Endothelin-1 Levels In Patients Research Articles

Prognostic significance of elevated endothelin-1 levels in patients with colorectal cancer.

Prognostic factors from clinical, laboratory and pathological data of patients with colorectal cancer are essential to identify high-risk groups to whom beneficial adjuvant therapy could be given. Endothelin-1, a growth factor, has been associated with the development and spread of solid tumours. This prospective study was performed to determine whether preoperative plasma big ET-1 levels might be useful as a prognostic indicator in patients with colorectal carcinoma. Sixty-five consecutive patients with colorectal cancer confirmed by biopsy were included prospectively into this study over a 12-month period. Plasma samples from a peripheral vein were obtained prior to surgery. Univariate analysis of survival using age (< or > 70 years), sex, Dukes' stage (A&B versus C), tumour size (< or > 50 mm), vascular invasion and plasma big ET-1 levels was performed and significant factors were then analysed with the Cox regression model. Three variables, age, Dukes' tumour stage and plasma big ET-1 levels, were found to have prognostic significance (p<0.05). Factors associated with a poorer prognosis were age >70 years (p=0.02), Dukes' C tumours (p=0.04) and plasma big ET-1 levels >4.2 pg/mL (p=0.02). The Cox regression model identified the same three variables as having independent prognostic value for overall survival. Preoperative plasma big ET-1 levels may be useful in predicting overall survival in patients with colorectal cancer. Plasma big ET-1 levels may be useful in the selection of high-risk lymph node-negative patients with colorectal cancer for adjuvant therapy.

Prognostic significance of elevated endothelin-1 levels in patients with colorectal cancer

Prognostic factors from clinical, laboratory and pathological data of patients with colorectal cancer are essential to identify high-risk groups to whom beneficial adjuvant therapy could be given. Endothelin-1, a growth factor, has been associated with the development and spread of solid tumours. This prospective study was performed to determine whether preoperative plasma big ET-1 levels might be useful as a prognostic indicator in patients with colorectal carcinoma. Sixty-five consecutive patients with colorectal cancer confirmed by biopsy were included prospectively into this study over a 12-month period. Plasma samples from a peripheral vein were obtained prior to surgery. Univariate analysis of survival using age (< or > 70 years), sex, Dukes' stage (A&B versus C), tumour size (< or > 50 mm), vascular invasion and plasma big ET-1 levels was performed and significant factors were then analysed with the Cox regression model. Three variables, age, Dukes' tumour stage and plasma big ET-1 levels, were found to have prognostic significance (p<0.05). Factors associated with a poorer prognosis were age >70 years (p=0.02), Dukes' C tumours (p=0.04) and plasma big ET-1 levels >4.2 pg/mL (p=0.02). The Cox regression model identified the same three variables as having independent prognostic value for overall survival. Preoperative plasma big ET-1 levels may be useful in predicting overall survival in patients with colorectal cancer. Plasma big ET-1 levels may be useful in the selection of high-risk lymph node-negative patients with colorectal cancer for adjuvant therapy.

Plasma and Bronchoalveolar Lavage Fluid Levels of Endothelin-1 in Patients with Chronic Obstructive Pulmonary Disease and Pulmonary Hypertension

Background: Secondary pulmonary hypertension (PH) and cor pulmonale are the major clinical cardiovascular complications affecting prognosis in patients with chronic obstructive pulmonary disease (COPD). It is also known that endothelin-1 (ET-1) is a potent vasoconstrictor peptide produced by the pulmonary vascular endothelium, and ET-1 may be implicated in the pathogenesis of PH. Objectives: The purpose of this study was to investigate the presence of ET-1 in patients with COPD and to assess the correlation of ET-1 levels in the plasma and bronchoalveolar lavage (BAL) fluid (BALF) in COPD patients with or without PH. Methods: Twenty-two patients with COPD and 15 healthy controls were enrolled in the study. Peripheral venous blood samples were collected in all patients and controls. BAL was obtained in COPD patients, and ET-1 levels were measured by radioimmunoassay in all plasma and BALF samples. Results: Plasma ET-1 levels were 2.46 ± 0.55 and 1.70 ± 0.42 pmol/dl in patients with COPD and controls, respectively (p < 0.0001). Sixteen of the 22 patients with COPD (73%) had PH established by echocardiography. The ET-1 level in these patients amounted to 2.59 ± 0.50 pmol/dl, and it was 2.10 ± 0.54 pmol/dl in 6 patients with COPD without PH. In COPD patients with and without PH, BALF ET-1 levels were 0.19 ± 0.08 and 0.24 ± 0.01 pmol/dl, respectively (p > 0.05). Conclusions: These results suggest that ET-1 is detectable in both the peripheral blood and BALF of COPD patients, but the levels do not statistically differ between patients with and without PH.

