endothelin-1 and Acute-Disease

Multiple methods exist to model permanent and transient ischemia under anesthesia in animals, however most human strokes occur while conscious. The use of endothelin-1 as a vasoconstrictor applied to the perivascular surface of the middle cerebral artery is one of the only methods for inducing stroke in conscious animals. Here, we describe standard operating procedures for stereotaxic placement of an ET-1 guide probe above the middle cerebral artery, induction of stroke in conscious rats, predictive outcome scoring during stroke, and neurological behavioral tests that we use to monitor transient and continuing deficits. The inclusion of long term neurological assessment is of particular importance when taking into consideration the effects of stroke on brain remodeling.

Topics: Acute Disease; Animals; Brain; Consciousness; Disease Models, Animal; Endothelin-1; Humans; Rats; Stroke

After ascent to high altitude (≥2500 m), the inability of the human body to adapt to the hypobaric and hypoxia environment can induce tissue hypoxia, then a series of high altitude illnesses including acute mountain sickness (AMS), high altitude pulmonary edema (HAPE), and high altitude cerebral edema (HACE) would develop. Symptoms of AMS include headache, dizziness, nausea, and vomiting; HAPE is characterized by orthopnea, breathlessness at rest, cough, pink frothy sputum, and results in obvious pulmonary edema that poses significant harm to people; HACE is characterized by ataxia and decreased consciousness, leading to coma and brain herniation which would be fatal if not treated promptly. This review article provides a current understanding of the pathophysiology of these three forms of high altitude illness and elaborates the current prevention and treatment measures of these diseases.

Topics: Acetazolamide; Acute Disease; Altitude Sickness; Calcium Channel Blockers; Carbonic Anhydrase Inhibitors; Cytokines; Dexamethasone; Endothelin-1; Hemodynamics; Humans; Hypertension, Pulmonary; Inflammation Mediators; Nifedipine; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Pulmonary Alveoli; Sildenafil Citrate

Psychosocial factors (i.e., social environment and emotional factors) contribute to an increased risk of cardiovascular disease (CVD). Perturbation in a potent vasoconstrictive peptide endothelin (ET)-1 could be one of the mechanisms linking psychosocial factors to CVD. Our aim was to evaluate the literature on the relationship between plasma ET-1 and psychosocial risk factors for CVD.. MEDLINE and PsycINFO databases were searched for articles on human studies published in peer-reviewed English-language journals through September 2012.. Of the 20 studies that met the inclusion criteria, 14 were experimental studies of acute psychological/mental challenges and 6 were observational studies of psychological and social factors. The inferences drawn from this review were as follows: a) laboratory-induced acute psychological/mental stress may result in exaggerated plasma ET-1 release in those with CVD and those at risk for CVD (positive studies: 5/10); b) chronic/episodic psychosocial factors may have a positive relationship to plasma ET-1 (positive studies: 3/5); and c) race (African American), sex (male), and individual differences in autonomic and hemodynamic responses to stress (parasympathetic withdrawal and elevated blood pressure responsiveness) may moderate the relationship between psychosocial factors and plasma ET-1.. This review indicates that psychosocial risk factors for CVD are associated with elevated plasma ET-1; however, the relatively small number of studies, methodological differences, and variable assessment tools preclude definitive conclusions about the strength of the association. Specific suggestions regarding the selection of psychosocial factors, optimization of acute challenge protocols, and standardization of methods and timing of the ET-1 measures are provided.

Topics: Acute Disease; Blood Pressure; Cardiovascular Diseases; Endothelin-1; Humans; Research Design; Risk Factors; Social Class; Social Environment; Stress, Psychological; Vasoconstriction

