endothelin-1 and Uremia

There is an increasing number of clinical studies suggesting that acute kidney injury (AKI) can be complicated by the onset of progressive renal disease. Indeed, given the frequency of AKI in hospitalized patients, it could potentially be a leading cause of, or contributor to, end-stage renal disease. Insights into the natural history of AKI and potential mechanisms for disease progression can be gleaned from experimental studies. Although such studies underscore the principle that AKI can 'heal with defects', whether ongoing renal disease develops remains a subject of debate. Indeed, in the aftermath of AKI, a variety of secondary renal protective pathways are activated, which may retard or prevent severe chronic kidney disease. Furthermore, the onset of acute uremia per se may exert surprisingly potent renal protective effects. The purpose of this brief report is to review some of the clinical and experimental data that deal with these complex issues.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Blood Urea Nitrogen; Disease Models, Animal; Disease Progression; Endothelin-1; Glucocorticoids; Humans; Kidney; Nephritis, Interstitial; Renal Insufficiency, Chronic; Renal Replacement Therapy; Reperfusion Injury; Uremia

Topics: Autonomic Nervous System; Blood Volume; Endothelin-1; Hemodynamics; Humans; Hypotension; Nitric Oxide; Renal Dialysis; Syncope, Vasovagal; Uremia

Topics: Biomarkers; C-Reactive Protein; Endothelin-1; Endothelium, Vascular; Humans; Hypertrophy, Left Ventricular; Inflammation Mediators; Interleukin-6; Nitric Oxide; Phosphorus; Tumor Necrosis Factor-alpha; Uremia; Ventricular Function, Left; Ventricular Remodeling

Endothelial dysfunction is a key initiating event in vascular disease in chronic kidney disease (CKD) patients and haemodialysis (HD) patients exhibit significant vascular abnormalities. To understand this further, we examined how ex vivo intrinsic function in isolated arteries correlates with in vivo assessments of cardiovascular status in HD patients. Abdominal fat biopsies were obtained from 11 HD patients and 26 non-uremic controls. Subcutaneous arteries were dissected and mounted on a wire myograph, and cumulative concentration-response curves to noradrenalin, endothelin-1, a thromboxane A2 agonist (U46619), angiotensin II, vasopressin, bradykinin (BK), acetylcholine (ACh) and sodium nitroprusside (SNP) were constructed. Pulse wave velocity and blood pressure were measured in HD patients. Enhanced (P<0.05-0.0001) maximal contractile responses (Rmax) to all spasmogens (particularly vasopressin) were observed in arteries from HD patients compared to controls, and this effect was more pronounced in arteries with an internal diameter>600 µm. The potency (pEC50) of U46619 (P<0.01) and vasopressin (P<0.001) was also increased in arteries>600 µm of HD patients. The maximal relaxant response to the endothelium-dependent dilators ACh and BK were lower in HD patients (P<0.01-P<0.0001) (worse for ACh than BK); however the endothelium-independent dilator SNP was similar in both groups. PWV was significantly correlated with the vasoconstrictor response to vasopressin (P = 0.042) in HD patients. HD patients are primed for hypertension and end organ demand ischaemia by a highly sensitised pressor response. The failure of arterial relaxation is mediated by endothelial dysfunction. Intrinsic vascular abnormalities may be important in sensitising HD patients to recurrent cumulative ischaemic end organ injury.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Aged; Angiotensin II; Arteries; Bradykinin; Endothelin-1; Female; Humans; Kidney; Male; Middle Aged; Muscle Contraction; Muscle Relaxation; Myography; Nitroprusside; Norepinephrine; Pulse Wave Analysis; Renal Dialysis; Uremia; Vasoconstrictor Agents; Vasopressins

Patients with chronic kidney disease (CKD) have increased risk of cardiovascular disease to which co-morbidity and associated conventional risk factors contribute. We hypothesised that arterial stiffness (AS) and endothelial dysfunction (ED), as surrogates of cardiovascular risk, would worsen as renal function declined even in patients without co-morbidity and that this would relate to emerging cardiovascular risk factors.. Carotid-femoral pulse wave velocity (PWV), as a measure of AS, and flow-mediated dilatation (FMD) of the brachial artery, as a measure of ED, were assessed in CKD patients without established cardiovascular disease or diabetes mellitus.. PWV increased linearly as renal function declined (r(2) = 0.08, p < 0.01) whereas FMD was reduced only in patients with advanced kidney disease. In multivariable analysis, blood pressure was the major determinant of PWV and FMD. High-sensitivity C-reactive protein and asymmetric dimethylarginine, and isoprostanes and endothelin-1, were independent predictors of PWV and FMD, respectively. However, renal function did not independently predict either AS or ED.. These findings suggest that declining renal function, in the absence of significant co-morbidity, is associated with progressive arterial stiffness, but only patients close to dialysis exhibit endothelial dysfunction. Whilst blood pressure remains the major determinant of PWV and FMD, inflammation, oxidative stress and endothelin-nitric oxide balance contribute to cardiovascular risk, in this non-comorbid cohort.

