Elevated Plasma Endothelin-1 Levels Research Articles

Mechanisms of elevated plasma endothelin-1 in CHF: congestion increases pulmonary synthesis and secretion of endothelin-1.

The pulmonary circulation may contribute to elevated plasma levels of endothelin-1 (ET-1) in congestive heart failure (CHF). The aims of the present study were to determine the mechanisms of increased secretion of ET-1 from the pulmonary circulation in CHF. Juvenile pigs were subjected to sham operation (n=9) or rapid cardiac pacing-induced CHF (215-240 bpm, n=15). Three weeks of rapid pacing led to significant left ventricular dilatation, increased cardiac filling pressures, and reduced contractility (CHF pigs). Arterial plasma ET-1 levels in the CHF pigs were increased 4-fold compared to sham pigs (P<0.001). Single-bolus multiple indicator-dilution experiments revealed that pulmonary synthesis and release of ET-1 was increased in CHF, while pulmonary clearance of plasma ET-1 remained unaltered despite significant reduction of pulmonary fractional extraction of plasma ET-1. Pulmonary ECE-1 isozyme activity (pmol.min-1.mg protein-1) was selectively increased in lower lobe segments of CHF pigs (2.0+/-0.3) compared to lower lobe segments of controls (1.1+/-0.1, P<0.02), and to upper lobe segments of CHF pigs (1.1+/-0.1, P<0.005), and correlated significantly with the wet/dry weight ratios of the pulmonary tissue samples (R=0.75, P<0.001), i.e. a marker of pulmonary congestion. Furthermore, alveolar macrophages in congested lobe segments were identified as likely sites of increased synthesis and release of ET-1. In rapid pacing-induced CHF, a complex cardiopulmonary interaction revealed by pulmonary congestion causes increased pulmonary production and secretion of ET-1 due to enhanced pulmonary ECE-1 activities. Pulmonary secretion of ET-1 during evolving CHF is an important contributor to elevated plasma ET-1 levels in the systemic circulation.

Elevated plasma endothelin-1 levels in coronary sinus during rapid right atrial pacing in patients with slow coronary flow

The aim of the study was to evaluate whether there was an imbalance between endothelin-1 (ET-1) and nitric oxide (NOx) release and diffuse atherosclerotic changes existed in patients with slow coronary flow (SCF). Baseline and post-atrial pacing coronary sinus ET-1 and NOx levels were measured in 19 patients with SCF (11 female, 56±9 years) and in 14 control subjects (nine female, 54±7 years). All patients underwent subsequent intravascular ultrasound (IVUS) investigation at the same setting with right atrial pacing. Baseline arterial (12.4±9.9 vs. 6.3±5.1 pg/ml, P<0.005) and coronary sinus (12.2±11.1 vs. 6.4±6.9 pg/ml, P<0.005) ET-1 plasma levels were higher in patients than in controls. After atrial pacing, concentration of ET-1 level from coronary sinus (24.7±14.6) significantly increased as compared to baseline (12.4±9.9, P<0.0001) and control levels (5.3±6.3, P<0.0001). Additionally, coronary sinus ET-1 level increased significantly with atrial pacing compared to femoral artery ET-1 level (16.3±8.5, P<0.005) in patients with SCF. After atrial pacing, the femoral artery ET-1 level also increased in patients compared to control level ( P<0.0001). No significant differences in arterial and coronary sinus NOx plasma levels were found between the two groups, both at baseline and after pacing. Upon IVUS investigation, the common finding was longitudinally extended massive calcification throughout the epicardial arteries in patients with SCF. Mean intimal thickness was 0.59±0.18 mm. The data of this study suggest that increased ET-1 levels and insufficient NOx response, as well as the pathological data of IVUS may be associated with coronary microvascular dysfunction and may be the manifestation of early diffuse epicardial atherosclerosis in these patients with SCF.

