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Haemodynamic and renal effects of endothelin receptor antagonism in patients with chronic kidney disease
... Values for r, estimated in normal humans from lithium clearances, range from 75 to 90% (2,4,19,54). In patients with chronic kidney disease (creatinine values ϳ3.5 mg/dl), r averaged 75% (10,44,50). Because loop and distal reabsorption of lithium cannot be ruled out or quantified in humans, r may be less than these estimates. ...
... One might guess that given chronic kidney disease PT fluid reabsorption would fall, but in animal micropuncture experiments fractional reabsorption of sodium and fluid is generally constant or falls only to a slight extent (22,42,61). In studies of humans with stages 2-4 nonnephrotic chronic kidney disease, lithium reabsorption has averaged 70 -75%, close to our assumed value (10,48); this means our calculations may well be valid even in PH1 patients who have lost significant renal function. ...
The sequence of events by which primary hyperoxaluria type 1 (PH1) causes renal failure is unclear. We hypothesize that proximal tubule (PT) is vulnerable because oxalate secretion raises calcium oxalate (CaOx) supersaturation (SS) there, leading to crystal formation and cellular injury. We studied cortical and papillary biopsies from 2 PH1 patients with preserved renal function, and 7 native kidneys removed from 4 patients at the time of transplant, after short-term (2) or longer-term (2) dialysis. In these patients, and another 5 PH1 patients without renal failure, we calculated oxalate secretion, and estimated PT CaOx SS. Plasma oxalate was elevated in all PH1 patients, and inverse to creatinine clearance. Renal secretion of oxalate was present in all PH1, but rare in controls. PT CaOx SS was > 1 in all non-pyridoxine responsive PH1 prior to transplant, most marked in patients who developed ESRD. PT from PH1 with preserved renal function had birefringent crystals, confirming the presence of CaOx SS, but had no evidence of cortical inflammation or scarring by histopathology or hyaluronan staining. PH1 with short ESRD showed CaOx deposition and hyaluronan staining particularly at the corticomedullary junction in distal PT while cortical collecting ducts were spared. Longer ESRD showed wide-spread cortical CaOx, and in both groups papillary tissue had marked intratubular CaOx deposits and fibrosis. CaOx SS in PT causes CaOx crystal formation, and CaOx deposition in distal PT appears to be associated with ESRD. Minimizing PT CaOx SS may be important for preserving renal function in PH1.
... The balance irregularities of local endothelin factors, such as endothelin-1 (ET-1) and nitric oxide (NO), are one of the suggested possible mechanisms included in hypertension caused by erythropoietin. [7][8][9][10][11][12][13][14][15] Endothelins are regulatory peptides, dis-tributed in many organic systems with a strong physiological function. ...
... 8,9 The blockade of endothelin receptors also shows signifi cant infl uence on hemodynamics and underlines the important role of ET-1 in the pathogenesis of hypertension in patients with a chronic kidney disease. 12 We also researched the infl uence of erythropoietin on the concentrations of NO in serum in the patients treated with hemodialysis, as well as consequential intradialytic hypotension. 10 In our study we separated the group of stable patients treated with hemodialysis without an inclination to intradialytic hypertension and/or hypotension, without a signifi cant increase of blood pressure and/or changes in therapy with antihypertension medicines during the prior 3 months. ...
OBJECTIVE
Examine the influence of the chronic use of erythropoietin on the value of endothelin-1 (ET-1) and nitric oxide (NO), as well as on ET-1/NO ratio in serum, before and after dialysis.METHODSA total of 30 patients on hemodialysis were included in the study. Different doses of erythropoietin were administered at least 3 weeks before study. All patients had stable blood pressure values, without changes in antihypertensive therapy in the last 3 months, and without significant intradialytic hypertension and hypotension. The concentration of ET-1 and NO was measured before and after dialysis treatment. Blood pressure was measured before dialysis, each hour during dialysis, and after dialysis. The control group had 20, age and sex matched, healthy examinees.RESULTSEndothelin-1 was increased in all patients treated with hemodialysis compared to healthy controls, but their values did not correlate with the weekly dosage of erythropoietin. The level of NO after dialysis was significantly lower in patients receiving hemodialysis compared to healthy controls. The ET-1/NO ratio is increased in patients treated with dialysis compared to healthy controls, but this does not correlate with the weekly dosage of erythropoietin. The decrease of the value of ET-1 and NO was noted at the end of dialysis compared to the values measured before dialysis.DISCUSSIONOur results show that the chronic use of erythropoietin in patients treated with hemodialysis does not affect the levels of serum ET-1 and NO as well as the ET-1/NO ratio. A significant decrease of ET-1 and NO is noted compared to the values before dialysis.
... ET-1 effect on the resistance of efferent vessels might be stronger because of their smaller diameter. Moreover, specific ET A receptor blockade elevates renal plasma flow, reduces filtration fraction, possibly reduces glomerular pressure but does not affect GFR in patients with chronic kidney disease (Goddard et al., 2004;Dhaun et al., 2007). Again, this points to a preferential constrictor effect of ET-1 on efferent arterioles. ...
... ET B receptors on EC counter the effect of ET A receptors and participate in tonic vasodilation via activation of eNOS and release of prostaglandins (Matsuura et al., 1997). However, ET B receptor antagonists have little effect on renal blood flow and GFR in rodents and humans (Evans et al., 2001;Dhaun et al., 2007). ...
Endothelin-1 (ET-1) is a multifunctional hormone which regulates the physiology of the cardiovascular and renal systems. ET-1 modulates cardiac contractility, systemic and renal vascular resistance, salt and water renal reabsorption, and glomerular function. ET-1 is responsible for a variety of cellular events: contraction, proliferation, apoptosis, etc. These effects take place after the activation of the two endothelin receptors ET(A) and ET(B), which are present - among others - on cardiomyocytes, fibroblasts, smooth muscle and endothelial cells, glomerular and tubular cells of the kidney. The complex and numerous intracellular pathways, which can be contradictory in term of functional response depending on the receptor type, cell type and physiological situation, are described in this review. Many diseases share an enhanced ET-1 expression as part of the pathophysiology. However, the use of endothelin blockers is currently restricted to pulmonary arterial hypertension, and more recently to digital ulcer. The complexity of the endothelin system does not facilitate the translation of the molecular knowledge to clinical applications. Endothelin antagonists can prevent disease development but secondary undesirable effects limit their usage. Nevertheless, the increasing understanding of the effects of ET-1 on the cardiac and renal physiology maintains the endothelin system as a promising therapeutic target.
... Thus, blockade of ETA, in contrast to ETB receptor blockade, has been recognized as a potential mean to lower filtration fraction and hence proteinuria. This property of selective ETA receptor blockers was nicely demonstrated in animals and in a small set of patients with CKDs [12,[23][24][25]. Interestingly, the impact of ETA receptor blockade was more prominent in CKD patients than in healthy subjects suggesting that the contribution of the endothelin system to the regulation of renal haemodynamics is important mainly in patients with renal diseases [22]. ...
... In CKD patients, several small studies using different agents have demonstrated that endothelin receptor blockers, essentially ETA receptor blockers, lower blood pressure and/or proteinuria [23,24,[26][27][28][29]. Of note, the anti-proteinuric effect of ETA blockade was observed even in patients already treated with a blocker of the reninangiotensin system, suggesting an additive effect [30,31]. ...
... Systemic and renal haemodynamics, as well as plasma immunoreactive ET-1, its precursor big ET-1 and the Cterminal fragment were measured before and after infusions [80]. No change in plasma ET-1 level was observed at the lower concentration of TAK-044. ...
... Both doses of TAK-044 altered renal dynamics by lowering the effective filtration fraction [80]. Systemic vasodilatation and lowered blood pressure were observed at both doses of TAK-044, supporting the idea that ET-1 contributes to the maintenance of vascular tone in patients with CKD. ...
Endothelial cells regulate vascular tone largely by the actions of endothelin-1. Endothelin-1 is a potent vasoconstrictor, with effects that are dependent on the receptors to which it binds as well as their location. Endothelin-1 dysregulation is implicated in pathological conditions, including those of the pulmonary vasculature and the kidney. In this review, we describe the physiology and actions of endothelin-1 in lung and renal tissues and discuss therapies that disrupt these interactions in disease states. We provide an overview of the current clinical progress of these targeted agents and provide perspectives on the treatment of pulmonary and renal diseases with endothelin receptor antagonists.
... The balance irregularities of local endothelin factors, such as endothelin-1 (ET-1) and nitric oxide (NO), are one of the suggested possible mechanisms included in hypertension caused by erythropoietin. [7][8][9][10][11][12][13][14][15] Endothelins are regulatory peptides, dis-tributed in many organic systems with a strong physiological function. ...
... 8,9 The blockade of endothelin receptors also shows signifi cant infl uence on hemodynamics and underlines the important role of ET-1 in the pathogenesis of hypertension in patients with a chronic kidney disease. 12 We also researched the infl uence of erythropoietin on the concentrations of NO in serum in the patients treated with hemodialysis, as well as consequential intradialytic hypotension. 10 In our study we separated the group of stable patients treated with hemodialysis without an inclination to intradialytic hypertension and/or hypotension, without a signifi cant increase of blood pressure and/or changes in therapy with antihypertension medicines during the prior 3 months. ...
To establish the role of endothelin-1 and nitric oxide in the pathogenesis of hypertension in patients on chronic hemodialysis by correlating endothelin-1 and NO plasma concentrations to the level of arterial hypertension with respect to angiotensin-converting enzyme (ACE) inhibitor therapy.
We determined plasma concentrations of endothelin-1 and NO in patients on chronic hemodialysis (CHD) before and after hemodialysis treatment. The study included 30 CHD patients and 20 healthy participants as controls. Correlation to blood pressure was determined, as well as the effect of ACE inhibitors on the relationship between both endothelin-1 and NO in correlation with arterial hypertension.
Endothelin-1 plasma concentration was significantly higher in CHD patients before hemodialysis treatment than in healthy controls. Endothelin-1 plasma concentration was also significantly higher in CHD patients after hemodialysis than in healthy controls. There was a significant decrease in endothelin-1 plasma concentration after hemodialysis in comparison with its values before hemodialysis. In CHD patients, a positive correlation was found between endothelin-1 plasma concentration and systolic blood pressure after hemodialysis, irrespective of ACE inhibitors therapy. In CHD patients taking ACE inhibitors, systolic blood pressure increased with increasing endothelin-1 plasma concentration before as well as after hemodialysis. In patients taking ACE inhibitors, there was a tendency for diastolic blood pressure to increase with an increase in endothelin-1 plasma concentration after hemodialysis and to decrease with an increase in NO plasma concentration.
NO and endothelin-1 play a significant role in etiology of the hemodynamic changes of blood pressure during the dialysis.
... The acute effect of atrasentan of -0.09 mL/min/1.73m 2 per month is considerably smaller relative to those of RAAS or SGLT2 inhibitors. Other clinical trials of ERAs have also demonstrated relatively small acute effects on GFR.(18,19) For interventions with little to no acute effect on GFR, lesser eGFR decline thresholds should increase statistical power without influencing the magnitude of observed treatment effects. ...
Doubling of serum creatinine (equivalent to a 57% decline in the estimated glomerular filtration rate (eGFR)) is an accepted component of a composite kidney endpoint in clinical trials. Smaller declines in eGFR (40%, 50%) have been applied in several recently conducted clinical trials. Here, we assessed the effects of newer kidney protective agents on endpoints including smaller proportional declines in eGFR to compare relative event rates and the magnitude of observed treatment effects. We performed a post hoc analysis of 4401 patients in the CREDENCE, 4304 in the DAPA-CKD, 5734 in the FIDELIO-DKD, and 3668 in the SONAR trials, which assessed the effects of canagliflozin, dapagliflozin, finerenone and atrasentan in patients with chronic kidney disease. Effects of active therapies versus placebo on alternative composite kidney endpoints incorporating different eGFR decline thresholds (40%, 50%, or 57% eGFR reductions from baseline) with kidney failure or death due to kidney failure were compared Cox-proportional hazards regression models were used to assess and compare treatment effects. During follow-up, event rates were higher for endpoints incorporating smaller versus larger eGFR decline thresholds. Compared to the treatment effects on kidney failure or death due to kidney failure, the magnitude of relative treatment effects was generally similar when considering composite endpoints incorporating smaller declines in eGFR. Hazard ratios for the four interventions ranged from 0.63 to 0.82 for the endpoint incorporating 40% eGFR decline and 0.59 to 0.76 for the endpoint incorporating 57% eGFR decline. Clinical trials incorporating a 40% eGFR decline in a composite endpoint would require approximately half the number of participants compared to 57% eGFR decline with equivalent statistical power. Thus, in populations at high risk of CKD progression, the relative effects of newer kidney protective therapies appear generally similar across endpoints based on varying eGFR decline thresholds.
... L/min/m 2 . 37 Our results were also similar to a study of 85 older adults with eGFR ≤20 mL/min/1.73 m 2 , in which median cardiac index measured by cardiac MRI was 2.5 L/min/m 2 (IQR 2.1-3.0). ...
Natriuretic peptide levels are elevated in persons with chronic kidney disease (CKD) stages 1–3, but it remains unclear whether this is associated with extracellular volume excess or early cardiovascular changes. We hypothesized that patients with CKD stages 1–3 would have evidence of cardiovascular changes, which would associate with brain natriuretic peptide (BNP), amino-terminal-pro-BNP (NT-pro-BNP), and patient-reported symptoms.
Outpatients with CKD stages 1–3 and non-CKD controls were enrolled. Cardiovascular parameters included extracellular water (ECW) normalized to body weight measured using whole-body multifrequency bioimpedance spectroscopy, and total peripheral resistance index (TPRI) and cardiac index measured by impedance cardiography. Dyspnea, fatigue, depression, and quality of life were quantified using questionnaires.
Among 21 participants (13 with CKD), median (IQR) BNP was 47.0 (28.0–302.5) vs 19.0 (12.3–92.3) pg/mL, p=0.07, and NT-pro-BNP was 245.0 (52.0–976.8) vs 26.0 (14.5–225.8) pg/mL, p=0.08, in the CKD and control groups, respectively. Those with CKD had higher pulse pressure (79 (66–87) vs 64 (49–67) mm Hg, p=0.046) and TPRI (3721 (3283–4278) vs 2933 (2745–3198) dyn×s/cm ⁵ /m ² , p=0.01) and lower cardiac index (2.28 (2.08–2.78) vs 3.08 (2.43–3.37) L/min/m ² , p=0.02). In the overall cohort, natriuretic peptides correlated with pulse pressure (BNP r=0.59; NT-pro-BNP r=0.58), cardiac index (BNP r=−0.76; NT-pro-BNP r=−0.62), and TPRI (BNP r=0.48), p<0.05 for each, but not with ECW/weight. TPRI and blood pressure correlated moderately with symptoms.
Elevated natriuretic peptides may coincide with low cardiac index and elevated peripheral resistance in patients with CKD stages 1–3. The role of these biomarkers to detect subclinical cardiovascular changes needs to be further explored.
... Early human studies were designed to test the effect of acute infusion of ERA in modifying renal perfusion and renal damage [40,41]. Interestingly, a study enrolling CKD patients with glomerulonephritis, showed that infusion of BQ-123 on top of maximum-tolerated RAASi caused a fall in BP and proteinuria while determining an increase in renal blood flow [42]. ...
