Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypertension is the main side effect developing in patients suffering from renal anemia who are treated with recombinant human erythropoietin (rhEPO). We investigated the effect of rhEPO on the vascular tone of rabbit aorta. rhEPO had no direct vasoconstrictor effect, but it enhanced norepinephrine (NE)-induced contractions of rabbit aortic rings. Relaxations to acetylcholine (ACh, 1 microM) were unaltered in the presence or absence of rhEPO, indicating that the endothelium-dependent NO pathway was not affected by rhEPO. In rings of human renal artery and rabbit aorta, rhEPO (200 U/ml) increased the synthesis of constrictor prostanoids. The cyclooxygenase inhibitors indomethacin and aspirin abolished the increase in prostanoid production. However, they did not completely suppress the rhEPO-induced enhancement of NE contractions in rabbit aorta. We further investigated the effect of rhEPO on prostanoid and endothelin-1 synthesis in cultured human endothelial cells. Endothelial cells from human umbilical veins (HUVEC) were isolated and cultured. After incubation with rhEPO, the formation of prostaglandin (PG) I2 (analyzed as its stable metabolite 6-keto-PGF1 alpha), PGF2 alpha, PGE2, thromboxane (Tx) B2, and of endothelin-1 (ET-1) was measured by radioimmunoassay (RIA). rhEPO (200 U/ml) increased the formation of PGF2 alpha and TxB2 and decreased the formation of PGI2 in HUVEC. The release of ET-1 was increased by nearly 90% in the presence of rhEPO (200 U/ml). We conclude that a shift in the balance of constrictor and relaxing prostanoids as well as an increased synthesis of ET-1 may contribute to the hypertensive side effect of rhEPO therapy. ET-1 may at least in part be responsible for the unexpectedly low inhibitory effect of indomethacin on rhEPO-enhanced contractions of rabbit aorta.
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PMID:Endothelin release and shift in prostaglandin balance are involved in the modulation of vascular tone by recombinant erythropoietin. 128 78

The mechanism of hypertension induced by recombinant human erythropoietin (rHuEPO) is unclear but may include an increase in peripheral vascular resistance. We studied changes of arterial pressure and plasma endothelin in nine consecutive hemodialysis patients before, and 6 and 12 weeks after, starting rHuEPO. In six patients, changes in cardiac index (CI), stroke index (SI) and total peripheral resistance index (TPRI) were measured by bioimpedance, and forearm vascular responsiveness to intra-arterial norepinephrine (30 to 240 pmol/min) and endothelin-1 (5 pmol/min) were assessed. Six healthy age and sex matched subjects also underwent assessment of forearm vascular responsiveness to norepinephrine and endothelin-1. Treatment with rHuEPO significantly increased hemoglobin and mean arterial pressure (MAP). TPRI also increased by 35 +/- 11%. Plasma endothelin, although elevated basally, remained unchanged. Intra-arterial infusion of norepinephrine caused a maximal increase in forearm vascular resistance (FVR) of 17 +/- 9% before rHuEPO, significantly less than the 32 +/- 5% increase in healthy control subjects (P = 0.04). The response increased to 65 +/- 15% (P = 0.03) after 12 weeks rHuEPO treatment (P = 0.51 vs. controls). Endothelin-1 caused a maximal increase of FVR at 60 minutes of 45 +/- 24% before rHuEPO, which was not significantly different from controls, and tended to decrease with rHuEPO therapy. The response to endothelin-1, but not norepinephrine, correlated inversely with MAP (r = -0.52; P = 0.03) and TPRI (r = -0.51; P = 0.04). In conclusion, these studies show that anemia in chronic renal failure is associated with depressed vascular responsiveness to norepinephrine which is restored by rHuEPO therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Erythropoietin enhances vascular responsiveness to norepinephrine in renal failure. 747 68

Low oxygen tension is a feature of many physiologic and pathologic conditions, including wound healing, fibrosis, and neoplasia. Increasing evidence suggests that low oxygen tension induces the transcription of a number of genes, and that this process depends on the cellular context. The proteins synthesized from these genes enable cells to adapt to the hypoxic environment and/or to fulfill their functional roles. The regulatory regions responsible for the induction of erythropoietin gene transcription and synthesis in response to hypoxia/anemia appear to be cis-acting deoxyribonucleic acid sequences located within the 5' and 3' flanking regions of the erythropoietin gene. Other proteins induced by hypoxia include cytokines (platelet-derived growth factor-beta chain, endothelin-1, transforming growth factor-beta), enzymes (tyrosine hydroxylase, glycolytic enzymes), and stress proteins. The molecular mechanisms of the hypoxia-induced expression of these genes are poorly understood. A heme protein may act as the oxygen tension sensor, or the redox state of certain nuclear transcription factors may function as second messengers.
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PMID:Gene expression in low oxygen tension. 832 8

