Circulating Endothelin-1 Concentrations Research Articles

Thermotherapy reduces blood pressure and circulating endothelin-1 concentration and enhances leg blood flow in patients with symptomatic peripheral artery disease

Leg thermotherapy (TT) application reduces blood pressure (BP) and increases both limb blood flow and circulating levels of anti-inflammatory mediators in healthy, young humans and animals. The purpose of the present study was to determine the impact of TT application using a water-circulating garment on leg and systemic hemodynamics and on the concentrations of circulating cytokines and vasoactive mediators in patients with symptomatic peripheral artery disease (PAD). Sixteen patients with PAD and intermittent claudication (age: 63 ± 9 yr) completed three experimental sessions in a randomized order: TT, control intervention, and one exercise testing session. The garment was perfused with 48°C water for 90 min in the TT session and with 33°C water in the control intervention. A subset of 10 patients also underwent a protocol for the measurement of blood flow in the popliteal artery during 90 min of TT using phase-contrast MRI. Compared with the control intervention, TT promoted a significant reduction in systolic (∼11 mmHg) and diastolic (∼6 mmHg) BP (P < 0.05) that persisted for nearly 2 h after the end of the treatment. The serum concentration of endothelin-1 (ET-1) was significantly lower 30 min after exposure to TT (Control: 2.3 ± 0.1 vs. TT: 1.9 ± 0.09 pg/ml, P = 0.026). In addition, TT induced a marked increase in peak blood flow velocity (∼68%), average velocity (∼76%), and average blood flow (∼102%) in the popliteal artery (P < 0.01). These findings indicate that TT is a practical and effective strategy to reduce BP and circulating ET-1 concentration and enhance leg blood flow in patients with PAD.

Statin therapy reduces plasma endothelin-1 concentrations: A meta-analysis of 15 randomized controlled trials.

Raised plasma endothelin-1 (ET-1) levels may be a risk factor for vascular dysfunction and cardiovascular (CV) disease. This meta-analysis assessed the effect of statins on circulating ET-1 concentrations. The search included PUBMED, Cochrane Library, Web of Science, Scopus, and EMBASE up to September 30, 2014 to identify randomized controlled trials (RCTs) with ET-1 measurement during statin therapy. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. Data from 15 RCTs showed that statin therapy significantly reduces plasma ET-1 concentrations (WMD:-0.30pg/mL, 95%CI:-0.47,-0.13; p<0.01). This effect was robust in sensitivity analysis, and not largely affected by the duration of statin therapy (<12 weeks - WMD:-0.51pg/mL, 95%CI:-0.89,-0.14, p<0.01; >12 week -WMD:-0.19pg/mL, 95%CI:-0.36,-0.02; p<0.05) or by dose of statins (<40mg/day - WMD:-0.27pg/mL, 95%CI:-0.49,-0.05; p=0.01; >40mg/day - WMD:-0.38pg/mL, 95%CI:-0.68,-0.08; p=0.01). Lipophilic (atorvastatin, simvastatin, fluvastatin, and cerivastatin - WMD:-0.34pg/mL, 95%CI:-0.55,-0.13; p<0.01), but not a hydrophilic statin (pravastatin - WMD:-0.18pg/mL, 95%CI:-0.44-0.08; p>0.05) had a significant effect in promoting ET-1 reduction. Statin therapy significantly reduces circulating ET-1 concentrations, regardless of treatment duration or dose of statins. This effect of statins may be influenced by statin lipophilicity. There is a need to establish whether lowering ET-1 levels has a beneficial effect on CV events.

Coronary Endothelial Vasomotor Function and Vascular Remodeling in Heart Transplant Recipients Randomized for Tacrolimus or Cyclosporine Immunosuppression

