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Background: Erythropoietin (EPO) administration in uremic rats leads to an increase in blood pressure (BP). Because chronic renal failure has been associated with oxidative stress, we hypothesize that EPO treatment could accentuate this condition and contribute to hypertension. The present study was designed to investigate the role of reactive oxygen species in EPO-induced hypertension and the effect of tempol, a superoxide dismutase-mimetic., Methods: Renal failure was induced by a two-stage 5/6 nephrectomy followed by a 3-week stabilization period. Uremic rats were divided into four groups and received for 4 weeks: vehicle; EPO (100 U/kg, subcutaneously, three times per week); vehicle + tempol (1 mmol/l in drinking water); and EPO + tempol. Systolic BP and biochemical parameters were assessed before and at the end of the treatment. Renal histology, creatinine clearance rate, endothelin-1 (ET-1) concentrations and superoxide anion production were assessed at the end of the study., Results: The uremic rats developed anemia and hypertension. ET-1 concentrations and superoxide anion production were increased. EPO administration corrected anemia, but accentuated hypertension and renal injuries such as glomerulosclerosis, interstitial fibrosis, and inflammation. EPO therapy further increased tissue levels of ET-1 and superoxide anion production. Tempol treatment improved hypertension and renal injury, and reduced ET-1 concentrations and superoxide anion production., Conclusion: Oxidative stress contributes to the development of hypertension and to the progression of renal injuries in uremic rats. EPO administration further increases oxidative stress, which might partly account for the accentuation of hypertension and renal injury.

Background: Recombinant human erythropoietin (rhEPO) increases blood pressure (BP) and the vascular production of endothelin-1 in renal failure rats. This study was designed to investigate the effect of rhEPO on BP and on the ET-1/ET(B)R system in rats with normal renal function. To further characterize the effect of rhEPO on the ET-1/ET(B)R system, we also studied heterozygous (+/-) ET(B)R knockout (KO) mice., Methods: The animals received either the vehicle or rhEPO (100 U/kg subcutaneously three times per week). ET(B)R(+/-) mice were compared with ET(A)R(+/-) and wild-type (WT) mice. In rats, the ET(B)R mRNA expression was assessed in blood vessels as well as the vascular ET(B)R density using immunohistochemistry. In mice, ET-1 concentration was measured in the thoracic aorta., Results: RhEPO administration increased hematocrit levels in all treated animals. This therapy had no effect on BP in normal rats, but it did increase vascular and renal cortex ET(B)R mRNA expression. Immunohistochemistry confirmed that the ET(B)R density was increased in blood vessel endothelium in these normal rats. In contrast, rhEPO increased BP in ET(B)R(+/-) mice and this pressor effect was associated with higher ET-1 concentrations in the thoracic aorta., Conclusions: RhEPO exerts a pleotropic effect on the endothelial ET-1/ET(B)R system. The increase in endothelial ET(B)R expression may contribute to maintaining normal BP during rhEPO administration in normal animals. Conversely, conditions with deficient ET(B)R expression, such as in ET(B)R(+/-) mice, may lead to hypertension while receiving the same therapy.

Background: Correcting anemia with recombinant human erythropoietin (rhEPO) in chronic renal failure has been associated with an increased blood pressure (BP), which may accelerate the decline in renal function. This has been attributed, in part, to the activation of the renin-angiotensin system. The present study was designed to investigate the protective effect of the angiotensin II-receptor blocker losartan compared with the angiotensin-converting enzyme inhibitor captopril and conventional triple therapy (TRx) in uremic rats receiving rhEPO therapy., Methods: Renal failure was induced by renal mass ablation followed by a 3-week stabilization period. Uremic rats were then divided into five groups with similar systolic BP: vehicle; rhEPO (100 U/kg, subcutaneously, three times per week); rhEPO + losartan (20 mg/kg/d); rhEPO + captopril (20 mg/kg/d); and rhEPO + TRx (reserpine 5 mg/L, hydralazine 80 mg/L, hydrochlorothiazide 20 mg/L). Systolic BP as well as blood and renal parameters were assessed before and after a 3-week treatment period. Renal histology was evaluated at the end of the study., Results: The uremic rats developed hypertension, anemia, proteinuria, and increased urinary endothelin-1 (ET-1) excretion. The rhEPO corrected the anemia but aggravated the hypertension (P < .01), glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Treatment with losartan, captopril, and the TRx prevented the rhEPO-induced increased in systolic BP. The TRx was less effective in preventing histologic injuries despite similar systolic BP reduction., Conclusions: Blockade of the renin-angiotensin system is highly effective in preventing both hypertension and renal histologic damage in rhEPO-treated uremic rats and this benefit seems to extend beyond the antihypertensive effect.