Introduction
Selective antagonists of Endothelin-1 receptors (ERA) have been tested in diabetic and nondiabetic chronic kidney disease (CKD). The SONAR trial (Study Of diabetic Nephropathy with AtRasentan) was the first randomized, phase 3, study assessing the long-term effect of ERA on CKD progression.
Areas covered
We examine the ERA effects in proteinuric CKD. We discuss the results of the main clinical studies on ERA in CKD and offer an opinion on the findings of SONAR study and future perspectives in this field. We searched in PubMed and ISI Web of Science databases for including experimental and clinical studies which evaluated ERA in proteinuric CKD.
Expert opinion
The SONAR study demonstrated that ERA confers protection against risk for CKD progression. This trial stimulated clinical research on ERA, to expand the therapeutic opportunities in CKD patients. Two novel phase 3 studies testing ERA in patients with glomerular disease are ongoing. Within the context of personalized medicine, we think it would be relevant to evaluate the effect of multiple treatments, including ERA, in proteinuric CKD patients. Testing ERA in clinical trials of novel design will also help at identifying the patients who would more benefit from these drugs.
... These properties identify ET-1 and downstream signaling pathways activated by this peptide as potential therapeutic targets in the treatment of DN. Indeed, several clinical trials of treatment of DN with members of the class of ET A R antagonists, and in particular the reported improvement in renal outcomes recently reported by the Study of Diabetic Nephropathy with Atrasentan (SONAR) trial of treatment of DN with atrasentan in combination with RAAS blockade, provides an impetus to better understand the underlying mechanisms resulting in the improved renal function and diminished proteinuria that was achieved in treated patients (15,16,26,57). ...
Podocyte loss and proteinuria are both key features of human diabetic nephropathy. The leptin deficient BTBR mouse strain with the ob/ob mutation develops progressive weight gain, Type II diabetes and diabetic nephropathy that has many features of advanced human diabetic nephropathy, including increased mesangial matrix, mesangiolysis, podocyte loss, and proteinuria. Selective antagonism of the endothelin-1 receptor, ET A R, by atrasentan treatment in combination with RAAS inhibition with losartan has been shown to have the therapeutic benefit of lowering proteinuria in patients with diabetic nephropathy, but the underlying mechanism for this benefit is not well understood. Using a similar therapeutic approach in diabetic BTBR ob/ob mice, this treatment regimen significantly increased glomerular podocyte number compared with diabetic BTBR ob/ob controls, and suggested parietal epithelial cells were a source for podocyte restoration. Atrasentan treatment alone also increased podocyte number, but to a lesser degree. Mice treated with atrasentan demonstrated a reduction in proteinuria, matching the functional improvement reported in humans. This is a first demonstration that treatment with the highly selective ET A R antagonist atrasentan can lead to restoration of the diminished podocyte number characteristic of diabetic nephropathy in humans, and thereby underlie the reduction in proteinuria in diabetic patients undergoing similar treatment. The benefit of ET A R antagonism in DN extended to a decrease in mesangial matrix as measured by a reduction in accumulations of collagen IV in both the atrasentan and atrasentan plus losartan treated groups compared to untreated controls.
... In two randomized clinical studies, the selective ET A receptor antagonist BQ123 resulted in an increase in renal blood flow in CKD patients but not in healthy volunteers suggesting that ET-1 activation is closely related to alterations of vascular beds in CKD [222,223]. In another randomized placebo-controlled study TAK-044, a non-selective ET receptor antagonist, decreased blood pressure in patients with CKD and exerted neutral effects on glomerular filtration rate by increasing renal plasma flow and decreasing filtration fraction [224]. There is evidence that ET A antagonists increase renal blood flow and reduce proteinuria in CKD patients. ...
Endothelins including its most abundant isoform, endothelin-1 (ET-1), are peptides acting as vasoconstrictors when binding to ETA and ETB receptors, and, in addition to their distinct roles in normal physiology, endothelins have a central role in the pathophysiology of many diseases including cardiovascular and renal diseases. Endothelin-1 (ET-1), the most potent vasoconstrictor in the cardiovascular system, regulates basal vascular tone and glomerular hemodynamics. ET-1 is involved also in vascular and cardiac hypertrophy, inflammation, and in the development and progression of cardiovascular diseases - e.g. essential hypertension, atherosclerosis, coronary artery disease, congestive heart failure, pulmonary arterial hypertension and cerebrovascular disease and renal diseases - e.g. acute renal failure, polycystic kidney disease and chronic kidney disease. Not surprisingly, the ET system has become a target for therapeutic interventions that now include a few already established and some new promising agents. In this narrative review, we summarize physiologic properties of the ET system, focusing especially on ET-1, and its role in the pathophysiology of ET system activated diseases, and discuss the potentials of therapeutic interventions targeting the ET system in cardiovascular and renal diseases. While ET receptor antagonists have already revolutionized the management of idiopathic pulmonary arterial hypertension, so far, this class of drugs have failed as medication for congestive heart failure. Clinical trials continue to explore new applications of endothelin receptor antagonists in treatment-resistant hypertension and chronic kidney disease and have shown some benefits in the latter group by reducing proteinuria; however, they have not been approved yet. We conclude that larger clinical trials are needed to validate the use of ET receptor antagonists in diseases with ET system activated diseases.
... The salutary effects of ERAs on kidney protection may in part be explained by hemodynamic effects. In hypertensive patients with CKD, ERA strategies increased effective renal plasma flow and reduced filtration fraction, suggesting that ET-1 activation is mediated by vasoconstriction of the efferent arteriole and glomerular hyperfiltration (197,198). However, other effects of ERAs contributing to long-term kidney preservation may also be involved. ...
Diabetic kidney disease remains the most common cause of end-stage kidney disease in the world. Despite reductions in incidence rates of myocardial infarction and stroke in people with diabetes over the past 3 decades, the risk of diabetic kidney disease has remained unchanged, and may even be increasing in younger individuals afflicted with this disease. Accordingly, changes in public health policy have to be implemented to address the root causes of diabetic kidney disease, including the rise of obesity and diabetes, in addition to the use of safe and effective pharmacological agents to prevent cardiorenal complications in people with diabetes. The aim of this article is to review the mechanisms of pathogenesis and therapies that are either in clinical practice or that are emerging in clinical development programs for potential use to treat diabetic kidney disease.
... [12][13][14][15] In clinical studies, endothelin receptor antagonists reduced albuminuria and blood pressure. 5,16,17 We therefore did this large, international, long-term trial examining the effects of adding atrasentan to the standard of care on clinically meaningful renal endpoints. The findings from SONAR support the value of atrasentan in protecting kidney function in carefully selected patients with type 2 diabetes and chronic kidney disease who show an initial reduction in albuminuria with short-term endothelin receptor blockade. ...
Background:
Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes.
Methods:
We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1·73 m2 of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days) or end-stage kidney disease (eGFR <15 mL/min per 1·73 m2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532.
Findings:
Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4-2·9). 79 (6·0%) of 1325 patients in the atrasentan group and 105 (7·9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0·65 [95% CI 0·49-0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%) of 1325 patients in the atrasentan group and 34 (2·6%) of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85-2·07]; p=0·208). 58 (4·4%) patients in the atrasentan group and 52 (3·9%) in the placebo group died (HR 1·09 [95% CI 0·75-1·59]; p=0·65).
Interpretation:
Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease.
Funding:
AbbVie.
... ET-1 has an important role in renal physiology and pathophysiology ( fig. 3). Proteinuria is a common feature of CKD, and the degree of proteinuria is closely associated with renal and [63][64][65][66][67][68][69] . In summary, ERAs reduce proteinuria, an effect that is probably in large part mediated by the systemic and renal haemodynamic effects of these drugs. ...
Cardiovascular disease is a major contributor to global morbidity and mortality and is the common end point of many chronic diseases. The endothelins comprise three structurally similar peptides of 21 amino acids in length. Endothelin 1 (ET-1) and ET-2 activate two G protein-coupled receptors — endothelin receptor type A (ET A ) and endothelin receptor type B (ET B ) — with equal affinity, whereas ET-3 has a lower affinity for ET A . ET-1 is the most potent vasoconstrictor in the human cardiovascular system and has remarkably long-lasting actions. ET-1 contributes to vasoconstriction, vascular and cardiac hypertrophy, inflammation, and to the development and progression of cardiovascular disease. Endothelin receptor antagonists have revolutionized the treatment of pulmonary arterial hypertension. Clinical trials continue to explore new applications of endothelin receptor antagonists, particularly in treatment-resistant hypertension, chronic kidney disease and patients receiving antiangiogenic therapies. Translational studies have identified important roles for the endothelin isoforms and new therapeutic targets during development, in fluid-electrolyte homeostasis, and in cardiovascular and neuronal function. Novel pharmacological strategies are emerging in the form of small-molecule epigenetic modulators, biologics (such as monoclonal antibodies for ET B ) and possibly signalling pathway-biased agonists and antagonists.
... In patients with hypertension and chronic kidney disease, ERAs cause a significant increase in effective renal blood flow and reduction in filtration fraction, suggesting that ET-1 causes vasoconstriction mediated by the efferent arteriole. 101,102 In addition to haemodynamic effects, use of the ERA atrasentan led to a reduction in albuminuria in one study, possibly through protection of the glycocalyx. 103 Other potential mechanisms of ERA-induced renoprotection involve preservation of podocyte morphology 104 and changes in production of growth factors and vasoconstrictors (eg, angiotensin II). ...
Type 2 diabetes is the leading cause of impaired kidney function, albuminuria, and renal replacement therapy globally, thus placing a large burden on health-care systems. Current treatment strategies rely on intensive glucose lowering as well as strict blood pressure control through blockade of the renin–angiotensin–aldosterone system. Such approaches might slow decline in kidney function, but many patients progress to end-stage kidney failure despite optimal therapy. In recent clinical trials, new-generation glucose-lowering drug classes, the sodium-glucose co-transporter-2 inhibitors and agents that target the incretin pathway, have been shown to improve kidney outcomes in patients with type 2 diabetes. Other new approaches, which have been developed on the basis of an improved understanding of the mechanisms that contribute to kidney damage in the context of diabetes, include use of drugs that block endothelin receptors (eg, atrasentan) and non-steroidal mineralocorticoid receptors (eg, finerenone). In this Review, we provide an overview of recent clinical data relevant to these new therapeutic approaches for management of kidney disease in the context of type 2 diabetes.
... ET-1 stimulates the activation of two receptor subtypes: endothelin receptor type A and B (ETAR, ETBR), leading to podocyte and mesangial dysfunction, renal inflammation, oxidative stress, and consequently to proteinuria and glomerulosclerosis [94]. TAK-044, an ET receptor antagonist, had no significant effect on the glomerular filtration rate but tended to increase renal plasma flow, in patients with CKD [95]. Avosentan, in combination with RAAS blockade, reduced albuminuria in patients affected by DKD, with adverse effects reported in a small percentage of patients only [96], although in a phase 3 study it induced significant fluid overload and congestive heart failure [97]. ...
Renal fibrosis is a condition characterized by excessive extracellular matrix accumulation in the kidney. Representing the final common result of a variety of injuries, it can lead to chronic kidney disease and end-stage renal disease. Although major efforts have been made in understanding the process of renal fibrosis, attempts to halt its progression have been successful only in a laboratory setting with limited success in clinical practice. Here, we review the current knowledge on the process of renal fibrogenesis and the emerging anti-fibrotic drugs that have shown encouraging results in experimental models and were subsequently tested in clinical trials. We also propose possible explanations that may account for clinical trial failures and poor translation outcomes. Finally, we will discuss alternative therapeutic options and future directions in which anti-fibrotic treatments may be coupled with drugs that can enhance endogenous tissue regeneration.
... The first clinical evidence supporting the renoprotective properties of ERAs was provided by studies showing that among patients with nondiabetic, proteinuric chronic kidney disease, intravenous administration of ERAs acutely improve systemic hemodynamic parameters and this effect is accompanied by a parallel increase in renal blood flow and decrease in effective filtration fraction [29][30][31]. The potential long-term benefits of ERAs in reducing proteinuria and retarding progression of diabetic nephropathy to ESRD were examined in a number of RCTs [32-34,35 && ], which are summarized in (Table 2) and discussed further. ...
Purpose of review:
Despite optimal therapy of diabetic nephropathy with agents blocking the renin-angiotensin-aldosterone system, the residual risk of nephropathy progression to end-stage renal disease (ESRD) remains high. The purpose of this review is to discuss the potential role of endothelin antagonism as a therapeutic tool to reduce residual proteinuria and delay kidney injury progression among patients with diabetic nephropathy.
Recent findings:
Preclinical studies have shown that endothelin receptor antagonists (ERAs) exert proteinuria lowering and nephroprotective actions in experimental models of diabetic nephropathy. ERAs reduce proteinuria in phase 2 trials that included therapy with renin-angiotensin-aldosterone system blockers. Safety of these agents and protection from ESRD needs to be demonstrated in phase 3 trials. Excess risk of fluid retention and heart failure risk remains.
Summary:
The hypothesis that the antiproteinuric effect of endothelin antagonism may be translated into a slower progression of diabetic nephropathy to ESRD is investigated in ongoing randomized trials assessing 'hard' renal endpoints. ERAs may represent a promising tool toward renoprotection in diabetic nephropathy by individualizing therapy and mitigating the risk of heart failure, if these trials are positive.
... Another possible mechanism is the hemodynamic effect of ET-1, which in conjunction with other vasoactive factors lead to an increase in intraglomerular capillary pressure which increases glomerular permeability and thus leads to increased filtration of proteins [18,19]. Considering the role of ET-1 in the development of proteinuria, the results of a number of experimental studies have pointed to renoprotective action of endothelin receptor blockers [20,21]. ...
Introduction. Microalbuminuria is a very important independent risk factor
for the progression of renal diseases as well as diseases of the
cardiovascular system. Pathophysiological mechanisms that lead to the
development of microalbuminuria in patients with diabetes are complex and
they are a result of numerous factors. In the past decade, endothelin-1, the
most potent vasoconstrictor peptide, was identified as an important factor
that significantly contributes to the functional and structural renal
changes. The objective of this study was to investigate the relationship
between plasma concentration of endothelin-1 and urinary albumin excretion in
patients with type 2 diabetes mellitus. Material and Methods. There were 76
patients with type 2 diabetes who were divided into those having
normoalbuminuria (n=33), microalbuminuria (n=29), and macroalbuminuria
(n=14), and 30 healthy controls. Plasma levels of endothelin-1 were measured
by enzyme-linked immunosorbent assay. Results. There were significant
differences in plasma concentration of endothelin-1 among groups (p
... BQ123 in particular has been used extensively in acute studies in volunteers and patients with no adverse effects reported at the concentrations tested. A second peptide antagonist, the cyclic hexapeptide TAK-044 (Masuda et al., 1996), also isolated from Streptomyces misakiensis with a more modest degree of ET A selectivity, has also been used in experimental Haynes et al., 1996;Ferro et al., 1997) and clinical studies including renal failure (Dhaun et al., 2007a) and in an a multicenter, randomized, doubleblind, placebo-controlled trial in patients with subarachnoid hemorrhage (Shaw et al., 2000). ...
