Increase In Endothelin-1 Levels Research Articles

Endothelin-1 as a Biomarker of Idiopathic Pulmonary Fibrosis and Interstitial Lung Disease Associated with Autoimmune Diseases.

The aim of this study was to determine the role of endothelin-1 (ET-1), a molecule involved in multiple vascular and fibrosing abnormalities, as a biomarker of interstitial lung disease (ILD), as well as its use for the differential diagnosis between idiopathic pulmonary fibrosis (IPF) and ILD associated with autoimmune diseases (AD-ILD), using a large and well-defined cohort of patients with ILD. A total of 112 patients with IPF, 91 patients with AD-ILD (28 rheumatoid arthritis (RA), 26 systemic sclerosis, 20 idiopathic inflammatory myositis and 17 interstitial pneumonia with autoimmune features) and 44 healthy controls were included. ET-1 serum levels were determined by enzyme-linked immunosorbent assay. A significant increase in ET-1 levels was found in patients with IPF compared to controls. Likewise, AD-ILD patients also showed higher ET-1 levels than controls when the whole cohort was stratified by the type of AD. Similar ET-1 levels were found in IPF and AD-ILD patients, regardless of the underlying AD. Interestingly, increased ET-1 levels were correlated with worse lung function in IPF and RA-ILD patients. Our study supports that serum ET-1 may be useful as a biomarker of ILD, although it could not help in the differential diagnosis between IPF and AD-ILD. Moreover, ET-1 levels may be associated with ILD severity.

Clinical, functional and molecular characteristics of vibration disease in combination with arterial hypertension

Introduction. The negative dynamics of the increase in the prevalence of cardiovascular pathology among industrial workers observed in recent decades within the framework of the tasks of the scientific specialty "occupational health" determines the importance of studying not only professional, but also comorbid pathology in workers, diseases accompanying the professional route, assessing the role of production factors in the development of somatic diseases, including diseases of the circulatory system, in in particular, arterial hypertension. The study aims to research the possibilities of early diagnosis of vascular disorders in vibration disease in combination with arterial hypertension based on the assessment of endothelial and hemostasiological parameters. Materials and methods. The study involved 253 patients of the Center for Occupational Pathology of the Novosibirsk State Medical Institution "City Clinical Hospital No. 2", including 144 people working in contact with local vibration for more than 15 years, among them 75 people with vibration disease, 69 people with a combination of vibration disease and hypertension; 72 people with hypertension those who work outside the influence of local vibration and 37 people who work outside of contact with local vibration and have no history of hypertension. The researchers conducted a comparative assessment of the indicators of systemic, vascular-platelet, plasma-coagulation hemostasis, the state of markers of endothelial-cellular hemostasis. Authors determined the aggregation activity of platelets, also studied adhesion molecules, the functional state of the endothelium. We considered the differences statistically significant at p≤0.05. Results. During the study the researchers found that endothelial dysfunction in vibration disease in combination with arterial hypertension is closely related to the expression of signaling molecules, an increase in endothelin-1 levels in combination with increased production of vascular endothelial growth factor and transforming growth factor. Endothelial markers can be associated with the frequency of unfavorable polymorphic gene variants. In systemic hemostasis, there are: an increase in the level of thrombospondin and thrombomodulin, platelet growth factor in conditions of decreased plasminogen activity, an increase in the concentration of α2-macroglobulin and fibrin breakdown products. We also identified earlier endothelial-hemostasiological markers of vascular disorders. Limitations. The study was conducted on the basis of Novosibirsk State Medical University and on the basis of the City Clinical Hospital No. 2. The limitations of the study may be the unidirectionality of the study performed and the small sample of patients participating in the research. Conclusion. As a result of studying the clinical, functional and molecular characteristics of vibration disease occurring in combination with arterial hypertension, scientists have obtained new knowledge. It is possible to use such knowledge to improve the diagnosis and treatment of patients, scientific justification of health risks, development of prevention and rehabilitation programs. Ethics. All patients have previously signed an informed consent form to participate in the study. The Ethics Committee of the Novosibirsk State Medical University and the State Medical Institution of the City Clinical Hospital No. 2 has approved the research program, the content of the informed consent, materials of the article.