Plasma endothelin-1 levels and clinical correlates in patients with chronic heart failure

Background: Endothelin-1 (ET-1) is a potent vasoconstrictor peptide, and patients with chronic heart failure (CHF) are reported to have high plasma ET-1 levels. The aim of this study was to investigate the relation between plasma ET-1 levels and clinical correlates in patients with CHF. The effects of maximal exercise on plasma ET-1 levels were also investigated. Methods: Plasma concentrations of ET-1, norepinephrine, and atrial and brain natriuretic peptide (ANP and BNP) both at rest and after maximal cardiopulmonary exercise test were determined in 100 patients with CHF (60 ± 12 years, New York Heart Association [NYHA] class I-III, left ventricular ejection fraction [LVEF] = 36 ± 8%, peak oxygen uptake [VO2] = 18.2 ± 5.0 mL/min/kg) and 27 controls. Results: Patients with NYHA class II and III CHF had higher ET-1 levels (controls, NYHA class I, II, III: 2.1 ± 0.6, 2.1 ± 1.0, 2.6 ± 0.9, 3.4 ± 0.8 pg/mL, analysis of variance P <.0001). Maximal exercise did not alter ET-1 levels in controls or in each CHF subgroup. When all CHF patients were analyzed together, cardiothoracic ratio (P <.01), peak VO2 (P <.001), plasma norepinephrine (P <.01), plasma ANP (P <.01), and plasma BNP (P <.001) were significantly related with resting ET-1 levels on univariate analysis. Multivariate analysis revealed peak VO2 and plasma BNP levels showed an independent and significant relationship with the resting plasma ET-1 levels. Conclusions: Resting ET-1 levels were increased in symptomatic patients with CHF, and maximal exercise did not increase ET-1 levels. Peak VO2 and plasma BNP levels were independently associated with resting plasma ET-1 levels in patients with CHF.

Endothelin-1 levels in the pathophysiology of chronic obstructive pulmonary disease and bronchial asthma

Background: Endothelin-1 (ET-1) has been implicated in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). The ET-1 levels are elevated during exacerbations of asthma and COPD in bronchoalveolar lavage, serum, and sputum and fails with treatment of the exacerbations. Hypoxemia stimulates ET-1 secretion. Objective: The aim of this study was to examine the serum ET-1 levels in stable asthmatic and COPD patients. Materials and methods: We examined 48 COPD and 26 asthmatic patients and 34 normal subjects. We collected arterial samples to measure baseline ET-1 levels in all patients and in the control group, during the day. All the patients underwent formal polysomnography (EEG, ECG, airflow, respiratory muscle movement, oximeter) to detect the presence of nocturnal, nonapneic, and oxyhemoglobin desaturation. Twelve of the COPD patients and six of the asthmatic patients were disqualified because of inadequate sleep or sleep apnea syndrome. Nineteen of the COPD patients desaturated below a baseline sleep saturation of 90% for 5 min or more, reaching a nadir saturation of at least 85%. We collected arterial samples to measure ET-1 levels, 5 min after the first period of desaturation in each of the 19 desaturators COPD patients. None of the 20 asthmatic patients exhibited oxyhemoglobin desaturation during sleep. Results: Baseline arterial ET-1 levels during the day were significantly higher in “desaturators” COPD patients (2.08±0.28 pg/ml) compared to “non-desaturators” COPD patients (1.38±0.16 pg/ml) ( P<0.001) and to asthmatics (0.72±0.85 pg/ml) ( P<0.001). ET-1 levels in normal subjects were 1.221±0.02 pg/ml. In “desaturators” COPD patients ET-1 levels during the night, 5 min after the first oxyhemoglobin desaturation, were significantly higher (4.28±1.10 pg/ml) compared to those during the day (2.08±0.28 pg/ml) ( P<0.001). A significant negative correlation was observed between ET-1 levels and degree of desaturation during the day ( P=0.005, r=0.632) and during the night ( P<0.001, r=0.930) in “desaturators” COPD patients. Conclusion: According to our results: (1) ET-1 levels were significantly higher in “desaturators” COPD patients than in “non-desaturators” COPD and in asthmatics; (2) ET-1 levels were significantly higher during the night than during the day in “desaturators” COPD patients; (3) the degree of desaturation correlated negatively with the ET-1 levels in “desaturators” COPD patients, both during daytime and nighttime. These findings are consistent with the hypothesis that ET-1 is implicated in the pathophysiology of asthma and COPD, especially if nocturnal, nonapneic, oxyhemoglobin desaturation exists.

