Different studies show that endothelin-1 levels are pathologically elevated in different diseases. These include different neurological disorders, diabetes, cardiovascular diseases, different cancers and pregnancy disorders, such as pre-eclampsia. The following page discusses these in more detail.
The following is a list of scientific and clinical research discussing the role of (elevated) endothelin-1 in different diseases. I have tried to put in bold the key points of each abstract.
A lot of studies including the ones below talk about the importance of blocking the endothelin system.
However, endothelin-1 is critical for normal physiological functions and using an endothelin antagonist that blocks the activity of endothelin-1 is associated with different side effects.
The following report nicely summarises the adverse effects of endothelin receptor antagonists/inhibitors:
It might be more useful to merely sequester the pathologically elevated levels of endothelin-1. The next page lists different foods that can help lower endothelin-1 levels.
Lowering the dosage of the inhibitor drug or the number of days administrated per week, might lower or help mitigate the side effects BUT a lower dose of the inhibitor drug may mean lower efficacy and therefore lower/less symptom relief. Therefore, it might be better to simply lower/reduce the blood endothelin-1 levels (to normal/physiological levels).
Diabetes and other endocrine disorders
The Endothelin System and Its Antagonism in Chronic Kidney Disease
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.
Chronic kidney disease (CKD) is common. A US population study suggested that >10% of the general adult population have an indicator of kidney damage: proteinuria, hematuria, and/or reduced GFR (1). Despite our best current treatments, progression to ESRD remains a major clinical and financial problem, and currently >1 million patients worldwide are on dialysis, with the number continuing to increase yearly. Medicare expenditure on dialysis totaled $14.8 billion in 2003 (2).
It is now widely recognized that cardiovascular disease (CVD) is strongly associated with CKD (1, 3) and constitutes one of its major causes of morbidity and mortality (1). Indeed, CKD has emerged as an important and powerful independent risk factor for CVD (1). As GFR declines, the risk for CVD increases, and patients with CKD that do not require dialysis are more likely to die from CVD than to develop ESRD (1). Furthermore, not only are individuals with CKD at increased risk for cardiovascular events, but also their outcome is worse than in those without CKD (4). Although the prevalence of traditional risk factors (e.g., diabetes, hypertension, dyslipidemia) in the CKD population is high, CVD events remain disproportionate to the underlying risk factor profile (1). Therefore, “nontraditional” risk factors, such as endothelial dysfunction, arterial stiffness, oxidative stress, and acute-phase inflammation, which may contribute to this excessive uremic cardiovascular risk, have become a major focus of interest.
There is an important unmet need for treatments that not only slow the rate of progression of renal impairment, delaying the onset of dialysis in CKD, but also improve the cardiovascular risk profile in these patients. Blockade of the endothelin (ET) system has emerged as one potential strategy. The ET system has been widely implicated in renal disease, including acute renal failure (5). However, the focus of this review is to examine our current understanding of the role that the ET system plays in CKD and whether inhibition of its actions might slow the progression of CKD and reduce the burden of CVD with which it is associated.
ET receptor antagonists have been shown to reduce BP, improve arterial stiffness and ED, and retard the progression of atherosclerosis. Some of these observations are confirmed by clinical studies.
preliminary evidence in patients with CKD suggests that both selective ETA and non- selective ETA/B receptor blockade reduces BP but that selective ETA blockade has additional desirable effects on renal hemodynamics.
Reference: Neeraj Dhaun et al, 2006
Loss of insulin action in the endothelium can cause endothelial dysfunction and atherosclerosis. Hyperglycemia and elevated fatty acids induced by diabetes mellitus can activate protein kinase C-β isoforms and selectively inhibit insulin signaling via phosphatidylinositol 3-kinase/Akt pathway to inhibit the activation of endothelial nitric oxide synthase and metabolic actions.
To demonstrate that overexpressing protein kinase C-β2 isoform in endothelial cells can cause selective insulin resistance and exacerbate atherosclerosis in the aorta.
