Endothelin ETA receptor blockade prevents the progression of renal failureand hypertension in uraemic rats

Background. Elevated plasma and urine endotheilin-1 (ET-I) levels have been reported in renal failure and may be involved in renal disease progression . We investigated whether these changes are related to increased vascular a nd renal ET-1 production in the pole resection remnant kidney model of chro nic renal failure in the rat. Methods. Uraemic Wistar rats were prepared by surgical renal mass 5/6 ablat ion and compared with sham-operated controls (protocol 1). Immunoreactive-E T-1 (ir-ET-1) concentration was measured by radioimmunoassay after sample e xtraction and purification. To investigate the functional role of ET-1 duri ng the progression of chronic renal failure, uraemic rats (protocol 2) were treated with either the vehicle or the ET-1 type A (ETA) receptor antagoni st LU135252 (LU). Results. Systolic blood pressure and serum creatinine, as well as urinary v olume and proteinuria, were significantly higher, whereas creatinine cleara nce was reduced in uraemic rats compared with sham-operated controls. As ex pected, plasma and urine ir-ET-1 concentrations were increased in uraemic r ats (P < 0.01) and were related to the increased ir-ET-1 levels in blood ve ssels and glomeruli (P < 0.01). Positive correlation was found between plas ma, thoracic aorta and mesenteric arterial bed ir-ET-1 levels and systolic blood pressure, as well as blood vessel hypertrophy. In addition, increased urinary ir-ET-1 excretion correlated with the rise in serum creatinine and proteinuria. In protocol 2, a 3-week treatment period with LU was initiate d once uraemia and hypertension were established. In untreated uraemic rats , systolic blood pressure increased further (P < 0.05), but this was not th e case in LU-treated uraemic rats. At the end of treatment, serum creatinin e and proteinuria were significantly lower (P < 0.05) and creatinine cleara nce was higher (P < 0.01) in LU-treated rats compared with uraemic-untreate d animals. While plasma ir-ET-1 concentration was similar in the two groups , ir-ET-l concentration in thoracic aorta, mesenteric arterial bed, renal c ortex and urine was significantly lower in LU-treated animals (P < 0.01). I n addition, heart, thoracic aorta and mesenteric arterial wet weight to bod y weight ratios were also significantly reduced in LU-treated uraemic rats (P < 0.05). Conclusions. Elevated plasma ET-1 concentration and urinary ET-1 excretion in rats with renal mass ablation are related to enhanced ET-1 production in vascular and renal tissues, thus suggesting an important role for ET-1 in the aggravation of hypertension and vascular hypertrophy as well as in the progression of renal insufficiency. These pathophysiological effects are pr evented by treatment with selective ETA receptor blockade.