Plasma endothelin-1 levels in patients with biliary atresia: possible role in development of portal hypertension.

Biliary atresia (BA) is a severe neonatal liver disease characterized by progressive extrahepatic biliary tract and intrahepatic inflammatory process. Hepatic fibrosis and portal hypertension (PH) still occur despite the disappearance of jaundice following successful hepatic portoenterostomy. Endothelin-1 (ET-1) is a potent vasoconstrictor and has been reported to stimulate hepatic collagen synthesis. The aim of this study was to demonstrate the potential role of ET-1 in the pathogenesis of the progressive inflammation, fibrosis and PH in BA. Thirty pediatric patients with biliary atresia post-hepatic portoenterostomy and 12 healthy children were examined. The ET-1 level was determined by commercially available enzyme-linked immunosorbent assay kits. Endothelin-1 levels were elevated in the patients compared with those of the controls (5.45+/-3.34 vs. 2.74+/-2.17 pg/ml, P = 0.01). Moreover, patients with PH also had greater levels of ET-1 than those without PH (6.73+/-3.27 vs. 3.26+/-2.2 pg/ml, P = 0.004). Patients with abnormal transaminase enzymes had significantly higher ET-1 levels than those with normal enzymes (6.43+/-3.33 vs. 3.17+/-2.1 pg/ml, P = 0.01). In the jaundice-free group, endothelin-1 levels were elevated in the patients with PH compared with those without PH (5.93+/-2.15 vs. 2.88+/-2.1 pg/ml, P = 0.02). Our findings showed elevation of plasma ET-1 levels in patients with BA, especially in those with PH. ET-1 levels were also higher in patients with elevated transminase enzymes as well as in the jaundice-free group with PH. ET-1 might play a role in the pathogenesis of the progressive inflammation, fibrosis and PH in BA.

464 Plasma level of endothelin-1 in patients with coronary artery disease

464 Plasma level of endothelin-1 in patients with coronary artery disease

Intravenous nesiritide (human B-type natriuretic peptide) reduces plasma endothelin-1 levels in patients with decompensated congestive heart failure

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Evaluation of plasma endothelin-1 levels in patients with cerebral infarction.

Endothelin-1 (ET-1) is a vasoconstrictor peptide derived from endothelium. Many authors have shown that ischemic stroke is associated with elevated plasma ET-1 levels. Also, the present findings related to plasma ET-1 levels with clinical status, size of the infarction, location of the infarction, and prognosis of the cerebral infarction were contradictory. In this study, plasma ET-1 levels in 30 patients with cerebral infarction within 72 hours after the onset of focal neurologic deficit and at their seventh day postinfarction were measured by a microplate enzyme immunoassay. Thirty sex- and age-matched healthy subjects were accepted as a control group. The mean plasma ET-1 concentrations in patients on admission, in patients at day 7, and in control subjects were 1.93 +/- 1.79, 1.03 +/- 1.02, and 0.65 +/- 0.32 fmol/mL, respectively. The mean plasma ET-1 level of patients on admission was found to be significantly higher than in patients at day 7 and in control subjects (p < 0.05). No significant difference in ET-1 levels was observed between the patients at day 7 and control subjects. Furthermore, there was no correlation between plasma ET-1 concentration and size of infarction, location of infarction, degree of clinical neurologic deficit, or prognosis of cerebral infarction. It was concluded that plasma ET-1 levels shortly after ischemic stroke were increased, which may be associated with the acute-phase reaction of cerebral infarction and may have deleterious effects on development of neuronal injury.