Methods and Results:
Protein kinase C-β2 isoform was overexpressed in endothelial cells using a promoter of vascular endothelial cell cadherin. These mice were cross-bred with apoE−/− mice [Tg (Prkcb)apoE−/−]. On a Western diet, Tg(Prkcb)apoE−/− and apoE−/− mice did not differ in systemic insulin sensitivity, glucose tolerance, plasma lipid, or blood pressure. Insulin action in endothelial cells and femoral artery from Tg(Prkcb)apoE−/− mice was impaired by ≈40% with respect to Akt/endothelial nitric oxide synthase activation, and leukocyte-endothelial cell binding increased in cultured lung endothelial cells from Tg(Prkcb)apoE−/− mice compared with that from apoE−/− mice. Basal and angiotensin-stimulated big endothelin-1 levels were elevated in Tg(Prkcb)apoE−/− mice compared with apoE−/− mice. The severity of atherosclerosis in the aorta from Tg(Prkcb)apoE−/−mice increased by ≈70% as measured by en face fat staining and plaque content of the number of smooth muscle cells, macrophages, and extracellular matrix.
Specific protein kinase C-β2 activation in the endothelial cells caused dysfunction and accelerated atherosclerosis because of loss of insulin-stimulated Akt/endothelial nitric oxide synthase activation and angiotensin-induced increases in endothelin-1 expression.
Reference: Qian Li et al. 2013
Plasma Endothelin-1 levels and albuminuria in patients with Type 2 Diabetes mellitus
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˂0.01). The correlation between endothelin-1, albuminuria, proteinuria and glomerular filtration rate was significant. In multiple regression analyses the plasma concentration of endothelin-1 was independently and significantly associated with albuminuria (β=0.01, p=0.009), proteinuria (β=0.02, p<0.001) and glomerular filtration rate (β=-0.01, p=0.0006).
Conclusion. Higher plasma concentrations of endothelin-1 are independently associated with the levels of urinary excretion of albumin which may corroborate the hypothesis of a potential role of this peptide in the development of microalbuminuria in diabetic nephropathy.
Reference: Radmila ŽERAVICA et al, 2016
Relationship between endothelin-1 levels in diabetics with and without microangiopathy and control subjects
Aim: To assess ET1 levels in diabetic patients with and without microangiopathy, and compared with normal subjects, nondiabetic, without underlying vascular pathology.
Introduction: The pathophysiology of diabetic microangiopathy is complex and many important aspects of it still are not fully understood. Endothelial dysfunction is of major importance in the pathogenesis of atherosclerosis and diabetic angiopathy. ET-1 is one of the most potent vasoconstrictors described and has been suggested to be involved in the development of cardiovascular disease.
Subjects and methods: We analyzed a group of 21 diabetic patients, 8 women and 13 men, aged (X±SD) of 61.3±12.6 years (range 21–78) with an evolution of diabetes in 8.4±9 years (range 1–30). 2 patients had type 1 diabetes and 19 had type 2 diabetes. The 67% was on insulin therapy and 52% had microvascular involvement. The control group were 34 persons, 21 women and 13 healthy men, aged 46±21.1 years (range 24–78 years) without known pathology. Statistical analysis was carried out by SPSS. ET1 was performed by RIA Levels.
Results: ET1 levels in diabetic patients without microvascular disease (n=10) were 5.6±3 vs 8.09±2.74 pg/ml (P=0.026) in the diabetic group affections of microangiopathy (n=11). In the control group (n=34) ET1 levels were 3.71±1.87 pg/ml.
Conclusions: – ET1 levels in diabetic patients, predominantly type 2, with microangiopathy appear to be higher than in the control group.
– The absence of microvascular disease raises no ET1 levels in diabetic patients compared to control subjects.
The production and the plasma levels of ET-1 are elevated in patients with diabetes, and a positive correlation between plasma ET-1 levels and diabetic microangiopathy has been reported, suggesting a potential role of the endothelin system in the pathophysiology of vascular complications in diabetes.