Association Between Plasma Endothelin-1 Levels and Cheyne-Stokes Respiration in Patients With Congestive Heart Failure

Elevated plasma endothelin-1 (ET-1) levels have been reported in association with hypoxia and congestive heart failure (CHF). Furthermore, Cheyne-Stokes respiration-central sleep apnea (CSR-CSA) has been found to correlate with the degree of pulmonary hypertension and the severity of CHF; however, the association between ET-1 levels and CSR-CSA has not been investigated previously. Veterans Affairs Medical Center. We studied 46 consecutive patients with CHF (left ventricular function < or = 40%) who underwent right-heart catheterization and overnight polysomnography. Thirty-nine patients completed the study. Sixteen patients (41%) had CSR-CSA, 5 patients (13%) had obstructive apnea, and 18 patients (46%) had no sleep-disordered breathing. Circulating plasma ET-1 levels were assayed in patients with CSR-CSA and in patients with no sleep-disordered breathing using commercially available enzyme-linked immunosorbent assay kits. ET-1 levels were significantly elevated in patients with CSR-CSA (mean +/- SD, 5.4 +/- 1.3 pg/mL) compared to those without central apnea (3.9 +/- 1.1 pg/mL; p < 0.01), and correlated with mean pulmonary artery pressure (r = 0.66, p < 0.01), pulmonary capillary wedge pressure (r = 0.56, p < 0.03), and central apnea frequency (r = 0.66, p < 0.01). In multivariate analysis, the severity of CSR-CSA was the only variable independently associated with plasma ET-1. We conclude that elevated plasma ET-1 levels are linked to the severity of CSR-CSA. Whether ET-1 represents an important pathogenic factor in CSR-CSA or marker of its occurrence requires further evaluation.

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.

Association between the endothelin-1 gene Lys198Asn polymorphism blood pressure and plasma endothelin-1 levels in normal and pre-eclamptic pregnancy.

This study examined the frequency of the Lys198Asn polymorphism in the endothelin-1 (ET-1) gene in women with pre-eclampsia and normal pregnancy; and its contribution to levels of plasma ET-1 and blood pressure. This was a retrospective study examining the frequency of the ET-1 Lys198Asn polymorphism in 72 proteinuric pre-eclamptics and 81 normal pregnant women. Height, weight, blood pressure and plasma ET-1 were measured antenatally and at 6 weeks post-partum. Using specific mutagenic primers, the frequency of the G/G (normal), G/T heterozygote and T/T (mutant) genotypes of the Lys198Asn polymorphism were examined. The polymorphism was not associated with pre-eclampsia. However, in the combined pregnant groups after correction for BMI and group, a significant effect of the T-allele (T/T,G/T) on systolic blood pressure was found (121 +/- 1.5 mmHg compared with 116 +/- 1.3 mmHg in the G/G homozygotes). A significant interaction was found between the T-allele and pregnancy in determining systolic blood pressure, so that the effect was no longer seen post-partum. Pregnant women with the T/T genotype had significantly elevated plasma ET-1 levels 5.8 pg/ml [confidence interval (CI) 3.7-9.1] compared with 3.1 pg/ml (CI 2.6-3.8) in the G/T heterozygotes and 3.6 pg/ml (CI 3.0-4.1) in the normal G/G homozygotes. The Lys198Asn polymorphism does not directly contribute to the incidence of pre-eclampsia. However, the association of the T-allele with raised blood pressure and the T/T genotype with increased plasma ET-1 levels suggest that this polymorphism may interact with other genes or environmental factors to sensitize pregnant women to develop pre-eclampsia.

The role of endothelin receptor antagonists in the treatment of chronic heart failure.

A role of the potent and long-acting vasoconstrictor peptide endothelin-1 in the pathophysiology of chronic human heart failure has been postulated based on indirect evidence such as elevated plasma endothelin-1 levels, their correlation with the degree of hemodynamic impairment, and their predictive value for patient survival. The advent of specific of endothelin-1 receptor antagonists has provided the opportunity to directly evaluate its pathophysiologic role and assess its potential role as a new approach to heart failure therapy. This review summarizes the evidence linking endothelin-1 to the pathophysiology of chronic heart failure, and analyzes the clinical results obtained thus far in patients during acute intravenous, and more prolonged, oral administration of endothelin-1-receptor antagonists.

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.

