To investigate the role of uremia in the development of human recombinant erythropoietin (r-HuEPO)-induced hypertension, Wistar rats were divided into a uremic (subtotal nephrectomy) and a control group. After three weeks, both groups were again divided and each subgroup received either r-HuEPO (100 u/kg s.c., 3 times weekly) or the vehicle for a further 3 weeks. Hematocrit, blood pressure and blood chemistry were measured prior to surgery, before either vehicle or r-HuEPO treatment and before euthanasia. The uremic group developed anemia, hypertension and all the biochemical features observed in humans with end-stage renal disease. r-HuEPO therapy increased hematocrit from 29 +/- 2.5% to 46 +/- 2% (p < 0.01) in the uremic rats. The mean baseline blood pressure was 119 +/- 10 mmHg. At week 3, mean blood pressure was unchanged in control rats, but it was increased to 151 +/- 5 mmHg (p < 0.01) in the nephrectomized group. At week 6, mean blood pressure in the untreated uremic rats remained unchanged from week 3, but blood pressure in the uremic animals treated with r-HuEPO increased significantly to 187 +/- 8 mmHg (p < 0.01). There was no significant correlation between hematocrit and blood pressure in the r-HuEPO treated uremic group (r = 0.01, NS). r-HuEPO had no effect on blood pressure in control rats despite a significant increase in hematocrit. These results indicate that the blood pressure response to r-HuEPO is enhanced in rats with chronic renal failure.