Reference: Maria Rosa Villar Vicente1, et al, 2013
Direct Action of Endothelin-1 on Podocytes Promotes Diabetic Glomerulosclerosis
The endothelin system has emerged as a novel target for the treatment of diabetic nephropathy. Endothelin-1 promotes mesangial cell proliferation and sclerosis. However, no direct pathogenic effect of endothelin-1 on podocytes has been shown in vivo and endothelin-1 signaling in podocytes has not been investigated. This study investigated endothelin effects in podocytes during experimental diabetic nephropathy. Stimulation of primary mouse podocytes with endothelin-1 elicited rapid calcium transients mediated by endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs). We then generated mice with a podocyte-specific double deletion of ETAR and ETBR (NPHS2-Cre×Ednralox/lox×Ednrblox/lox [Pod-ETRKO]). In vitro, treatment with endothelin-1 increased total β-catenin and phospho-NF-κB expression in wild-type glomeruli, but this effect was attenuated in Pod-ETRKO glomeruli. After streptozotocin injection to induce diabetes, wild-type mice developed mild diabetic nephropathy with microalbuminuria, mesangial matrix expansion, glomerular basement membrane thickening, and podocyte loss, whereas Pod-ETRKO mice presented less albuminuria and were completely protected from glomerulosclerosis and podocyte loss, even when uninephrectomized. Moreover, glomeruli from normal and diabetic Pod-ETRKO mice expressed substantially less total β-catenin and phospho-NF-κB compared with glomeruli from counterpart wild-type mice. This evidence suggests that endothelin-1 drives development of glomerulosclerosis and podocyte loss through direct activation of endothelin receptors and NF-κB and β-catenin pathways in podocytes. Notably, both the expression and function of the ETBR subtype were found to be important. Furthermore, these results indicate that activation of the endothelin-1 pathways selectively in podocytes mediates pathophysiologic crosstalk that influences mesangial architecture and sclerosis.
Diabetic nephropathy (DN) is the major microvascular complication of diabetes and the leading cause of ESRD in industrialized countries.1Clinically, DN is manifested by microalbuminuria, proteinuria, and progressive glomerular dysfunction. The main pathologic features of DN include podocyte loss, mesangial cell hypertrophy, glomerular basement membrane thickening, glomerulosclerosis, and tubulointerstitial fibrosis.2–4 With the current standard therapies, including angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers, only partial renal protection is obtained.5–7 Thus, it is of particular importance to understand more about the pathogenesis of DN and to identify novel therapeutic targets in order to develop new therapies that will prevent or delay the progression of DN.
The endothelin (ET) system has recently emerged as an interesting novel target for the treatment of DN. ET-1 is a powerful mitogen and vasoconstrictor that influences a wide variety of organ functions and has been implicated in several cardiovascular and renal pathologies.8,9 ET-1 signals through two G protein–coupled receptors (GPCRs), endothelin receptor type A (ETAR) and endothelin receptor type B (ETBR), and can lead to the activation of a variety of signaling cascades such as NF-κB,10 β-catenin, phosphoinositide 3-kinase, or mitogen-activated protein kinase.11–13Both receptors are present in the kidney.14–17 It was early recognized that ET-1 displays proliferative effects on mesangial cells that are mediated by ETAR.18,19 At the glomerular level, ET-1 promotes mesangial cell proliferation, sclerosis, and podocyte injury, although it is not demonstrated whether this latter effect is direct.8,18,20
Several lines of evidence suggest a specific role for the ET signaling pathway in the pathogenesis of DN. ET-1 expression is increased in kidneys with DN and higher ET-1 concentrations are found in the circulation of patients with DN as well as in animal models of DN.21–25 In diabetic db/db mice, mesangial matrix expansion was shown to be temporally and spatially associated with glomerular immunoreactivity for ET-1.26 ET receptor (ETR) blockers have been shown to be nephroprotective in diabetic animals in a BP-independent manner.27–32 In patients with DN, results from clinical trials of ETR blockers depend on the general cardiovascular status of patients modulating tolerance to sodium and water retention as well as on the drug used.33,34 Nevertheless, recent clinical studies are encouraging and suggest that ETAR antagonists are not only capable of promoting a regression of proteinuria, but may also limit glomerulosclerosis-related renal injury.31,32,35ETAR antagonists were found to have anti-inflammatory and antifibrotic effects during experimental DN,29,36 but the cell types that promote DN under the influence of ET-1 are still not known. Furthermore, despite the major role of podocyte dysfunction in DN, the specific involvement of ET-1 signaling in podocytes has not been fully investigated.8 Therefore, this study aimed to investigate the ET-1 signaling pathway in podocytes during diabetes-induced nephropathy.