Topics: Adult; Analysis of Variance; Arginine; Biomarkers; Blood Pressure; Brachial Artery; C-Reactive Protein; Carotid Arteries; Case-Control Studies; Chronic Disease; Comorbidity; Compliance; Cross-Sectional Studies; Disease Progression; Endothelin-1; Endothelium, Vascular; Female; Femoral Artery; Glomerular Filtration Rate; Humans; Isoprostanes; Kidney; Kidney Diseases; Linear Models; Male; Middle Aged; Peripheral Arterial Disease; Prospective Studies; Pulsatile Flow; Risk Assessment; Risk Factors; Scotland; Uremia; Vasodilation

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.. 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.. 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.. 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.

Topics: Anemia; Animals; Blood Pressure; Endothelin-1; Erythropoietin; Hypertension; Kidney Failure, Chronic; Male; Oxidative Stress; Rats; Rats, Wistar; Recombinant Proteins; Uremia

The endothelin-1 (ET-1) system has been implicated in cardiovascular disease associated with chronic renal failure. We investigated the expression and localization of ET-1 and the ET(B) and ET(A) receptors in vascular and renal tissues of uremic hypertensive rats. Uremia was induced by renal artery branches ligation. At week 6, blood and renal parameters, and plasma and urine ET-1 levels were evaluated. The ET-1, and the ET(B) and ET(A) receptors expression and localization were determined by Northern and Western blotting, and by immunofluorescence, respectively. Blood pressure, serum creatinine, proteinuria, and urinary ET-1 were increased in uremic rats. The ET-1 expression was increased in the aorta, mesenteric arteries, and the renal cortex of uremic rats, whereas the ET(B) receptor expression was reduced. Immunofluorescence analysis using the thoracic aorta revealed that the endothelial ET-1 levels were increased 4-fold in uremic rats. In contrast, the ET(B) receptor expression, which was localized exclusively in the endothelium, was markedly reduced. The ET(A) receptor expression, however, was increased 1.6-fold and was detected in the media only. Similar changes in ET-1 and ET(B) receptor expression were observed in renal cortex vessels and glomeruli of uremic rats. This study reveals that ET-1 levels are augmented in the vascular endothelium of uremic rats, whereas the ET(B) receptor expression is reduced which may play a major role in hypertension and renal failure progression.

Topics: Animals; Blotting, Western; Endothelin-1; Endothelium, Vascular; Gene Expression; Hypertension; Kidney Cortex; Male; Microscopy, Fluorescence; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; RNA; Uremia

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.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta, Thoracic; Aspirin; Blood Pressure; Cyclooxygenase Inhibitors; Disease Models, Animal; Endothelin-1; Epoprostenol; Erythropoietin; Humans; Hypertension; Kidney Cortex; Kidney Function Tests; Male; Mesenteric Arteries; Rats; Rats, Wistar; Recombinant Proteins; Thromboxane B2; Uremia

