EFFECTS OF LOSARTAN AND CAPTOPRIL ON ENDOTHELIN-1 PRODUCTION IN BLOOD-VESSELS AND GLOMERULI OF RATS WITH REDUCED RENAL MASS

Recently, we have reported that endothelin-1 (ET-1) production is incr eased in blood vessels and glomeruli of rats with chronic renal failur e. This study was design to investigate the role of angiotensin II (An g II) in endogenous ET-1 production in rats with reduced renal mass. O ne week after subtotal (5/6) nephrectomy, uremic rats were divided int o three groups, and received either no treatment, the Ang II subtype 1 receptor (AT(1)) antagonist losartan (10 mg/kg/day), or the angiotens in-converting enzyme inhibitor (ACE-I) captopril (30 mg/kg/day) for 6 weeks. Sham-operated rats were used as controls and received no treatm ent. The levels of immunoreactive ET-1 (ir-ET-1) in plasma and urine, as well as in vascular and renal tissues, were determined by radioimmu noassay (RIA) after extraction. In uremic rats, losartan and captopril completely prevented the increase in systolic blood pressure. At week 6, plasma ir-ET-l was similar in the different groups of uremic rats and in the controls. However, ir-ET-1 concentration in the mesenteric arterial bed, the thoracic aorta, preglomerular arteries, and glomerul i, as well as urinary ir-ET-1 excretion were significantly greater in uremic-untreated rats compared to controls (P <.01). Treatment of urem ic rats with losartan or captopril reduced ir-ET-1 concentration in th e thoracic aorta and preglomerular arteries (P <.05), but ir-ET-l conc entration in the mesenteric arterial bed was unchanged. Although both drugs completely prevented the increase in proteinuria, losartan but n ot captopril significantly reduced ir-ET-l concentration in glomeruli (P <.05) and normalized urinary ir-ET-l excretion. This indicates that increased ET-1 production in blood vessels and glomeruli of uremic ra ts is modulated, at least in part by Ang II through the AT(1) receptor . The beneficial effects of the AT(1) antagonist losartan could be att ributable to the attenuation of Ang II-induced ET-1 production in this rat remnant kidney model of chronic renal failure, whereas those of t he ACE-I captopril are not related to changes in ET-1 production in gl omeruli. Am J Hypertens 1998;11:989-997 (C) 1998 American Journal of H ypertension, Ltd.