The endothelins comprise three structur- ally similar 21-amino acid peptides. Endothelin-1 and -2 activate two G-protein coupled receptors, ETA and ETB, with equal affinity, whereas endothelin-3 has a lower affinity for the ETA subtype. Genes encoding the peptides are present only among vertebrates. The ligand-receptor signaling pathway is a vertebrate innovation and may reflect the evolution of endothelin-1 as the most potent vasoconstrictor in the human cardiovascular system with remarkably long lasting action. Highly selective peptide ETA and ETB antagonists and ETB agonists together with radiolabeled analogs have accurately delineated endothelin pharmacology in humans and animal models, although surprisingly no ETA agonist has been discovered. ET antagonists (bosentan, ambrisentan) have revolutionized the treatment of pulmonary arterial hypertension, with the next generation of antagonists exhibiting improved efficacy (macitentan). Clinical trials continue to explore new applications, particularly in renal failure and for reducing proteinuria in diabetic nephropathy. Translational studies suggest a potential benefit of ETB agonists in chemotherapy and neuroprotection. However, demonstrating clinical efficacy of combined inhibitors of the endothelin converting enzyme and neutral endopeptidase has proved elusive. Over 28 genetic modifications have been made to the ET system in mice through global or cell-specific knockouts, knock ins, or alterations in gene expression of endothelin ligands or their target receptors. These studies have identified key roles for the endothelin isoforms and new therapeutic targets in development, fluid-electrolyte homeostasis, and cardiovascular and neuronal function. For the future novel pharmacological strategies are emerging via small molecule epigenetic modulators, biologicals such as ETB monoclonal antibodies and the potential of signaling pathway biased agonists and antagonists.
... Endogenous ET-1 acts through ETA receptors to reduce medullary and cortical perfusion, thus reducing renal blood flow. However, no effects on the glomerular filtration rate (GFR) have been seen in any of these studies [43][44][45][46]. In contrast, the ETB receptor mediated vasodilation in the efferent arteriole [42]. ...
Diabetic kidney disease (DKD) remains the most common cause of chronic kidney disease and multiple therapeutic agents, primarily targeted at the renin-angiotensin system, have been assessed. Their only partial effectiveness in slowing down progression to end-stage renal disease, points out an evident need for additional effective therapies. In the context of diabetes, endothelin-1 (ET-1) has been implicated in vasoconstriction, renal injury, mesangial proliferation, glomerulosclerosis, fibrosis and inflammation, largely through activation of its endothelin A (ETA) receptor. Therefore, endothelin receptor antagonists have been proposed as potential drug targets. In experimental models of DKD, endothelin receptor antagonists have been described to improve renal injury and fibrosis, whereas clinical trials in DKD patients have shown an antiproteinuric effect. Currently, its renoprotective effect in a long-time clinical trial is being tested. This review focuses on the localization of endothelin receptors (ETA and ETB) within the kidney, as well as the ET-1 functions through them. In addition, we summarize the therapeutic benefit of endothelin receptor antagonists in experimental and human studies and the adverse effects that have been described.
... TAK-044 had no effect on sodium or lithium clearance, or on the fractional excretion of sodium and lithium. 54 Combining the results from a number of different studies has led to the proposal that antagonism of ET B may be undesirable in conditions such as chronic renal failure, and therefore ET A -selective antagonists might be superior to mixed ET A /ET B antagonists. This hypothesis was tested experimentally by comparing the action of BQ123 or BQ788 alone or in combination in hypertensive patients with chronic renal failure. ...
All three members of the endothelin (ET) family of peptides, ET-1, ET-2, and ET-3, are expressed in the human kidney, with ET-1 being the predominant isoform. ET-1 and ET-2 bind to two G-protein-coupled receptors, ETA and ETB, whereas at physiological concentrations ET-3 has little affinity for the ETA receptor. The human kidney is unusual among the peripheral organs in expressing a high density of ETB. The renal vascular endothelium only expresses the ETB subtype and ET-1 acts in an autocrine or paracrine manner to release vasodilators. Endothelial ETB in kidney, as well as liver and lungs, also has a critical role in scavenging ET-1 from the plasma. The third major function is ET-1 activation of ETB in in the nephron to reduce salt and water re-absorption. In contrast, ETA predominate on smooth muscle, causing vasoconstriction and mediating many of the pathophysiological actions of ET-1. The role of the two receptors has been delineated using highly selective ETA (BQ123, TAK-044) and ETB (BQ788) peptide antagonists. Nonpeptide antagonists, bosentan, macitentan, and ambrisentan, that are either mixed ETA/ETB antagonists or display ETA selectivity, have been approved for clinical use but to date are limited to pulmonary hypertension. Ambrisentan is in clinical trials in patients with type 2 diabetic nephropathy. This review summarizes ET-receptor antagonism in the human kidney, and considers the relative merits of selective versus nonselective antagonism in renal disease.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
... Several studies have investigated the potential benefits of endothelin antagonists in patients with CKD. 28,38,[45][46][47] A comparison of selective and dual endothelin receptor blockade with BQ-123 or BQ-788 or the combination of BQ 123/788 in 8 patients with stage 2-3 CKD has shown that selective ET A receptor blockade with BQ-123 reduces BP and effective renal vascular resistance, and increases renal blood flow more than dual blockade with BQ-123/788. The effects of ET A receptor blockade and dual blockade on systemic hemodynamics were similar but less pronounced in healthy subjects than in patients, and there were no effects on renal hemodynamics in healthy subjects. ...
Endothelin (ET) is an important modulator of renal function through its binding to ETA and ETB receptors in renal tissue. Various renal cells have the ability to synthesize and release endothelin-1 and elevated plasma and urinary endothelin levels have been measured in patients with chronic kidney diseases. Within the last 5 year, several studies have demonstrated that ET plays a role in the pathogenesis and progression of chronic kidney diseases and associated cardiovascular diseases. With this increasing evidence, several ET receptor antagonists have been developed, some of them being specifically investigated for their ability to provide renal protection in diabetic nephropathy. For this indication, a selective blockade of ETA receptors appears to be the preferred approach. Thus, recent clinical phase II and phase III studies have shown that ETA receptor blockers such as avosentan are able to lower proteinuria significantly in type 2 diabetic patients even on top of a full treatment with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers. However, today, the clinical benefits of ET receptor antagonists appear to be limited by the development of fluid retention and peripheral edema which have been reported to occur with all antagonists, but more so with non-selective ET antagonists. Fluid retention, like headache, nausea and nasal congestion probably represent class side-effects. Nevertheless, provided a good equilibrium can be obtained between their clinical benefits and their tolerability profile, ET receptor blockers remain promising for the management of patients with chronic kidney diseases.
... This result was expected considering the high endogenous production of ET in renal disease. 36 The studies on endothelin receptor antagonists have shown that renal hemodynamic and microcirculation are under the influence of both endogenous and exogenous ET-1. 37 On the other hand, in some studies there was no significant relationship between plasma concentration of ET-1 and GFR. ...
Background:
Endothelin-1 (ET-1) is potent vasoconstrictor peptide which is able to contribute to the functional and structural renal changes. The aim of this study was to investigate the relationship between plasma concentration of ET-1 and indices of renal function in patients with diabetic nephropathy.
Methods:
We measured plasma ET-1 levels in 99 patients with type 2 diabetes, divided into two groups according to the values of their glomerular filtration rate (GFR): group I (GFR ≥ 60 mL/min/1.73 m(2); n = 50), group II (GFR ≥ 60 mL/min/1.73 m(2), n = 49), and the control group (n = 30) with clinically healthy subjects who were matched by age and sex. GFR and effective renal plasma flow (ERPF) were measured by the radioisotopic clearance. Other renal function parameters, such as serum concentrations of cystatin C, urea, creatinine, uric acid, 24-h albuminuria and proteinuria were additionally measured.
Results:
There were significant differences in plasma concentration of ET-1 among groups I, II and the control group (1.45 vs. 2.40 vs. 0.80 pg/mL, p < 0.001). The correlation between ET-1 and mGFR (r = -0.52, p < 0.001), ERPF (r = -0.42, p < 0.001), albuminuria and proteinuria (r = 0.36, p < 0.001; r = 0.48, p < 0.001) and cystatin C (r = 0.42, p < 0.001) was significant. In multiple regression analyses, only plasma concentration of ET-1 (p < 0.001) and duration of hypertension (p < 0.05) were independently and significantly associated with mGFR.
Conclusion:
A higher plasma concentration of ET-1 is independently associated with a decreased value of GFR in patients with diabetic nephropathy.
... Acute BQ123 administration also reduced proteinuria and PWV in 22 nondiabetic CKD patients to a greater extent than that seen with nifedipine (61); a subsequent sub-analysis determined that these BQ123 effects were greater in the setting of combined angiotensin converting inhibitors (ACEI) and angiotensin receptor blocker (ARB) administration, as compared to ACEI alone, suggesting the ET A blockade in CKD may be most effective in the setting of maximal renin-angiotensin system (RAS) blockade (62). Lastly, infusion of TAK-044 (~17-fold greater affinity for ET A as compared to ET B ) to 7 nondiabetic CKD patients tended to increase renal plasma flow (63). These above studies collectively suggest that ERAs, and particularly ET A antagonists, might increase renal blood flow and reduce proteinuria in CKD patients. ...
The incidence and prevalence of chronic kidney disease (CKD), with diabetes and hypertension accounting for the majority of cases, is on the rise, with up to 160 million individuals worldwide predicted to be affected by 2020. Given that current treatment options, primarily targeted at the renin-angiotensin system, only modestly slow down progression to end-stage renal disease, the urgent need for additional effective therapeutics is evident. Endothelin-1 (ET-1), largely through activation of endothelin A receptors, has been strongly implicated in renal cell injury, proteinuria, inflammation, and fibrosis leading to CKD. Endothelin receptor antagonists (ERAs) have been demonstrated to ameliorate or even reverse renal injury and/or fibrosis in experimental models of CKD, whereas clinical trials indicate a substantial antiproteinuric effect of ERAs in diabetic and nondiabetic CKD patients even on top of maximal renin-angiotensin system blockade. This review summarizes the role of ET in CKD pathogenesis and discusses the potential therapeutic benefit of targeting the ET system in CKD, with attention to the risks and benefits of such an approach.Kidney International advance online publication, 7 May 2014; doi:10.1038/ki.2014.143.
... A later analysis of this data revealed that BQ123-induced reductions in proteinuria and PWV were greater in individuals taking combined angiotensin converting inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), as compared with ACEIs alone, supporting the notion that ERAs have a potential protective renal role in the setting of maximal renin-angiotensin system (RAS) blockade [36]. Finally, this same group reported that intravenous infusion of TAK-044, a relatively non-selective ERA (~17-fold greater affinity for ETA as compared with ETB receptors), to seven non-diabetic CKD patients reduced BP and tended to increase renal plasma flow [37]. Taken together, these findings using acute ERA administration suggest that ETA blockade exerts protective renal and vascular effects in CKD patients (the choice of which ET receptor to target in CKD is reviewed in detail in [38]). ...
Numerous pre-clinical studies have implicated endothelin-1 in the pathogenesis of diabetic and nondiabetic chronic kidney disease (CKD). Renal endothelin-1 production is almost universally increased in kidney disease. The pathologic effects of endothelin-1, including vasoconstriction, proteinuria, inflammation, cellular injury and fibrosis, are likely mediated by the endothelin A (ETA) receptor. ETA antagonism alone, and/or combined ETA/B blockade, reduces CKD progression. Based on the strong pre-clinical data, several clinical trials using ETA antagonists were conducted. Small trials involving acute intravenous endothelin receptor blockade suggest that ETA, but not ETB, blockade exerts protective renal and vascular effects in CKD patients. A large phase 3 trial (ASCEND) examined the effects of avosentan, an endothelin receptor antagonist, on renal disease progression in diabetic nephropathy. Proteinuria was reduced after 3-6 months of treatment, however the study was terminated due to increased morbidity and mortality associated with avosentan-induced fluid retention. Several phase 2 trials using avosentan at lower doses than in ASCEND, atrasentan or sitaxsentan (the latter two being highly ETA-selective) showed reductions in proteinuria on top of renin-angiotensin system blockade; infrequent and clinically insignificant fluid retention was observed at the most effective doses. Additional trials using ETA blockers are ongoing or being planned in patients with diabetic nephropathy or focal segmental glomerulosclerosis. Moving forward, such studies must be conducted with careful patient selection and attention to dosing in order to minimize adverse side effects. Nonetheless, there is cause for optimism that this class of agents will ultimately prove to be effective for the treatment of CKD.
... Additional studies brought another perspective on the potential clinical development of ET-1 receptor antagonists based on the interactions between ET-1 and angiotensin II. ET-1 receptor inhibition combined with angiotensinconverting enzyme (ACE) inhibitors has been shown to improve renal hemodynamics and sodium excretion in patients with chronic kidney diseases [84, 85]. Most interestingly, dual ET A/B antagonism improved endothelium-dependent dilation in the forearm in atherosclerotic patients treated with an ACE inhibitor [86] . ...
... Endothelin receptor antagonists were used in addition to an ACE inhibitor, and reduced proteinuria (40%) has been achieved [61,62], although one study [ASCEND (Avosentar on doubling of Serum Creatinine, End stage renal disease and death in Diabetic Nephropathy)] has been stopped as a result of drug-related adverse events, including fluid retention [61]. More recently, the combination of ET receptor antagonism and ACE inhibition has been shown to improve endothelial function [63,64], renal hemodynamics and sodium excretion in patients with chronic kidney disease [65]. ...
Chronic kidney diseases are increasing worldwide at an alarming rate, and they are emerging as a major public health problem. Treatments that slow the progression of chronic kidney disease are needed. Endothelin-1 (ET-1) is a potent vasoconstrictor with proinflammatory, mitogenic and profibrotic effects that is closely involved in both normal renal physiology and pathology. Increasing evidence suggests that ET-1 and its cognate receptors are involved in a variety of progressive renal disorders to the extent that renal ET-1 expression correlates with disease severity and renal function impairment. Endothelin receptor antagonists have been used in renoprotection studies owing to their capacity of improving renal hemodynamics and reducing proteinuria. Whether selective ET(A) or non-selective ET(A)/ET(B) receptor antagonists are preferable is still a matter of debate. As angiotensin II blockers are not invariably effective in retarding disease progression when treatment is started late in the course of the disease, it is foreseeable that an ET-1 antagonist in addition to angiotensin-converting enzyme inhibitors could represent a combined treatment for progressive nephropathies. The focus of this review is to examine the role endothelin-1 plays in kidney diseases and to determine the ideal setting for antagonizing its biological activity in chronic nephropathies.
... ET A R antagonists likely act to reduce glomerular hypertension by decreasing efferent arteriolar vasoconstriction to reduce filtration fraction. 19 ET A R antagonists may directly attenuate podocyte dysfunction through downregulation of TGF and inhibition of macrophage infiltration. 20 In a recent study of a type 1 DN model, 21 the addition of an ET A R antagonist to RAS blockade in animals with established DN resulted in reduced albuminuria and regression of glomerulosclerosis. ...