Evidence for the involvement of endothelial cells in the pathogenesis or erythropoietin-induced hypertension, and for endothelial cell damage in patients with chronic renal failure, has emerged and appears to be of major concern. We, therefore, investigated the effect of recombinant human erythropoietin (rHuEPO) therapy on endothelium-derived hormones in predialysis patients with progressive renal anemia. At the entry to the trial, the serum thrombomodulin concentration (Tm) and plasma endothelin-1 concentration (ET-1) in the predialysis patients were significantly higher than those in age- and sex-matched normal subjects. Following a 16 week period of treatment with 6000IU rHuEPO given intravenously once a week, patients' hematocrit increased from 27.1 +/- 2.6% to 34.6 +/- 3.2% (n = 16, P < .001). A positive correlation was found between Tm and serum creatinine concentration (Cr) (r = 0.61, P < .05 (n = 16), but no correlation was found between ET-1 and Cr. Tm and Tm/Cr significantly decreased from 7.9 +/- 2.8 ng/mL to 6.6 +/- 2.4 ng/mL (P < .01, n = 16), and from 2.1 +/- 0.7 (x10(-10) to 1.6 +/- 0.7 (x10(-10), P < .01, n = 16), respectively. However, there was no change in ET-1 as a result of the rHuEPO therapy. Creatinine clearance (Ccr), Cr, total amount of daily Tm excretion, Tm clearance/Ccr, daily urinary protein and albumin excretion, and blood pressure also remained unchanged throughout the trail. The present study indicates that correcting anemia by rHuEPO therapy reduces an abnormally elevated Tm in predialysis patients while blood pressure and renal function remain unchanged, suggesting that rHuEPO has a beneficial effect on endothelial cell dysfunction in chronic renal failure patients. This effect may be mediated via an improved oxygen supply to the endothelial cells due to the amelioration of anemia by rHuEPO.
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PMID:Evidence for amelioration of endothelial cell dysfunction by erythropoietin therapy in predialysis patients. 873 72

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.
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PMID:Hemodynamic and hormonal changes during erythropoietin therapy in hemodialysis patients. 944 93

Recently, it was reported that blood vessel immunoreactive endothelin-1 (irET-1) content is increased in hypertensive uremic rats treated with recombinant human erythropoietin (rhEPO). The present study was designed to evaluate whether ET-1 receptor blockade can prevent the progression of hypertension in renal failure rats receiving rhEPO and, if so, whether selective ET(A) and nonselective ET(A)/ET(B) receptor antagonists are equally effective. Renal failure was induced by a two-stage 5/6 nephrectomy; the animals developed uremia, anemia, and hypertension. After a 4-wk stabilization period, the animals received either rhEPO (100 U/kg, subcutaneously, three times per week) or the vehicle for 4 wk. In protocol A, half of the rats in each group were simultaneously treated with the ET(A)/ET(B) receptor antagonist bosentan (100 mg/kg per d). In protocol B, half of the rats in each group received the selective ET(A) receptor antagonist LU 135252 (50 mg/kg per d). Systolic BP was recorded before and at 2 and 4 wk after the onset of treatment. Serum creatinine levels and hematocrit were measured before treatment and at the end of the study. Creatinine clearance rates and plasma irET-1 concentrations were determined at the end of the study. rhEPO corrected the anemia, but aggravated the hypertension. There was a slight and similar increase in serum creatinine throughout the treatment period in all groups of rats. Both ET-1 receptor antagonists bosentan and LU135252 were effective in attenuating the progression of hypertension in uremic rats receiving the vehicle (P < 0.05). Treatment with LU135252 corrected the increase in BP in rhEPO-treated rats (160+/-7 mmHg versus 187+/-9 mmHg, P < 0.05). In contrast, bosentan did not attenuate the progression of hypertension in rhEPO-treated rats (172+/-10 mmHg versus 168+/-9 mmHg, NS). In summary, selective ET(A) but not ET(A)/ET(B) receptor blockade can prevent the aggravation of hypertension in renal failure rats treated with rhEPO. These results suggest that the endothelin system may be involved in the pathogenesis of rhEPO-induced hypertension in uremic rats with a differential role for ET(A) and ET(B) receptors.
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PMID:Differential effects of endothelin-1 antagonists on erythropoietin-induced hypertension in renal failure. 1040 99