PATHOGENESIS OF ENDOTHELIAL DYSFUNCTION IN DIABETIC RETINOPATHY DURING STREPTOZOTOCIN-INDUCED DIABETES MELLITUS

One of the main diabetes complications that can lead to the disability of patients is diabetic retinopathy. The purpose of the study was to investigate endothelial dysfunction markers in modelled diabetic retinopathy. Material and methods. The experiment was conducted on male rats of the Wistar line, weighing 180-220 grams, up to 3 months of age (inclusive). During the experiment, the animals were divided into two groups. The 1st group included 20 intact animals; the 2nd group had 60 animals with modelled diabetes mellitus and non-proliferative diabetic retinopathy. Results and discussion. Having studied endothelial nitric oxide synthase, we have found out significant differences (p <0.001) when comparing the findings obtained in the 2nd group with the findings of the intact animals. The 2nd group rats were simulated with diabetic retinopathy without following correction. We also observed the decreasing dynamics of this index. For a more detailed study of the functional state of the endothelium and its disruption, we selected the von Willebrand factor, which is one of the common markers showing the damage to the functional state of the endothelium. In the group with simulated pathology, the level of the investigated marker increased compared with intact animals (p <0.001). There was an increase in endothelin-1 level (p <0.001) in the laboratory rats with modelled diabetic retinopathy. Conclusion. The study results have proven that our experimental model of diabetes mellitus and one of its complications, diabetic retinopathy is accompanied by the development of endothelial dysfunction. There has been found as increase in the von Willebrand factor in the modelled pathological process. We have detected an increase in endothelin-1, a marker of vasoconstriction and endothelial dysfunction, 30 days since the beginning of the experiment. Inhibition of endothelial NO synthase activity indicates an impairment of the physiological NO synthesis.

Assessment of infusion therapy impact on the dynamics of endothelin-1 in patients with acute ischemic stroke

The impact of infusion solutions on endothelial damage correction in acute ischemic stroke (AIS) remains an insufficiently studied. Purpose. To investigate the dynamics of endothelin-1 as one of the main markers of vasoconstriction and endothelial dysfunction (ED) with the use of 0.9 % NaCl, HES 130, HAES-LX-5 % and mannitol in patients with AIS. Materials and methods. The study included 32 patients with AIS. As the investigated solutions were used: colloid hyperosmolar HAES-LX-5 % (Gecoton), colloid isoosmolar hydroxyethylstarch 6% 130/04 (HES 130), hyperosmolar mannitol 15 %, isoosmolar 0.9 % NaCl. The control group consisted of patients who received only 0.9 % NaCl, comparison group patients received 0.9% NaCl + HES 130 or 0.9 % NaCl + HAES-LX-5 %, or 0.9 % NaCl + mannitol. The level of endothelin-1 (EN-1) served as a vasoconstriction marker of ED at a fixed time (days 1, 4 and 7). Results . Infusion therapy with only 0.9 % NaCl negatively affected the level of EN-1, since its level was 3.17 times increased on the 7th day of observation in comparison with the 4th day (P 0.05) at the end of observation in comparison with mannitol and 0.9 % NaCl groups, which showed a paradoxical increase in its level at the 7th day of infusion. Conclusions. The dynamics of EN-1 level as the main vasoconstrictor marker of ED were negative in the group of patients with 0.9 % NaCl and mannitol: its level was 3.17 and 3.48 times increased in the 0.9 % NaCl and mannitol groups (P < 0,05), respectively, on day 7 compared to day 4 of observation. Intensive therapy with HAES-LX-5 % and HES 130 had a better depressing effect on an increase in EN-1 level than other solutions.

Synergistic effect of renalase and chronic kidney disease on endothelin-1 in patients with coronary artery disease \u2012 a cross-sectional study

Endothelin-1 (ET-1) is associated with endothelial dysfunction and vasoconstriction. Increased circulating ET-1 levels are associated with long-term cardiovascular mortality. Renalase, released from kidney, metabolizes catecholamines and regulates blood pressure. An increase in circulating renalase levels has been reported in patients with chronic kidney disease (CKD) and is associated with coronary artery disease (CAD). We hypothesized the existence of a synergistic effect of serum renalase levels and CKD on ET-1 levels in patients with CAD. We evaluated 342 non-diabetic patients with established CAD. ET-1 and renalase levels were measured in all patients after an overnight fast. Patients with CKD had higher ET-1 (1.95 ± 0.77 vs. 1.62 ± 0.76 pg/ml, P < 0.001) and renalase levels (46.8 ± 17.1 vs. 33.9 ± 9.9 ng/ml, P < 0.001) than patients without CKD. Patients with both CKD and high renalase levels (>the median of 36.2 ng/ml) exhibited the highest serum ET-1 (P value for the trend <0.001). According to multivariate linear regression analysis, the combination of high serum renalase levels with CKD was a significant risk factor for increased serum ET-1 levels (regression coefficient = 0.297, 95% confidence interval = 0.063‒0.531, P = 0.013). In conclusion, our data suggest a synergistic effect of high serum renalase levels and CKD on increases in ET-1 levels in patients with established CAD.