Pulmonary vasoconstriction represents a physiological adaptive mechanism to high altitude. If exaggerated, however, it is associated with important morbidity and mortality. Recent mechanistic studies using short-term acute high altitude exposure have provided insight into the importance of defective vascular endothelial and respiratory epithelial nitric oxide (NO) synthesis, increased endothelin-1 bioavailability, and overactivation of the sympathetic nervous system in causing exaggerated hypoxic pulmonary hypertension in humans. Based on these studies, drugs that increase NO bioavailability, attenuate endothelin-1 induced pulmonary vasoconstriction, or prevent exaggerated sympathetic activation have been shown to be useful for the treatment/prevention of exaggerated pulmonary hypertension during acute short-term high altitude exposure. The mechanisms underpinning chronic pulmonary hypertension in high altitude dwellers are less well understood, but recent evidence suggests that they differ in some aspects from those involved in short-term adaptation to high altitude. These differences have consequences for the choice of the treatment for chronic pulmonary hypertension at high altitude. Finally, recent data indicate that fetal programming of pulmonary vascular dysfunction in offspring of preeclampsia and children generated by assisted reproductive technologies represents a novel and frequent cause of pulmonary hypertension at high altitude. In animal models of fetal programming of hypoxic pulmonary hypertension, epigenetic mechanisms play a role, and targeting of these mechanisms with drugs lowers pulmonary artery pressure. If epigenetic mechanisms also are operational in the fetal programming of pulmonary vascular dysfunction in humans, such drugs may become novel tools for the treatment of hypoxic pulmonary hypertension.

Topics: Acute Disease; Adaptation, Physiological; Altitude Sickness; Anti-Inflammatory Agents; Antihypertensive Agents; Biomarkers; Chronic Disease; Endothelin-1; Female; Fetal Development; Foramen Ovale, Patent; Humans; Hypertension, Pulmonary; Nitric Oxide; Oxidative Stress; Pre-Eclampsia; Pregnancy; Pulmonary Edema; Risk Factors; Sympathetic Nervous System; Vasodilator Agents

Although we have recently witnessed substantial progress in management and outcome of patients with chronic heart failure, acute heart failure (AHF) management and outcome have not changed over almost a generation. Vasodilators are one of the cornerstones of AHF management; however, to a large extent, none of those currently used has been examined by large, placebo-controlled, non-hemodynamic monitored, prospective randomized studies powered to assess the effects on outcomes, in addition to symptoms. In this article, we will discuss the role of vasodilators in AHF trying to point out which are the potentially best indications to their administration and which are the pitfalls which may be associated with their use. Unfortunately, most of this discussion is only partially evidence based due to lack of appropriate clinical trials. In general, we believe that vasodilators should be administered early to AHF patients with normal or high blood pressure (BP) at presentation. They should not be administered to patients with low BP since they may cause hypotension and hypoperfusion of vital organs, leading to renal and/or myocardial damage which may further worsen patients' outcome. It is not clear whether vasodilators have a role in either patients with borderline BP at presentation (i.e., low-normal) or beyond the first 1-2 days from presentation. Given the limitations of the currently available clinical trial data, we cannot recommend any specific agent as first line therapy, although nitrates in different formulations are still the most widely used in clinical practice.

Topics: Acute Disease; Atrial Natriuretic Factor; Benzoates; Elapid Venoms; Endothelin-1; Heart Failure; Humans; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nitrates; Peptide Fragments; Prognosis; Pyridines; Receptors, Endothelin; Relaxin; Tetrazoles; Vasoconstriction; Vasodilator Agents

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Acute Disease; Angioplasty, Balloon; Calcium Channel Blockers; Cell Membrane; Combined Modality Therapy; Endothelin-1; Hemoglobins; Humans; Muscle, Smooth, Vascular; Nicardipine; Nitric Oxide; Oxidative Stress; Subarachnoid Hemorrhage; Vasodilator Agents; Vasospasm, Intracranial; Verapamil

Pancreatic encephalopathy (PE) is a serious complication of severe acute pancreatitis (SAP). In recent years, more and more PE cases have been reported worldwide, and the onset PE in the early stage was regarded as a poor prognosis sign of SAP, but the pathogenesis of PE in SAP still has not been clarified in the past decade. The purpose of this review is to elucidate the possible pathogenesis of PE in SAP.. The English-language literature concerning PE in this review came from the Database of MEDLINE (period of 1991-2005), and the keywords of severe acute pancreatitis and pancreatic encephalopathy were used in the searching.. Many factors were involved in the pathogenesis of PE in SAP. Pancreatin activation, excessive release of cytokines and oxygen free radicals, microcirculation abnormalities of hemodynamic disturbance, ET-1/NO ratio, hypoxemia, bacterial infection, water and electrolyte imbalance, and vitamin B1 deficiency participated in the development of PE in SAP.. The pathogenesis of PE in SAP has not yet been fully understood. The development of PE in SAP may be a multi-factor process. To find out the possible inducing factor is essential to the clinical management of PE in SAP.