In this study, we show that mice with a podocyte-specific double deletion of Ednar and Ednbr alleles are protected from diabetes-induced glomerulosclerosis and podocyte loss. We found the first evidence that ET-1 activation in the kidney drives development of diabetic glomerulosclerosis and podocyte loss with direct activation of ETRs and NF-κB and β-catenin pathways in podocytes. Surprisingly, the ETBR subtype was found to be important both at the expression level and the functional level. Ednbr mRNA expression in primary podocytes was found to be two times higher than Ednar expression, and a ETB agonist elicited calcium mobilization with β-catenin and NF-κB signaling. Furthermore, these results indicate that selective activation of the ETR pathways in podocytes is involved in pathophysiologic cellular crosstalk that influences mesangial architecture and sclerosis.
Reference: Olivia Lenoir et al, 2014
Diabetes-induced Myocardial Structural Changes: Role of Endothelin-1 and its Receptors
Several metabolic abnormalities may be triggered secondary to hyperglycemia in diabetes. Some of these abnormalities may alter expression of vasoactive factors in the target organs of diabetic complications. We investigated alterations of endothelin-1 (ET-1) and its receptors, ETA and ETB, and associated structural changes in the myocardium of streptozotocin-induced diabetic rats after 6 months of hyperglycemia. We further assessed the preventive effects of an ET-receptor antagonist bosentan on these changes. Compared to the non-diabetic, age- and sex-matched control animals, diabetic rats showed hyperglycemia, glucosuria, reduced body weight gain and elevated glycated Hb levels. Measurement of ET-1, ETA and ETB mRNAs by semiquantitative RT-PCR showed significantly increased mRNA levels in the hearts of diabetic rats. Treatment with bosentan failed to reduce ET-1 or ETB mRNA expression in diabetes, however ETAmRNA expression was reduced. Immunocytochemically, ET-1 was detected in the cardiomyocytes, endothelium and smooth muscle cells of the larger blood vessels and was increased in diabetes. Autoradiographic localization of ET-1 receptors, using125I-ET-1, showed increased binding in the endothelium and myocardium of diabetic animals. Histologically, focal fibrous scarring with apoptotic cardiomyocytes, consistent with changes secondary to microvascular occlusion, was only present in the diabetic rats. In keeping with focal fibrosis, myocardium from diabetic rats further showed significantly increased mRNA expression of two extracellular matrix protein transcripts, fibronectin and collagen α 1(IV) which were completely prevented by treatment with bosentan. These data suggest that hyperglycemia-induced upregulation of the ET-system in the heart may be important in the pathogenesis of cardiac involvement in diabetes.
Reference: Shali Chen et al, 2000
Association of Elevated Plasma Endothelin-1 Levels With Pulmonary Hypertenion, Mortality, and Heart Failure in African American Individuals
Importance: Despite pathophysiological links between endothelin-1 and pulmonary vascular remodeling, to our knowledge, the association between plasma endothelin-1 levels and pulmonary hypertension has not been studied in the general population. Also, whether endothelin-1 can predict future heart failure and mortality, outcomes that are associated with pulmonary hypertension, in a population cohort is unclear.
Objective: To determine whether elevated plasma endothelin-1 levels are associated with pulmonary hypertension, mortality, and heart failure.