Factors relating caesarean section to persistent pulmonary hypertension of the newborn.

Several studies have clearly demonstrated a significantly higher incidence of persistent pulmonary hypertension of the newborn (PPHN) in neonates delivered by caesarean section (CS) compared to those delivered vaginally. The pathophysiological factors underlying the link between CS and PPHN are still poorly understood. In this review, we describe the mechanisms that could explain the association between CS delivery and subsequent PPHN, as well as potential preventive measures. A literature search was conducted by electronic scanning of databases such as PubMed and Web of Science using the key words "persistent pulmonary hypertension of the newborn", "caesarean section", "iatrogenic prematurity", "oxidative stress", "late preterm", "labor" and "vasoactive agents". Iatrogenic prematurity, higher rates of late preterm delivery and lack of physiological changes of labor play an important role in the association between CS and PPHN. CS delivery also results in limited endogenous pulmonary vasodilator synthesis and lower levels of protective anti-oxidants in the neonates. In addition, CS delivery exposes infants to a higher risk of respiratory distress syndrome and its concomitant increase in endothelin-1 levels, which might indirectly lead to a higher risk of developing PPHN. We believe that neonates delivered by CS are exposed to a combination of these pathophysiological events, culminating in an endpoint of respiratory distress, hypoxia, acidosis, and delayed transition and thereby increased risks of PPHN. The use of antenatal corticosteroids prior to elective CS in late preterm deliveries, promoting accurate informedconsent process, delaying elective CS to 39 weeks of gestation or beyond and antenatal maternal anti-oxidant supplementation could potentially mitigate the effects of CS delivery and minimize CS-related PPHN. The link between CS delivery and PPHN is complex. In view of the rising rates of CS worldwide, there is an urgent need to further explore the mechanisms linking CS to PPHN and experimentally test therapeutic options in order to allow effective targeted interventions.

Three-year change in endothelin-1 and markers of vascular remodelling in a bi-ethnic South African cohort: the SABPA study.

South Africans are at high risk for developing cardiovascular disease. Endothelin-1 is known for its vasoconstrictive properties and its ability to contribute to vascular structural changes. In this study we investigated the association of change in endothelin-1 levels and change in markers implicated in vascular remodelling after 3 years. Serum endothelin-1 levels and markers of vascular remodelling such as carotid intima-media thickness, carotid cross-sectional wall area (CSWA) and arterial compliance were measured. Participants were divided into two groups according to an increase (n=185) and a decrease (n=152) in plasma endothelin-1 levels after 3 years. In partial regression analysis, the extent of endothelin-1 increase correlated positively with a change in pulse pressure and inversely with the change in arterial compliance in the group with increased endothelin-1 levels after 3 years. In the group with decreased endothelin-1 levels, the extent of decreased endothelin-1 correlated inversely with a change in CSWA. In multiple regression analysis, after splitting for race, the increase in endothelin-1 levels associated positively with the change in pulse pressure (Adj. R2=0.092; β=0.278; P=0.036) in the black participants only. In conclusion, with increased endothelin-1 levels after 3 years, the positive association between endothelin-1 and pulse pressure suggest subclinical haemodynamic changes with potential premature onset of cardiovascular disease in the black participants.