Topics: Acute Disease; Animals; Brain Diseases; Cytokines; Endothelin-1; Humans; Hypoxia; Nitric Oxide; Pancreatin; Pancreatitis; Thiamine Deficiency

Vascular damage caused by cerebral ischemia leads to edema, hemorrhage formation, and worsened outcomes in ischemic stroke patients. Therapeutic interventions need to be developed to provide vascular protection. The purpose of this review is to identify the pathophysiologic processes involved in vascular damage after ischemia, which may lead to strategies to provide vascular protection in ischemic stroke patients.. The pathologic processes caused by vascular injury after an occlusion of a cerebral artery can be separated into acute (hours), subacute (hours to days), and chronic (days to months). Targets for intervention can be identified for all 3 stages. Acutely, superoxide is the predominant mediator, followed by inflammatory mediators and proteases subacutely. In the chronic phase, proapoptotic gene products have been implicated.. Pharmacological agents designed to target specific pathologic and protective processes affecting the vasculature should be used in clinical trials of vascular protection after acute ischemic stroke.

Topics: Acute Disease; Angiopoietins; Angiotensin II; Antioxidants; Apoptosis; Blood-Brain Barrier; Brain Edema; Brain Ischemia; Cerebral Arteries; Cerebral Hemorrhage; Chronic Disease; Endothelin-1; Endothelium, Vascular; Humans; Inflammation Mediators; Matrix Metalloproteinases; Neuroprotective Agents; Neutrophils; Oxidative Stress; Reactive Oxygen Species; Vascular Endothelial Growth Factor A; Vasculitis

In the pulmonary circulation, a decrease in oxygen tension results in the development of hypoxic pulmonary vasoconstriction (HPV), although the exact mechanism by which HPV occurs remains unclear. Evidence gathered from many laboratories suggests that while pulmonary arterial smooth muscle cells (PASMCs) can sense and respond to changes in oxygen tension, full expression of HPV requires modulating influences from the endothelium. In this review, we propose a model of HPV, based on recent studies from our laboratory, in which endothelin-1 (ET-1), a vasoactive peptide released from the endothelium, plays a central role and discuss how this model may be involved in the long-term adaptation to hypoxia.

Topics: Acute Disease; Animals; Chronic Disease; Endothelin-1; Hypoxia; Pulmonary Circulation; Vasoconstriction

Endothelins are 21 amino acid peptides that are produced ubiquitously by vascular endothelial cells, smooth muscle cells, and other cells in different organs. Endothelins are secreted as big-endothelins that are converted to active proteins by the endothelin-converting enzyme. These peptides possess many biological activities, such as vasoconstriction and mitogenesis, and are involved in numerous physiological and pathophysiological processes in humans. Elevated plasma levels of endothelin have been associated with heart failure, and increased immunoreactivity for endothelin is observed in transplant coronary artery disease. In this brief review, we will discuss the regulation of endothelin in cardiac transplantation and the pathological role this peptide plays in renal impairment, systemic hypertension, graft rejection and arteriosclerosis after heart transplantation.

Topics: Acute Disease; Animals; Aspartic Acid Endopeptidases; Cells, Cultured; Coronary Artery Disease; Endothelin-1; Endothelin-Converting Enzymes; Endothelium, Vascular; Graft Rejection; Heart Transplantation; Humans; Metalloendopeptidases; Muscle, Smooth, Vascular; Transplantation, Homologous; Up-Regulation