We previously reported that thromboxane (TX)A2 synthesis and receptor blockade prevented recombinant human erythropoietin (rhEPO)-induced hypertension in chronic renal failure rats. The present study was designed to investigate the effect of a cyclooxygenase inhibitor, acetylsalicylic acid (ASA), on blood pressure, renal function, and the concentration of eicosanoïds and endothelin-1 (ET-1) in vascular and renal tissues of rhEPO-treated or rhEPO-untreated uremic rats. Renal failure was induced by a 2-stage 5/6 renal mass ablation. Rats were divided into 4 groups: vehicle, rhEPO (100 U/kg, s.c., 3 times per week), ASA (100 mg x kg(-1) x day(-1), and rhEPO + ASA; all animals were administered drugs for 3 weeks. The TXA2- and prostacyclin (PGI2)-stable metabolites (TXB2 and 6-keto-PGF1alpha, respectively), as well as ET-1, were measured in renal cortex and either the thoracic aorta or mesenteric arterial bed. The uremic rats developed anemia, uremia, and hypertension. They also exhibited a significant increase in vascular and renal TXB2 (p < 0.01) and 6-keto-PGF1alpha (p < 0.01) concentrations. rhEPO therapy corrected the anemia but aggravated hypertension (p < 0.05). TXB2 and ET-1 tissue levels further increased (p < 0.05) whereas 6-keto-PGF1alpha was unchanged in rhEPO-treated rats compared with uremic rats receiving the vehicle. ASA therapy did not prevent the increase in systolic blood pressure nor the progression of renal disease in rhEPO-treated or rhEPO-untreated uremic rats, but suppressed both TXB2 and 6-keto-PGF1alpha tissue concentrations (p < 0.05). ASA had no effect on vascular and renal ET-1 levels. Cyclooxygenase inhibition had no effect on rhEPO-induced hypertension owing, in part, to simultaneous inhibition of both TXA2 and its vasodilatory counterpart PGI2 synthesis, whereas the vascular ET-1 overproduction was maintained. These results stress the importance of preserving PGI2 production when treating rhEPO-induced hypertension under uremic conditions.

Recent studies suggest a possible link between recombinant human erythropoietin (rhEPO)-induced hypertension and endothelium-derived vasoconstrictor autocoids. The current study was designed to evaluate the role of eicosanoids such as thromboxane (TX) A and prostacyclin (PGI ) and of endothelin-1 (ET-1) and the relationship between these vasoactive substances in rhEPO-induced hypertension in uremic rats. Renal failure was induced by a two-stage 5/6 nephrectomy followed by a 6-week stabilization period. In protocol A, rats were divided into four groups: vehicle, rhEPO (100 u/kg, subcutaneously, three times per week), a selective ET receptor antagonist (ABT-627, 10 mg/kg/d), and rhEPO + ABT-627 for 5 weeks. In protocol B, uremic animals were divided into two groups: rhEPO and rhEPO + a TX receptor antagonist and synthesis inhibitor, ridogrel (25 mg/kg/d), for 5 weeks. At the end of the study, immunoreactive eicosanoid metabolites (TXB and 6-keto-PGF, stable metabolites of TXA and PGI ), and ET-1 were measured in either the thoracic aorta or in the mesenteric arterial bed. After 5/6 nephrectomy, the animals developed uremia, anemia, and hypertension. rhEPO corrected the anemia but aggravated the hypertension. Both drugs were effective in preventing the progression of hypertension in rhEPO-treated rats although ABT-627 was more potent than ridogrel. rhEPO increased the concentration of ET-1 and TXB in blood vessels and ABT-627 decreased tissue levels of both vasopressors. The concentration of 6-keto-PGF was not significantly changed. Ridogrel significantly decreased tissue TXB concentrations but had no effect on ET-1 levels. These results suggest that endothelium-derived vasoconstrictor autacoids (TXA and ET-1) are involved in the pathogenesis of rhEPO-induced hypertension in uremic rats. TXA probably serves as a mediator of the vascular effect of ET-1.