Evaluation of the relationship between concentration of endothelin-1 and magnesium in the blood and the severity of ischemic heart disease

Aim. To study the relationship between concentrations of endothelin-1 and magnesium in blood depending on functional class and old myocardial infarction in patients with stable angina.Methods. The study included 58 patients with ischemic heart disease, II and III functional class stable angina. 19 of these patients suffered a myocardial infarction in the past. The control group consisted of 25 healthy volunteers. Endothelin-1 level in blood serum was determined by enzyme immunoassay, the concentration of magnesium by colorimetric method.Results.Endothelin-1 level in the general group of patients with stable angina was 1.28±0.23 fmol/ml and was significantly higher than that of control group (0.52±0.13 fmol/ml, pConclusion. In patients with II-III functional class stable angina statistically significant increase in level of endothelin-1 and a decrease in the concentration of magnesium in blood serum compared with the control group was revealed; a negative correlation between endothelin-1 and magnesium levels in the blood, which is characterized by increasing the degree of correlation depending on the severity of the ischemic heart disease clinical form was established.

Significant Endothelin Release in Patients Treated with Foam Sclerotherapy

Foam sclerotherapy has been proven to be a safe and effective treatment for superficial venous insufficiency, but transient visual and neurologic disturbances continue to be reported. These side effects have been theorized to be related to the presence of air or gases in the sclerosing foam that results in "bubble" migration into the cerebral circulation. We present a differing hypothesis that significant amounts of endothelin are released from the treated veins, amounts capable of causing these complications. We tested the release of endothelin 1 (ET-1) in 12 rats after sclerotherapy with sodium tetradecyl sulfate (STS) in liquid and foam preparations. In 11 human subjects, we measured ET-1 in systemic circulation and in a draining vein after foam sclerotherapy with polidocanol. Rats treated with STS showed a significant increase in ET-1 levels 1 and 5minutes after foam sclerotherapy. Patients treated with foam sclerotherapy showed a marked increase in ET-1 levels that correlated significantly with local ET-1 levels. Evidence of ET-1 release represents a plausible relationship explaining neurologic and visual disturbances reported after sclerotherapy.

Variability in pulmonary function following rapid altitude ascent to the Amundsen–Scott South Pole station

The impact of acute altitude exposure on pulmonary function is variable. A large inter-individual variability in the changes in forced expiratory flows (FEFs) is reported with acute exposure to altitude, which is suggested to represent an interaction between several factors influencing bronchial tone such as changes in gas density, catecholamine stimulation, and mild interstitial edema. This study examined the association between FEF variability, acute mountain sickness (AMS) and various blood markers affecting bronchial tone (endothelin-1, vascular endothelial growth factor (VEGF), catecholamines, angiotensin II) in 102 individuals rapidly transported to the South Pole (2835 m). The mean FEF between 25 and 75% (FEF(25-75)) and blood markers were recorded at sea level and after the second night at altitude. AMS was assessed using Lake Louise questionnaires. FEF(25-75) increased by an average of 12% with changes ranging from -26 to +59% from sea level to altitude. On the second day, AMS incidence was 36% and was higher in individuals with increases in FEF(25-75) (41 vs. 22%, P = 0.05). Ascent to altitude induced an increase in endothelin-1 levels, with greater levels observed in individuals with decreased FEF(25-75). Epinephrine levels increased with ascent to altitude and the response was six times larger in individuals with decreased FEF(25-75). Greater levels of endothelin-1 in individuals with decreased FEF(25-75) suggest a response consistent with pulmonary hypertension and/or mild interstitial edema, while epinephrine may be upregulated in these individuals to clear lung fluid through stimulation of β(2)-adrenergic receptors.

Endothelin-1 Is Not Predictive of Ventricular Ectopy or Ventricular Fibrillation during Acute Myocardial Ischemia

Endothelin(ET)-1 (ET-1) increases after myocardial infarction and may have effects on myocardial function. ET-1 has also been shown to affect the action potential (AP) which may be arrhythmogenic and predispose to ventricular fibrillation (VF). The effects of ET-2 and ET-3 are uncertain. We hypothesized that the ETs increase during acute ischemia and that plasma levels are predictive of ischemically induced VF. Thirty-four domestic swine underwent balloon occlusion of the proximal LAD coronary artery. Occlusion was confirmed angiographically. Venous samples were collected from the right atrium at baseline and at 5 min intervals for 30 min or until VF induction. ET-1, ET-2, and ET-3 were measured using ELISA. Changes in plasma concentrations were assessed using repeated measures ANOVA with Dunnett's. A p < 0.05 was considered statistically significant. All animals had angiographic evidence of successful proximal LAD occlusion. ET-1 levels were significantly increased from a baseline at 20 min and remained elevated during 30 min of occlusion. ET-2 and ET-3 levels did not change from baseline values (figure, mean +/- SE). VF occurred in 60% of animals. Peak ET-1 values were not significantly different between VF and non-VF animals (6.2 +/- 2.2 vs. 4.8 +/- 2.3 pg/mL). No single ET-1 value had a VF predictive value >50%. There is a significant increase in ET-1 level within 20 min of acute myocardial ischemia. Despite known effects of ET-1 on the AP, this increase did not correlate with the occurrence of VF.