Design, Setting, and Participants: Data from the Jackson Heart Study, a longitudinal, prospective observational cohort study of heart disease in African American individuals from Jackson, Mississippi, were analyzed. The community population sample was limited to participants with detectable tricuspid regurgitation on echocardiography. The study participants included self-identified African American individuals with plasma endothelin-1 levels and tricuspid regurgitation on echocardiogram (n = 3223) at the time of first examination (2000-2004). The analysis of the data began on April 14, 2014, and was completed on February 23, 2016.
Exposure Log-transformed plasma endothelin-1 level.
Main Outcomes and Measures Cross-sectional analysis: presence of pulmonary hypertension (defined as an elevated pulmonary artery systolic pressure >40 mm Hg on echocardiogram). Longitudinal outcomes were all-cause mortality (median follow-up, 7.75 years) and heart failure admissions (median follow-up, 5.32 years).
Results: Of the 3223 participants enrolled in the study, 1051 were men (32.6%). Mean (SD) endothelin-1 levels were 1.36 (0.64) pg/mL; 217 of 3223 cohort members (6.7%) had pulmonary hypertension. After adjusting for potential confounders, log-transformed endothelin-1 levels were associated with increased odds of pulmonary hypertension (adjusted odds ratio per log increment in endothelin-1, 1.66; 95% CI, 1.16-2.37). Log-transformed endothelin-1 levels were associated with mortality (adjusted hazard ratio per log increment in endothelin-1, 1.69; 95% CI, 1.27-2.25; median follow-up, 7.75 years) and heart failure (adjusted hazard ratio per log increment in endothelin-1, 1.57, 95% CI, 1.05-2.37; median follow-up, 5.32 years) in the study cohort. Phenotyping by pulmonary hypertension and endothelin-1 level showed mortality decreasing in order from subgroup with pulmonary hypertension and high endothelin-1 (high endothelin-1: ≥1.7 pg/mL; upper quartile); pulmonary hypertension and low endothelin-1 <1.7 pg/mL; lower 3 quartiles); no pulmonary hypertension and high endothelin-1; and no pulmonary hypertension and low endothelin-1 (log-rank χ2 = 77.16; P < .01 ).
Conclusions and Relevance: Elevated plasma endothelin-1 levels, especially associated with an elevated pulmonary artery systolic pressure on echocardiogram, may identify an at-risk population that could be evaluated for targeted prevention and management strategies in future studies.
Increased Plasma Endothelin-1 in Pulmonary Hypertension: Marker or Mediator of Disease?
Objective: To explore the role of endothelin-1, a potent endothelial-derived vasoconstrictor peptide, in pulmonary hypertension, by measuring its concentration in arterial and venous plasma.
Design: A survey, case series study.
Setting: University-affiliated hospitals and outpatient clinics.
Patients: Twenty-seven patients with pulmonary hypertension: 7 with primary, and 20 with secondary pulmonary hypertension of various causes. The control groups (n= 16) comprised 8 healthy volunteers and 8 patients with coronary artery disease but without evidence of pulmonary hypertension.
Measurements and Main Results: Pulmonary artery pressure was markedly increased (94/43 ±23/13 mm Hg) in the patients with pulmonary hypertension. Venous plasma immunoreactive endothelin-1, measured by a specific radioimmunoassay, was significantly higher in patients with pulmonary hypertension (3.5 ±2.5 pg/mL, P < 0.001) than in normal subjects (1.45 ±0.45 pg/mL), or patients with coronary disease (0.75 ± 0.64 pg/mL). The arterialto-venous ratio of immunoreactive endothelin-1 was significantly greater than unity in primary pulmonary hypertension (2.21 ± 0.72, P = 0.01), whereas the patients with secondary pulmonary hypertension had a mean ratio not different from 1 (0.97 ± 0.42). In contrast, the mean arterial-to-venous ratios were significantly less than unity in both control groups (0.59 ± 0.35, and 0.54 ± 0.64; P < 0.02, for normal subjects and coronary disease patients, respectively), indicating a possible clearance of endothelin-1 across the healthy lung.
