Blood pressure-independent effect of angiotensin AT(1) receptor blockade on renal endothelin-1 production in hypertensive uremic rats

Objective We recently reported that treatment of uremic rats with reduced r enal mass with the angiotensin II (Ang II) subtype 1 receptor (AT(1)) antag onist losartan reduces endothelin-1 (ET-1) levels in blood vessels and in g lomeruli. Although this suggests an important role for Ang II in the modula tion of ET-1 production, the concomitant decrease in blood pressure may als o be involved. The present study was designed to investigate whether the mo dulation of ET-1 production in uremic rats is related to tissue-specific ef fects of AT(1) receptor blockade or to the antihypertensive effect of losar tan. Design One week after renal mass reduction, uremic rats were treated with t he conventional triple therapy (TRx) [reserpine (5 mg/l), hydralazine (80 m g/l) and hydrochlorothiazide (25 mg/l)] or losartan (20 mg/kg per day) for 6 weeks. Immunoreactive-ET-1 (ir-ET-1) levels in plasma and urine, as well as in vascular and renal tissues were measured by a specific radioimmunoass ay after sample extraction and purification. Results Before treatment, systolic blood pressure was significantly higher in uremic animals compared to sham-operated controls (165 +/- 4 versus 123 +/- 2 mmHg, respectively; P <0.01). Treatment with the TRx or with losartan normalized systolic blood pressure in uremic rats, whereas it was further increased in untreated uremic animals. At week 6, serum creatinine, protein uria and urinary ET-1 and transforming growth factor-beta1 (TGF-beta1) excr etion, as well as vascular and glomerular ET-1 content were increased in ur emic rats compared to the controls (P <0.01). Treatment of uremic rats with the TRx or with losartan reduced ET-1 content in the thoracic aorta and th e mesenteric arterial bed (P <0.01). However, losartan, but not the TRx, si gnificantly attenuated the rise of serum creatinine, proteinuria and urinar y ET-1 and TGF-beta1 excretion, as well as ET-1 content in glomeruli of ure mic rats. Compared with the controls, renal preproET-1 mRNA expression was also significantly higher in uremic rats. Treatment of uremic rats with los artan prevented renal preproET-1 mRNA overexpression, indicating that chang es in glomerular ET-1 content and urinary ET-1 excretion were related to mo dulation of renal ET-1 production. Conclusions These findings indicate that the effect of losartan on ET-1 pro duction in peripheral blood vessels may be mediated, in part, by the reduct ion of blood pressure. In contrast, the reduction of renal ET-1 production is mediated by tissue-specific effects of AT, receptor blockade, and may co ntribute to the renal protective effects of losartan. (C) 2001 Lippincott W illiams & Wilkins.