We investigate the role of transforming growth factor-beta (TGF-beta) in hypertension and renal failure progression in uremic rats, and whether it modulates the endothelin (ET) system.. Following renal mass reduction, uremic rats (Nx) received the pan-specific TGF-beta neutralizing antibody 1D11 (0.5 mg/kg, three times/week), the isotype control antibody 13C4 or the AT1 antagonist losartan (10 mg/kg per day) for 6 weeks.. Before treatment, the blood pressure was higher in Nx rats and increased further over time in Nx+13C4 rats. At the end of the study, Nx+13C4 rats exhibited increased serum creatinine, proteinuria and renal expression and excretion of TGF-beta1 and ET-1. ET-1 concentrations were greater in vascular and renal tissues, whereas the ETB receptor expression was reduced. Renal injuries were comprised of blood vessel hypertrophy, glomerular sclerosis, tubular atrophy and interstitial fibrosis, which was associated with increased alpha-smooth muscle actin expression. Treatment of uremic rats with the 1D11 antibody attenuated the increase in blood pressure and the decline in renal function. Losartan normalized the blood pressure and significantly attenuated the increase in serum creatinine and proteinuria. However, both treatments prevented renal TGF-beta1 and ET-1 overexpression, and prevented all renal histological injuries. The 1D11 antibody only improved ETB receptor expression.. Neutralization of TGF-beta attenuates hypertension and renal failure progression in uremic animals, in part, by preventing renal injury processes. These effects may be related to the modulation of the ET system, preventing renal ET-1 overproduction and the reduction of ETB receptor expression. Our data also suggest that TGF-beta1 is involved, at least in part, in the pathological effects related to angiotensin II in chronic renal failure.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antibodies; Aorta, Thoracic; Blood Pressure; Blotting, Northern; Blotting, Western; Creatinine; Endothelin-1; Gene Expression; Hypertension; Kidney; Losartan; Male; Neutralization Tests; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta; Uremia

This study was designed to investigate the role of eicosanoids, thromboxane A2 (TXA2) and prostacyclin (PGI2) as well as their relationship with endothelin-1 (ET-1) in the pathogenesis of renal parenchymal hypertension. Uremic rats were prepared by renal mass ablation and compared with sham-operated controls. The stable metabolites of TXA2 (TXB2) and PGI2 (6-keto-PGF1alpha) and immunoreactive ET-1 concentrations were measured by specific RIAs in biological fluids and in vascular and renal tissues. To investigate the functional role of TXA2 in the progression of hypertension and renal failure, a group of uremic rats were treated with ridogrel (25 mg/kg/day), a TXA2 synthase inhibitor and receptor antagonist. Renal preproET-1 expression was assessed by Northern blot analysis. Systolic blood pressure (SBP), serum creatinine and proteinuria were found to be higher in uremic rats as compared to sham-operated controls (P < 0.01). TXB2 and ET-1 concentrations were increased in blood vessels, the renal cortex and in urine (P < 0.05). 6-keto-PGF1alpha concentrations were also increased in blood vessels and the renal cortex but decreased in urine (P < 0.05). Ridogrel significantly lowered SBP and proteinuria (P < 0.05) and blunted the increase of serum creatinine. Treatment with ridogrel resulted in a marked fall in vascular, renal and urine TXA2 concentrations, while ET-1 and 6-keto-PGF1alpha concentrations remained unchanged. The preproET-1 expression was higher in uremic rats than in the controls and was unaffected by ridogrel. These results suggest that TXA2 is involved in the pathogenesis of hypertension and renal failure progression in rats with subtotal 5/6 nephrectomy and that this effect is independent of the ET-1 system.

Topics: Animals; Blood Pressure; Disease Models, Animal; Disease Progression; Eicosanoids; Endothelin-1; Epoprostenol; Male; Rats; Rats, Wistar; Renal Insufficiency; Thromboxane A2; Time Factors; Uremia

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.

Topics: Animals; Eicosanoids; Endothelin Receptor Antagonists; Endothelin-1; Erythropoietin; Humans; Hypertension; Male; Rats; Rats, Wistar; Receptor, Endothelin A; Receptors, Endothelin; Recombinant Proteins; Uremia