Nitric oxide plays a pivotal role in regulating vascular tone. Different studies show endothelial function is impaired during hyperglycemia. Dark chocolate increases flow-mediated dilation in healthy and hypertensive subjects with and without glucose intolerance; however, the effect of pretreatment with dark chocolate on endothelial function and other vascular responses to hyperglycemia has not been examined. Therefore, we aimed to investigate the effects of flavanol-rich dark chocolate administration on (1) flow-mediated dilation and wave reflections; (2) blood pressure, endothelin-1 and oxidative stress, before and after oral glucose tolerance test (OGTT). Twelve healthy volunteers (5 males, 28.2±2.7 years) randomly received either 100 g/d dark chocolate or flavanol-free white chocolate for 3 days. After 7 days washout period, volunteers were switched to the other treatment. Flow-mediated dilation, stiffness index, reflection index, peak-to-peak time, blood pressure, endothelin-1 and 8-iso-PGF(2α) were evaluated after each treatment phase and OGTT. Compared with white chocolate, dark chocolate ingestion improved flow-mediated dilation (P=0.03), wave reflections, endothelin-1 and 8-iso-PGF(2α) (P<0.05). After white chocolate ingestion, flow-mediated dilation was reduced after OGTT from 7.88±0.68 to 6.07±0.76 (P=0.027), 6.74±0.51 (P=0.046) at 1 and 2 h after the glucose load, respectively. Similarly, after white chocolate but not after dark chocolate, wave reflections, blood pressure, and endothelin-1 and 8-iso-PGF(2α) increased after OGTT. OGTT causes acute, transient impairment of endothelial function and oxidative stress, which is attenuated by flavanol-rich dark chocolate. These results suggest cocoa flavanols may contribute to vascular health by reducing the postprandial impairment of arterial function associated with the pathogenesis of atherosclerosis.

Topics: Acute Disease; Adult; Blood Pressure; Cacao; Dinoprost; Endothelin-1; Endothelium, Vascular; Female; Flavanones; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin Resistance; Insulin-Secreting Cells; Male; Pulse Wave Analysis

We sought to determine the influence of sildenafil on the diffusing capacity of the lungs for carbon monoxide (DLCO) and the components of DLCO (pulmonary capillary blood volume VC, and alveolar-capillary membrane conductance DM) at rest and following exercise with normoxia and hypoxia. This double-blind placebo-controlled, cross-over study included 14 healthy subjects (age = 33 +/- 11 years, ht = 181 +/- 8 cm, weight = 85 +/- 14 kg, BMI = 26 +/- 3 kg/m2, peak normoxic VO2 = 36 +/- 6 ml/kg, mean +/- SD). Subjects were randomized to placebo or 100 mg sildenafil 1 h prior to entering a hypoxic tent with an FiO2 of 12.5% for 90 min. DLCO, VC, and DM were assessed at rest, every 3 min during exercise, at peak exercise, and 10 and 30 min post exercise. Sildenafil attenuated the elevation in PAP at rest and during recovery with exposure to hypoxia, but pulmonary arterial pressure immediately post exercise was not different between sildenafil and placebo. Systemic 02 saturation and VO2peak did not differ between the two conditions. DLCO was not different between groups at any time point. VC was higher with exercise in the placebo group, and the difference in DM between sildenafil and placebo was significant only when corrected for changes in VC (DM/VC = 0.57 +/- 0.29 vs. 0.41 +/- 0.16, P = 0.04). These results suggest no effect of sildenafil on DLCO, but an improvement in DM when corrected for changes in VC during short-term hypoxic exposure with exercise.

Topics: Acute Disease; Adult; Capillaries; Cross-Over Studies; Cyclic GMP; Double-Blind Method; Endothelin-1; Exercise; Female; Heart Rate; Humans; Hypoxia; Male; Natriuretic Peptide, Brain; Oxygen; Piperazines; Pulmonary Alveoli; Pulmonary Circulation; Pulmonary Gas Exchange; Purines; Rest; Sildenafil Citrate; Stroke Volume; Sulfones; Vasodilator Agents