This study aimed to compare changes in coronary endothelial function, systemic endothelin-1 (ET-1) levels, and vascular remodeling in heart transplant recipients randomized to cyclosporin A (CyA) or tacrolimus (Tac) immunosuppression. Functional endothelial abnormalities and intimal thickening are sensitive measures of early cardiac allograft vasculopathy (CAV). The randomized, prospective study was performed in two groups of 22 patients, maintained on Tac or CyA and mycophenolate mofetil immunosuppression, 1 and 12 months after heart transplantation. We investigated epicardial luminal diameter, coronary blood flow velocity, and ET-1 plasma levels at 1 and 12 months after transplantation. Structural coronary alterations were determined using intravascular ultrasound. Epicardial vasomotor function at baseline and during follow-up was comparable between the groups. Deterioration of microvascular endothelial function during follow-up was significantly enhanced in the CyA versus Tac group (p < 0.05). Circulating ET-1 concentration increased in the CyA group but significantly decreased over time in the Tac group (CyA +17% vs. Tac -25%; p < 0.05). The time-dependent increase in mean intimal area was significantly enhanced in the CyA versus Tac group, whereas the vessel area significantly increased during follow-up in the Tac compared with the CyA group. Epicardial endothelial function is comparable between CyA- and Tac-treated patients. Microvascular endothelial function deteriorates more in CyA-treated patients, a finding that correlates with enhanced ET-1 concentration and an increased intimal area during follow-up. The mean vessel area in the Tac group increased over time, indicating positive vascular remodeling. Tac is superior to CyA with respect to microvascular endothelial function, intimal thickening, and vascular remodeling.

Endothelial activation in patients with cardiac syndrome X.

The presence of endothelial dysfunction with increased endothelin-1 plasma concentrations in patients with cardiac syndrome X is still under debate. The aim of the present study was to evaluate the presence of endothelial dysfunction in patients with cardiac syndrome X. ++Endothelin-1 levels were evaluated with a sensitive radioimmunoassay with previous purification through reverse phase HPLC in 24 patients (3 men and 21 women, mean age 54+/-7 years) with typical angina, instrumental evidence of ischemia, and normal coronary angiograms both under baseline conditions and after oral glucose load (75 g D-glucose). We also measured plasma nitrite-plus-nitrate levels, a sharp index of endothelial nitric oxide production, and circulating concentrations of the soluble fraction of the endothelial adhesion molecule vascular cell adhesion molecule-1, a well-recognized marker of early endothelial dysfunction. Fourteen healthy subjects (1 man and 13 women, mean age 47+/-15 years) served as controls. There were no significant differences in baseline plasma endothelin-1 concentrations between patients and control subjects (0.55+/-0.34 versus 0.48+/-0.22 pg/mL, P=0.503). Plasma nitrite-plus-nitrate and soluble vascular cell adhesion molecule-1 concentrations were also similar between the 2 groups. After glucose ingestion, circulating endothelin-1 concentrations were significantly higher in patients with cardiac syndrome X than in control subjects (P<0.03 at 60, 90, and 120 minutes). Our findings show that no basal endothelial damage is present in patients with cardiac syndrome X. Nevertheless, increased responsiveness of endothelin-1 to glucose loading suggests that patients with cardiac syndrome X present an increased susceptibility to releasing endothelin-1 under stressful circumstances.

Renal and vascular effects of chronic nitric oxide synthase inhibition: involvement of endothelin 1 and angiotensin II

Endothelin 1 (ET-1) is a potent vasoconstrictor implicated in the control of blood pressure and renal function. Its effects can be modulated by nitric oxide (NO), which inhibits ET-1 production and action. Recently, we reported that ET-1 production can also be modulated by angiotensin II (AngII) in vivo. To investigate the interactions between NO, ET-1, and AngII in hypertension and renal dysfunction, we assessed immunoreactive ET-1 (ir-ET-1) concentration in plasma and urine as well as in vascular and renal tissues of rats with chronic inhibition of NO synthesis, in the presence and the absence of the AngII type 1 receptor antagonist losartan. Normal (protocols A and B) and uninephrectomized rats (protocol C) received the L-arginine analog NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, 0.05% (protocol A) or 0.1% (protocols B and C), with or without losartan (20 mg·kg-1·day-1). After 6 weeks, systolic blood pressure was significantly increased in L-NAME rats compared with the controls (p &lt; 0.01), while serum creatinine and urea, creatinine clearance, and proteinuria were similar to control values. However, ir-ET-1 concentration in plasma and in the thoracic aorta was augmented in animals receiving 0.1% L-NAME (p &lt; 0.01), while it was unchanged in the mesenteric arterial bed, preglomerular arteries, and glomeruli. In contrast, ir-ET-1 concentration was decreased in the renal papilla (p &lt; 0.05) as well as in the urine of L-NAME rats (p &lt; 0.01). Treatment with losartan significantly attenuated the rise in systolic blood pressure induced by L-NAME (p &lt; 0.01). Losartan also normalized the increased ir-ET-1 concentration in plasma and in the thoracic aorta, but had no effect on tissues with normal or reduced ir-ET-1 levels. These results indicate that chronic inhibition of NO synthase with L-NAME induces hypertension without renal dysfunction. Increased ET-1 production in some blood vessels and elevated circulating ET-1 concentration may contribute to the maintenance of high blood pressure. The reduction of systolic blood pressure by losartan supports a role for AngII in the pathogenesis of this form of hypertension, which may be due, at least in part, to the modulation of ET-1 production.Key words: endothelin, nitric oxide, L-NAME, angiotensin II, losartan, hypertension, blood vessel, glomeruli.