We documented recently that increased endothelin-1 (ET-1) production in blood vessels and glomeruli of uraemic rats plays a crucial role in the development of hypertension and the progression of chronic renal failure. Normally, biological effects and local production of ET-1 are attenuated by the immediate release of nitric oxide (NO). Increasing evidence suggest, however, that NO release is impaired in chronic renal failure. We investigated whether supplementation with L-arginine, the natural precursor of NO, improves NO synthesis in uraemic rats with reduced renal mass and modulates vascular and renal ET-1 production as well as blood pressure and renal failure progression.. One week after surgical renal mass reduction, the uraemic and sham-operated animals received either no treatment or 0.1% L-arginine in drinking water for 5 weeks. In another series of experiments, uraemic rats received 1% L-arginine for 5 weeks. Immunoreactive-ET-1 (ir-ET-1) levels in plasma, urine, and vascular and renal tissue preparations was measured by radioimmunoassay after sample extraction and purification.. Before treatment, systolic blood pressure was significantly elevated in uraemic animals compared to sham-operated controls (156+/-7 vs 111+/-3 mmHg, respectively; P<0.01). Thereafter, systolic blood pressure increased further in uraemic-untreated rats (systolic blood pressure at week 5; 199+/-9 mmHg, P<0.01), whereas it remained similar in uraemic rats supplemented with 0.1% L-arginine (171+/-9 mmHg, NS). At the end of the study, serum creatinine and urea, proteinuria and ir-ET-1 excretion were significantly augmented, while creatinine clearance was reduced in uraemic animals compared to the controls. Ir-ET-1 level was also increased in glomeruli as well as in thoracic aorta, mesenteric arterial bed, and pre-glomerular arteries, and was associated with vascular hypertrophy as assessed by tissue weight. In contrast, ir-ET-1 level was diminished in the renal papilla of uraemic rats. Treatment with 0.1% L-arginine significantly reduced proteinuria and urinary ir-ET-1 excretion (P<0.05) as well as ir-ET-1 level in glomeruli (P<0.01) and in thoracic aorta (P<0.05). These changes were associated with increased plasma NO metabolites NO2/NO3 levels in L-arginine-treated animals (P<0.01) and reduced aortic hypertrophy (P<0.05). In contrast, supplementation with 1% L-arginine had no effect on systolic blood pressure in uraemic rats, but exacerbated proteinuria and urinary ir-ET-1 excretion and increased serum urea (P<0.05) were observed.. These results indicate that improvement of NO release with a low dose but not with a high dose of L-arginine significantly attenuates the development of hypertension and the progression of renal insufficiency in rats with reduced renal mass. These protective effects may be mediated in part by the reduction of vascular and renal ET-1 production.

Topics: Animals; Arginine; Blood Pressure; Dietary Supplements; Endothelin-1; Hypertension, Renal; Male; Rats; Rats, Sprague-Dawley; Up-Regulation; Uremia

We recently reported that treatment of uremic rats with reduced renal mass with the angiotensin II (Ang II) subtype 1 receptor (AT1) antagonist losartan reduces endothelin-1 (ET-1) levels in blood vessels and in glomeruli. Although this suggests an important role for Ang II in the modulation of ET-1 production, the concomitant decrease in blood pressure may also be involved. The present study was designed to investigate whether the modulation of ET-1 production in uremic rats is related to tissue-specific effects of AT1 receptor blockade or to the antihypertensive effect of losartan.. One week after renal mass reduction, uremic rats were treated with the conventional triple therapy (TRx) [reserpine (5 mg/l), hydralazine (80 mg/l) and hydrochlorothiazide (25 mg/l)] or losartan (20 mg/kg per day) for 6 weeks. Immunoreactive-ET-1 (ir-ET-1) levels in plasma and urine, as well as in vascular and renal tissues were measured by a specific radioimmunoassay after sample extraction and purification.. Before treatment, systolic blood pressure was significantly higher in uremic animals compared to sham-operated controls (165+/-4 versus 123+/-2 mmHg, respectively; P < 0.01). Treatment with the TRx or with losartan normalized systolic blood pressure in uremic rats, whereas it was further increased in untreated uremic animals. At week 6, serum creatinine, proteinuria and urinary ET-1 and transforming growth factor-beta1 (TGF-beta1) excretion, as well as vascular and glomerular ET-1 content were increased in uremic rats compared to the controls (P < 0.01). Treatment of uremic rats with the TRx or with losartan reduced ET-1 content in the thoracic aorta and the mesenteric arterial bed (P < 0.01). However, losartan, but not the TRx, significantly attenuated the rise of serum creatinine, proteinuria and urinary ET-1 and TGF-beta1 excretion, as well as ET-1 content in glomeruli of uremic rats. Compared with the controls, renal preproET-1 mRNA expression was also significantly higher in uremic rats. Treatment of uremic rats with losartan prevented renal preproET-1 mRNA overexpression, indicating that changes in glomerular ET-1 content and urinary ET-1 excretion were related to modulation of renal ET-1 production.. These findings indicate that the effect of losartan on ET-1 production in peripheral blood vessels may be mediated, in part, by the reduction of blood pressure. In contrast, the reduction of renal ET-1 production is mediated by tissue-specific effects of AT1 receptor blockade, and may contribute to the renal protective effects of losartan.