The degree of pulmonary hypertension in healthy subjects exposed to acute hypobaric hypoxia at high altitude was found to be related to increased plasma endothelin (ET)-1. The aim of the present study was to investigate the effects of ET-1 antagonism on pulmonary hypertension, renal water, and sodium balance under acute and prolonged exposure to high-altitude-associated hypoxia.. In a double-blind fashion, healthy volunteers were randomly assigned to receive bosentan (62.5 mg for 1 day and 125 mg for the following 2 days; n=10) or placebo (n=10) at sea level and after rapid ascent to high altitude (4559 m). At sea level, bosentan did not induce any significant changes in hemodynamic or renal parameters. At altitude, bosentan induced a significant reduction of systolic pulmonary artery pressure (21+/-7 versus 31+/-7 mm Hg, P<0.03) and a mild increase in arterial oxygen saturation versus placebo after just 1 day of treatment. However, both urinary volume and free water clearance (H2OCl/glomerular filtration rate) were significantly reduced versus placebo after 2 days of ET-1 antagonism (1100+/-200 versus 1610+/-590 mL; -6.7+/-3.5 versus -1.8+/-4.8 mL/min, P<0.05 versus placebo for both). Sodium clearance and segmental tubular function were not significantly affected by bosentan administration.. The present results indicate that the early beneficial effect of ET-1 antagonism on pulmonary blood pressure is followed by an impairment in volume adaptation. These findings must be considered for the prevention and treatment of acute mountain sickness.

Topics: Acute Disease; Adaptation, Physiological; Adult; Altitude; Altitude Sickness; Arginine Vasopressin; Bosentan; Creatinine; Diuresis; Double-Blind Method; Endothelin Receptor Antagonists; Endothelin-1; Female; Glomerular Filtration Rate; Humans; Hypertension, Pulmonary; Hypoxia; Kidney; Kidney Diseases; Male; Middle Aged; Muscle, Smooth, Vascular; Osmolar Concentration; Oxygen; Potassium Channels, Voltage-Gated; Pulmonary Artery; Pulmonary Edema; Receptors, Endothelin; Sulfonamides; Vasoconstriction

For almost 50 years it has been known that hemolysed blood can increase blood pressure. Although preclinical studies suggest that this pressor response is due to an interaction of hemoglobin with endothelium-derived vasoactive substances, its mechanism in humans is unknown. We investigated the involvement of endothelin-1 in the blood pressure response to the oxygen carrier diaspirin cross-linked hemoglobin (DCLHb) in stroke patients.. In a randomized phase II study, increasing doses of DCLHb (25, 50 and 100 mg/kg, n=8, 8 and 11, respectively) or placebo (n=26) were infused intravenously every 6 h for 72 h to patients with an acute ischemic stroke. Blood pressure and heart rate were measured every 15 min and plasma concentrations of endothelin-1, catecholamines, renin, vasopressin and atrial natriuretic peptide were measured before and 24 and 66 h after the start of the infusions.. In the placebo group, mean arterial pressure (MAP) was 112 (109-115) mmHg (mean and 95% confidence interval) at baseline and decreased spontaneously by 11.4 (5.4-17.5) and 12.5 (5.4-19.5) mmHg after 24 and 66 h, respectively. This decrease in MAP was attenuated in patients treated with DCLHb, reaching statistical significance in the highest dose group. The plasma endothelin-1 concentration decreased slightly in the placebo group, from 4.2 (3.1-5.3) pg/ml (median and range) at baseline to 2.4 (1.9-3.7) pg/ml after 24 h (P=0.0044) and 2.8 (1.9-3.7) pg/ml after 66 h (P=0.0042), but increased dose-dependently in response to DCLHb infusion. With the highest dose of DCLHb, the plasma endothelin-1 concentration rose from 4.8 (0.1-7.8) pg/ml at baseline to 21.2 (13.4-53.2) pg/ml after 24 h (P< 0.001) and to 27.6 (11.9-47.8) pg/ml after 66 h (P< 0.001). The increases in the plasma endothelin-1 concentration and in MAP were correlated (r=0.30, P=0.02). Other vasoactive hormones were not affected by the DCLHb infusion.. Infusion of DCLHb in patients with acute ischemic stroke was associated with a dose-dependent increase in plasma endothelin-1 concentration. This may underlie the attenuation by DCLHb of the natural decrease in blood pressure that we observed in these patients.