Blood endothelin-1 levels before and after carotid endoarterectomy for atherosclerotic stenosis

Background: Elevated plasma levels of endothelin-1 (ET-1) have been reported in advanced atherosclerosis. Further in vivo demonstration of cause-effect relationship between atherosclerotic lesion and high levels of ET-1 needs to be carried out. The aim of this study was to determine whether circulating levels of ET-1 are influenced by removing haemodynamically significant atherosclerotic stenosis in selected patients with mono or bilateral carotid atherosclerotic stenosis. Methods: Cubital venous ET-1-immunoreactive (IR) levels were measured in 20 patients: 11 (mean age±S.D. 63.1±5.36 years; range 53–70 years) were affected by monolateral, and nine patients (mean age±S.D. 64.7±9.8 years; range 52–78 years) by bilateral extracranial carotid artery atherosclerotic stenosis. ET-1-IR levels were evaluated before and 7 days after monolateral surgical endoarterectomy. Pre-surgery levels of ET-1-IR were compared with those obtained from 18 healthy younger volunteers (mean age±S.D. 27.8±2.7 years; range 20–50 years). Findings: The mean cubital venous levels of ET-1-IR in the atherosclerotic patients before endoarterectomy (mean±S.D. 4.50±3.35 pg/ml; range 1.28–10.66 pg/ml) were significantly higher than those observed in healthy subjects (mean±S.D. 0.641±0.137 pg/ml; range 0.36–1.02 pg/ml) ( P=0.000). The mean ET-1-IR level decreased significantly after endoarterectomy in the group of patients with monolateral stenosis (pre-surgery: mean±S.D. 4.35±3.11 pg/ml; range 1.28–10.66 pg/ml; post-surgery: mean±S.D. 3.05±2.94 pg/ml, range 0.28–8.86 pg/ml) ( P=0.005), but not in patients with bilateral extracranial carotid stenosis submitted to monolateral endoarterectomy (pre-surgery: mean±S.D. 4.77±3.79 pg/ml; range 2.18–10.3 pg/ml; post-surgery: mean±S.D. 4.60±3.70 pg/ml; range 2.20–11.10 pg/ml). Interpretation: The removal of a haemodynamically significant atherosclerotic vascular stenosis is associated with a decrease in the circulating ET-1-IR levels 7 days after surgery when haemodynamically significant atherosclerotic lesions are absent.

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.

Tissue-Specific Modulation of Endothelin Receptors in a Rat Model of Hypertension

Summary: Adenovirus gene transfer of endothelin-1 (ET-1) in rats causes a transient elevation of plasma ET-1 levels, leading to systemic hypertension. Our aim was to evaluate modulation of both ET receptor subtypes in this experimental model. Recombinant adenovirus encoding either the human preproendothelin-1 (Ad.CMV.ET-1) or β-galactosidase (Ad.CMV.β-gal) as control was injected systemically into rats. Elevated plasma ET-1 levels and systemic blood pressure were confirmed 96 h after viral administration. Competition binding studies were carried out using tissues from liver, heart, kidney and brain to measure affinities and receptor densities. In the liver, both ET receptor densities were significantly reduced in the Ad.CMV.ET-1 group. In the heart, only the endothelin-A-(ETA) receptor density was significantly reduced. In the kidney and brain, the density of the ET receptors did not differ from the control group. In all tissues studied, there was no change in affinities between the two groups. The tissue-specific modulation of ET receptors and the fine regulation of ETA-receptors in the heart support the suggested role of the ET system in the development of cardiovascular diseases.

Tissue-specific modulation of endothelin receptors in a rat model of hypertension.

Adenovirus gene transfer of endothelin-1 (ET-1) in rats causes a transient elevation of plasma ET-1 levels, leading to systemic hypertension. Our aim was to evaluate modulation of both ET receptor subtypes in this experimental model. Recombinant adenovirus encoding either the human preproendothelin-1 (Ad.CMV.ET-1) or beta-galactosidase (Ad.CMV.beta-gal) as control was injected systemically into rats. Elevated plasma ET-1 levels and systemic blood pressure were confirmed 96 h after viral administration. Competition binding studies were carried out using tissues from liver, heart, kidney and brain to measure affinities and receptor densities. In the liver, both ET receptor densities were significantly reduced in the Ad.CMV.ET-1 group. In the heart, only the endothelin-A- (ET(A)) receptor density was significantly reduced. In the kidney and brain, the density of the ET receptors did not differ from the control group. In all tissues studied, there was no change in affinities between the two groups. The tissue-specific modulation of ET receptors and the fine regulation of ET(A)-receptors in the heart support the suggested role of the ET system in the development of cardiovascular diseases.

Endothelin-1 is a candidate mediating intestinal dysmotility in patients with acute pancreatitis.