Topics: Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Blood Pressure; Endothelin-1; Endothelins; Hypertension; Kidney; Losartan; Male; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Systole; Uremia

Patients with chronic renal failure (CRF) face a markedly increased risk of cardiovascular death. CRF is frequently complicated by hypertension and changes in both the heart (left ventricular hypertrophy) and the vasculature (endothelial dysfunction and accelerated atherosclerosis). The mechanisms underlying changes in vascular function and specifically endothelial dysfunction are unclear. This present study therefore examined subcutaneous resistance artery function in vitro, comparing adult uremic patients and controls using wire myography.. Subcutaneous fat biopsies were obtained from 12 patients with CRF (median serum creatinine 735 micromol/L) at the time of renal transplantation or peritoneal dialysis catheter insertion, and from eight controls without renal disease at the time of abdominal surgery. Resistance arteries were mounted on a wire myograph. Their contractile ability was tested with high potassium depolarization, and endothelial integrity was tested by relaxation to acetylcholine. Cumulative concentration-response curves were then constructed for norepinephrine, endothelin-1, acetylcholine, and sodium nitroprusside (SNP).. Following preconstriction with norepinephrine, vessels from uremic patients vasodilated less well to acetylcholine compared with vessels from controls [maximum % relaxation 77% (range 41, 97) vs. 98% (78, 100), P < 0.001]. The vasodilation to SNP was similar [95% (63, 100) vs. 94% (71, 100), P = 0.751]. There was a trend toward increased maximum pressure (kPa) achieved with both norepinephrine and endothelin-1 in vessels from uremic patients, and the contractions to both of these agents were more prolonged in the uremic vessels.. The pattern of normal vasodilation to SNP but reduced vasodilation to acetylcholine is consistent with endothelial dysfunction due to impaired nitric oxide (NO) production in uremic vessels. Similar results have been demonstrated in vivo in uremia, one suggested mechanism being accumulation of endogenous inhibitors of NO synthase such as asymmetric dimethylarginine (ADMA). This in vitro study suggests that a short-lived circulating factor is not entirely responsible and that there may be an inherent abnormality in endothelial function in uremia, although the exact pathophysiology remains unclear. Endothelial dysfunction may predispose the patient to accelerated atherosclerosis and may be involved in the pathogenesis of hypertension in end-stage renal failure.

Topics: Acetylcholine; Adult; Aged; Arteries; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Humans; In Vitro Techniques; Kidney Failure, Chronic; Middle Aged; Myography; Nitroprusside; Norepinephrine; Uremia; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents

Topics: Animals; Arginine; Blood Pressure; Endothelin-1; Hypertension, Renal; Nitric Oxide; Rats; Uremia

In the heart of uremic animals and patients, the number of capillaries per volume of myocardium is reduced. Immunohistochemical studies demonstrated increased cardiac endothelin-1 (ET-1) expression in the left ventricle of uremic animals. Therefore, whether treatment with a selective ET(A)-receptor antagonist prevented such capillary-myocyte mismatch was investigated. Twenty-four h after subtotal nephrectomy, rats were left untreated or started on treatment with the ET(A)-receptor antagonist LU 135252 (20 mg/kg per d) and with the angiotensin-converting enzyme (ACE) inhibitor trandolapril (0.3 mg/kg per d), respectively. BP was monitored by telemetry. Myocardial capillary length density was analyzed by stereologic techniques that avoid anisotropy artifacts. In addition, cardiac ET-1 protein and mRNA were measured using immunohistochemistry, in situ hybridization, and quantitative reverse transcription-PCR. Changes in cardiac ET(A)-and ET(B)-PCR. receptor mRNA were measured using reverse transcription-PCR. Fifteen wk after subtotal nephrectomy, significantly reduced left ventricular capillary length density (3307 +/- 535 mm/mm(3)) was found compared with sham-operated controls (3995 +/- 471 mm/mm(3)); this was also seen in animals that were treated with trandolapril (3503 +/- 533 mm/mm(3)) but not in animals that were treated with LU 135252 (3800 +/- 303 mm/mm(3)). The results support a role of ET-1 in the genesis of left ventricular capillary/myocyte mismatch in uremia.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Capillaries; Coronary Circulation; Endothelin Receptor Antagonists; Endothelin-1; Immunohistochemistry; In Situ Hybridization; Indoles; Male; Molecular Biology; Myocardium; Nephrectomy; Phenylpropionates; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; RNA, Messenger; Uremia

