Supplementation with a low dose of L-arginine reduces blood pressure and endothelin-1 production in hypertensive uraemic rats

Background. We documented recently that increased endothelin-1 (ET-1) production in blood vessels and glomeruli of uraemic rats plays a crucial role in the development of hypertension and the progression of chronic renal failure. Normally, biological effects and local production of ET-1 are attenuated by the immediate release of nitric oxide (NO). Increasing evidence suggest, however, that NO release is impaired in chronic renal failure. We investigated whether supplementation with L-arginine, the natural precursor of NO, improves NO synthesis in uraemic rats with reduced renal mass and modulates vascular and renal ET-1 production as well as blood pressure and renal failure progression. Methods. One week after surgical renal mass reduction: the uraemic and sham-operated animals received either no treatment or 0.1% L-arginine in drinking water for 5 weeks. In another series of experiments, uraemic rats received 1% L-arginine for 5 weeks. Immunoreactive-ET-1 (ir-ET-1) levels in plasma, urine, and vascular and renal tissue preparations was measured by radioimmunoassay after sample extraction and purification. Results. Before treatment, systolic blood pressure was significantly elevated in uraemic animals compared to sham-operated controls (156+/-7 vs 111+/-3 mmHg, respectively; P < 0.01). Thereafter, systolic blood pressure increased further in uraemic-untreated rats (systolic blood pressure at week 5; 199+/-9 mmHg, P < 0.01), whereas it remained similar in uraemic rats supplemented with 0.1% L-arginine (171+/-9 mmHg, NS). At the end of the study, serum creatinine and urea, proteinuria and ir-ET-1 excretion were significantly augmented, while creatinine clearance was reduced in uraemic animals compared to the controls. Ir-ET-1 level was also increased in glomeruli as well as in thoracic aorta, mesenteric arterial bed, and pre-glomerular arteries, and was associated with vascular hypertrophy as assessed by tissue weight. In contrast, ir-ET-1 level was diminished ill the renal papilla of uraemic rats. Treatment with 0.1% L-arginine significantly reduced proteinuria and urinary ir-ET-1 excretion (P < 0.05) as well as ir-ET-1 level in glomeruli (P < 0.01) and in thoracic aorta (P < 0.05). These changes were associated with increased plasma NO metabolites NO2/NO3 levels in L-arginine-treated animals (P<0.01) and reduced aortic hypertrophy (P < 0.05). In contrast, supplementation with 1% L-arginine had no effect on systolic blood pressure in uraemic rats, but exacerbated proteinuria and urinary ir-ET-1 excretion and increased serum urea (P < 0.05) were observed. Conclusions. These results indicate that improvement of NO release with a low dose but not with a high dose of L-arginine significantly attenuates the development of hypertension and the progression of renal insufficiency in rats with reduced renal mass. These protective effects may be mediated in part by the reduction of vascular and renal ET-1 production.