The relation between plasma endothelin-1 levels and metabolic control, risk factors, treatment modalities, and diabetic microangiopathy in patients with Type 2 diabetes mellitus

We evaluated the possible relation between plasma endothelin-1 (ET-1) levels and metabolic control, risk factors, treatment modalities, and diabetic microangiopathy, including nephropathy, neuropathy, and retinopathy in patients with Type 2 diabetes and healthy control group. Sixty-eight (39 females and 29 males) patients with Type 2 diabetes and 14 (6 females and 8 males) healthy subjects were included in the study. Plasma ET-1 levels were found to be 10.46±1.24 pmol/l in the diabetic group, whereas 7.97±0.41 pmol/l in the control group, which was statistically significant ( P<.01). We also found elevated plasma ET-1 levels in patients with the least one microvascular complication when compared with the uncomplicated diabetes group ( P=.02). Moreover, plasma ET-1 levels of the uncomplicated group was higher than the control group ( P<.05). Plasma ET-1 levels were significantly elevated in hypertensive diabetics than normotensive diabetics ( t=2.58, P=.012). It was also found to be elevated in diabetic patients with diabetes duration of more than 10 years when compared with patients less than 10 years ( P=.02). These findings can be interpreted as the increased damage of microvascular complications in the disease process that may lead to elevated ET-1 levels. Mean plasma ET-1 levels in diabetic patients with a family history of diabetes was found to be higher than patients with no family history of diabetes. Genetical and environmental factors may have an effect on ET-1 level. We also studied the correlations of plasma ET-1 levels on age, sex, fasting blood glucose levels, treatment modalities HbA1c, hyperlipidemia, C-peptide, Body Mass Index, and smoking, but did not find any statistically significant difference. In conclusion, plasma ET-1 levels are well correlated with microangiopathy, hypertension, increased disease duration, and family history of diabetes, but poorly correlated with metabolic control, treatment modalities, age, sex, hyperlipidemia, obesity, and smoking.

Effect of nesiritide on endothelin-1 levels in patients with decompensated congestive heart failure Doron Aronson, Andrew J. Burger. Beth Israel Deaconess Medical Center, Boston, MA, Harvard Medical School, Boston, MA

Effect of nesiritide on endothelin-1 levels in patients with decompensated congestive heart failure Doron Aronson, Andrew J. Burger. Beth Israel Deaconess Medical Center, Boston, MA, Harvard Medical School, Boston, MA

Elevated serum endothelin-1 levels in patients with colorectal cancer; relevance for prognosis.

It has been demonstrated that the Doppler Perfusion Index (DPI) is increased in patients who are at risk of developing liver metastases from colorectal cancer. It has been postulated that a circulating hormonal factor is involved in the relative vasoconstriction throughout the splanchnic bed. Endothelin-1 (ET-1), a potent vasoconstrictor which has been associated with tumor growth and is produced by colorectal tumors, may play an important role in this phenomenon. In this paper the prognostic value of serum ET-1 in colorectal cancer is discussed. Preoperative serum levels of ET-1 were assessed in three groups of patients: group A underwent resection of the colorectal tumor and remained free of recurrence (n=20); group B developed metachronous liver metastases at least six months after colorectal resection (n=14); and group C presented with colorectal cancer and synchronous liver metastases (n=22). The mean (SD) serum ET-1 levels in groups A, B and C were 1.59 (0.41) pmol/L, 1.70 (0.32) pmol/L and 1.85 (0.47) pmol/L, respectively. These values were significantly different from those of healthy controls (1.22 (0.31), p<0.05). Kaplan-Meier analyses revealed no prognostic value of preoperative serum ET-1 levels. These preliminary results demonstrate that serum ET-1 levels are raised in patients with colorectal cancer. Serum ET-1 levels do not seem to be of prognostic value for survival.