Increased endothelin-1 (ET-1) levels were found in patients with chronic renal failure. These correlate with the severity of renal failure. Patients with elevated ET-1 concentrations show an increased cardiovascular mortality. The prevalence of severe left ventricular hypertrophy (LVH) is a very important factor for survival and morbidity in uremic patients The aim of this study was to assess the protective effect of ET-receptor antagonists in chronic uremia. Sprague Dawley rats were subtotally nephrectomized (SNX) and treated either with the endothelin-A- (ET(A)) receptor antagonist LU302146 or with the unselective ET(A)/ET(B)-receptor antagonist LU302872 (30 mg/kgbw/day both). After subtotal nephrectomy protein excretion SNX (130.0 +/- 22.5 mg/24 h) was increased in comparison to the ET(A)-group (446 +/- 103 mg/24 h) and the ET(AB)-group (23.2 +/- 37 mg/24 h) vs sham: 115 +/- 19 mg/24 h). Heart weight was decreased by the ET(A)/ET(B)-receptor antagonist LU302146. Left ventricular contractility was impaired in SNX by about 40%. Treatment with the ET-receptor antagonists prevented the impairment in left ventricular function. Our study results provide a possible therapeutic approach using ET receptor antagonists to reduce cardiac hypertrophy and renal proteinuria. Further human studies are needed to show whether this protection of the heart and kidney might influence the survival and life-expectancy of patients suffering from chronic renal failure.

Topics: Animals; Cardiomegaly; Endothelin Receptor Antagonists; Endothelin-1; Male; Nephrectomy; Propionates; Proteinuria; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Uremia

Elevated plasma and urine endothelin-1 (ET-1) 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 and renal ET-1 production in the pole resection remnant kidney model of chronic renal failure in the rat.. Uraemic Wistar rats were prepared by surgical renal mass 5/6 ablation and compared with sham-operated controls (protocol 1). Immunoreactive-ET-1 (ir-ET-1) concentration was measured by radioimmunoassay after sample extraction and purification. To investigate the functional role of ET-1 during the progression of chronic renal failure, uraemic rats (protocol 2) were treated with either the vehicle or the ET-1 type A (ET(A)) receptor antagonist LU135252 (LU).. Systolic blood pressure and serum creatinine, as well as urinary volume and proteinuria, were significantly higher, whereas creatinine clearance was reduced in uraemic rats compared with sham-operated controls. As expected, plasma and urine ir-ET-1 concentrations were increased in uraemic rats (P<0.01) and were related to the increased ir-ET-1 levels in blood vessels and glomeruli (P<0.001). Positive correlation was found between plasma, 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 initiated once uraemia and hypertension were established. In untreated uraemic rats, systolic blood pressure increased further (P<0.05), but this was not the case in LU-treated uraemic rats. At the end of treatment, serum creatinine and proteinuria were significantly lower (P<0.05) and creatinine clearance was higher (P<0.01) in LU-treated rats compared with uraemic-untreated animals. While plasma ir-ET-1 concentration was similar in the two groups, ir-ET-1 concentration in thoracic aorta, mesenteric arterial bed, renal cortex and urine was significantly lower in LU-treated animals (P<0.01). In addition, heart, thoracic aorta and mesenteric arterial wet weight to body weight ratios were also significantly reduced in LU-treated uraemic rats (P<0.05).. 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 prevented by treatment with selective ET(A) receptor blockade.

Topics: Animals; Disease Progression; Endothelin Receptor Antagonists; Endothelin-1; Hypertension; Kidney; Kidney Failure, Chronic; Male; Osmolar Concentration; Phenylpropionates; Pyrimidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptors, Endothelin; Uremia

This study investigated potential reasons why erythropoietin (EPO) given therapeutically to patients with renal failure may increase peripheral, but not renal, vascular resistance. This was done by comparing the effects of EPO on resting tension in normal renal interlobular and subcutaneous vessels from uraemic patients. In human subcutaneous arteries from uraemic subjects, noradrenaline- and KCl-induced vasoconstrictions were enhanced when nitric oxide (NO) production was blocked with N(G)-nitro-L-arginine methyl ester (L-NAME), but were unaffected by EPO, while acetylcholine- and bradykinin-induced concentration-dependent relaxations were markedly attenuated by L-NAME, but not by EPO. The noradrenaline- and KCl-induced vasoconstrictions of human renal interlobular arteries were unaffected by the presence of L-NAME, but were attenuated by EPO (20 units.ml(-1)) by some 33% (P<0.01); this effect was enhanced by the co-administration of L-NAME. Acetylcholine and bradykinin caused comparable dilatations of the interlobular arteries; the response to the former was attenuated by L-NAME, but none of these responses were changed by EPO. EPO given alone, at a concentration of either 0.1 or 20 units.ml(-1), had no effect on basal resting tone. NO production mediated both acetylcholine- and bradykinin-induced relaxation in this vessel type. In contrast, in the interlobular arteries there was no indication of NO modulating the level of vasoconstriction, and it only mediated acetylcholine-induced dilation. These acute responses to EPO only partially explain its differential effects on the vasculature in renal failure.