Conclusions: Patients with pulmonary hypertension have substantial alterations in plasma immunoreactive endothelin-1, which may reflect changes in net release or clearance of endothelin-1 by the lung. In patients with primary pulmonary hypertension, the high levels in arterial compared with venous plasma suggest pulmonary production of endothelin-1, which may contribute to elevated pulmonary vascular resistance.
Reference: Stewart et al. 1991
Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1
Decreased cerebral blood flow (CBF) may contribute to the pathology of multiple sclerosis (MS), but the underlying mechanism is unknown. We investigated whether the potent vasoconstrictor endothelin-1 (ET-1) is involved. We found that, compared with controls, plasma ET-1 levels in patients with MS were significantly elevated in blood drawn from the internal jugular vein and a peripheral vein. The jugular vein/peripheral vein ratio was 1.4 in patients with MS vs. 1.1 in control subjects, suggesting that, in MS, ET-1 is released from the brain to the cerebral circulation. Next, we performed ET-1 immunohistochemistry on postmortem white matter brain samples and found that the likely source of ET-1 release are reactive astrocytes in MS plaques. We then used arterial spin-labeling MRI to noninvasively measure CBF and assess the effect of the administration of the ET-1 antagonist bosentan. CBF was significantly lower in patients with MS than in control subjects and increased to control values after bosentan administration. These data demonstrate that reduced CBF in MS is mediated by ET-1, which is likely released in the cerebral circulation from reactive astrocytes in plaques. Restoring CBF by interfering with the ET-1 system warrants further investigation as a potential new therapeutic target for MS.
Multiple sclerosis (MS) is a poorly understood chronic disorder of the CNS, characterized by focal inflammatory demyelinating lesions and degenerative processes (1). Immune responses play a crucial role in the pathogenesis of focal lesions that constitute the pathological substrate for relapses. However, the underlying mechanism of the progressive degeneration of axons, which is the primary determinant of long-term disability in MS, is not clear (2), and treatment is lacking.
A number of studies found that cerebral blood flow (CBF) is globally impaired in early diagnosed relapsing-remitting MS and primary progressive MS, indicating that it is an integral part of the disease that is already present at the time of diagnosis (3⇓–5). Animal studies have shown that chronic hypoperfusion of the brain can lead to neurodegenerative changes, including axonal degeneration (6).
The underlying mechanism of reduced CBF in MS is unknown. Plasma levels of the potent vasoconstrictor endothelin-1 (ET-1) (7) were found to be elevated in patients with MS (8), and this was associated with alterations of extraocular blood flow (9). The reason for the increase in ET-1 levels in MS was unclear, and the findings have not received much attention. We hypothesized that ET-1 might play a role in reducing CBF in MS.
Compared with controls, patients with MS had increased ET-1 levels in plasma derived from the internal jugular vein (mean ± SD, 3.92 ± 1.68 vs. 2.34 ± 1.6 pg/dL; P = 0.004) and peripheral vein (2.74 ± 0.69 vs. 2.24 ± 1.68 pg/dL; P = 0.01; Fig. 1). In patients with MS, but not in control subjects, internal jugular ET-1 plasma levels were significantly higher than those in peripheral vein plasma (P = 0.008). Internal jugular vein/peripheral vein ET-1 ratios were 1.40 ± 0.38 in patients with MS and 1.10 ± 0.25 in controls (P = 0.03).
