Nitric Oxide Production Is Reduced in Patients With Chronic Renal Failure

Abstract

—In patients with chronic renal failure (CRF), atherosclerosis is a major cause of cardiovascular morbidity and mortality. Generally, atherosclerosis has been associated with a reduced bioavailability of nitric oxide (NO). Experimental studies have indicated the presence of enhanced NO degradation by reactive oxygen species as well as decreased NO production as possible causes for this reduced NO bioavailability. So far, the question whether or not NO production is impaired in patients with CRF has never been investigated. Therefore, we measured whole body NO production in 7 patients with CRF, and in 7 matched healthy subjects. To assess the relative importance of a dysfunction of NO synthase (NOS), we compared the NO production of these patients to that of 2 other groups known to have endothelial dysfunction, ie, 7 patients with familial hypercholesterolemia (FH) who did not yet have signs of clinical cardiovascular disease (all nonsmokers), and 5 cigarette smokers. These groups were also compared with 7 nonsmoking, age-matched healthy subjects. Whole body NO production, determined as in vivo arginine-to-citrulline conversion, was assessed by giving an intravenous infusion of [¹⁵N₂]-arginine as a substrate for NOS and measuring isotopic plasma enrichment of [¹⁵N]-citrulline by LC-MS. NO production in the CRF patients (0.13±0.02 μmol · kg^–1 · h^–1) was significantly lower (P–1 · h^–1). NO production also tended to be lower in the FH patients (0.16±0.04 μmol · kg^–1 · h^–1), but the difference with the corresponding control group did not reach significance (0.22±0.06 μmol · kg^–1 · h^–1). In the group of smokers, NO production was similar to that in nonsmokers (0.22±0.09 μmol · kg^–1 · h^–1). In conclusion, it is demonstrated for the first time that basal whole body NO production is reduced in patients with CRF. This finding implies that therapeutic interventions to endothelial dysfunction in these patients should be primarily directed toward improvement of NO production. The finding of only a tendency toward reduction of NO production in patients with FH and the absence of a reduction in cigarette smokers suggests that other mechanisms such as enhanced NO degradation may be involved in the decrease of NO bioavailability in these groups.