Renal and vascular effects of chronic nitric oxide synthase inhibition: involvement of endothelin 1 and angiotensin II.

Endothelin 1 (ET-1) is a potent vasoconstrictor implicated in the control of blood pressure and renal function. Its effects can be modulated by nitric oxide (NO), which inhibits ET-1 production and action. Recently, we reported that ET-1 production can also be modulated by angiotensin II (AngII) in vivo. To investigate the interactions between NO, ET-1, and AngII in hypertension and renal dysfunction, we assessed immunoreactive ET-1 (ir-ET-1) concentration in plasma and urine as well as in vascular and renal tissues of rats with chronic inhibition of NO synthesis, in the presence and the absence of the AngII type 1 receptor antagonist losartan. Normal (protocols A and B) and uninephrectomized rats (protocol C) received the L-arginine analog N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, 0.05% (protocol A) or 0.1% (protocols B and C), with or without losartan (20 mg x kg(-1) x day(-1)). After 6 weeks, systolic blood pressure was significantly increased in L-NAME rats compared with the controls (p < 0.01), while serum creatinine and urea, creatinine clearance, and proteinuria were similar to control values. However, ir-ET-1 concentration in plasma and in the thoracic aorta was augmented in animals receiving 0.1% L-NAME (1 < 0.01), while it was unchanged in the mesenteric arterial bed, preglomerular arteries, and glomeruli. In contrast, ir-ET-1 concentration was decreased in the renal papilla (p < 0.05) as well as in the urine of L-NAME rats (p < 0.01). Treatment with losartan significantly attenuated the rise in systolic blood pressure induced by L-NAME (p < 0.01). Losartan also normalized the increased ir-ET-1 concentration in plasma and in the thoracic aorta, but had no effect on tissues with normal or reduced ir-ET-1 levels. These results indicate that chronic inhibition of NO synthase with L-NAME induces hypertension without renal dysfunction. Increased ET-1 production in some blood vessels and elevated circulating ET-1 concentration may contribute to the maintenance of high blood pressure. The reduction of systolic blood pressure by losartan supports a role for AngII in the pathogenesis of this form of hypertension, which may be due, at least in part, to the modulation of ET-1 production.

Role of plasma and urinary endothelin-1 in early diabetic and hypertensive nephropathy

To evaluate the role of circulating and renal endothelin-1 (ET-1) in early diabetic nephropathy, plasma ET-1 levels and urinary ET-1 excretion were evaluated in lean, normotensive patients affected by non–insulin-dependent diabetes (NIDDM) either with (n = 9, NIDDM+) or without microalbuminuria (n = 18, NIDDM−); in never-treated, lean, essential hypertensive patients with (n = 12, EH+) or without microalbuminuria (n = 10, EH−); and in healthy volunteers (n = 12). Results showed higher plasma ET-1 levels in NIDDM+ (1.97 ± 0.58 pg/mL) than in NIDDM− (1.59 ± 0.14 pg/mL, P = .013), EH+ (1.40 ± 0.21 pg/mL, P = .005), EH− (0.91 ± 0.19 pg/mL, P < .0001), and controls (0.60 ± 0.10 pg/mL, P < .0001). The circulating ET-1 concentration was also higher in EH+ than EH− and controls ( P < .0001). Urinary ET-1 excretion did not differ ( P = .387, NS) between NIDDM+ (48.5 ± 20.1 pg/min) and NIDDM− (40.9 ± 21.6 pg/min), but was significantly reduced ( P < .0001) in both groups compared with controls (70.0 ± 15.5 pg/min). Similar findings were observed in hypertensive subgroups. No correlations were found between urinary ET-1 and other variables, including plasma ET-1 levels, in all groups. In conclusion, NIDDM+ is accompanied by a significant increase in plasma ET-1 levels. A significant elevation of circulating ET-1 concentration was evident also in NIDDM−, suggesting that early abnormalities of ET-1 production might precede the microalbuminuric phase of diabetes-related renal damage.