We studied whether gastrointestinal transit was disturbed during acute pancreatitis and attempted to identify which mechanisms might be involved in acute pancreatitis. Using a noninvasive hydrogen breath test to determine the orocecal transit time, 24 patients with the clinical diagnosis of acute pancreatitis were enrolled into the intestinal motility study. Orocecal transit time was measured twice in all patients: once at the acute stage and once at recovery. Blood was obtained to study amylase, lipase, C-reactive protein, erythrocyte sedimentation rate, and endothelin-1 and nitrate/nitrite levels. Orocecal transit times measured at the acute stage were significantly delayed compared with those at recovery (mean values +/- SEM, 130.0 +/- 9.0 vs 80.8 +/- 7.4 min, P < 0.001). Plasma endothelin-1 levels exhibited a positive correlation with orocecal transit times in the acute stage (r = 0.509, P = 0.011). The percentages of altered orocecal transit times also correlated with the percentages of altered plasma endothelin-1 levels (r = 0.751, P < 0.001). Plasma nitrate/nitrite levels significantly decreased at the acute stage compared with those at recovery (5.25 +/- 0.82 vs 10.20 +/- 1.24 microM, P < 0.05). We conclude that intestinal transit is delayed in patients with mild to moderate acute pancreatitis. Elevated plasma endothelin-1 levels in the acute stage may be one mechanism mediating intestinal dysmotility.

Elevated plasma endothelin-1 levels in sickle cell anemia: relationships to oxygen saturation and left ventricular hypertrophy.

Endothelin-1 (Et-1) is a vasoconstrictor produced by endothelial and vascular smooth muscle cells in response to hypoxia, which induces hypertrophy in cultured cardiac myocytes. We measured plasma Et-1 levels and left ventricular dimensions in 13 patients with sickle cell anemia (SCD) and in 12 African-American controls ages 16-29 years. Endothelin-1 concentrations are significantly higher in SCD subjects than controls (10.6 +/- 1.9 vs. 3.0 +/- 1.3 pmol/L). There was a negative correlation between oxygen saturation and Et-1 levels in SCD patients (r = -0.71, P = 0.01). SCD subjects have more dilated and hypertrophied hearts corrected for body surface area than controls as evidenced by significant increases in left ventricular end diastolic dimension (31 +/- 0.8 vs. 24 +/- 0.9 mm/m2, P < 0.001), left ventricular end systolic dimension (20 +/- 0.9 vs. 16 +/- 0.8 mm/m2, P = 0.002), left ventricular posterior wall thickness (5.0 +/- 0.1 vs. 4.0 +/- 0.1 mm/m2, P < 0.001), and left ventricular mass (125 +/- 7.2 vs. 69 +/- 5.1 g/m2, P < 0.001). The index of left ventricular function, the shortening fraction, was not different between groups (34 +/- 1.2% in SCD vs. 35 +/- 1.5% in controls). The correlation between left ventricular mass and levels of Et-1 in SCD subjects was not significant (r = 0.47, P = 0.121).

Prognostic value of plasma endothelin-1 in patients with chronic heart failure

Endothelin-1 is a potent vasoconstrictive and multifunctional peptide. Elevated concentrations have been reported in congestive heart failure. We hypothesized that the level of endothelin-1 in plasma is a prognostic marker in congestive heart failure. Plasma levels of endothelin-1 were measured by radioimmunoassay in 120 congestive heart failure patients with ischaemic or non-ischaemic cardiomyopathy (mean ejection fraction 28 +/- 11%, in New York Heart Association (NYHA) functional class I:21, class II 35, class III: 61, class IV: 3). During a median follow-up of 361 +/- 338 days, 14 cardiac deaths occurred. In the univariate Cox model, endothelin-1 was the most powerful prognostic marker among the variables tested (P = 0.0001). A multivariate model, including plasma atrial natriuretic peptide and noradrenaline, NYHA class, age, and echocardiographic left ventricular end-diastolic diameter index was highly predictive of mortality (P = 0.00008), but only endothelin-1 remained significantly associated with outcome (P = 0.02). Patients with plasma endothelin-1 > or = 5 pg. ml-1 had a higher mortality rate than those with endothelin-1 < 5 pg. ml-1 (21% vs 4%, P = 0.001). Our results suggest that elevated endothelin-1 plasma levels are associated with a poor prognosis and routine plasma endothelin-1 determination provides important prognostic information in mild to moderate heart failure.

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.

Elevated Levels of Plasma Endothelin-1, von Willebrand Factor, and Urinary Albumin Excretion in Three Relatives with Pseudoxanthoma Elasticum

Elevated Levels of Plasma Endothelin-1, von Willebrand Factor, and Urinary Albumin Excretion in Three Relatives with Pseudoxanthoma Elasticum

Endothelin-1 as one of the mediators of the interaction between endothelium and platelets in humans.