Endothelin-1 in exhaled breath condensate of stable and unstable asthma patients

Endothelins are proinflammatory, profibrotic, broncho- and vasoconstrictive peptides, which play an important role in the development of airway inflammation and remodeling in asthma. The study was undertaken to evaluate the endothelin-1 (ET-1) levels in exhaled breath condensate (EBC) of asthmatics with different degree in asthma severity. EBC was collected from 31 patients with allergic asthma (11 with steroid-naïve mild asthma, 10 with ICS-treated, stable mild-to-moderate asthma, 10 with ICS-treated unstable, severe asthma) and 7 healthy volunteers. In the three groups of asthmatics, ET-1 concentrations in EBC were significantly higher than in healthy volunteers. ET-1 levels were significantly higher in patients with unstable asthma than in the two groups with stable disease. There was a significant correlation between ET-1 levels and FENO in the three groups of asthmatics and between ET-1 and blood eosinophil counts in the group of patients with unstable asthma. Measurements of ET-1 in EBC may provide another useful diagnostic tool for detecting and monitoring inflammation in patients with asthma.

Inflammatory Murine Skin Responses to UV-B Light Are Partially Dependent on Endothelin-1 and Mast Cells

Endothelin (ET-1) has been shown to crucially contribute to UV-induced skin responses such as tanning. To test whether ET-1 is also involved in early cutaneous reactions to UV, we assessed ET-1 skin levels in UV-irradiated mice. In correlation with the levels of UV-induced skin inflammation, ET-1 concentrations increased substantially and continually. Moreover, blocking of ET-1 receptors (ETA) resulted in significantly decreased cutaneous inflammation following UV irradiation. When we assessed skin responses to ET-1 injections, we observed prominent mast cell degranulation and mast cell-dependent inflammation. Since mast cells also critically contributed to UV-induced inflammation, we determined the ET-1-dependent inflammatory response to UV in the absence and presence of these cells. Interestingly, ETA blockade did not decrease UV-induced inflammation in mast cell-deficient mice, unless these mice had been adoptively transferred with mast cells before irradiation. This indicates that skin inflammation due to UV irradiation is caused in part by ET-1 acting on skin mast cells.

INHIBITION OF ENDOTHELIN-1-MEDIATED UP-REGULATION OF INOS BY BOSENTAN AMELIORATES ENDOTOXIN-INDUCED LIVER INJURY IN CIRRHOSIS

Endothelin-1 (ET-1) has been shown to regulate the expression of various genes in addition to its vasoconstrictor role in the liver. Elevated levels of ET-1 during cirrhosis play an important role in the observed microcirculatory dysfunction; however, its role as a transcription regulator remains unclear. This study aimed to determine the role of ET-1 in the hepatic gene expression of vasomediators after cirrhosis in response to LPS. Cirrhosis was induced by bile duct ligation (BDL) for 1 or 3 weeks in male Sprague-Dawley rats. Following 1 or 3 weeks of BDL or sham operation (sham), rats received an intravenous (i.v.) injection of bosentan, a dual-selective ETA/B receptor antagonist (30 mg/kg bw) or saline, and an intraperitoneal (i.p.) injection of LPS (1 mg/kg bw). Plasma alanine aminotransferase (ALT) levels were significantly elevated in 1- and 3-week BDL animals. Six hours following LPS, the elevated ALT levels were markedly exacerbated in 3-week BDL animals, which were significantly ameliorated with bosentan treatment. LPS resulted in increased ET-1, inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX)-2 mRNA expressions in both sham and BDL rats. Bosentan significantly inhibited the up-regulations of ET-1, iNOS, and COX-2 mRNA. Our data strongly suggest that ET-1 plays an important role in up-regulating the expression of iNOS, COX-2, and ET-1 itself in hepatic tissue following LPS challenge, which may contribute to the observed hepatocellular injury during endotoxemia in cirrhosis. Thus, due to significant increases in ET-1 levels during cirrhosis, ET-1 receptor blockade may prove to be of great therapeutic value in the treatment of cirrhotic patients exposed to secondary injuries such as endotoxemia.