Topics: Acute Disease; Aged; Aspirin; Blood Pressure; Blood Substitutes; Brain Ischemia; Dose-Response Relationship, Drug; Endothelin-1; Female; Follow-Up Studies; Hemoglobins; Humans; Infusions, Intravenous; Male; Middle Aged; Safety

The renin-angiotensin system is activated in acute severe asthma. The precise mechanism of activation is at present unknown, but may involve, beta2-agonists, catecholamines or proteases released in airway inflammation. This study aims to identify potential factors involved in the activation of the renin-angiotensin system in acute asthma. Forty asthmatics with severe exacerbations of asthma, assessed by measurement of peak expiratory flow rate (mean (SD) 35 (18)% predicted), oxygen saturation (94 (4)%) and pulse rate (108 (16) beats x min(-1)) were recruited. Nineteen (48%) asthmatics had elevated plasma angiotensin II levels (median (interquartile range) 10.9 (4.3-23.5) pg x mL(-1) (normal range 3-12 pg x mL(-1))) and 10 (25%) had elevated plasma renin concentration (22.0 (10.0-50.0) microU x mL(-1) (normal range 9-50 microU x mL(-1))). Plasma renin and angiotensin II correlated strongly, implying renin-dependent angiotensin II formation. No correlation was found between plasma salbutamol, adrenaline, nor-adrenaline, endothelin-1, histamine, eosinophilic cationic protein, serum angio-tensin-converting enzyme (ACE) activity, total immunoglobulin E (IgE), urea and electrolytes, indicators of the severity of the attack, atopic status, blood pressure and renin or angiotensin II levels. We conclude that although a subpopulation of asthmatics appear to have raised renin and angiotensin II during attacks of acute, severe asthma, the mechanism of activation of the renin-angiotensin system remains unclear.

Topics: Acute Disease; Adolescent; Adult; Angiotensin II; Asthma; Catecholamines; Endothelin-1; Female; Forced Expiratory Volume; Heart Rate; Humans; Male; Middle Aged; Oxygen Consumption; Peak Expiratory Flow Rate; Peptidyl-Dipeptidase A; Renin; Renin-Angiotensin System; Sensitivity and Specificity; Severity of Illness Index

Acute mountain sickness (AMS) is caused by rapid ascent to altitude (>2500 m) and remains a poorly understood pathophysiological condition. Accordingly, we investigated the relationship between acute exposure to high altitude and hypoxia related biochemical proteins. 21 healthy subjects (Female (8) and male (13), Age: 36.7±8.5, BMI: 23.2±3.1) volunteers participated in this project and fasting blood samples were taken before (sea level) and after 1 and 24-h exposure to high altitude (3,550 m). Blood oxygen saturation (SpO2), AMS status (Lake Louise Score) and serum HIF-1, Endothelin-1, VEGF and Orexin-A were measured (via ELISA) at 1, 6 and 24 h after exposure to high altitude. Pre-ascent measurement of hypoxia related proteins (Orexin-A, HIF-1, VEGF and Endothelin-1) where all significantly (<0.05) higher in the AMS-resistant individuals (No-AMS) when compared to AMS susceptible individuals (AMS+). Upon ascent to high altitude, 11 out of 21 volunteers had AMS (10.1±0.6 in AMS+ vs. 0.9±0.6 in No-AMS, P<0.05) and presented with lower resting SpO2 levels (77.7±0.4 vs. 83.5±0.3 respectively, p<0.05). Orexin-A, HIF-1, VEGF and Endothelin-1, significantly increased 24 hrs after exposure to high altitude in both AMS+ and No-AMS. The response of Orexin-A was similar between two groups, also, HIF-1 elevation 24 hrs after exposure to altitude was more in AMS+ (13% vs. 19%), but the increase of VEGF and Endothelin-1, 1 and 24 hrs after exposure to altitude in No-AMS was double that of AMS+. Hypoxia related proteins include Orexin-A, HIF-1, VEGF and Endothelin-1 may play a pathophysiological role in those who are susceptible to AMS.