Although endothelin-receptor antagonists reduce albuminuria in diabetic nephropathy, fluid retention limits their use. Here, we examined the effect of atrasentan, a selective endothelin A receptor (ET(A)R) antagonist, on albuminuria in a randomized, double-blind, placebo-controlled trial of subjects with diabetic nephropathy already receiving stable doses of renin-angiotensin system (RAS) inhibitors. We randomly assigned 89 subjects with eGFR >20 ml/min per 1.73 m(2) and a urinary albumin-to-creatinine ratio (UACR) of 100 to 3000 mg/g to placebo or atrasentan (0.25, 0.75, or 1.75 mg daily) for 8 weeks. Compared with placebo, atrasentan significantly reduced UACR only in the 0.75- and 1.75-mg groups (P=0.001 and P=0.011, respectively). Compared with the 11% reduction in the geometric mean of the UACR from baseline to final observation in the placebo group during the study, the geometric mean of UACR decreased by 21, 42, and 35% in the 0.25-, 0.75-, and 1.75-mg atrasentan groups (P=0.291, P=0.023, and P=0.073, respectively). In the placebo group, 17% of subjects achieved ≥40% reduction in UACR from baseline compared with 30, 50, and 38% in the 0.25-, 0.75-, and 1.75-mg atrasentan groups, respectively (P=0.029 for 0.75 mg versus placebo). Peripheral edema occurred in 9% of subjects receiving placebo and in 14, 18, and 46% of those receiving 0.25, 0.5, and 1.75 mg atrasentan, respectively (P=0.007 for 1.75 mg versus placebo). In summary, atrasentan, at the doses tested, is generally safe and effective in reducing residual albuminuria and may ultimately improve renal outcomes in patients with type 2 diabetic nephropathy.
... Elevated ET-1 levels are found in DM2 patients, as well as in patients with CKD (43,44). In CKD, administration of endothelin receptor antagonists (particularly ETA) result in blood pressure reductions, implicating its role in clinical hypertension (45). A discussion of a trial involving one of these drugs in diabetic nephropathy is included later. ...
Hypertension is highly prevalent in patients with diabetic nephropathy. Diabetic nephropathy is the leading cause of CKD and end-stage kidney disease in the United States. The etiology of hypertension in diabetic nephropathy involves mechanisms with multiple inter-related mediators that result in renal sodium reabsorption and peripheral vasoconstriction. The management of hypertension in these patients is focused on treatments that target these mediators. Clinical trials have established that drugs that inhibit the renin-angiotensin-aldosterone system should be used as first-line agents on the basis of their ability to slow down progression of kidney disease and lower albuminuria. There is further interest into how the combination of drugs that inhibit this pathway at multiple steps will contribute further to the management of hypertension and diabetic nephropathy. This article presents an updated review of the mechanisms involved in hypertension in patients with diabetic nephropathy. It also reviews the past clinical trials using single agents as therapeutics and the more recent trials involving novel drugs or drug combinations used to treat these patients. Retrospective analyses of multiple studies are included to better examine the significance of the currently proposed blood pressure targets for patients with diabetic nephropathy.
... Additional studies brought another perspective on the potential clinical development of ET-1 receptor antagonists based on the interactions between ET-1 and angiotensin II. ET-1 receptor inhibition combined with angiotensin-converting enzyme (ACE) inhibitors has been shown to improve renal hemodynamics and sodium excretion in patients with chronic kidney diseases [84,85]. Most interestingly, dual ET A/B antagonism improved endotheliumdependent dilation in the forearm in atherosclerotic patients treated with an ACE inhibitor [86]. ...
One year after the revelation by Dr. Furchgott in 1980 that the endothelium was obligatory for acetylcholine to relax isolated arteries, it was clearly shown that the endothelium could also promote contraction. In 1988, Dr. Yanagisawa's group identified endothelin-1 (ET-1) as the first endothelium-derived contracting factor. The circulating levels of this short (21-amino acid) peptide were quickly determined in humans, and it was reported that, in most cardiovascular diseases, circulating levels of ET-1 were increased, and ET-1 was then tagged as "a bad guy." The discovery of two receptor subtypes in 1990, ET(A) and ET(B), permitted optimization of the first dual ET-1 receptor antagonist in 1993 by Dr. Clozel's team, who entered clinical development with bosentan, which was offered to patients with pulmonary arterial hypertension in 2001. The revelation of Dr. Furchgott opened a Pandora's box with ET-1 as one of the actors. In this brief review, we will discuss the physiological and pathophysiological role of endothelium-derived ET-1 focusing on the regulation of the vascular tone, and as much as possible in humans. The coronary bed will be used as a running example in this review because it is the most susceptible to endothelial dysfunction, but references to the cerebral and renal circulation will also be made. Many of the cardiovascular complications associated with aging and cardiovascular risk factors are initially attributable, at least in part, to endothelial dysfunction, particularly dysregulation of the vascular function associated with an imbalance in the close interdependence of nitric oxide and ET-1.
Our growing understanding of the role of the endothelin (ET) system in renal physiology and pathophysiology is based on the results of emerging studies in humans and animal models of renal disease. ET receptor antagonists reduce blood pressure and proteinuria in chronic kidney disease, and cause regression of renal injury in animals. However, the therapeutic potential of ET receptor antagonism has not been fully explored and clinical studies have been largely limited to patients with diabetic nephropathy. There remains a need for more work in non-diabetic chronic kidney disease, end-stage renal disease (patients requiring maintenance dialysis and those with a functioning kidney transplant), ischemia reperfusion injury and sickle cell disease. The current review summarises the most recent advances in both pre-clinical and clinical studies of ET receptor antagonists in the field of kidney disease.
Background: Angiotensin converting enzyme inhibitors (ACEi) reduce proteinuria and preserve kidney function in proteinuric renal diseases. Their nephroprotective effect exceeds that attributable to lowering of blood pressure alone. This study examines the potential of ACEi to protect from progression of injury after a highly specific injury to podocytes in a mouse model.
Methods: We created transgenic (Podo-DTR) mice in which graded specific podocyte injury could be induced by a single injection of diphtheria toxin. Transgenic and wild-type mice were given the ACEi captopril in drinking water, or water alone, commencing 24h after toxin injection. Kidneys were examined histologically at 8 weeks and injury assessed by observers blinded to experimental group.
Results: After toxin injection, Podo-DTR mice developed acute proteinuria, and at higher doses transient renal impairment, which subsided within 3 weeks to be followed by a slow glomerular scarring process. Captopril treatment in Podo-DTR line 57 after toxin injection at 5ng/g body weight reduced proteinuria and ameliorated glomerular scarring, matrix accumulation and glomerulosclerosis almost to baseline (toxin: 17%; toxin + ACEi 10%, p<0.04; control 7% glomerular scarring). Podocyte counts were reduced after toxin treatment and showed no recovery irrespective of captopril treatment (7.1 and 7.3 podocytes per glomerular cross section in water and captopril-treated animals compared with 8.2 of wild-type controls, p<0.05).
Conclusions: Observations in Podo-DTR mice support the hypothesis that continuing podocyte dysfunction is a key abnormality in proteinuric disease. Our model is ideal for studying strategies to protect the kidney from progressive injury following podocyte depletion. Demonstrable protective effects from captopril occur, despite indiscernible preservation or restoration of podocyte counts, at least after this degree of relatively mild injury.
Endothelin receptor antagonists (ERAs) have the potential to be a new paradigm in the treatment of chronic kidney disease (CKD). ERAs inhibit the effects of endothelin-1 (ET-1), which is known to promote CKD by causing renal cellular injury, proteinuria, inflammation, fibrosis, and hypertrophy. ERAs have been extensively studied preclinically in models of CKD and now in a large clinical trial to determine their effect on slowing the progression of CKD. Initial clinical trials show promise with regard to ERA effects on reducing proteinuria in patients with diabetic nephropathy (DN) who are already on renin-angiotensin system (RAS) blocking agents. A common side effect of peripheral edema has been consistently reported in clinical trials using ERAs; hence, finding a safe balance between renoprotective actions and side effects needs to be achieved.
The incidence and prevalence of chronic kidney disease (CKD) is increasing. Despite current therapies, many patients with CKD have suboptimal blood pressure, ongoing proteinuria, and develop progressive renal dysfunction. Further therapeutic options therefore are required. Over the past 20 years the endothelin (ET) system has become a prime target. Experimental models have shown that ET-1, acting primarily via the endothelin-A receptor, plays an important role in the development of proteinuria, glomerular injury, fibrosis, and inflammation. Subsequent animal and early clinical studies using ET-receptor antagonists have suggested that theses therapies may slow renal disease progression primarily through blood pressure and proteinuria reduction. This review examines the current literature regarding the ET system in nondiabetic CKD.
Copyright © 2015 Elsevier Inc. All rights reserved.
Objectives
We aimed to investigate hypercholesterolaemia-induced early renal lesions which result in abnormal expression of endothelin A receptor (ETAR), induced nitric oxide synthase (iNOS) and matrix metalloproteinase 9 (MMP-9). We hypothesized that this is due to an upregulated endothelin (ET) pathway consequent to hypercholesterolaemia and that CPU0213, a dual ET antagonist, could mitigate these changes.
Methods
Rats were randomly divided into four groups: (1), control; (2), high-fat diet for 60 days (HFD); HFD rats medicated in the last 15 days with either (3) CPU0213 (30 mg/kg daily, s.c.) or (4) simvastatin (4 mg/kg daily, p.o.).
Key findings
Body weight, serum triglycerides, total cholesterol and low-density-lipoprotein cholesterol were significantly increased, whereas high-density lipoprotein cholesterol decreased in the HFD group, relative to normal. Meanwhile, these changes were associated with upregulation of mRNA and protein of ETAR, iNOS and MMP-9 in the kidney. The lipid-lowering effect of simvastatin was predominant, lessening abnormal expression of these molecules in the kidney dramatically. Interestingly, CPU0213 significantly normalized expression of mRNA and protein of ETAR, iNOS and MMP-9, comparable with simvastatin, leaving no changes in hyperlipidaemia.
Conclusions
CPU0213 relieves renal lesions by blunting hypercholesterolaemia caused by the upregulated ET system, iNOS and MMP-9 in the kidney. This indicates that CPU0213 is promising in treating patients with end stage renal disease.
Endothelin-1 (ET-1) is a short chained peptide primarily of endothelial origin. Concentrations of this peptide are increased in subjects with hypertension, primary pulmonary hypertension and myocardial infarction, however its short half-life makes quantification difficult. The C-terminal of proET-1 (CTproET-1) is stoichiometrically secreted with its bioactive peptide and would be a valid method of measuring the active peptide as it has a stable half-life and is less resistant to proteolytic cleavage. The objective of this study was to understand the factors (clinical, echocardiographic and biochemical) that specifically influence plasma CTproET-1 in healthy subjects. 518 healthy volunteers were recruited from a screening study. Plasma CTproET-1 concentrations were quantified using a novel immunoluminometric sandwich assay. In multivariate analyses, age (P<0.001), diastolic BP (P=0.007), LA size (P=0.001) and eGFR (P<0.001) were independently predictive of plasma CTproET-1 levels in the healthy subjects. Therefore the interpretation of plasma CTproET-1 levels in such individuals should take into account these variables to avoid potential confounding.
: Although short-term allograft survival after solid organ transplantation has improved during the past two decades, improvement in long-term graft survival has been less pronounced. Common complications after transplantation include chronic allograft rejection, nephrotoxicity from calcineurin inhibitors (CNIs), and systemic hypertension, which all impact posttransplantation morbidity and mortality. Endothelin (ET)-1, a potent endogenous vasoconstrictor, inducer of fibrosis, and vascular smooth muscle cell proliferation, may play a key role in both the development of CNI-induced nephrotoxicity and endothelial vasculopathy in chronic allograft rejection. ET-1 levels increase after isograft implantation, and ET-1 plays a key role in CNI-induced renal vasoconstriction, sodium retention, and hypertension. Preclinical studies have demonstrated that endothelin receptor antagonists (ERAs) can reduce or prevent CNI-induced hypertension after renal transplantation. In addition, ERAs can ameliorate CNI-induced renal vasoconstriction and improve proteinuria and preserve renal function in animal models of renal transplantation. ET-1 may also play a significant role in cardiac allograft vasculopathy, and in animal models, ERAs improve pulmonary function and ischemic-reperfusion injury in lung transplantation and hepatic function and structure in liver transplantation. Emerging pharmacokinetic data suggest that the selective ERA ambrisentan may be used safely in conjunction with the most commonly used immunosuppressive agents tacrolimus and mycophenolate, albeit with appropriate dose adjustment. The weight of available evidence pointing toward a potential beneficial role of ERAs in ameliorating common complications after solid organ transplantation must be balanced with potential toxicities of ERAs but suggests that a randomized clinical trial of ERAs in transplant patients is warranted.
Diabetic nephropathy constitutes a major health care challenge. In the current review we summarize the rationale and preclinical data that suggest involvement of the endothelin (ET) system in the pathogenesis of this complication of diabetes. Early clinical studies suggest that blockade of the ET system indeed may have renoprotective effects, as reflected by a strong reduction in albumin excretion. A major challenge in the clinical development of ET receptor blockades for this indication will be to tease out the protective effects from potential off-target effects. Of particular concern is the edema formation during ET receptor blockade.
The therapeutic implications of the actions of endothelin (ET)-1 upon renal and cardiovascular function are evident. Among other diseases, ET-1 is recognized to be involved in hypertension and renal failure and, in a rush to develop novel treatments, has been extensively studied. However, given the broad localization of the two receptors (ET(A) and ET(B)) and the diverse effects resulting from their activation, analysis of the role of ET-1 in kidney-regulated blood pressure remains complicated. Moreover, the actions of ET-1 depend upon the cell type and physiological situation. To add to the complexity, both receptors often activate opposing signaling pathways within a single cell. Thus, until recently, reliable insights into the respective involvement of both receptors in the physiology and pathology of the kidney were eagerly awaited. These have been obtained using mice that are genetically modified for different members of the ET system. In this article, the molecular biology of ET-1 and its receptors in the control of renal vasculature tonicity, glomerular function, and management of water and salt reabsorption is discussed. The role of renal ET-1 in the context of blood pressure regulation will be discussed, and the potential of utilizing ET receptor antagonism in the treatment and prevention of glomerular and proteinuric diseases is also outlined.
Endothelin (ET)-1 is the major isoform in the human kidney where it interacts with two G protein-coupled receptors, ET(A) and ET(B). It contains high densities of ET receptors, but in contrast to most other peripheral organs, the majority (70%) are of the ET(B) subtype and largely have a differential distribution to ET(A) receptors within renal cells, thus mediating contrasting physiological and pathophysiological actions. ET-1 remains the most potent constrictor of human-isolated vessels, including those of the kidney which are particularly sensitive to the actions of this peptide. The pharmacological response is unusual in being sustained for a considerable period of time and slow to wash out. Smooth muscle cells of the renal vasculature mainly express ET(A) receptors, and ET(A)-selective antagonists fully block these constrictor responses. The vascular endothelium only expresses ET(B) receptors. ET-1 also acts in an autocrine or paracrine manner, and binds to ET(B) receptors to stimulate the release of vasodilators. ET-1 is unusual amongst the mammalian bioactive peptides in possessing two disulphide bridges, conferring resistance to enzymatic degradation. However, the plasma half-life of ET-1 is surprisingly short as a result of the second major function of endothelial ET(B) receptors in removing ET-1 from the circulation, mainly in the kidneys and lungs. Thus, ET(B) receptors have a critical role in protecting target organs such as the heart and may limit the detrimental vasoconstrictor effect caused by upregulation of ET-1 associated with disease. Inhibition of the renal medullary ET(B) system causes sodium retention because of its role in systemic fluid and electrolyte homeostasis. ET(A)/ET(B) antagonists would be expected to block the beneficial vasodilatory, clearing, and natriuretic actions of ET(B) receptors. Since many of the deleterious actions of ET-1, vasoconstriction, mesangial cell proliferation, and inflammation occur mainly via ET(A) receptors, selective ET(A) blockade may be more beneficial in renal disease.
