PHARMACODYNAMICS OF PLASMA NITRATE NITRITE AS AN INDICATION OF NITRIC-OXIDE FORMATION IN CONSCIOUS DOGS/

Background The present investigation was undertaken to better understa nd the production of nitric oxide (NO) in vivo as measured by alterati ons in plasma nitrite or nitrate in blood samples from studies in expe rimental animals or clinical studies in humans. Methods and Results Pl asma samples were taken from the aorta, the coronary sinus, a peripher al vein in the leg (skeletal muscle), or the right ventricle (mixed ve nous) in chronically instrumented conscious dogs. Plasma nitrite was c onverted to NO gas in an argon environment by use of hydrochloric acid , and plasma nitrate was converted first to nitrite with nitrate reduc tase and then to NO gas with acid. Standard curves were constructed, a nd the amount of nitrite and nitrate in plasma was determined. The pri mary metabolite was nitrate, whereas nitrite was approximately 10% of the total and remained constant. In the resting dog, the only vascular bed with a positive arterial-venous nitrate difference, evidence for production of NO, was the heart. Nitrate infusion into quietly resting dogs resulted in increases in plasma nitrate up to 38 +/- 3.4 mmol/L, increases in systemic arterial pressure, and a marked diuresis. The p lasma half-life was calculated as 3.8 hours. The volume of distributio n was calculated as 0.215 L/kg, or equivalent to the extracellular vol ume. Conclusions These studies indicate that nitrate is a reliable mea sure of NO metabolism in vivo but that because of the long half-life, nitrate will accumulate in plasma once it is produced. Because of the large volume of distribution (21% of body weight versus the 4% of body weight usually attributed to plasma volume, the compartment in which nitrate is measured), simple measures of plasma nitrate underestimate by a factor of 4 to 6 the actual production of nitrate or NO by the bo dy. In disease states, such as heart failure, in which renal function and extracellular volume are altered, caution should be exercised when increases in nitrate in plasma as an index of NO formation are evalua ted.