The correction of anemia with human recombinant erythropoietin (rHuEPO) in end stage renal disease is associated with hypertension in about one third of hemodialysis patients. The pathogenesis of the rHuEPO-induced hypertension is still uncertain, though evidence of the involvement of endothelial cells has emerged. The aim of this study was to determine plasma endothelin-1 during hemodialysis and to compare the endothelin-1 levels in hemodialysis patients with and without rHuEPO substitution. Nineteen stable patients (13 male and 6 female, mean age 62 +/- 11 years) with end stage renal disease were studied. Cuprophan dialysers (GFS 12, Gambro, Lund, Sweden) were used for hemodialysis in all cases. rHuEPO (40 U/kg s.c.) was administered to 10 patients. Blood pressure (BP; RR mmHg) and blood volume changes (deltaBV; hemoglobinometry %) were serially measured. Samples were taken before and every hour during hemodialysis. Plasma endothelin-1 was measured by ELISA (R&D Systems, Minneapolis, USA) and corrected for hemoconcentration. Endothelin-1 concentration was elevated before commencement of hemodialysis (1.16 +/- 0.36 pg/ml) when compared to healthy controls (ref. 0.3-0.9) and increased to 1.47 +/- 0.51 pg/ml by the end of the session (p<0.05). In patients under rHuEPO-substitution plasma endothelin-1 was higher when compared to patients without substitution before (1.25 +/- 0.3 vs. 1.05 +/- 0.3 pg/ml) and at the end of HD (1.62 +/- 0.5 vs. 1.28 +/- 0.3 pg/ml, p<0.05). There was no difference in BP and deltaBV between the two groups during treatment. Plasma endothelin-1 was higher in hemodialysis patients and there was a continuous rise in plasma endothelin-1 during a session. Comparison of two groups of hemodialysis patients with and without s.c. rHuEPO-replacement treatment revealed a significantly higher plasma endothelin-1 concentration in patients with s.c. rHuEPO treatment. However, the elevated endothelin-1 levels were not accompanied by arterial hypertension.
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PMID:Influence of recombinant human erythropoietin therapy on plasma endothelin-1 levels during hemodialysis. 1148 2

We studied levels of plasma endothelin-1 (ET-1) in 25 beta-thalassemia/Hb E patients before and after blood transfusion. Baseline ET-1 levels in these patients were significantly higher than in normal controls (10.17 +/- 2.1 pg/mL vs. 8.9 +/- 2.0 pg/mL, P < 0.05). After blood transfusion, levels of plasma ET-1 tend to slightly increase during the first 24 hr but significantly decline at the 7th day to levels (8.01 +/- 1.7 pg/mL) which do not differ from those of controls. This study highlights a different alteration of plasma ET-1 in patients with beta-thalassemia compared to that of patients with sickle-cell anemia.
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PMID:Baseline levels of plasma endothelin-1 (ET-1) and changes during transfusion in thalassemic patients. 1211 30

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.
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PMID:Relationship between eicosanoids and endothelin-1 in the pathogenesis of erythropoietin-induced hypertension in uremic rats. 1260 17

Investigation into the role of endothelin-1 (ET-1) in renal function has revealed two major direct actions leading to the control of extracellular volume and blood pressure. These are the regulation of renal hemodynamics and glomerular filtration rate and the modulation of sodium and water excretion. In the rat remnant kidney model of chronic renal failure, ET-1 production is increased in blood vessels and renal tissues. These changes are related to an increase in preproET-1 expression and correlate with the rise in blood pressure, the development of cardiovascular hypertrophy, and the degree of renal insufficiency and injury. Selective ETA receptor blockade prevents the progression of hypertension and the vascular and renal damage, supporting a role for ET-1 in chronic renal failure progression. The increase in ET-1 production can be associated with other local mediators, including angiotensin II, transforming growth factor-beta1 and nitric oxide, the local production of which is also altered in chronic renal failure. In human patients with essential hypertension, atherosclerosis, and nephrosclerosis, plasma ET-1 levels are increased compared with patients with uncomplicated essential hypertension. Similarly, plasma ET-1 concentrations are markedly increased in patients with end-stage renal disease undergoing dialysis, and this correlates with blood pressure, suggesting that ET-1 may contribute to hypertension in these patients. The treatment of anemia in patients with renal failure with human recombinant erythropoietin increases blood pressure by accentuating the underlying endothelial dysfunction and the elevated vascular ET-1 production. Overall, these results support a role for ET-1 in hypertension and the end-organ damage associated with chronic renal failure. ETA receptor blockade may then represent a potential target for the management of hypertension and cardiovascular and renal protection.
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PMID:Endothelin-1 in chronic renal failure and hypertension. 1283 72


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