Endothelin (ET) is a potent vasoconstrictory peptide with proinflammatory and profibrotic properties that exerts its biological effects through two pharmacologically distinct receptor subtypes, namely ET(A) and ET(B). In addition to its substantial contribution to normal renal function, a large body of evidence suggests that derangement of the renal ET system is involved in the initiation and progression of chronic kidney disease (CKD) in diabetes, hypertension and glomerulonephritis. Thus, the use of ET receptor antagonists (ERAs) may offer potential novel treatment strategies in CKD. Recent literature on the role of the renal ET system in the healthy kidney was reviewed. In addition, an unbiased PubMed search was performed for studies published during the last 5 years that addressed the effects of ERAs in CKD. A particular objective was to extract information regarding whether selective or nonselective ERAs may have therapeutic potential in humans. ET-1 acts primarily as an autocrine or paracrine factor in the kidney. In normal physiology, ET-1 promotes diuresis and natriuresis by local production and action through ET(B) receptors in the renal medulla. In pathology, ET-1 mediates vasoconstriction, mesangial-cell proliferation, extracellular matrix production and inflammation, effects that are primarily conveyed by ET(A) receptors. Results obtained in animal models and in humans with the use of ERAs in CKD are encouraging; nevertheless, it is still under debate which receptor subtype should be targeted. According to most studies, selective inhibition of ET(A) receptors appears superior compared with nonselective ERAs because this approach does not interfere with the natriuretic, antihypertensive and ET clearance effects of ET(B) receptors. Although preliminary data in humans are promising, the potential role of ERAs in patients with CKD and the question of which receptor subtype should be targeted can only be clarified in randomized clinical trials.
Proteinuria is associated with adverse cardiovascular and renal outcomes that are not prevented by current treatments. Endothelin 1 promotes the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism in proteinuric chronic kidney disease patients, assessing proteinuria, blood pressure (BP), and arterial stiffness, key independent, surrogate markers of chronic kidney disease progression and cardiovascular disease risk. In a randomized, double-blind, 3-way crossover study, 27 subjects on recommended renoprotective treatment received 6 weeks of placebo, 100 mg once daily of sitaxsentan, and 30 mg once daily of nifedipine long acting. Twenty-four-hour proteinuria, protein:creatinine ratio, 24-hour ambulatory BP, and pulse wave velocity (as a measure of arterial stiffness) were measured at baseline and week 6 of each treatment. In 13 subjects, renal blood flow and glomerular filtration rate were assessed at baseline and week 6 of each period. Compared with placebo, sitaxsentan reduced 24-hour proteinuria (-0.56±0.20 g/d; P=0.0069), protein:creatinine ratio (-38±15 mg/mmol; P=0.0102), BP (-3.4±1.2 mm Hg; P=0.0069), and pulse wave velocity (-0.64±0.24 m/s; P=0.0052). Nifedipine matched the BP and pulse wave velocity reductions seen with sitaxsentan but did not reduce proteinuria. Sitaxsentan alone reduced both glomerular filtration rate and filtration fraction. It caused no clinically significant adverse effects. Endothelin-A receptor antagonism may provide additional cardiovascular and renal protection by reducing proteinuria, BP, and arterial stiffness in optimally treated chronic kidney disease subjects. The antiproteinuric effects of sitaxsentan likely relate to changes in BP and renal hemodynamics.
Blocking the renin-angiotensin system (RAS) with angiotensin receptor blockers or angiotensin-converting enzyme inhibitors protects against renal injury in patients with chronic kidney disease (CKD). The aim of this study was to compare the chronic effects of telmisartan and enalapril on proteinuria, urinary liver-type fatty acid-binding protein (L-FABP) and endothelin (ET)-1 levels in patients with mild CKD.
Thirty CKD patients with mild to moderate renal insufficiency (20 men and 10 women; mean age, 37 years; estimated glomerular filtration rate (eGFR) > 60 mL min(-1) and blood pressure > 130/85 mmHg) were included in the study. Patients were randomly assigned to receive telmisartan at 80 mg day(-1) (n = 15) or enalapril at 10 mg day(-1) (n = 15). We measured blood pressure, serum creatinine, eGFR, urinary protein, L-FABP and ET-1 before the start of treatment and 6 and 12 months after the start of treatment.
The blood pressure reduction rate was similar between the two groups. Urinary protein, L-FABP and ET-1 levels were significantly reduced in both groups 6 and 12 months (P < 0.001) after treatment, but the reduction rates were more pronounced in patients receiving telmisartan than in those receiving enalapril (P < 0.001). Estimated glomerular filtration rate was increased similarly in both groups at 12 months.
The study results suggest that telmisartan results in a greater reduction of urinary markers than does enalapril and that this effect occurs by a mechanism independent of blood pressure reduction. It would be needed to investigate whether the differences may be distinct or not the same when other dosages are used.
The aim of this study was to investigate the behaviour of plasma endothelin-1 (ET-1) levels in patients affected by retinitis pigmentosa (RP) and syndromic RP.
Blood samples were obtained from a group of 40 consecutive patients with RP matched with 35 healthy subjects (HS) as control. We carried out a complete ophthalmological examination. The study group included 26 patients with RP and 14 patients with syndromic RP. Plasma ET-1 levels were determined in duplicate with a specific radioimmunoassay method.
In the HS plasma ET-1 levels were 7.48+/-2.58 pg/mL. The mean of plasma ET-1 concentrations in all patients with RP ( 16.2+/-5.6 pg/mL) was significantly (P<0.01) higher than that of HS. Moreover, in the syndromic RP patients, plasma ET-1 levels (18.9+/-6.8 pg/mL) were higher than those of HS and RP patients (P<0.01).
The increase of plasma ET-1 levels in RP patients suggests that ET-1 may play a role in the pathophysiology of the diseases involving retinal pigment epithelial cells and the retinal vascular system such as RP.
The endothelin system, and in particular endothelin receptors, are targets for therapeutic intervention in human diseases. Endothelin receptor antagonists have reached clinical use for treating pulmonary arterial hypertension, and are under clinical investigation for several other diseases, such as cancer, vasospasm or fibrogenic diseases. We review the molecules that have been evaluated in the main clinical trials, from the point of view of receptor selectivity and of their chemical characteristics which were important for efficacy in pulmonary hypertension. We will also discuss future use of antagonists to endothelin receptor(s) in several human diseases and what should be the necessary properties of the future molecules for efficacy in diseases where the presently tested molecules displayed suboptimal efficacy.
Endothelin 1 is implicated in the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism with BQ-123 on key independent surrogate markers of cardiovascular risk (blood pressure, proteinuria and renal hemodynamics, arterial stiffness, and endothelial function) in patients with nondiabetic chronic kidney disease. In a double-blind, randomized crossover study, 22 subjects with proteinuric chronic kidney disease received, on 2 separate occasions, placebo or BQ-123. Ten of these subjects also received nifedipine (10 mg) as an active control for the antihypertensive effect of BQ-123. Blood pressure, pulse wave velocity, flow-mediated dilation, renal blood flow, and glomerular filtration rate were monitored after drug dosing. BQ-123 reduced blood pressure (mean arterial pressure: -7+/-1%; P<0.001 versus placebo) and increased renal blood flow (17+/-4%; P<0.01 versus placebo). Glomerular filtration rate remained unchanged. Proteinuria (-26+/-4%; P<0.01 versus placebo) and pulse wave velocity (-5+/-1%; P<0.001 versus placebo) fell after BQ-123, but flow-mediated dilation did not change. Nifedipine matched the blood pressure and renal blood flow changes seen with BQ-123. Nevertheless, BQ-123 reduced proteinuria (-38+/-3% versus 26+/-11%; P<0.001) and pulse wave velocity (-9+/-1% versus -3+/-1%; P<0.001) to a greater extent than nifedipine. Selective endothelin-A receptor antagonism reduced blood pressure, proteinuria, and arterial stiffness on top of standard treatment in renal patients. Furthermore, these studies suggest that the reduction in proteinuria and arterial stiffness is partly independent of blood pressure. If maintained longer term, selective endothelin-A receptor antagonism may confer cardiovascular and renal benefits in patients with chronic kidney disease.
We aimed to investigate hypercholesterolaemia-induced early renal lesions which result in abnormal expression of endothelin A receptor (ET(A)R), induced nitric oxide synthase (iNOS) and matrix metalloproteinase 9 (MMP-9). We hypothesized that this is due to an upregulated endothelin (ET) pathway consequent to hypercholesterolaemia and that CPU0213, a dual ET antagonist, could mitigate these changes.
Rats were randomly divided into four groups: (1), control; (2), high-fat diet for 60 days (HFD); HFD rats medicated in the last 15 days with either (3) CPU0213 (30 mg/kg daily, s.c.) or (4) simvastatin (4 mg/kg daily, p.o.).
Body weight, serum triglycerides, total cholesterol and low-density-lipoprotein cholesterol were significantly increased, whereas high-density lipoprotein cholesterol decreased in the HFD group, relative to normal. Meanwhile, these changes were associated with upregulation of mRNA and protein of ET(A)R, iNOS and MMP-9 in the kidney. The lipid-lowering effect of simvastatin was predominant, lessening abnormal expression of these molecules in the kidney dramatically. Interestingly, CPU0213 significantly normalized expression of mRNA and protein of ET(A)R, iNOS and MMP-9, comparable with simvastatin, leaving no changes in hyperlipidaemia.
CPU0213 relieves renal lesions by blunting hypercholesterolaemia caused by the upregulated ET system, iNOS and MMP-9 in the kidney. This indicates that CPU0213 is promising in treating patients with end stage renal disease.
Liuwei Dihuang (Rehmannia complex, RC) decoction, a classic prescription of Traditional Chinese Medicine (TCM), has been used in treating diabetic nephropathy (DN). Among the 6 crude medicines which contains Corni fructus is recognized as the active fraction for its effectiveness. We aimed to investigate, first, if without Corni fructus a modified RC could be still effective, second, if the ethanol extracts could be better than that of water extract and third, the beneficial effect is mainly stemmed from suppressing the endothelin (ET-1) pathway associated with a moderate hypoglycemic effect.
Diabetes for 8 weeks was induced by a single dose of streptozotocin (STZ, 65 mg/kg, i.p.) in rats and treated with RC extracts in either 95%, 70% ethanol or water separately during 5-8th week. The efficacy of extracts was compared with aminoguanidine (AMG).
An increase in albumin and creatinine in 24h urine, blood urea nitrogen (BUN) was found in STZ rats. Oxidative stress was found in renal cortex in association with upregulated plasma ET-1 and mRNA of ETA, decreased MMP 2,9 (matrix matelloproteinases) and increased hydroxyproline.
The RC without Corni fructus was very effective in alleviating DN and ethanol extracts provided greater effects against water extracts. The efficacy in alleviating DN is attributed to normalizing the activated ET system, oxidative stress and MMP 2,9 in combination with a moderate hypoglycemic activity.
The physiological role of endogenous nitric oxide in regulation of renal function in humans is unclear. Eight healthy men received an inhibitor of nitric oxide synthase, N(G)-monomethyl-L-arginine (L-NMMA, 3 mg/kg), and saline placebo intravenously on two occasions. L-NMMA significantly increased mean arterial pressure (+7%) and total peripheral resistance (+36%). However, because renal plasma flow did not decrease significantly, the increase in renal vascular resistance (+21%) was significantly less than the increase in total peripheral resistance. Glomerular filtration rate (-19%), filtration fraction (-10%), urine flow rate (-18%), sodium (-28%), and free water excretion (-25%) all decreased significantly. Fractional distal, but not proximal, sodium reabsorption increased. L-NMMA also significantly decreased plasma nitrate and urinary excretion of nitrate and dopamine. There were no significant changes in plasma renin activity, plasma endothelin, and aldosterone or in platelet number and ex vivo aggregation. L-NMMA had a plasma half-life of 75 min. Basal generation of nitric oxide appears to contribute less to vascular tone in the kidney than systemically but may alter afferent arteriolar tone. Decreased fractional sodium excretion supports an important physiological role for nitric oxide in inhibition of tubular sodium reabsorption, possibly mediated by the renal dopaminergic system.
BACKGROUND:
Angiotensin II (Ang II) is assumed to play a pathophysiological role in a variety of vascular diseases. Animal studies indicate that these effects are partly attributed to stimulation of endothelin-1 (ET-1) release. The aim of the present study was to investigate whether the acute effects of Ang II on systemic and renal haemodynamics in healthy subjects can be influenced by endothelin ET(A)-receptor blockade.
DESIGN:
The study design was balanced, randomized, placebo-controlled, double blind, two-way cross-over, in 10 healthy male subjects.
METHODS:
Subjects received stepwise increasing intravenous doses of Ang II (0.65, 1.25, 2.5, 5 ng kg(-1) min(-1) for 15 min per dose level) in the presence or absence of BQ-123 (60 microg min(-1)), a specific ETA-receptor antagonist. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were assessed by the para-aminohippurate and inulin plasma clearance method, respectively. Renal vascular resistance (RVR) was calculated from mean arterial pressure (MAP) and renal plasma flow.
RESULTS:
Ang II decreased RPF by 34% and GFR by 9% and increased RVR by 94% and MAP by 27% (ANOVA, P < 0.001 vs. baseline, for all parameters). BQ-123 did not alter these renal and systemic haemodynamic responses to a significant degree. In addition, BQ-123 had no significant haemodynamic effect under baseline conditions.
CONCLUSIONS:
Short-term increase of circulating Ang II levels causes systemic and renal pressor effects, which are not mitigated by endothelin ETA-receptor blockade. This suggests that the pressor response to Ang II cannot be accounted for by the acute release of vasoactive ET-1.
The effect on systemic haemodynamics of BQ‐123, a selective endothelin A (ETA) receptor antagonist, was investigated in healthy men by giving, on separate occasions, ascending intravenous doses of 100, 300, 1000 and 3000 nmol min ⁻¹ BQ‐123, each for 15 min, in a randomized, placebo‐controlled, double‐blind study. The response of forearm blood flow to brachial artery infusion of endothelin‐1 (ET‐1; 5 pmol min ⁻¹ for 90 min) was also studied using bilateral forearm plethysmography, after systemic pre‐treatment, on separate occasions, with one of two doses of BQ‐123 (300 and 1000 nmol min ⁻¹ for 15 min) or placebo.
Systemic BQ‐123 dose‐dependently decreased systemic vascular resistance ( P <0.01 for all doses vs placebo) and mean arterial pressure ( P <0.05 for 300 nmol min ⁻¹ and P <0.01 for 1000 and 3000 nmol min ⁻¹ ) during the 60 min following infusion. There were concurrent increases in heart rate and cardiac index. BQ‐123, when infused systemically for 15 min, appeared to reach a maximum effect at 1000 nmol min ⁻¹ .
Intra‐brachial ET‐1 infusion, after pre‐treatment with placebo, caused a slow onset progressive forearm vasoconstriction without systemic effects. This vasoconstriction was attenuated by pre‐treatment with BQ‐123 at 300 nmol min ⁻¹ and abolished by BQ‐123 at 1000 nmol min ⁻¹ ( P <0.01 vs placebo).
These effects occurred at concentrations of BQ‐123 in the plasma (510±64 nmol l ⁻¹ ) that were ETA receptor selective, and were not accompanied by an increase in plasma ET‐1 that would have indicated ETB receptor blockade.
We conclude that ETA‐mediated vascular tone contributes to the maintenance of basal systemic vascular resistance and blood pressure in healthy men.