Topics: Acute Disease; Adult; Altitude; Altitude Sickness; Endothelin-1; Female; Hormones; Humans; Hypoxia; Male; Middle Aged; Orexins; Vascular Endothelial Growth Factor A

The aim of the study was to provide a theoretical basis for the early diagnosis and prediction of acute altitude sickness, to provide a better entry mode for healthy people from plain areas to plateau areas, and to preliminarily clarify the possible mechanism of this approach.. We measured endothelin-1 (ET-1), asymmetric dimethylarginine (ADMA), vascular endothelial growth factor (VEGF), nitric oxide (NO), and hypoxia-inducible factor 1 (HIF-1) levels in each sample and determined flow-mediated dilation (FMD) values using a portable OMRON color Doppler with a 7.0- to 12.0-MHz linear array probe. We used the Lewis Lake score to diagnose acute mountain sickness (AMS) and to stratify the disease severity.. We found no cases of AMS at any of the studied elevation gradients. We found significant differences in FMD values between individuals when at 400 m above sea level and when at 2200, 3200, and 4200 m above sea level (P < .05) but found no significant differences among those at 2200, 3200, and 4200 m. Our variance analysis showed that serum ET-1, VEGF, ADMA, NO, and HIF-1 levels in individuals at ≥3000 m and those at subplateau and plain areas (<3000 m) significantly differed (P < .05). The level of these factors also significantly differed between individuals at elevation gradients of plateau areas (3260 m vs 4270 m) (P < .05). We found no significant differences in serum ET-1, VEGF, and ADMA levels between individuals at the plateau (2260 m) and plain (400 m) areas (P > .05). NO and HIF-1 levels were significantly different in serum samples from individuals between the plateau (2260 m) and plain (400 m) areas (P < .05). However, with increasing altitude, the NO level gradually increased, whereas ET-1, ADMA, VEGF, and HIF-1 levels showed a decreasing trend. With the increase of altitude, there is no correlation between the trend of FMD and hematologic-related factors such as VEGF, NO, and HIF-1.. A healthy young male population ascending to a high-altitude area experiences a low incidence of AMS. Entering an acute plateau exposure environment from different altitude gradients may weaken the effect of acute highland exposure on vascular endothelial dysfunction in healthy individuals. Changes in serum ET-1, VEGF, ADMA, NO, and HIF-1 levels in healthy young men may be related to the body's self-regulation and protect healthy individuals from AMS. A short stay in a subplateau region may initiate an oxygen-free preconditioning process in healthy individuals, thereby protecting them from AMS. Noninvasive brachial artery endothelial function test instead of the detection of invasive hematologic-related factors for early diagnosis and prediction of the occurrence and severity of acute high-altitude disease is still lack of sufficient theoretical basis.

Topics: Acute Disease; Adult; Altitude; Altitude Sickness; Analysis of Variance; Biomarkers; China; Early Diagnosis; Endothelin-1; Healthy Volunteers; Humans; Hypoxia-Inducible Factor 1; Male; Military Personnel; Nitric Oxide; Reference Values; Sensitivity and Specificity; Vascular Endothelial Growth Factor A; Young Adult

Previous investigations have indicated that environmental and genetic factors collectively contribute to the development of acute mountain sickness (AMS), but whether the EDN1 gene is involved in AMS remains to be elucidated. A total of 356 healthy male soldiers who had not traveled to high altitudes in the previous 12 months were enrolled in our study. All participants were taken by plane from 500 m (Chengdu in Sichuan Province) to a 3700 m highland (Lhasa) within 2 hours. Clinical data were collected within 24 hours, and pulmonary function parameters were completed simultaneously. Genotypes were obtained by using iMLDR genotyping assays. A total of 237 soldiers (66.57%) presented AMS symptoms, including headache, dizziness, gastrointestinal upset and fatigue. Soldiers with AMS showed an increase in heart rate (HR), plasma tryptophan and serotonin, and a decrease in SaO2, FEV1, PEF, FVC, V75, V50, V25 and MMF (all P < 0.01). Notably, allele T in single nucleotide polymorphism (SNP) rs2070699 showed a positive correlation with the occurrence of AMS. A general linear regression analysis showed that rs2060799, Mean Arterial Pressure (MAP), SaO2, FVC, tryptophan and serotonin were independent predictors for the occurrence of AMS. Importantly, the area under the curve (AUC) values for tryptophan (0.998), serotonin (0.912) and FVC (0.86) had diagnostic specificity and sensitivity. Our results demonstrated that AMS is accompanied by changes in lung function parameters, increased plasma tryptophan and serotonin levels, and that the EDN1 polymorphism is a potential risk factor for AMS.

