Oral Administration of Both Tetrahydrobiopterin and L-Arginine Prevents Endothelial Dysfunction in Rats With Chronic Renal Failure

We examined the mechanism of endothelial dysfunction in chronic renal failure (CRF), with reference to NO synthase. CRF was induced by 5/6 nephrectomy in rats. Either L-arginine (1.25 g/L in drinking water), tetrahydrobiopterin (BH4, 10 mg/kg per day in food), or a combination of the 2 were orally administered to CRF rats for 9 weeks. CRF rats showed elevation of systolic blood pressure compared with sham-operated rats. Endothelium-dependent relaxation induced by acetylcholine or A23187 in the isolated aorta was significantly reduced, and in vitro treatment with L-arginine, BH4, or superoxide dismutase restored the relaxation. Aortic segments from CRF rats showed significantly higher superoxide production in response to A23187, which was inhibited by L-NAME. Plasma concentrations of asymmetric dimethylarginine and symmetric dimethylarginine were higher in CRF rats. These changes in CRF rats were totally or partially decreased by L-arginine or BH4 supplementation in vivo. Interestingly, the combined treatment showed additive effects in certain parameters. These results suggest that vascular disorders in CRF rats may be partly due to NOS uncoupling caused by a relative deficiency of BH4 and partially due to accumulation of endogenous inhibitors of NOS and L-arginine uptake, resulting in the decrease of NO production and the increase of reactive oxygen species.