Alterations in nitric oxide (NO) and endothelin-1 (ET-1) production have recently been reported in erythropoietin (r-HuEPO)-induced hypertension in renal failure rats. The present study was designed to evaluate the effect of NO synthase inhibition with the L-arginine analog NG-nitro-L-arginine methyl ester (L-NAME) on blood pressure (BP) and ET-1 production in control and in uremic rats treated or not treated with r-HuEPO. Renal failure was induced by a two-stage 5/6 nephrectomy. Control and uremic rats were studied separately and subdivided into four groups: vehicle, r-HuEPO, L-NAME + vehicle and L-NAME + r-HuEPO. L-NAME (100 mg/kg/day), r-HuEPO (100 U/kg, subcutaneously, three times per week), the vehicle or both were administered during 4 weeks in control rats and during 2 weeks in uremic rats. Systolic BP was recorded before and after the onset of treatment at weeks 2 and 4 in control rats and at weeks 1 and 2 in uremic rats. Hematocrit, serum creatinine, plasma, blood vessel (thoracic aorta and mesenteric artery bed) and renal cortex immunoreactive (ir) ET-1 concentrations were measured at the end of the protocol. L-NAME enhanced BP in control and uremic rats and the increase was significantly higher in uremic rats under r-HuEPO therapy (222 +/- 7 mmHg vs 198 +/- 6 mmHg, p<0.05). L-NAME induced an increase in thoracic aorta ir-ET-1 concentrations in control and uremic rats. In contrast, ir-ET-1 concentrations were unchanged in the mesenteric arterial bed and the renal cortex of control and uremic animals. R-HuEPO increased thoracic aorta ir-ET-1 contents in L-NAME treated control and uremic rats. These results underline the important role of NO release in opposing the action of vasopressors on blood vessel tone which appears more important in uremic rats treated with r-HuEPO. L-NAME treatment increased large vessel, but not small resistance artery ir-ET-1 concentrations, suggesting differential regulation of ET-1 production in different vascular beds under chronic NO synthase inhibition.

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 vs Nx + vehicle). Hematocrit in control rats was 41.3+/-0.4% vs 32.6+/-1.8% in the Nx + vehicle group (p <0.01) and 47.6+/-1.5% in the Nx + r-HuEPO group (p <0.01). Plasma ir-ET-1 levels 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). Similar results were obtained in the mesenteric arterial bed. There were significant correlations between blood pressure and ir-ET-1 content in the thoracic aorta (r= 0.45, 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.

The aim of the study was to determine the ET-1 concentration in peritoneal dialysate fluid and to investigate the relationship between peritoneal and plasma ET-1 levels and blood pressure in stable continuous ambulatory peritoneal dialysis (CAPD) patients with and without human recombinant erythropoietin (r-HuEPO) replacement therapy. Twenty-seven stable CAPD patients were investigated. They completed their overnight exchange at the Dialysis Centre. Blood pressure was recorded and a blood sample was drawn. Biochemical parameters and ET-1 were measured in plasma and peritoneal dialysate fluid. Mean plasma ET-1 levels were increased by about four-fold in CAPD patients. ET-1 was detectable in peritoneal dialysate fluid and a significant correlation was observed between plasma and peritoneal ET-1 concentrations (r = 0.65, p < 0.01). The peritoneal clearance of ET-1 was lower than the creatinine clearance (1.69 +/- 0.08 ml/min vs. 3.96 +/- 0.15 ml/min, p < 0.01). There was also a significant correlation between the time (months) on dialysis and plasma (r = 0.68, p < 0.01) or peritoneal dialysate ET-1 levels (r = 0.46, p < 0.05). Mean blood pressure was higher in patients treated with r-HuEPO than in untreated patients (97 +/- 4 mmHg vs. 81 +/- 4 mmHg, p < 0.01). Plasma and peritoneal dialysate ET-1 concentrations were comparable in the two groups with or without r-HuEPO replacement therapy and plasma ET-1 values correlated significantly with mean blood pressure only in r-HuEPO-treated patients (r = 0.63, p < 0.05 vs. r = 0.10, N.S. in untreated patients). In conclusion, plasma ET-1 concentrations are elevated in CAPD patients and the levels appear to increase with time on dialysis. ET-1 is cleared by the peritoneal membrane but at a much lower rate than creatinine. Blood pressure is higher in CAPD patients or r-HuEPO replacement therapy and blood pressure correlates with plasma ET-1 levels in these patients.