Reduction in hepatic endothelin-1 clearance in cirrhosis.

Circulating endothelin-1 (ET-1) levels are increased in cirrhosis. The liver is an important site for circulating ET-1 clearance through the ET(B) receptor. We evaluated ET-1 kinetics in cirrhosis to determine if a reduced liver clearance contributes to this process. Cirrhosis was induced by carbon tetrachloride in rats. Hepatic ET-1 clearance was measured in isolated perfused livers using the single bolus multiple indicator-dilution technique. Plasma ET-1 levels doubled in cirrhosis from 0.49+/-0.04 fmol/ml (mean+/-S.E.M.) to 1.0+/-0.18 fmol/ml ( P <0.01). Liver ET-1 extraction was reduced from 81+/-1% (mean+/-S.E.M.) in controls to 50+/-6% in cirrhosis ( P <0.01). Kinetic modelling revealed a major irreversible binding site for ET-1 that is blocked by the selective ET(B) receptor antagonist BQ788 and a minor non-specific reversible binding site that cannot be blocked with BQ788 or the selective ET(A) antagonist BQ123. Reduced hepatic clearance correlated with the biochemical markers of cirrhosis, portal vein perfusion pressure ( r =-0.457; P <0.001) and the increase in ET-1 levels ( r =-0.462; P =0.002). Immunohistofluorescence with specific anti-(ET(B) receptor) antibodies revealed a preponderant distribution of ET(B) receptors on hepatic stellate cells, which was increased in cirrhosis. We conclude that cirrhosis reduces ET-1 clearance probably by capillarization of hepatic sinusoids and reduced access to ET(B) receptors. This relates to the severity of cirrhosis and may contribute to the increase in circulating ET-1 levels.

Secretion of interleukin-1beta by astrocytes mediates endothelin-1 and tumour necrosis factor-alpha effects on human brain microvascular endothelial cell permeability.

Evidence suggests that endothelin-1 (ET-1) plays an essential role in brain inflammation. However, whether ET-1 contributes directly to blood-brain barrier (BBB) breakdown remains to be elucidated. Using an in vitro BBB model consisting of co-cultures of human primary astrocytes and brain microvascular endothelial cells (BMVECs), we first investigated the expression of ET-1 by BMVECs upon stimulation with tumour necrosis factor (TNF)-alpha, which plays an essential role in the induction and synthesis of ET-1 during systemic inflammatory responses. Increased ET-1 mRNA was detected in the human BMVECs 24 h after TNF-alpha treatment. This was correlated with an increase in ET-1 levels in the culture medium, as determined by sandwich immunoassay. Both TNF-alpha and ET-1 increased the permeability of human BMVECs to a paracellular tracer, sucrose, but only in the presence of astrocytes. The increase in BMVEC permeability by TNF-alpha was partially prevented by antibody neutralization of ET-1 and completely by monoclonal antibody against IL-1beta. Concomitantly, TNF-alpha induced IL-1beta mRNA expression by astrocytes in co-culture and this effect was partially prevented by ET-1 antibody neutralization. In parallel experiments, treatment of human primary astrocytes in single cultures with ET-1 for 24 h induced IL-1beta mRNA synthesis and IL-1beta protein secretion in the cell culture supernatant. Taken together, these results provide evidence for paracrine actions involving ET-1, TNF-alpha and IL-1beta between human astrocytes and BMVECs, which may play a central role in BBB breakdown during CNS inflammation.

Endothelin-1 and functional tissue factor: a possible relationship with severity in primary pulmonary hypertension.

Although dysfunctional endothelium, vasoconstriction, and in situ thrombosis are characteristics of primary pulmonary hypertension, the role that plasma vasomotor and coagulation factors play in this phenomenon are not completely understood. The aim of this work was to ascertain the diagnostic value of endothelin-1, thrombomodulin, tissue factor, and tissue factor pathway inhibitor, as well as their correlation with endothelial dysfunction in primary pulmonary hypertension patients. We analyzed the plasmatic concentration and chromogenic of the above-mentioned molecules using immunoenzymatic techniques. Patients were divided into responders and nonresponders on the basis of their hemodynamic response to a vasodilator trial. We found a continuous increase in endothelin-1 levels and a continuous decrease in functional tissue factor in the control group, responders, and nonresponders, respectively. Moreover, the patients showed a moderate decrease in thrombomodulin levels compared with the control group, without statistical significance. These results support a previous description of a decrease in thrombomodulin levels in primary pulmonary hypertension patients and suggests that an alteration of endothelin-1 and functional tissue factor could be related to a worsening of endothelial function and, indirectly, with the clinical severity of primary pulmonary hypertension.