Plasma levels of endothelin-1 in patients with the hepatorenal syndrome after successful liver transplantation

Plasma levels of endothelin-1 in patients with the hepatorenal syndrome after successful liver transplantation

Increased plasma endothelin-1 levels in patients with intracerebral hemorrhage

Endothelins (ETs) are discovered peptides that are widely distributed in neurons and nonneuronal cells of the human nervous system. Previous studies showed that ischemic stroke may be associated with increased plasma ET-1 levels. There are no studies to show plasma ET-1 levels in intracerebral hemorrhage. Plasma ET-1 levels in 30 patients with cerebral hemorrhage within 72 hours after the onset of focal neurological deficit were measured by a microplate enzyme immunoassay. Thirty sex- and age-matched healthy subjects were accepted as a control group. The clinical neurological status in the patients was evaluated according to the modified Matthew Scale. The mean plasma ET-1 level in hemorrhagic stroke patients was significantly higher than in control subjects (2.39±2.08 v 0.65±0.32 fmol/mL, ( P < .05). There was a significant difference in ET levels between patients who died in the hospital and patients who survived ( P < .05). The mean ET-1 concentration in patients with severe neurologic deficit was significantly higher than in patients with mild neurologic deficit ( P < .05). There was a correlation between hematoma volumes and plasma ET-1 levels in the patients (r = 0.66, Pt < .001). The mean plasma ET-1 concentration was found to be significantly higher in patients with intraventricular hemorrhage than in patients without intraventricular hemorrhage ( P < 0.05). There were no significant differences in ET-1 levels between supratentorial and infratentorial subgroups or among supratentorial subgroups ( P > .05). It was concluded that plasma ET-1 levels were increased in the acute period of hemorrhagic stroke. Plasma ET-1 levels may be associated with hematoma volume, which is related to a poor prognosis of the cerebral hematoma. We suggest that increased plasma ET-1 levels may be a consequence of local cerebral hemorrhage or the acute stress condition of the disease.

Relationship between endothelin-1 concentration and metabolic alterations typical of the insulin resistance syndrome

The purpose of the study was to examine the relationship between the endothelin-1 (ET-1) concentration and the metabolic variables characteristic of the insulin resistance syndrome ([IRS] hyperinsulinemia, insulin resistance, hypertriglyceridemia, low high-density lipoprotein [HDL] cholesterol, visceral obesity, and glycemic abnormalities). The measurement of circulating ET-1 is a well-recognized marker of endothelial atherosclerotic and cardiovascular disease. Two hundred subjects were divided into 3 groups. Group 1 included 50 subjects with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) with IRS. Group 2 included 50 subjects with IGT or NIDDM without IRS. Group 3 included 100 normal subjects as controls. ET-1 levels were higher in group 1 versus groups 2 and 3 in women (11.2 +/- 0.7 v 7.9 +/- 0.5 and 6.6 +/- 0.4 pg/mL, P < .01) and men (10.1 +/- 0.6 v 6.5 +/- 0.8 and 7.2 +/- 0.3 pg/mL, P < .01). No differences were found between groups 2 and 3. With simple regression analysis, ET-1 levels significantly correlated with insulin, glycosylated hemoglobin, body weight, waist to hip ratio, and triglyceride values. However, with multiple regression analysis, only triglycerides (P < .009) and glycosylated hemoglobin (P < .001) remained independently correlated with ET-1. In conclusion, this cross-sectional study indicates that glycosylated hemoglobin and triglycerides are independently correlated with ET-1 levels in patients with IRS.

Endothelin-1: a new target of therapeutic intervention for the treatment of heart failure.