British Journal of Pharmacology (2001) 134 , 648–654; doi: 10.1038/sj.bjp.0704304
The incidence of chronic kidney disease (CKD) is increasing worldwide. Cardiovascular disease (CVD) is strongly associated with CKD and constitutes one of its major causes of morbidity and mortality. Treatments that slow the progression of CKD and improve the cardiovascular risk profile of patients with CKD are needed. The endothelins (ET) are a family of related peptides, of which ET-1 is the most powerful endogenous vasoconstrictor and the predominant isoform in the cardiovascular and renal systems. The ET system has been widely implicated in both CVD and CKD. ET-1 contributes to the pathogenesis and maintenance of hypertension and arterial stiffness and more novel cardiovascular risk factors such as oxidative stress and inflammation. Through these, ET also contributes to endothelial dysfunction and atherosclerosis. By reversal of these effects, ET antagonists may reduce cardiovascular risk. In particular relation to the kidney, antagonism of the ET system may be of benefit in improving renal hemodynamics and reducing proteinuria. ET likely also is involved in progression of renal disease, and data are emerging to suggest a synergistic role for ET receptor antagonists with angiotensin-converting enzyme inhibitors in slowing CKD progression.
We previously demonstrated that urinary endothelin excretion is increased in rats with extensive renal mass reduction, a model of progressive renal disease. Here we explored whether the increased urinary endothelin in this model were due to induction of renal pre-pro-endothelin-1 gene and whether changes in endothelin synthetic pathway correlated with the development of glomerulosclerosis. Four groups of rats with renal mass reduction and four groups of sham-operated control rats were studied 7, 30, 60 and 120 days after the surgical procedure. Urinary protein excretion in renal mass ablation animals did not differ from controls at seven days, but was already significantly elevated (P < 0.01) 30 days after surgery. Then proteinuria progressively increased in rats with remnant kidney at values above 400 mg/day at day 120. Serum creatinine concentration also progressively increased with time in renal mass ablation rats, unlike sham-operated animals, and values were significantly different (P < 0.01) at each of the points considered. Rats with renal mass reduction, unlike sham-operated animals, developed focal glomerulosclerosis that affected 8% of glomeruli at day 30, and 24% of glomeruli at day 120. Seven days after renal mass reduction renal pre-pro-endothelin-1 (pre-pro ET) mRNA was comparable to that of sham-operated rats, while a 2.5-, 5- and fourfold increase in 2.3 Kb pre-proET-1 transcript was observed at 30, 60 and 120 days, respectively. Urinary excretion of endothelin was significantly elevated (P < 0.01) in rats with renal mass reduction with respect to sham-operated rats, starting from 30 days after surgery and increased further thereafter.(ABSTRACT TRUNCATED AT 250 WORDS)
Endothelin-1 (ET-1) regulates vascular tone in congestive heart failure and modulates renal function. Its role in patients with normal left ventricular (LV) function and its renal effects are unclear. Cardiac and renal hemodynamics were studied in 24 patients with normal LV function and coronary arteries after single-dose, double-blind, randomized administration of TAK-044 (25, 50, or 100 mg, i.v.), an ETA/B-receptor antagonist, or placebo. Hemodynamics were monitored using Swan-Ganz and arterial catheters, and ET levels were measured. Renal function was assessed by clearance techniques. In the absence of a dose-response relation, TAK-044 patients were analyzed as a single group. Most hemodynamic effects occurred during the first 4 h. TAK-044 reduced mean arterial (-9.3 mm Hg, p < 0.001), pulmonary (-1.8 mm Hg, p = 0.01), and pulmonary capillary wedge pressure (-1.6 mm Hg, p < 0.001) between 30 min and 4 h. Mean reduction in systemic vascular resistance was 279 dyne/s/cm2 (p < 0.001), whereas heart rate increased 6.1 beats/min (p < 0.001) and cardiac index by 0.37 L/m2 (p = 0.01). Stroke volume index, right atrial pressure, and pulmonary vascular resistance did not change. TAK-044 increased renal plasma flow in proportion to the increase in cardiac output (+119 ml/min, 4 h after TAK-044; p < 0.05) and ET-1 levels (2.5-fold; p < 0.05). No serious side effects were noted. In patients with normal cardiac function, ET-receptor blockade causes vasodilation and reduces systemic but not pulmonary vascular resistance and increases cardiac index and renal plasma flow.
Endothelin is a powerful vasoconstrictor peptide derived from the endothelium. We evaluated the contribution of endothelin to blood-pressure regulation in patients with essential hypertension by studying the effect of an endothelin-receptor antagonist, bosentan.
We studied 293 patients with mild-to-moderate essential hypertension. After a placebo run-in period of four to six weeks, patients were randomly assigned to receive one of four oral doses of bosentan (100, 500, or 1000 mg once daily or 1000 mg twice daily), placebo, or the angiotensin-converting-enzyme inhibitor enalapril (20 mg once daily) for four weeks. Blood pressure was measured before and after treatment.
As compared with placebo, bosentan resulted in a significant reduction in diastolic pressure with a daily dose of 500 or 2000 mg (an absolute reduction of 5.7 mm Hg at each dose), which was similar to the reduction with enalapril (5.8 mm Hg). There were no significant changes in heart rate. Bosentan did not result in activation of the sympathetic nervous system (as determined by measurement of the plasma norepinephrine level) or the renin-angiotensin system (as determined by measurements of plasma renin activity and angiotensin II levels).
An endothelin-receptor antagonist, bosentan, significantly lowered blood pressure in patients with essential hypertension, suggesting that endothelin may contribute to elevated blood pressure in such patients. The favorable effect of treatment with bosentan on blood pressure occurred without reflexive neurohormonal activation.
1. Sramek and Bernstein's method of impedance cardiography is a simple, non-invasive and inexpensive computerised way of measuring stroke volume and systolic time intervals. In this study measurements made using the method were compared with those found simultaneously using established reference techniques. 2. In healthy volunteers there was no significant bias (d) and narrow 95% limits of agreement (d +/- 2s) when impedance and mechanophonocardiographic measurements of pre-ejection period (PEP, d = 0.3, d + 2s = 7.3, d-2s = -6.6 ms), ventricular ejection time (VET, d = 1.5, d + 2s = 17.7, d-2s = 14.6 ms) and PEP/VET ratio were compared. 3. In critically ill patients there was moderate agreement between impedance and thermodilution measurements of stroke volume (d = 8.1 (P < 0.05), d + 2s = 35.5, d-2s = -19.4 ml) and drug-induced changes in stroke volume were accurately detected. 4. In healthy volunteers agreement between impedance and dye dilution measurements of stroke volume was moderate, and similar at rest and during exercise (d = 3.4, d-2s = -31.1, d + 2s = 37.9 ml), however impedance underestimated exercise-induced increases in stroke volume (P < 0.05). 5. In patients with coronary heart disease impedance measurements correlated with angiographic left ventricular ejection fraction included the PEP/VET ratio (r = -0.81), stroke volume index (r = 0.65) and Heather index (r = 0.58, all P < 0.001), however the PEP/VET ratio could not be used to estimate the left ventricular ejection fraction with sufficient accuracy. 6. This impedance method provides reproducible semi-quantitative measurements of cardiac performance and blood flow. Its use for making pharmacodynamic measurements can be justified when invasive methods are considered inappropriate.
Plasma immunoreactive endothelin concentrations were measured in patients with uraemia and in non-uraemic controls. Concentrations were beneath the detection limit of the assay in most patients without uraemia but were readily detectable in those undergoing haemodialysis. Plasma endothelin concentrations in patients with uraemia who were not undergoing haemodialysis were lower than in those on maintenance dialysis.
The linear tetrapeptide radioligand, [ ¹²⁵ I]‐PD151242 was used to characterize ET A receptors in human kidney which is an ET B ‐rich tissue. Saturation binding assays with [ ¹²⁵ I]‐PD151242 revealed a single population of high affinity endothelin receptors: K D = 0.75 ± 0.07 n m and B max = 48.4 ± 1.6 fmol mg ⁻¹ protein ( n = 3 individuals ± s.e.mean). Hill slopes were close to unity and a one site fit was preferred to a two site model.
ET A ‐receptor‐selective ligands competed for [ ¹²⁵ I]‐PD151242 binding with sub‐nanomolar affinity: BQ123 K D = 0.43 ± 0.10 n m , B max = 46.6 ± 7.9 fmol mg ⁻¹ protein; FR139317, K D = 0.37 ± 0.06nM, B max = 39.5 ± 6.5 fmol mg ⁻¹ protein ( n = 3 individuals ± s.e.mean). In each case, monophasic inhibition curves were obtained and a one site fit was preferred to a two site model. The ET B ‐selective agonist, BQ3020 at the highest concentration tested (10 μ m ) inhibited binding by only 50%. The non‐selective RO462005 competed for the binding of [ ¹²⁵ I]‐PD151242: K D = 1.31 ± 1.38 μ m , B max = 33.0 ± 9.7 fmol mg ⁻¹ protein. Endothelin‐2 and sarafotoxin S6B inhibited [ ¹²⁵ I]‐PD151242 binding to renal tissue whereas ET‐3 and sarafotoxin S6C were less effective. Non‐endothelin and non‐sarafotoxin peptides did not compete.
No degradation of [ ¹²⁵ I]‐PD151242 was detected following incubation of the ligand with renal tissue under the conditions of the binding assay.
Polymerase chain reaction products corresponding to the expected size for mRNA encoding ET A and ET B receptor sub‐types were detected in cortex and medulla in each of the five individuals examined.
Autoradiographical studies showed that ET A receptors visualised with [ ¹²⁵ I]‐PD151242 were mainly localized to blood vessels including interlobular and arcuate arteries, arterioles and adjacent arcuate veins. ET B receptors localized with [ ¹²⁵ I]‐BQ3020 were concentrated in the medulla and the density of binding to vessels was low.
These data suggest [ ¹²⁵ I]‐PD151242 is selective for ET A receptors in human kidney and this sub‐type is mainly localized to the renal vasculature. The results provide further evidence that the human vasculature mainly expresses the ET A receptor.
Endothelin-1 is an endothelium-derived vasoconstrictor peptide, possibly involved in the pathophysiology of cardiovascular disease. We examined the contribution of endogenously generated endothelin-1 to maintenance of peripheral vascular tone in healthy subjects by local intraarterial administration of an inhibitor of endothelin converting enzyme, phosphoramidon, and of a selective endothelin receptor A antagonist, BQ-123. Brachial artery infusion of local doses of proendothelin-1, the precursor to endothelin-1, caused a slow-onset dose-dependent forearm vasoconstriction which was abolished by co-infusion of phosphoramidon. Phosphoramidon did not affect responses to endothelin-1. Phosphoramidon caused slow-onset vasodilatation when infused alone, with blood flow increasing by 37% at 90 min (p = 0.03). Vasoconstriction to endothelin-1 was abolished by co-infusion of BQ-123 (p = 0.006), with forearm blood flow tending to increase. Infusion of BQ-123 alone caused progressive vasodilatation, with blood flow increasing by 64% after 60 min (p = 0.007). These results show that endogenous production of endothelin-1 contributes to the maintenance of vascular tone. Endothelin converting enzyme inhibitors and receptor antagonists may have therapeutic potential as vasodilators.
Elevated levels of the vasocontrictor peptide endothelin-1 have been demonstrated in various pathological conditions that are characterized by sodium retention and/or renal vasoconstriction, such as heart failure, hepatorenal syndrome, renal failure and during administration of cyclosporin and radiocontrast. In the present study we studied in seven healthy subjects the renal and endocrine effects of systemic administration of endothelin-1 (0.5, 1.0 and 2.5 ng/kg/min). During endothelin-1 infusion plasma levels rose from 3.2 +/- 0.5 to respectively 5.0 +/- 0.8, 6.2 +/- 0.5 and 8.5 +/- 1.1 pmol/liter, values that can also be observed in physiological and pathological conditions. Infusion of low dosages of endothelin-1, that result in a twofold increase in plasma levels, decreased sodium excretion by 36%, without a significant effect on systemic and renal hemodynamics. Infusion of 2.5 ng/kg/min of endothelin-1 further enhanced sodium retention and, in addition, increased renal vascular resistance by 37%. Blood pressure did not change significantly. Pretreatment with the calcium channel blocker nifedipine caused renal vasodilation, which compensated for the renal vasocontriction by endothelin-1 and prevented sodium retention. Apparently, endothelin-1 participates in volume homeostasis in human, whereas pathophysiological concentrations can contribute to renal vasoconstriction and sodium retention. Calcium channel blockers may protect against these effects of endothelin-1.
Animal kidneys are exquisitely sensitive to the effects of endothelin (ET), but little is known of its binding characteristics, isoform prevalence, or receptor subtype distribution in human kidney. We investigated these parameters using high-performance liquid chromatography, radioimmunoassay (RIA), and the recently synthesized ETA and ETB receptor-selective peptide ligands BQ123 (cyclo[D-Asp-L-Pro-D-Val-L-Leu-D-Trp-]) and BQ3020 (Ala11,15-Ac-ET-1[6-21]). Fresh-frozen normal segments of kidneys excised for carcinoma were solid-phase-extracted using Amprep C2 columns, and parallel eluates were oxidized. All were subjected to RIA for ET and pro-ET-1, in triplicate. ET isoforms were characterized by RP-HPLC and subsequent RIA of eluates. Total amounts of immunoreactive ET were 6.9 +/- 3.8 and 4.5 +/- 1.6 pmol/g wet weight in medulla and cortex, respectively. Reverse-phase high performance liquid chromatography showed peaks of immunoreactivity with retention times identical to synthetic ET-1 and metsulphoxide ET-1. ET-2, ET-3, and pro-ET-1 were not detected. Saturation assays using 0.01-8.0 nM 125I-ET-1 or 125I-BQ3020, gave Kd values (mean +/- SEM) of 0.17 +/- 0.04 and 0.36 +/- 0.06 nM, respectively, with Bmax values of 57.7 +/- 15.4 and 30.0 +/- 5.0 fmol/mg protein, respectively. Hill coefficients were 0.86 +/- 0.03 and 0.77 +/- 0.04, but a two-site fit was not preferred. Receptor autoradiography has detected both subtypes, mainly present in medulla, with ETB predominating.(ABSTRACT TRUNCATED AT 250 WORDS)
Exogenous endothelin (ET) is rapidly cleared from the circulation. We investigated which ET receptor subtypes (ETA and ETB) participate in ET-1 clearance. Following an intravenous (i.v.) bolus dose of [125I]ET-1 in anesthetized rats, radioactivity was rapidly cleared from the circulation and trapped by the lungs, kidneys and liver. Tissue distribution of the radioactivity was significantly inhibited in the lungs and kidneys, but not in the liver by infusion of the ETB antagonist BQ-788 (0.1 mg/kg/min i.v.), and the ET-1 clearance rate was reduced, while the ETA antagonist BQ-123 had no such effect. Furthermore, in isolated perfused rat lungs, about 80% of bolus-injected [125I]ET-1 was retained by the lungs after one passage. The retention of ET-1 was significantly inhibited by infusion of 1 microM BQ-788, but not BQ-123. These results suggest that ETB receptors play an important role in the clearance of ET-1.