Enhanced endothelin-converting enzyme immunoreactivity in early atherosclerosis.

Endothelin-1 (ET-1) is a 21-amino-acid local and circulating factor whose plasma concentrations are increased in advanced atherosclerosis. ET-1 is cleaved from a prohormone (big ET-1) by endothelin-converting enzymes (ECEs) into the biologically active mature form which mediates vasoconstriction and cell proliferation. This study was designed to test by immunohistochemistry the hypothesis that ECE is present locally in the neointima of atherosclerotic vessels. Two groups of rabbits, control (n = 6) and cholesterol-fed (1% cholesterol diet for 8 weeks; n = 6) were sacrificed. Aortas were excised and divided for determination of tissue ET-1 concentration by RIA and immunohistochemical analysis of ECE. Vascular wall ET-1 was increased in the atherosclerotic aorta (6.1 +/- 0.8 vs. 9.8 +/- 0.9 pg/mg protein; p < 0.05), whereas circulating ET-1 concentrations were similar in the two groups (3.8 +/- 0.4 vs. 2.4 +/- 1.4 pg/ml). Immunostaining revealed the presence of ECE in endothelial and vascular smooth-muscle cells of the control group. Enhanced ECE immunoreactivity was present in atherosclerotic aortas, particularly in the neointimal macrophages and smooth-muscle cells. We conclude that local vascular wall, but not circulating ET-1, is increased in early atherosclerosis. In addition, ECE immunoreactivity is increased in early atherosclerosis and may therefore contribute to the generation of local ET-1 in early experimental atherosclerosis. These studies provide important insights into the regulation of ET-1 in early atherosclerosis, which may contribute to the elucidation of factors involved in the progression of atherosclerosis.

Elevated plasma endothelin-1 levels as an additional risk factor in non-obese essential hypertensive patients with metabolic abnormalities.

Circulating endothelin-1 concentration was evaluated in 93 lean patients with essential hypertension, of whom 16 had impaired glucose tolerance and hyperlipidaemia, 25 had impaired glucose tolerance, 28 had hyperlipidaemia and 24 had no metabolic abnormalities; we also studied 22 control subjects. All groups were age- and sex-matched. Plasma endothelin-1 levels were higher (p < 0.05) in hypertensive patients with impaired glucose tolerance and hyperlipidaemia than in the remaining groups and were directly correlated with fasting insulin levels (r = 0.506, p = 0.045). Therefore, circulating endothelin-1 concentrations are elevated in hypertensive patients with a high-risk profile due to the presence of metabolic abnormalities, and might favour the development of vascular damage.

Tissue Expression of Endothelin-1 mRNA in Endotoxaemia

Circulating endothelin-1 concentrations are elevated in animal models of sepsis. The major actions of endothelin-1 appear to be as a local autocrine and paracrine factor, rather than as a circulating hormone, and plasma concentrations may not reflect local tissue concentrations. We therefore measured tissue expression of mRNA encoding pre-pro-endothelin-1 by RNase protection assays, as an indicator of local production of ET-1 in anin vivorat model of endotoxaemia. The effects of dexamethasone pre-treatment were also examined. There was a tissue-specific increase in pre-pro-endothelin-1 mRNA in endotoxaemia, apparent at 6h after endotoxin challenge in heart and lung. No significant changes in expression were seen in kidney or skeletal muscle. Dexamethasone pre-treatment significantly attenuated the rise in pre-pro-endothelin-1 mRNA in heart at 6h. Therefore, we have demonstrated tissue-specific differences in the effect of endotoxin upon pre-pro-endothelin-1 mRNA expression and in sensitivity to dexamethasone. This could account for some of the inter-tissue differences seen in local vascular response to endotoxin.

Circulating endothelin-1 concentrations in patients with chronic hypoxia.

