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) produ ction in blood vessels and glomeruli of uraemic rats plays a crucial role i n the development of hypertension and the progression of chronic renal fail ure. Normally, biological effects and local production of ET-1 are attenuat ed by the immediate release of nitric oxide (NO). Increasing evidence sugge st, however, that NO release is impaired in chronic renal failure. We inves tigated whether supplementation with L-arginine, the natural precursor of N O, improves NO synthesis in uraemic rats with reduced renal mass and modula tes 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 drinki ng water for 5 weeks. In another series of experiments, uraemic rats receiv ed 1% L-arginine for 5 weeks. Immunoreactive-ET-1 (ir-ET-1) levels in plasm a, urine, and vascular and renal tissue preparations was measured by radioi mmunoassay after sample extraction and purification. Results. Before treatment, systolic blood pressure was significantly elevat ed in uraemic animals compared to sham-operated controls (156+/-7 vs 111+/- 3 mmHg, respectively; P < 0.01). Thereafter, systolic blood pressure increa sed further in uraemic-untreated rats (systolic blood pressure at week 5; 1 99+/-9 mmHg, P < 0.01), whereas it remained similar in uraemic rats supplem ented with 0.1% L-arginine (171+/-9 mmHg, NS). At the end of the study, ser um creatinine and urea, proteinuria and ir-ET-1 excretion were significantl y augmented, while creatinine clearance was reduced in uraemic animals comp ared 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 uraemi c rats. Treatment with 0.1% L-arginine significantly reduced proteinuria an d urinary ir-ET-1 excretion (P < 0.05) as well as ir-ET-1 level in glomerul i (P < 0.01) and in thoracic aorta (P < 0.05). These changes were associate d 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, s upplementation 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 l ow 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 p art by the reduction of vascular and renal ET-1 production.