Topics: Acetylcholine; Adolescent; Adult; Aged; Aged, 80 and over; Arteries; Bradykinin; Child; Child, Preschool; Dose-Response Relationship, Drug; Endothelin-1; Enzyme Inhibitors; Erythropoietin; Female; Humans; Infant; Male; Middle Aged; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitroprusside; Norepinephrine; Potassium Chloride; Renal Artery; Skin; Uremia; Vascular Resistance; Vasoconstriction; Vasodilator Agents

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.

Topics: Animals; Blood Pressure; Creatinine; Endothelin-1; Erythropoietin; Hematocrit; Humans; Hypertension; Male; Rats; Rats, Wistar; Recombinant Proteins; Uremia

Elevated plasma and urinary endothelin-1 (ET-1) levels have been reported in patients with renal failure as well as in remnant kidney models of chronic renal failure. We investigated whether these changes are related to increased ET-1 production in cardiovascular and renal tissues of rats with reduced renal mass. In uremic rats, systolic blood pressure rose in parallel with the progression of renal insufficiency. At week 6, changes in systolic blood pressure were positively correlated with serum creatinine levels (r = 0.728, p < 0.01). Plasma immunoreactive ET-1 (ir-ET-1) concentration was similar in uremic rats and sham-operated controls. In contrast, urinary ir-ET-1 excretion was significantly greater in uremic rats and was correlated with the elevation of serum creatinine and proteinuria (r = 0.795, and 0.922, p < 0.01, respectively). Compared to the controls, ir-ET-1 concentration in the thoracic aorta, preglomerular arteries and glomeruli were 1.4-, 3.5- and 6.7-fold higher, respectively, in uremic rats (p < 0.01) than in the controls. However, ir-ET-1 concentration in the mesenteric arterial bed and the left ventricle remained similar in the 2 groups, whereas it was significantly lower in the renal papilla of uremic rats (p < 0.01). Thus, ET-1 production is unchanged or slightly increased in extrarenal cardiovascular tissues of rats with reduced renal mass. In contrast, ET-1 production is significantly augmented in preglomerular arteries and glomeruli, but reduced in the papilla, suggesting that increased urinary ir-ET-1 excretion in uremic rats reflects ET-1 overproduction in the former renal tissues. Elevated ET-1 production in blood vessels and glomeruli may thus play a key role in the aggravation of hypertension and the progression of renal insufficiency in this rat remnant kidney model of chronic renal failure.

Topics: Animals; Biomarkers; Blood Vessels; Disease Models, Animal; Disease Progression; Endothelin-1; Hypertension, Renal; Kidney; Kidney Failure, Chronic; Kidney Glomerulus; Male; Organ Size; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Uremia

We analysed the effect of hemodialysis (HD) on endothelin (ET) plasma level in children with terminal renal failure. Twenty-five patients (pts) and 27 healthy children as controls were included in the study. There was no difference in ET plasma levels in pts before HD (1.97 +/- 1.45) and controls (2.08 +/- 1.47), but ET increased in plasma of pts after HD (4.10 +/- 3.66). To estimate the relationship of volume depletion or depuration on ET plasma level changes in pts during HD, ET was measured at three time points of HD (before ultrafiltration-UF, after UF, and after HD without fluid removal) in 10 pts. ET level was not significantly changed after UF (1.93 +/- 2.25 vs 1.71 +/- 1.50; ns), but was significantly increased after depuration (4.46 +/- 3.56; p < 0.05). There was no correlation between ET and blood pressure in controls and pts in either period of testing, neither with plasma renin activity, left ventricular mass index, and body weight changes during HD.

Topics: Adolescent; Child; Endothelin-1; Female; Humans; Kidney Failure, Chronic; Male; Renal Dialysis; Uremia