Role of ERK and p38 mitogen-activated protein kinase cascades in gastric mucosal inflammatory responses to Helicobacter pylori lipopolysaccharide.

The animal model of H. pylori lipopolysaccharide (LPS)-induced gastritis was used to study the role of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) in the mucosal release of tumor necrosis factor-alpha (TNF-alpha) and endothelin-1 (ET-1) in response to H. pylori infection. Rats, pretreated with specific inhibitors of p38 and ERK pathways, SB203580 and PD98059, were submitted to intragastric application of H. pylori LPS and maintained on the daily regimen of the inhibitors for 4 days. In the absence of inhibitors, the LPS elicited a pattern of mucosal inflammatory responses resembling that of acute gastritis, and reflected in a massive increase in the mucosal level of ET-1 and TNF-alpha. Administration of SB203580 led to a 63.4% reduction in the extent of inflammatory involvement, the level of ET-1 fell by a 42% and TNF-alpha declined by a 52.3%, whereas PD98059 elicited a 21.2% reduction in the extent of inflammatory involvement and a 22.7% decrease in TNF-alpha, but had no effect on the LPS-induced increase in ET-1. A combination of both inhibitors, while exerting additive effect on TNF-alpha, produced no additional reduction in ET-1 and the extent of inflammatory involvement achieved with SB203580 alone. The findings suggest that the p38 MAPK signaling pathway plays a key role in the mediation of gastric mucosal inflammatory reaction to H. pylori infection.

Impaired Endothelin-1 Release in Tilt-Induced Syncope

The neurohumoral events associated with neurocardiogenic syncope remain unclear. The simultaneous assessment of changes in endothelium-dependent and independent hormones and in autonomic balance in patients with tilt-induced syncope has been incompletely studied. Forty-six healthy subjects aged between 21 and 83 years (mean ± SEM 47 ± 3) underwent a 30-minute head-up tilt test at 60°. Fourteen subjects (10 females and 4 male subjects) exhibited syncope at 16 ± 2 minutes into the tilt. Hemodynamics were recorded every 5 minutes and blood samples for the measure of catecholamines, endothelin-1 (ET-1), and angiotensin-II (AT-II), were drawn at baseline, and 5, 10, 15, and 30 minutes into the tilt and immediately before syncope. Heart rate variability was analyzed by 5-minute segments during the test. Both catecholamines and ET-1 levels increased consistently in response to head-up tilt in subjects able to tolerate the test. Epinephrine increased to a greater extent before syncope. In contrast, ET-1 failed to increase at any time during the tilt and just before syncope. AT-II increased at 30 minutes into the tilt only in the control group. Finally, power in high-frequency bands decreased less in the group with syncope. Thus, compared with subjects able to tolerate a head-up tilt test, patients with syncope exhibit a greater increase in adrenomedullary activation, no significant increase in ET-1 levels, and a blunting in the decrease of vagal tone before syncope. The lack of increase in ET-1 during tilt may play a role in the inability to support orthostatic stress.

Outcome of carpal tunnel release surgery in patients with diabetes.

The surgical outcomes in 149 patients with diabetes and carpal tunnel syndrome who underwent transverse carpal ligament release surgery are reported. Associated factors such as insulin dependence, length of time with diabetes, electrodiagnostic studies, severity of neurological deficit, presence of polyneuropathy, and cervical disc disease were considered. Analysis of preoperative and postoperative symptoms, clinical findings, diagnostic studies, and patient self-assessment indicated that the majority of patients with diabetes experienced a favorable surgical outcome, regardless of any associated factors. Eighty-four percent of the patients reported good to excellent postoperative results in their hands. Further analysis of the subpopulation of insulin-dependent diabetics showed that 81% experienced good to excellent postoperative results. These results compare favorably with those of the control group: 200 nondiabetic patients, of whom 90% rated their results from carpal tunnel release surgery as good to excellent. There were no major complications in any group.