The effect of intravenous infusion of endothelin-1 (ET-1) at a rate of 1 pmol.min-1.kg-1 for 60 min (n = 9) or placebo (n = 9) was investigated in 18 healthy human volunteers with a mean age of 30 yr. In response to ET-1 infusion, concentration of ET-1 increased from 0.88 +/- 0.27 to 10.73 +/- 4.79 (SD) pmol/l. Diastolic blood pressure increased by 7.8% (P < 0.01) and heart rate decreased by 14.0% (P < 0.01), whereas systolic blood pressure did not change. Renal plasma flow decreased by 34.7%, glomerular filtration rate decreased by 16.1%, and renal vascular resistance increased by 66.0% (P < 0.01 all). Urinary sodium excretion decreased by 57.9% and urinary flow rate by 40.2% (P < 0.01 for both). As judged from the clearance of lithium, we found that ET-1 did not change absolute reabsorption of sodium and water in the proximal tubules, but in the distal tubules absolute reabsorption of both sodium and water decreased significantly. Plasma concentrations of angiotensin II, aldosterone, arginine vasopressin, and atrial natriuretic peptide did not change in response to ET-1 infusion. It is suggested that ET-1 at plasma concentrations found in certain pathophysiological conditions in humans may influence renal perfusion and renal sodium and water excretion.
We have recently reported that renal preproendothelin-1 gene is up-regulated in rats with renal mass reduction (RMR) and that time-dependent increase in urinary excretion of the corresponding peptide correlates with renal disease progression. Here we evaluated whether a specific endothelin subtype A (ETA) receptor antagonist, FR139317, reduced signs of disease activity in this model. Two groups of rats were given FR139317 or its vehicle (saline) from day 7 to day 60 after the surgical procedure. Sham-operated animals were the control group. Blood pressure, urinary protein excretion and serum creatinine were evaluated at days 0, 7 (before FR139317 or saline administration), 30, 45 and 60. At sacrifice, histological evaluation of renal tissue was performed. The results showed that ETA receptor blocker reduced the abnormal permeability to proteins, limited glomerular injury and prevented renal function deterioration thus confirming the working hypothesis. These findings suggest that this class of compounds may eventually prove useful in the treatment of human progressive nephropathies.
Drugs that inhibit angiotensin-converting enzyme slow the progression of renal insufficiency in patients with diabetic neuropathy. Whether these drugs have a similar action in patients with other renal diseases is not known. We conducted a study to determine the effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of renal insufficiency in patients with various underlying renal diseases.
In a three-year trial involving 583 patients with renal insufficiency caused by various disorders, 300 patients received benazepril and 283 received placebo. The underlying diseases included glomerulopathies (in 192 patients), interstitial nephritis (in 105), nephrosclerosis (in 97), polycystic kidney disease (in 64), diabetic nephropathy (in 21), and miscellaneous or unknown disorders (in 104). The severity of renal insufficiency was classified according to the base-line creatinine clearance: 227 patients had mild insufficiency (creatinine clearance, 46 TO 60 ml per minute), and 356 had moderate insufficiency (creatinine clearance, 30 to 45 ml per minute). The primary end point was a doubling of the base-line serum creatine concentration or the need for dialysis.
At three years. 31 patients in the benazepril group and 57 in the placebo group had reached the primary end point (P<0.001). In the benazepril group, the reduction in the risk of reaching the end point was 53 percent overall (95 percent confidence interval, 27 to 70 percent), 71 percent (95 percent confidence interval, 21 to 90 percent) among the patients with mild renal insufficiency, and 46 percent (95 percent confidence interval, 12 to 67 percent) among those with moderate renal insufficiency. The reduction in risk was greatest among the male patients; those with glomerular diseases, diabetic nephropathy, or miscellaneous or unknown causes of renal disease; and those with base-line urinary protein excretion above 1 g per 24 hours. Benazepril was not effective in patients with polycystic disease. Diastolic pressure decreased by 3.5 to 5.0 mm Hg in the benazepril group and increased by 0.2 to 1.5 mm Hg in the placebo group.
Benazepril provides protection against the progression of renal insufficiency in patients with various renal diseases.
Although local inhibition of the generation or actions of endothelin-1 has been shown to cause forearm vasodilatation, the systemic effects of endothelin receptor blockade in healthy humans are unknown. We therefore investigated the cardiovascular effects of a potent peptide endothelin ETA/B receptor antagonist, TAK-044, in healthy men.
Two randomized, placebo-controlled, crossover studies were performed. In nine subjects, TAK-044 (10 to 1000 mg IV over a 15-minute period) caused sustained dose-dependent peripheral vasodilatation and hypotension. Four hours after infusion of the highest dose (1000 mg), there were decreases in mean arterial pressure of 18 mm Hg and total peripheral resistance of 665 AU and increases in heart rate of 8 bpm and cardiac index of 0.9 L x min(-1) x m(-2) compared with placebo. TAK-044 caused a rapid, dose-dependent increase in plasma immunoreactive endothelin (from 3.3 to 35.7 pg/mL within 30 minutes after 1000 mg). In a second study in eight subjects, intravenous administration of TAK-044 at doses of 30, 250, and 750 mg also caused peripheral vasodilatation, and all three doses abolished local forearm vasoconstriction to brachial artery infusion of endothelin-1. Brachial artery infusion of TAK-044 caused local forearm vasodilation.
The endothelin ETA/B receptor antagonist TAK-044 decreases peripheral vascular resistance and, to a lesser extent, blood pressure; increases circulating endothelin concentrations; and blocks forearm vasoconstriction to exogenous endothelin-1. These results suggest that endogenous generation of endothelin-1 plays a fundamental physiological role in maintenance of peripheral vascular tone and blood pressure. The vasodilator properties of endothelin receptor antagonists may prove valuable therapeutically.
We investigated the synthesis and localization of endothelin isoforms in the human kidney using the reverse-transcriptase polymerase chain reaction (RT-PCR) and immunocytochemistry. PCR products corresponding to the expected size for mRNA encoding ET-1, ET-2 and ET-3 were found in homogenates of renal medulla, cortex and vessels from each of five individuals. Using four rabbit polyclonal antibodies to assess the distribution of mature ET, Big ET-1, Big ET-2 and Big ET-3 immunoreactivity in the human kidney, mature IR ET localized to the cytoplasm of endothelial cells lining intra-renal blood vessels including interlobular and arcuate arteries, arterioles and adjacent arcuate veins, all of which showed strongly positive staining. IR Big ET-1 co-localized with the mature peptide. No specific staining was detected within these anatomical regions when pre-immune sera were substituted or primary antibody omitted. Mature IR ET also localized to the cytoplasm of endothelial cells within the glomerulus. Other capillary endothelial cells did not stain, and other structures stained only faintly by comparison. IR Big ET-2 and Big ET-3 could not be detected. These results show that human kidney contains mRNA encoding all three peptide isoforms, but only mature ET and Big ET-1 peptides could be detected by immunocytochemical staining. This provides further evidence that ET-1 may function as a renal peptide in humans, as it is locally synthesized within the kidney.
We examined the effects of systemic infusion, in healthy human volunteers, of the endothelin antagonist TAK‐044 on the plasma concentrations of mature endothelin, big endothelin‐1 and the C‐terminal fragment of big endothelin‐1, by selective solid‐phase extraction and specific radioimmunoassays.
Unlabelled TAK‐044 competed with specific [ ¹²⁵ I]‐endothelin‐1 binding to human left ventricle tissue in a biphasic manner giving K D values of 0.11 nM and 26.8 nM at the ET A and ET B receptor subtypes, respectively, indicating a 244 fold selectivity for the ET A receptor subtype.
A 15 min intravenous infusion of placebo or 30 mg TAK‐044 (giving a serum concentration of 2 nM, calculated to block > 95% of ET A but <5% ET B receptors) had no effect on the immunoreactive plasma concentrations of the three peptides.
At the higher dose of 750 mg TAK‐044 (giving a serum concentration of 80 nM, calculated to block > 99% of ET A and > 75% ET B receptors), the immunoreactive plasma endothelin concentrations were increased 3.3 fold over basal levels ( P < 0.01). The concentrations of big endothelin‐1 or C‐terminal fragment of big endothelin‐1 were unchanged.
At both doses of TAK‐044, there were significant decreases in diastolic blood pressure, and peripheral vascular resistance, with corresponding increases in cardiac index and stroke index. There were no changes in systolic or mean arterial blood pressures or heart rate.
Since only the concentrations of the mature peptide were increased, we conclude that the most likely sources of endothelin contributing to the observed rise were displacement of receptor‐bound peptide and reduction in plasma clearance rather than peptide synthesis.
Endothelin-1 (ET-1) is a 21-amino acid peptide that potently modulates renal function. ET-1 is produced by, and binds to, most renal cell types. ET-1 exerts a wide range of biologic effects in the kidney, including constriction of most renal vessels, mesangial cell contraction, inhibition of sodium and water reabsorption by the nephron, enhancement of glomerular cell proliferation, and stimulation of extracellular matrix accumulation. ET-1 functions primarily as an autocrine or paracrine factor; its renal effects must be viewed in the context of its local production and actions. This is particularly important when comparing ET-1 biology in the nephron, where it promotes relative hypotension through increased salt and water excretion, with ET-1 effects in the vasculature, where it promotes relative hypertension through vasoconstriction. Numerous studies indicate that ET-1 is involved in the pathogenesis of a broad spectrum of renal diseases. These include those characterized by excessive renal vascular resistance, such as ischemic renal failure, cyclosporine (CyA) nephrotoxicity, radiocontrast nephropathy, endotoxemia, rhabdomyolysis, acute liver rejection, and others. ET-1 appears to play a role in cell proliferation in the setting of inflammatory glomerulonephritides. The peptide also may mediate, at least in part, excessive extracellular matrix accumulation and fibrosis occurring in chronic renal failure, diabetes mellitus, and other disorders. Deranged ET-1 production in the nephron may cause inappropriate sodium and water retention, thereby contributing to the development and/or maintenance of hypertension. Finally, impaired renal clearance of ET-1 may cause hypertension in patients with end-stage renal disease. Many ET-1 antagonists have been developed; however, their clinical usefulness has not yet been determined. Despite this, these agents hold great promise for the treatment of renal diseases; it is hoped that the next decade will witness their introduction into clinical practice.
The aim of this study was to examine the role of endothelin-A (ET(A)) receptors in mediating the hypertension and renal injury associated with high salt intake in Dahl salt-sensitive (DS) rats. To achieve this goal, we examined the effects of chronic selective ET(A) antagonist (A-127722) treatment at a dose of 10 mg/kg/d on arterial pressure, renal function, and morphology in DS and Dahl salt-resistant (DR) rats placed on a high sodium (8% NaCl) diet (HSD) for 3 weeks. Placement of DS rats (n=13) on HSD for 3 weeks caused a progressive increase in systolic pressure (from 118+/-3 to 186+/-15 mm Hg). The increase in systolic pressure was significantly attenuated (from 125+/-4 to 167+/-12 mm Hg) in DS rats treated with A-127722 (n=13). Mean arterial pressure (MAP) measured directly at the end of the study was also significantly lower by 18 mm Hg (P<.02) in the DS rats treated with A-127722. The slope of the chronic pressure-natriuresis curve was shifted to the right in DS rats and to the left by chronic ET(A) receptor blockade in DS rats. The hypertension in DS rats was associated with marked proteinuria (from 4.1+/-1.1 to 74.3+/-5.3 mg/24 h/100 g body weight) that was significantly attenuated (from 5.7+/-1.2 to 55.2+/-6.5 mg/24 h/100 g body weight) in DS rats treated with A-127722. The percentage of glomeruli displaying fibrosis, hypercellularity, and hyalinization was also significantly reduced after treatment with A-127722 in DS rats. Arterial pressure, protein excretion, renal hemodynamics, and morphologic structure were not significantly changed in response to ET(A) receptor blockade in DR rats placed on HSD. These data indicate that endothelin-A receptor activation may play a role in the exacerbation of hypertension and development of renal injury in DS rats.
To compare the acute and sustained renal hemodynamic effects on hypertensive patients of 100 mg irbesartan and 20 mg enalapril each once daily.
Twenty patients (aged 35-70 years) with uncomplicated, mild-to-moderate essential hypertension and normal serum creatinine levels completed this study.
After random allocation to treatment (n=10 per group), administration schedule (morning or evening) was determined by further random allocation, with crossover of schedules after 6 weeks' therapy. Treatment and administration assignments were double-blind. Twenty-four-hour ambulatory blood pressure was monitored before and after 6 and 12 weeks of therapy. Renal hemodynamics were determined on the first day of drug administration and 12 and 24 h after the last dose during chronic treatment.
Administration of each antihypertensive agent induced a renal vasodilatation with no significant change in glomerular filtration rate. However, the time course appeared to differ: irbesartan had no significant acute effect 4 h after the first dose, but during chronic administration a renal vasodilatory response was found 12 and 24 h after the dose; enalapril was effective acutely and 12 h after administration, but no residual effect was found 24 h after the dose. Both antihypertensive agents lowered mean ambulatory blood pressure effectively, with no significant difference between treatments or between administration schedules (morning versus evening).
Irbesartan and enalapril have comparable effects on blood pressure and renal hemodynamics in hypertensive patients with normal renal functioning. However, the time profiles of the renal effects appear to differ, which might be important for long-term renoprotective effects.
We previously showed that chronic administration of an angiotensin converting enzyme (ACE) inhibitor to rats with passive Heymann nephritis (PHN), a model of membranous nephropathy with proteinuria and increased renal synthesis of endothelin-1 (ET-1), reduces urinary proteins and partially limits the exaggerated ET-1 renal synthesis. Here we compared the effect of an ETA receptor antagonist and an ACE-inhibitor given as single therapies with a combination of the two drugs in uninephrectomized PHN rats.
PHN was induced with a single i.v. injection of rabbit anti-Fx1A antibody in 40 male Sprague Dawley rats. To accelerate the onset of renal damage rats underwent uninephrectomy seven days later and were subsequently treated until eight months with the ETA receptor antagonist LU-135252 (50 mg/kg b.i.d. p.o.) or the ACE-inhibitor trandolapril (1 mg/kg in the drinking water) or the combination of the two drugs.
Either LU-135252 or trandolapril given alone prevented the increase in systolic blood pressure (SBP). Combined therapy was even more effective than single drugs. While LU-135252 and trandolapril reduced proteinuria by 23 to 25%, the drug combination resulted in 45% lowering of urinary proteins. Serum creatinine was significantly decreased by the combination, but not by the single drugs. Glomerulosclerosis and tubulointerstitial damage were more reduced by combined therapy than by LU-135252 or trandolapril alone.
These data suggest that contemporary blocking angiotensin II (Ang II) and ET-1 in an accelerated model of PHN had an additive renoprotective effect than single blocking Ang II or ET-1 and would represent a therapeutic advantage for renal disease patients who do not completely respond to ACE inhibitors.
Non-steroidal anti-inflammatory drugs are known to promote sodium retention and to blunt the blood pressure lowering effects of several classes of antihypertensive agents including beta-blockers, diuretics and angiotensin converting enzyme (ACE) inhibitors. The purpose of the present study was to investigate the acute and sustained effects of indomethacin on the renal response to the angiotensin II receptor antagonist valsartan and to the ACE inhibitor enalapril.
Twenty normotensive subjects maintained on fixed sodium intake (100 mmol sodium/day) were randomized to receive for one week: valsartan 80 mg o.d., enalapril 20 mg o.d., valsartan 80 mg o.d. + indomethacin 50 mg bid and enalapril 20 mg o.d. + indomethacin 50 mg bid. This single-blind study was designed as a parallel (valsartan vs. enalapril) and cross-over trial (valsartan or enalapril vs. valsartan + indomethacin or enalapril + indomethacin). Renal hemodynamics and urinary electrolyte excretion were measured for six hours after the first and seventh administration of each treatment regimen.