To better understand the mechanism of recombinant human erythropoietin (rhEPO)-induced increase in BP, hemodynamic parameters, body fluid volumes, and the hormones implicated in BP regulation were studied in 32 anemic hemodialysis patients before and after 3 to 4 mo of rhEPO therapy. Hemoglobin levels increased from 83 +/- 1.5 to 119 +/- 2.3 g/L (P < 0.01) after rhEPO therapy (25 to 43 U/kg) administered subcutaneously three times weekly. Mean 24-h systolic and diastolic ambulatory BP were significantly increased by 14 +/- 3 and 10 +/- 2 mmHg, respectively (P < 0.01 for both groups). Systemic vascular resistance consistently increased by 28 +/- 5% (P < 0.01), whereas cardiac output was decreased by 6 +/- 3% (P < 0.05). Red blood cell mass increased by 510 +/- 35 ml (P < 0.01), whereas plasma volume decreased by 420 +/- 66 ml (P < 0.01), which resulted in a nonsignificant increase in total blood volume. Extracellular fluid volume and exchangeable sodium were decreased by 873 +/- 255 ml (P < 0.01) and 125 mmol (P < 0.01), respectively. There was a positive correlation between the changes in exchangeable sodium and in systolic BP (r = 0.41, P < 0.05). Furthermore, a greater increase in 24-h systolic BP was observed in patients in whom exchangeable sodium increased or remained unchanged (n = 10) compared with patients (n = 22) with decreased exchangeable sodium (20 +/- 4 mmHg versus 8 +/- 2 mmHg, respectively, P < 0.01). Plasma catecholamines, plasma renin concentration, plasma atrial natriuretic peptide, and plasma endothelin-1 did not significantly change with rhEPO treatment, whereas plasma aldosterone increased significantly (P < 0.01). Although volume-independent mechanisms may contribute to rhEPO-induced BP increase, the results presented here suggest the importance of optimally reducing extracellular fluid volume to prevent, at least in part, the development of hypertension often observed with improved uremic anemia in these patients.

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.

The effect of recombinant human erythropoietin (r-HuEPO) on ambulatory blood pressure (ABP) was studied in 13 anemic hemodialysis patients. Eight patients were normotensive and five patients had untreated borderline systolic hypertension. Mean hemoglobin increased from 82 +/- 3 g/L to 114 +/- 3 g/L (P < .01) after 3 to 4 months of r-HuEPO therapy (30 to 40 U/kg) administered subcutaneously three times weekly. Mean 24-h systolic and diastolic ABP measurements were significantly increased by 16 +/- 4 mm Hg and 10 +/- 2 mm Hg, respectively (P < .01 for both). Blood pressure was increased in all but one patient. In six patients, the mean 24-h systolic and diastolic ABP measurements were more than 160 mm Hg or 90 mm Hg at the end of the study. The increase in ABP was slightly but not significantly greater during the waking period as compared with the sleeping period and the circadian blood pressure pattern was not modified by r-HuEPO treatment. The blood pressure load (percentage of ABP reading exceeding 140/90 mm Hg during the waking period and 120/90 mm Hg during the sleeping period) was significantly increased (P < .05) after r-HuEPO therapy. Nine of the 13 patients failed to show the expected reduction in blood pressure during the sleeping period and were defined as "nondippers"; the others were defined as "dippers." During r-HuEPO therapy, the increase in ABP was similar in both dippers and nondippers. This suggests that the nondipper condition is not a risk factor for the development of hypertension during r-HuEPO therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated plasma endothelin (ET) concentration and blood pressure in 44 patients with end stage renal failure chronically treated with either hemodialysis (n = 24) or continuous ambulatory peritoneal dialysis (CAPD) (n = 20). Half of the subjects were on chronic erythropoietin (r-HuEPO) replacement therapy (30-60 U/kg) subcutaneously, 3 times weekly. The mean plasma ET level of the whole group was about five fold higher than the normal range. Plasma ET concentration and mean blood pressure were higher in hemodialysis than in CAPD patients (33.3 +/- 2.1 vs 24.8 +/- 1.2 pg/ml, p < 0.01, and 101 +/- 2.4 vs 91 +/- 3 mmHg, p < 0.025). There was a significant correlation between plasma ET levels and systolic blood pressures in both groups (r = 0.45, p < 0.05). Patients (hemodialysis and CAPD) receiving subcutaneous r-HuEPO had higher mean blood pressure (99 +/- 3 vs 85 +/- 4 mmHg, p < 0.01), while their plasma ET levels were similar to untreated patients independent of the dialysis mode. However, a statistically significant correlation between plasma ET and systolic blood pressure was present only in the r-HuEPO treated group (r = 0.46, p < 0.05 vs r = 0.29, N.S., for the untreated group). These results show that plasma ET levels are markedly increased on both dialysis mode, but the values are lower in CAPD patients. Plasma ET concentrations significantly correlated with systolic blood pressures in the whole group of patients, and also in those receiving r-HuEPO replacement therapy.