Endothelin-1 has been appreciated in animals and humans as a potential target for inhibition in patients with acutely decompensated congestive heart failure (CHF), as well as patients with a chronic low-output state. There has been intense interest in determining the effects of endothelin-1 on the cardiovascular system. Elevated plasma levels of endothelin-1 in patients with CHF portend a poorer prognosis than similar patients without elevated levels. Endothelin-1 levels correlate inversely with maximum oxygen consumption, and inhibition of the myocardial endothelin pathway in rats with CHF improves survival. An association between endothelin-1 and the development of CHF has recently been supported. Selectively inhibiting the endothelin A receptors in dogs with CHF produced hemodynamic improvement. Similarly, in rabbits, a structural advantage was demonstrated. Benefits in cardiac remodeling have been demonstrated in several models of CHF by nonselectively antagonizing endothelin receptors. In human trials using nonselective endothelin-1 inhibitors, researchers have demonstrated hemodynamic benefit and improvement in cardiac function in patients with decompensated CHF. Inhibition of endothelin-1 in patients with CHF appears to have potential therapeutic value, and ongoing clinical trials will further investigate the safety, efficacy, and role of this new potential therapeutic target for the treatment of CHF.

Superiority of endothelin-1 over norepinephrine in exercise-induced alterations of the conduit artery tone of the non-exercised arm in patients with chronic heart failure

This study is aimed at examining the relative importance of norepinephrine and endothelin-1 in treadmill exercise-induced changes in brachial arterial tone of the non-exercised arm in patients with chronic heart failure (CHF). Brachial artery diameter and blood flow were measured before and after exercise in eight healthy volunteers and 18 patients with stable chronic heart failure by high-resolution ultrasound. Maximal exercise resulted in brachial artery dilatation in controls (4.42±0.39 vs. 4.77±0.39 mm; P<0.0001) in contrast to constriction seen in the patients (5.27±0.67 vs. 5.12±0.66 mm; P=0.07). Both groups demonstrated a significant increase in blood flow after exercise. The pre-exercise (2.83±0.76 vs. 1.69±0.15 pmol/l; P=0.0004), post-exercise (4.15±1.5 vs. 2.02±0.34 pmol/l; P=0.0004) and the percent increase (47.15±32.5 vs. 19.0±10.5%; P=0.02) in endothelin-1 levels were significantly greater in patients than in controls. In contrast to endothelin-1, the exercise-induced percent increase in norepinephrine was greater in controls than patients (100.7±51.8 vs. 49.8±43.4%; P=0.01). The percent change in the diameter of the brachial artery in response to maximal exercise was significantly correlated to pre- ( r=0.634; P=0.003) and post-exercise ( r=0.467; P=0.05) endothelin-1 levels in patients but not in controls [pre-exercise ( r=0.07; P=0.86), post-exercise ( r=0.310; P=0.47)]. The change in the diameter of the brachial artery did not correlate with pre- or post-exercise plasma norepinephrine levels in either group. These findings suggest that endothelin-1 is potentially more important than norepinephrine in contributing exercise-induced brachial artery constriction in patients with chronic heart failure.

Plasma endothelin-1 levels in patients with left-to-right shunt with or without pulmonary hypertension

The aim of this study was to evaluate the role of endothelin-1 (ET-1) in pathophysiology of pulmonary hypertension (PH) secondary to congenital heart disease with left-to-right shunt. Twenty-three children (12 male, 11 female) aged 0.58–13 years were enrolled the study. Blood samples were drawn from superior vena cava, right atrium, right ventricle, pulmonary artery and pulmonary wedge or pulmonary vein during cardiac catheterization. Plasma ET-1 levels were assayed by ELISA. Patients were divided into two groups according to the presence or absence of PH. Plasma ET-1 levels of the study group were compared to the peripheral venous and arterial ET-1 levels of 11 healthy infants and children (aged 0.75–13 years). Plasma ET-1 levels in patients with left-to-right shunt were found significantly higher than those of controls. However, plasma ET-1 levels were similar between the two groups of the patients. Pulmonary venous ET-1 levels were higher than the levels of superior vena cava, this suggested an increased production of ET-1 in pulmonary vascular bed in patients with PH. No correlations were found between plasma ET-1 levels and pulmonary arterial pressure, pulmonary vascular resistance and pulmonary blood flow in the patients. Plasma ET-1 levels of the patients with left-to-right shunt were increased independently from pulmonary arterial pressure and pulmonary vascular resistance. This increase was related to the production of ET-1 in pulmonary vascular bed in patients with PH. ET-1 could not be found to be directly related to the development of PH in the patients with left-to-right shunt.