The results show that valsartan and enalapril have comparable renal effects characterized by no change in glomerular filtration rate and significant increases in renal plasma flow and sodium excretion. The valsartan- and enalapril-induced renal vasodilation is not significantly blunted by indomethacin. However, indomethacin similarly abolishes the natriuresis induced by the angiotensin II antagonist and the ACE inhibitor.
This observation suggests that although angiotensin receptor antagonists do not affect prostaglandin metabolism, the administration of a non-steroidal anti-inflammatory drug blunts the natriuretic response to angiotensin receptor blockade.
Endothelin-1 (ET-1) is an important mediator of vascular tone in humans, and a number of endothelin receptor antagonists are currently in clinical development as vasodilator agents. While the vasoconstrictor role of the ETA receptor is undisputed, the role of the ETB receptor remains unclear. Hemodynamic effects of systemic doses of the ETB-selective antagonist BQ-788 were investigated in 5 healthy male volunteers (age range, 33 to 48 years) in a placebo-controlled, four-way crossover study. After a 15-minute infusion of BQ-788 (3, 30, or 300 nmol/min) or placebo, plasma ET-1 and big ET-1, blood pressure, heart rate, cardiac index, and stroke index were measured. Total peripheral vascular resistance was calculated from cardiac index and mean arterial pressure. Hemodynamic data are expressed as maximum, placebo-corrected, percentage change from baseline following BQ-788 (300 nmol/min) and were examined by ANOVA. Plasma ET-1 increased by 3.7+/-1.2 pg/mL (maximum at 15 minutes, P=0.02), whereas there was no significant change in plasma big ET-1. Although BQ-788 had no effect on mean arterial pressure, there was a reduction in heart rate (13+/-7% at 50 minutes; P=0.002), cardiac index (17+/-5% at 40 minutes; P<0. 0001), and stroke index (8+/-4% at 40 minutes; P=0.002) and an increase in total peripheral vascular resistance (24+/-5% at 40 minutes; P<0.0001). The selective ETB receptor antagonist BQ-788 causes peripheral vasoconstriction in healthy volunteers, suggesting that the overall balance of effects of endogenous ET-1 at the vascular ETB receptor favors vasodilatation. Further investigation is now clearly required to address whether selective ETA or combined ETA/ETB receptor blockade will be more effective in the clinical setting.
Endothelin-1 generated by the vascular endothelium contributes to basal vascular tone and blood pressure in healthy humans. Plasma concentrations of endothelin-1, which are elevated in chronic renal failure (CRF), may contribute to increased vascular tone.
We investigated the contribution of endogenous and exogenous endothelin-1 to the maintenance of vascular tone in patients with CRF (creatinine > or = 200 mumol/liter) and in age- and sex-matched healthy subjects. In a series of experiments, we measured forearm vascular responses to intra-arterial norepinephrine (30 to 240 pmol/min), endothelin-1 (5 pmol/min), the selective endothelin A (ETA) receptor antagonist BQ-123 (3 mg/hr), the mixed endothelin-converting enzyme and neutral endopeptidase inhibitor phosphoramidon (30 nmol/min), and the selective neutral endopeptidase inhibitor thiorphan (30 nmol/min).
The maximum reduction in forearm blood flow (FBF) to norepinephrine in CRF (33 +/- 7%) was similar to that in controls (43 +/- 7%, P = 0.53). Endothelin-1 also produced a similar reduction in FBF in CRF (35 +/- 6%) and controls (36 +/- 5%, P = 0.81). BQ-123 increased FBF in CRF (11 +/- 4%) but significantly less than in controls (44 +/- 10%, P = 0.02). Phosphoramidon increased FBF in CRF (68 +/- 20%), again significantly less than in controls (181 +/- 41%, P = 0.001). Thiorphan reduced FBF similarly in CRF (22 +/- 6%) and controls (14 +/- 6%, P = 0.39). Responses to phosphoramidon were substantially greater than to BQ-123.
These studies show that endogenous generation of endothelin-1 contributes to the maintenance of resting vascular tone in patients with CRF, as well as in healthy subjects. Although the contribution of endogenous endothelin-1 to resting vascular tone appears to be reduced in CRF, ETA receptor antagonism, and particularly endothelin-converting enzyme inhibition, should be explored as means by which to reduce vascular tone and blood pressure in patients with CRF.
To evaluate the pharmacokinetics and pharmacodynamics of an infusion of SB 209670, a non-peptide endothelin-A/endothelin-B receptor antagonist.
The study was conducted in 2 parts. Part 1 was a placebo-controlled, single-blind, rising-dose crossover evaluation of the pharmacokinetics and safety of SB 209670 infused at doses that ranged from 0.2 to 1.5 mirog kg(-1) for approximately 8 hours in 17 healthy male volunteers. In part 2, renal hemodynamic effects of a 4-hour infusion of SB 209670 were assessed in 10 healthy male volunteers in a 2-period, period-balanced, single-blind, randomized, placebo-controlled crossover study.
SB 209670 appeared to display linear kinetics over the dose range from 0.2 to 1.5 microg kg(-1) min(-1). The half-life was approximately 4 to 5 hours. Plasma immunoreactive endothelin-1 increased in an apparent dose-dependent manner. Mean renal hemodynamic responses (para-aminohippurate clearance) increased by approximately 15% relative to placebo (P = .007). Renal sodium excretion was similar during SB 209670 and placebo infusion.
The pharmacokinetics of intravenous SB 209670 appeared to be linear, and infusion resulted in dose-related increases in immunoreactive endothelin-1. The lack of anti-natriuretic effect and the renal vasodilator response observed in this study indicate that SB 209670 does not possess any partial agonist activity. Further, the renal hemodynamic response supported a potential physiologic role for endogenous endothelin in the maintenance of renal vascular tone in humans.
Eight Na-repleted volunteers underwent 3 separate 90-minute infusions of either N(G)-nitro-L-arginine methyl ester (L-NAME) 3.0 mg. kg(-1). min(-1) or endothelin-A receptor (ET-A) blocker BQ-123 (BQ) 0.125 nmol. kg(-1). min(-1) or both. Mean arterial pressure (MAP), glomerular filtration rate (GFR), renal blood flow (RBF), renal vascular resistances (RVR), and sodium excretion rate (UNaV) were measured at baseline (b) and from 0 to 45 minutes (period 1) and 45 to 90 minutes (period 2) of infusion. BQ alone had no effect. GFR declined by 4.9% (P<0.001 versus b) in period 1, to 9.9% (P<0. 001) in period 2 with L-NAME, and by 3.3% (P<0.01) to 6.6% (P<0.001) with L-NAME plus BQ (P=NS between L-NAME and L-NAME plus BQ). UNaV fell equally with L-NAME or L-NAME plus BQ. MAP rose significantly in period 2 with L-NAME (6.9%; P<0.001) but not with coinfused BQ (2. 1%; P=NA versus b, P=0.005 versus L-NAME alone). RBF declined by 12. 2% (P<0.001) to 18.3% (P<0.001) with L-NAME and by 4.6% (P<0.005) to 8.2% (P<0.001) with L-NAME plus BQ. These changes were smaller with L-NAME plus BQ (P<0.05 in period 1 and P<0.02 in period 2). Blunted changes were also seen for RVR (P<0.005 in period 1 and P<0.001 in period 2 between L-NAME alone and L-NAME plus BQ). These findings show that systemic and renal vasoconstriction due to L-NAME are attenuated by BQ, which suggests that an interaction between endogenous nitric oxide production and ET-A activity participates in the maintenance of baseline systemic and renal vascular tone in humans.
Endothelin-1 (ET-1) is a potent vasoconstrictor produced by the vascular endothelium. The interactions of ET with the mediators of the sympathetic nervous system and the renin-angiotensin-system in humans are unclear.
We studied the effects of the ETA-selective antagonist BQ-123 and the ETB-selective antagonist BQ-788 (both 10(-10)-10(-8) M) on ET-1 (10(-16)-10(-10) M), angiotensin II (AT, 10(-16)-10(-10) M) and noradrenaline (NA, 10(-16)-10(-10) M) induced vasoconstriction in the human skin microcirculation in vivo in 25 healthy male volunteers using laser Doppler flowmetry and double injection technique.
BQ-123 caused a dose-dependent vasodilatation (maximum effect: + 949 +/- 84 AUC-PU, P < 0.001), whereas BQ-788 induced mild vasoconstriction (maximum effect: -388 +/- 96 AUC-PU, P < 0.01). In the presence of BQ-123, but not BQ-788, ET-1, AT and NA caused markedly less vasoconstriction at any tested agonist dose; the effect was most pronounced on ET-1 (maximum effect at 10(-14) M: + 814 +/- 93 AUC-PU vs ET alone, P < 0.001), followed by noradrenaline (maximum effect at 10(-16) M: +580 +/- 107 AUC-PU vs NA alone, P < 0.01) and angiotensin II (maximum effect at 10(-14) M: + 493 +/- 111 AUC-PU vs AT alone, P < 0.001).
ETA-selective antagonism inhibits vasoconstriction to AT and NA in vivo in healthy subjects. This beneficial effect may be useful for the treatment of patients with cardiovascular disease including hypertension especially in combination therapy with sympatholytic agents and inhibitors of the renin-angiotensin system.
Endothelin-A-receptor-antagonists inhibit angiotensin II- and noradrenaline-induced vasoconstriction. Whether functional constrictive endothelin-B-receptors play a role in the endothelin-1-mediated potentiation of vasoconstriction to angiotensin II and noradrenaline is thus far unknown.
We studied the effects of noradrenaline and angiotensin II (10 mol/l) in the presence of exogenous endothelin-1 (10 mol/l) with and without selective endothelin-B-receptor-blockade by BQ-788 (10 mol/l) and dual receptor blockade with BQ-788 and the endothelin-A-selective antagonist BQ-123 (10 mol/l) in 14 healthy male volunteers (aged 20-28). Studies were performed in the human skin microcirculation under in vivo conditions using laser-Doppler flowmetry and double injection technique. The area under the time-response curve of all doses was calculated.
Endothelin-1 potentiated the effects of angiotensin II and noradrenaline (-944 +/- 139 perfusion units (PU), P < 0.01; -926 +/- 117 PU, P < 0.05, respectively). In the presence of BQ-788, the potentiating effect of endothelin-1 was significantly blunted (-624 +/- 132 PU, P < 0.01; -549 +/- 136 PU, P < 0.01, respectively). In the presence of BQ-123 and BQ-788 the vasoconstriction was fully inhibited (431 +/- 108 PU, P < 0.001 and 421 +/- 86 PU, P < 0.001, respectively).
These data suggest that functional vasoconstrictive endothelin-B receptors on vascular smooth muscle cells may contribute to the potentiating effects of high local concentrations of endothelin-1 on the vasoconstriction to noradrenaline and angiotensin II in human microcirculation.
Endothelin (ET) is implicated in the pathophysiology of chronic renal failure (CRF). We therefore studied the systemic and renal hemodynamic effects of ET receptor antagonists in CRF and examined differences between selective ETA, selective ETB, and combined ETA/B receptor blockade.
We conducted a randomized, placebo-controlled, double-blind, 4-way crossover study comparing selective ET receptor antagonists BQ-123 (ETA) and BQ-788 (ETB), given alone and in combination, in acute studies in 8 hypertensive CRF patients and 8 matched healthy controls. BQ-123, alone and in combination with BQ-788, reduced blood pressure in CRF, particularly with BQ-123 alone (mean arterial pressure: controls -4+/-2%, CRF -13+/-2%, P<0.01 versus placebo). In CRF, in the face of this fall in blood pressure, BQ-123 substantially increased renal blood flow (38.8+/-23.9%, P<0.01 versus placebo) and reduced renal vascular resistance (-44.5+/-11.3%, P<0.01 versus placebo) when given alone but not when combined with BQ-788. These changes were accompanied by a reduction in effective filtration fraction. BQ-123, alone or in combination with BQ-788, had minimal effects on the renal circulation in healthy controls, and BQ-788 alone produced both systemic and renal vasoconstriction in CRF and healthy controls.
ETA receptor antagonism was highly effective in lowering blood pressure in CRF patients currently treated for hypertension. In addition, there were effects consistent with a renoprotective action. However, because the ETB receptor appears to play a key role in the maintenance of tonic renal vasodilation, combined ETA/B receptor antagonism, although it lowered blood pressure, did not confer these renal benefits.
Animal studies suggest that endothelin A (ETA) receptor antagonism and angiotensin-converting enzyme (ACE) inhibition may be synergistic. This interaction and the role of ETB receptors and endothelial mediators were investigated in terms of systemic and renal effects in humans in two studies. In one study, six subjects received placebo, the ETA receptor antagonist BQ-123 alone, and BQ-123 in combination with the ETB receptor antagonist BQ-788 after pretreatment with the ACE inhibitor enalapril (E) or placebo. In the other, six subjects who were pretreated with E received placebo, BQ-123, and BQ-123 with concomitant inhibition of nitric oxide (NO) synthase or cyclo-oxygenase (COX). Both were randomized, double-blind, crossover studies. Mean arterial pressure was reduced by BQ-123, an effect that was doubled during ACE inhibition (mean area under curve +/- SEM; BQ-123, -2.3 +/- 1.8%; BQ-123+E, -5.1 +/- 1.1%; P < 0.05 versus placebo). BQ-123 increased effective renal blood flow (BQ-123, -0.1 +/- 2.4%; BQ-123+E, 10.9 +/- 4.2%; P < 0.01 versus BQ-123), reduced effective renal vascular resistance (BQ-123, -1.2 +/- 3.1%; BQ-123+E, -12.8 +/- 3.0%; P < 0.01 versus placebo and versus BQ-123), and increased urinary sodium excretion markedly (BQ-123, 2.6 +/- 12.8%; BQ-123+E, 25.2 +/- 12.6%; P < 0.05 versus BQ-123, P < 0.01 versus placebo and versus E) only during ACE inhibition. These effects were abolished by both ETB receptor blockade and NO synthase inhibition, whereas COX inhibition had no effect. In conclusion, the combination of ETA receptor antagonism and ACE inhibition is synergistic via an ETB receptor-mediated, NO-dependent, COX-independent mechanism. The reduction of BP and renal vascular resistance and associated substantial natriuresis make this a potentially attractive therapeutic combination in renal disease.
Molecular studies have predicted the existence in human tissue of splice variants and modifications to the amino acid sequence of endothelin receptors that may modulate function. Endothelin-A (ETA) receptors were visualized by ligand binding and autoradiography to the renal vasculature throughout the cortex and medulla, including the large arcuate arteries, adjacent veins and arterioles. Lower binding densities were visualized to the vasa recta and glomeruli. A similar pattern of staining was revealed by ETA selective antisera, with the higher resolution demonstrating ETA receptors confined to smooth muscle cells. Staining was also detected to the vasa recta and glomeruli. Ligand binding revealed a more heterogeneous endothelin-B (ETB) receptor distribution with high densities concentrated in the medulla. Three different site-directed ETB antisera demonstrated a similar pattern of staining to the endothelium lining all renal vessels but not to the smooth muscle. Staining was also detected to glomerular endothelial cells as well as epithelial cells lining the renal tubule, particularly the collecting ducts, consistent with high binding densities observed in the medulla by autoradiography. There was no evidence for a differential distribution in either ETA or ETB receptors visualized by the two techniques that might have indicated modified receptors or further subtypes in the human kidney.
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