Plasma and Blood Vessel Endothelin-1 Concentrations in Hypertensive Uremic Rats Treated with Erythropoietin

Abstract

The present study was designed to evaluate whether changes in plasma and blood vessel endothelin-1 (ET-1) concentrations may play a role in the enhanced blood pressure response to recombinant human erythropoietin (r-HuEPO) replacement therapy in uremia. Renal failure was induced by 5/6 nephrectomy (Nx). Uremic rats received either r-HuEPO (100 u s.c. three times a week) or the vehicle for 5 weeks. They were compared to control rats receiving the vehicle. Systolic blood pressure (tail cuff method), hematocrit, serum creatinine, plasma and tissue ET-1 were measured at the end of the protocol. Immunoreactive ET-1 (ir-ET-1) was determined by radioimmunoassay of acid-extracts from the plasma, thoracic aorta and mesenteric arterial bed. Creatinine increased about three fold in Nx animals. Blood pressure in control rats was 120 ± 3 mmHg compared to 161 ± 6 mmHg in the Nx + vehicle group (p<0.01) and 199 ± 9 mmHg in the Nx + r-HuEPO group (p±0.01). Plasma ir-ET-1 levals were similar in the Nx + vehicle and Nx + r-HuEPO Groups (7.9 ± 1.0 and 7.8 ± 0.8 pg/ml). In contrast, thoracic aorta ir-Et-1 content was significantly higher in the Nx + r-HuEPO group than in the Nx + vehicle group (20.3 ± 2.9 vs 13.4 ± 1.9 pg, p<0.05). Simlar results were obtained in the mesenteric arterial bed. There were significant ocrrelations between blood pressure and ir-ET-1 content in the thoracic aorta (r=0.045, p<0.05) and in the mesenteric arterial bed (r=0.41, p<0.05). Vascular ET-1 content but not plasma levels are increased in uremic rats treated with r-HuEPO suggesting an increase in blood vessel ET-1 production which may play a role in the pathogenesis of r-HuEPO-induced hypertension