Anti-ulcerogenic properties of endothelin receptor antagonists in the rat.

Endothelins have been implicated in gastric mucosal damage in a variety of animal models. Exogenous ET-1 and ET-3 are causally associated with experimental gastric ulcers. Furthermore, clinical reports also show elevated plasma and gastric mucosal endothelin-1 levels in patients suffering from peptic ulcers. To study the possibility that endothelin receptor antagonists may have beneficial effects and prevent the development of gastric ulcers. We have tested in rats the orally-active endothelin antagonist bosentan (Ro 47-0203) and Ro 48-5695, which is 10-30 times more potent than bosentan on endothelin receptors. Water immersion restrained stress (WIRS) and indomethacin were used to provoke gastric mucosal damage. Endothelin receptor antagonists were administered orally prior to the induction of gastric damage. The gastric lesion index (mm), assessed macroscopically, and myeloperoxidase (MPO) activity were used as markers of the extent of mucosal injury. Bosentan at 100 and 30 mg/kg administered orally caused attenuation of gastric damage in the WIRS model by 58% and 42%, respectively. Bosentan also caused complete reduction of MPO activity. In indomethacin-induced gastric damage, 100 mg/kg bosentan attenuated gastric damage by 45% and 61% as measured by the gastric lesion index and MPO activity respectively. Ro 48-5695 was at least 30 times more potent than bosentan in reducing indomethacin-induced mucosal damage and at 3 mg/kg, caused a decrease of 49% in the gastric lesion index and a reduction in MPO activity of 41%. Bosentan and Ro 48-5695 possess weak antisecretory properties as tested in the mouse gastric gland assay, than cannot, alone, account for their anti-ulcer properties. Both endothelin receptor antagonists prevented the development of gastric mucosal injury in the rat. Disturbances in the gastric microcirculation are responsible for the development of experimental gastric ulcers. The anti-ulcer properties of these two endothelin antagonists suggest possible new therapeutic approaches to controlling gastric inflammation.

Influence of Non–Insulin-Dependent Diabetes Mellitus on Plasma Endothelin-1 Levels in Patients With Advanced Atherosclerosis

Endothelin-1 (ET-1) is an endothelium-derived vasoactive peptide with mitogen properties. Increased circulating ET-1 levels were found in patients with atherosclerosis as well as in patients with non–insulin-dependent diabetes mellitus (NIDDM) suggesting a role in the pathogenesis of these disorders. The aim of the present study was to ascertain the influence of the NIDDM on plasma ET-1 levels in patients with advanced atherosclerotic lesions. The circulating ET-1 levels were measured in 16 NIDDM patients (68.4 ± 8.4 years) with macroangiopathy and in ten patients (65.3 ± 11 years) with atherosclerosis without NIDDM. Twenty-two healthy subjects (43.1 ± 18.3 years) served as controls. Circulating ET-1 levels were higher in NIDDM patients (6.8 ± 2.8 pg/mL) than both controls (3.1 ± 1 pg/mL; p < 0.001) and patients with vascular disease but without NIDDM (4.7 ± 1.6 pg/mL; p < 0.04). No significant relationship was found between age and ET-1 concentrations, and no differences were noted between men and women in the control group. This study demonstrated that circulating ET-1 levels are increased in patients with atherosclerosis and that those with NIDDM showed the highest ET-1 levels. These observations strongly support a role for ET-1 in the pathogenesis of atherosclerosis and also suggest that this peptide may be involved in the development of atherosclerotic lesions in the NIDDM. We speculated that chronic exposure to hyperinsulinemia and hypertriglyceridemia in the diabetic patients could account for the increased ET-1 levels found in these patients.