds studies with arginine, the only natural precursor for NO formation. Our hypothesis is that tracking the production rate of NO by means of a surrogate index can be used to categorize and stratify clinical outcome in sepsis syndromes, inflammatory disease, cardiovascular and neurodegenerative disorders, and other conditions in which oxidant stress is a contributing factor. In particular, our ultimate goal is to develop a bedside procedure, based on this tracer diagnostic paradigm, and to elaborate new, physiologically significant information that can be used for patient management whenever NO-modulating therapies need to be titrated. PROPOSED COMMERCIAL APPLICATIONS: Our business objective is to provide a diagnostic test for nitric oxide production capacity in health and in diseases that are mediated by oxidant stress. The test and related tracers will be sold initially to critical care segments of the health care market for patient stratification, outcome prediction and therapy management. The market potential for this activity exceeds $500 million annually in the US alone