To evaluate the behavior of plasma endothelin-1 in patients with chronic hypoxia. Fifteen male patients (mean age 52.1 +/- 3.1 years) with mild chronic obstructive pulmonary disease (COPD) were studied. Twelve healthy men (mean age 48.3 +/- 5.4 years) served as controls. Both patients and controls underwent standard pulmonary function tests, echocardiographic evaluation, and arterial blood gas evaluation. Blood samples for endothelin-1 assay were taken from a previously incannulated antecubital vein after 60 minutes of rest in the supine position. Endothelin-1 was measured by radioimmunoassay after extraction from plasma. Patients with chronic hypoxia had lower PaO2 values (66.1 +/- 6.2 mmHg) than controls (83.8 +/- 2.7 mmHg) but PaCO2 values were similar (38.1 +/- 2.5 v 36.7 +/- 3.1 mmHg, respectively). Arterial pulmonary pressure, therefore, was higher in patients (18.1 +/- 3.7 mmHg) than in controls (10.4 +/- 2.7 mmHg) as were circulating endothelin-1 concentrations (1.22 +/- 0.36 v 0.57 +/- 0.1 pg/ml). Furthermore, plasma endothelin-1 concentrations were negatively correlated with PaO2 and directly correlated with pulmonary pressure levels. No significant correlations were found in controls. These results show a clear relation between chronic hypoxia and circulating endothelin-1 concentrations. Therefore, chronic hypoxia may be regarded as an important stimulus for endothelin-1 release and as one of the main contributors to increased vasoconstriction in the vascular pulmonary bed which often accompanies lung disease.

Circulating Endothelin-1 Concentrations in Acute Respiratory Failure

To elucidate the pathophysiologic role of endogenous endothelin (ET)-1 in acute respiratory failure, we measured plasma immunoreactive ET-1 levels in 13 patients with acute respiratory failure, and compared those with hemodynamic and respiratory parameters. The mean plasma ET-1 levels (10.7 +/- 5.0 pg/ml) in 13 patients with acute respiratory failure at the time of hospital admission were about sevenfold greater than those of healthy subjects (1.5 +/- 0.5 pg/ml, n = 16). Plasma ET-1 levels positively correlated with right atrial pressure (r = 0.626), systolic pulmonary arterial pressure (r = 0.726), mean pulmonary arterial pressure (r = 0.591), and the resistance ratio (pulmonary vascular resistance/systemic vascular resistance) (r = 0.658). They also showed correlations with peak airway pressure (r = 0.588), mean airway pressure (r = 0.607), and airway resistance (r = 0.756). Stepwise multiple regression analysis confirmed the significance of these observations. Our data suggest that raised circulating ET-1 levels may partly contribute to the development of pulmonary vasoconstriction and bronchoconstriction associated with acute respiratory failure.

Endothelin in thoracic inferior vena caval constriction model of heart failure.

Recent studies have found endothelin-1 (ET), a potent vasoconstrictor of endothelial cell origin, is increased in congestive heart failure (CHF) in plasma and correlates with increased atrial pressures. Additionally, it has been shown that, despite increased circulating ET concentrations in CHF, a decreased responsiveness to exogenous ET infusion exists in an experimental model of CHF induced by rapid pacing. The present study was designed to determine whether plasma ET would be increased in a model of low cardiac output congestive failure without elevated atrial pressures produced by thoracic inferior vena caval constriction (TIVCC). In addition, we sought to determine whether this model of low cardiac output would show a full vasoconstrictive response to exogenous ET infusion and whether atrial natriuretic factor (ANF) infused acutely to achieve pathophysiological concentrations would modulate the systemic and renal hemodynamic responses to exogenous ET. Dogs were studied in the anesthetized state at 8-9 days after the TIVCC or sham operation. Baseline ET levels were significantly increased in the TIVCC dogs (n = 14) compared with sham operated dogs (n = 6; 41.4 +/- 7.1 vs. 17.9 +/- 1.5 pg/ml, respectively; P less than 0.05). With exogenous ET infusion (5 ng.kg-1.min-1), an intact systemic and renal vasoconstrictor response in the TIVCC dogs was observed. ANF prevented the systemic vascular and arterial pressure responses to ET. However, the potent renal vasoconstricting action of ET was not prevented by ANF. These studies suggest that ET may play an important role in maintaining blood pressure in the setting of low cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)