Reference: Miguel et al. 2013
Endothelin-1 is elevated in Alzheimer’s disease and upregulated by amyloid-β
Vascular dysfunction and lowered cerebral blood flow are thought to contribute to the development and progression of Alzheimer’s disease (AD). Endothelin-1 (ET-1) is a potent vasoconstrictor, the production of which is mainly catalyzed by endothelin-converting enzymes (ECEs). We previously showed that ECE-2 is upregulated by amyloid-β (Aβ), and its expression elevated in AD postmortem brain tissue. We have now investigated whether there is a concomitant increase in ET-1. We studied temporal cortex from 20 cases of sporadic AD and 20 matched controls. The cellular distribution of ET-1 was assessed immunohistochemically in paraffin sections. PreproET-1 (EDN1) mRNA and ET-1 protein were measured in homogenates of superior temporal cortex by real-time PCR and sandwich ELISA respectively. Cultured SH-SY5Y human neuroblastoma cells were incubated with 10 μM oligomeric Aβ42 for 24 h, and ET-1 protein level was measured in cell culture supernatants by sandwich ELISA. Antibody to ET-1 labeled neurons throughout the temporal cortex, and the walls of some cerebral blood vessels. ET-1 mRNA measured in the temporal neocortex was significantly elevated in AD when normalized for expression of GAPDH (p = 0.0256) or the neuronal marker neuron-specific enolase (NSE, p = 0.0001). ET-1 protein was also significantly higher in AD than in control tissue, when adjusted for neuronal content by measurement of NSE (p = 0.0275). ET-1 protein in SH-SY5Y cell supernatant rose 1.7-fold after exposure to 10 μM oligomeric Aβ (p = 0.024). These findings provide evidence of overactivity of the endothelin system in AD, further supporting the suggestion that endothelin receptor antagonists may be of value for the treatment of this disease.
Reference: Palmer JC, et al. J Alzheimers Dis. 2012.
Increased Endothelin-1 Plasma Levels in Patients With Multiple Sclerosis
We tested the hypothesis that the plasma level of endothelin-1 (ET-1) is increased in patients with multiple sclerosis (MS). The peptide ET-1 is one of the most potent known vasoconstrictors. An increased level of endothelin could explain some of the vascular symptoms of these patients. A specific radioimmunoassay was used to determine ET-1 plasma levels. Twenty patients with MS were compared to 20 age- and sex-pair-matched healthy subjects. The plasma ET-1 levels were, on average, 224% higher in the patients with MS than in the controls (p < 0.005). The mean ET-1 levels (mean +/- standard deviation [SD]) were 3.5 +/- 0.83 pg/mL (min 2.13, max 5.37 pg/mL) in patients with MS and 1.56 +/- 0.3 pg/mL (min 0.9, max 2.13 pg/mL) in healthy volunteers. Neither the different forms nor stages of MS had an influence on the results. The ET-1 level was also not correlated with the duration of the disease. The plasma ET-1 level is markedly and significantly increased in patients with MS. Neither the cause of such an increase nor the pathogenetic role is known.
Reference: Haufschild, et al. 2001
Endothelin: Key Mediator of Hypertension in Preeclampsia
Preeclampsia is a pregnancy-induced hypertensive disorder characterized by proteinuria and widespread maternal endothelial dysfunction. It remains one of the most common disorders in pregnancy and remains one of the leading causes of maternal and fetal morbidity. Recent research has revealed that placental insufficiency, resulting in hypoxia and ischemia, is a central causative pathway in the development of the disorder. In response, the placenta secretes soluble substances into the maternal circulation which are responsible for the symptomatic phase of the disease. Among the most well characterized factors in the disease pathology are the anti-angiogenic protein soluble fms-like tyrosine kinase-1 (sFlt-1), inflammatory cytokines, and agonistic angiotensin II type-1 receptor autoantibodies. Each of these factors has been shown to induce hypertension experimentally through the production of endothelin-1 (ET-1), a powerful vasoconstrictor. Antagonism of the endothelin-A receptor has proved beneficial in numerous animal models of gestational hypertension, and it remains an intriguing target for pharmacological intervention in preeclampsia.
A lot of studies including the ones above talk about the importance of blocking the endothelin system.
However, endothelin-1 is critical for normal physiological functions and therefore using an endothelin antagonist that blocks the activity of endothelin-1 is associated with different side effects.
The following report nicely summarises the adverse effects of endothelin receptor antagonists/inhibitors:
It might be more useful to merely sequester the pathologically elevated levels of endothelin-1. The next page lists different foods that can help lower endothelin-1 levels.