Endothelin-1 (ET-1) is an endothelium-derived peptide with multiple functions affecting the cardiovascular, renal, neuroendocrine, pulmonary and gastrointestinal system1,2. Elevated plasma levels of ET-1 were found in diseases associated with the activation of platelets, e.g. myocardial infarction, disseminated intravascular coagulation and diabetes. These findings prompted us to investigate the ET-1 effect on platelet aggregation in human whole blood and in platelet rich plasma (PRP).KeywordsPlatelet AggregationPlatelet Rich PlasmaDisseminate Intravascular CoagulationMaximal AggregationPlatelet Poor PlasmaThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Elevated levels of plasma endothelin-1 in young patients with pulmonary hypertension caused by congenital heart disease are decreased after successful surgical repair

R E F E R E N C E S 1. Hill PE. Complications of permanent transvenous car: diac pacing: a 14-year review of all transvenous pacemakers inserted at one community hospital. PACE Pacing Clin Electrophysiol 1987;10:564-70. 2. Ellis GL. Pacemaker twiddler's syndrome: a case report. Am J Emerg Med 1990;8:48-50. 3. Roberts JS, Wenger NK. Pacemaker twiddler's syndrome. Am J Cardiol 1989;63:1013-6. 4. Lal RB, Avery Rd. Aggressive pacemaker twiddler's syndrome: dislodgement of an active fixation ventricular pacing electrode. Chest 1990;97:756-7.

Inhibition of Thrombus Formation by Endothelin-1 in Canine Models of Arterial Thrombosis

The effect of endothelin-1 (ET-1) on thrombus formation in vivo was evaluated in two well-established canine models of coronary artery thrombosis. First, the possible antithrombotic effect of ET-1 was examined using the cyclic flow reduction (CFR) model of coronary artery stenosis, vascular endothelial cell and intimal smooth muscle cell injury, and periodic acute platelet thrombus formation. Using a rating system of 0 (no inhibition) to 3 (complete inhibition), ET-1 administration at 0.1, 0.5, and 1.0 microgram/kg, i.v. bolus, produced scores of 1.0 +/- 0.2 (n = 10), 1.8 +/- 0.4 (n = 8), and 2.1 +/- 0.3 (n = 7), respectively. ET-1 injection inhibited ex vivo platelet aggregation induced by ADP and U-46619 by 30-60%. When aspirin was administered at 5 mg/kg prior to ET-1 administration at 0.5 microgramoff, ET-1 produced a CFR rating of 2.7 +/- 0.2 (n = 6). However, higher dose aspirin (30 mg/kg, i.v.) significantly inhibited the antithrombotic effect of ET-1 (0.5 +/- 0.5, n = 4). The antithrombotic effect of ET-1 was also examined using an electrolytic injury model of arterial thrombosis. The time required to produce an occlusive thrombus during the experiments in which ET-1 was administered at 10 and 20 ng.kg-1.min-1 was 77 +/- 15 (p < 0.08) and 105 +/- 16 min (p < 0.05), respectively, compared to 44 +/- 5 min when vehicle was infused. Cardiovascular changes following occlusion were not significantly different between dogs given ET-1 and those given vehicle, suggesting that elevated plasma levels of ET-1 did not exacerbate the adverse effects of coronary occlusion. In addition, plasma ET-1 levels were elevated significantly after occlusion in the dogs given vehicle (from 7.4 to 12.4 pg/ml). Taken together, these date provide further evidence to support the notion that ET-1 release during ischemia may be involved in a protective mechanism that impeded thrombus formation in the stenosed coronary artery.

Lack of Effect of ET Antibody or SB 209670 on Endotoxin-Induced Renal Failure

Elevated plasma levels of endothelin-1 (ET-1) in patients with septic shock have implicated ET-1 in the vascular hypoperfusion and organ dysfunction, including renal failure, that occur in this condition. Administration of endotoxin to rats induces renal dysfunction characterized by increased blood urea nitrogen (BUN) and plasma creatinine (Cr) levels. Here, we have found that neither SB 209670 (an ETA and ETB receptor antagonist) nor an affinity-purified ET antibody blocked the endotoxin-induced changes in renal function, suggesting that ET-1 is not involved in the pathophysiology of endotoxin-induced renal dysfunction.