Topics: Acute Disease; Adult; Altitude; Altitude Sickness; Area Under Curve; Arterial Pressure; Endothelin-1; Heart Rate; Humans; Lung; Male; Oxygen; Risk Factors; Young Adult

Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allografts, non-anti-HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed.. We conducted a nationwide study to identify kidney transplant recipients without anti-HLA donor-specific Abs who experienced acute graft dysfunction within 3 months after transplantation and showed evidence of microvascular injury, called acute microvascular rejection (AMVR). We developed a crossmatch assay to assess serum reactivity to human microvascular endothelial cells, and used a combination of transcriptomic and proteomic approaches to identify non-HLA Abs.. We identified a highly selected cohort of 38 patients with early acute AMVR. Biopsy specimens revealed intense microvascular inflammation and the presence of vasculitis (in 60.5%), interstitial hemorrhages (31.6%), or thrombotic microangiopathy (15.8%). Serum samples collected at the time of transplant showed that previously proposed anti-endothelial cell Abs-angiotensin type 1 receptor (AT1R), endothelin-1 type A and natural polyreactive Abs-did not increase significantly among patients with AMVR compared with a control group of stable kidney transplant recipients. However, 26% of the tested AMVR samples were positive for AT1R Abs when a threshold of 10 IU/ml was used. The crossmatch assay identified a common IgG response that was specifically directed against constitutively expressed antigens of microvascular glomerular cells in patients with AMVR. Transcriptomic and proteomic analyses identified new targets of non-HLA Abs, with little redundancy among individuals.. Our findings indicate that preformed IgG Abs targeting non-HLA antigens expressed on glomerular endothelial cells are associated with early AMVR, and that

Topics: Acute Disease; Adult; Aged; Endothelial Cells; Endothelin-1; Female; Graft Rejection; Hemorrhage; Humans; Immunoglobulin G; Kidney Glomerulus; Kidney Transplantation; Male; Microvessels; Middle Aged; Receptor, Angiotensin, Type 1; Thrombotic Microangiopathies; Time Factors; Vasculitis

The anti-inflammatory and cardioprotective properties of curcumin (Cur), a natural polyphenolic flavonoid isolated from the rhizomes of Curcuma longa, are increasingly considered to have beneficial effects on the progression of Chagas heart disease, caused by the protozoan parasite Trypanosoma cruzi.. To evaluate the effects of oral therapy with Cur on T. cruzi-mediated cardiovasculopathy in acutely infected mice and analyse the in vitro response of parasite-infected human microvascular endothelial cells treated with this phytochemical.. Inflammation of heart vessels from Cur-treated and untreated infected mice were analysed by histology, with benznidazole (Bz) as the reference compound. Parasitaemia was monitored by the direct method. Capillary permeability was visualised by Evans-blue assay. Myocardial ET-1, IL-6, and TNF-α mRNA expressions were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Microvascular endothelial HMEC-1 cells were infected in vitro with or without addition of Cur or Bz. Induction of the Ca2+/NFAT pathway was assessed by fluorometry, immunoblotting, and reporter assay.. Oral Cur therapy of recently infected mice reduced inflammatory cell infiltration of myocardial arteries without lowering parasite levels. Compared to that of the phosphate-buffered saline-receiving group, hearts from Cur-treated mice showed significantly decreased vessel inflammation scores (p < 0.001), vascular permeabilities (p < 0.001), and levels of IL-6/TNF-α (p < 0.01) and ET-1 (p < 0.05) mRNA. Moreover, Cur significantly (p < 0.05 for transcript; p < 0.01 for peptide) downregulated ET-1 secretion from infected HMEC-1 cells. Remarkably, Cur addition significantly (p < 0.05 at 27.0 μM) interfered with T. cruzi-dependent activation of the Ca2+/NFATc1 signalling pathway that promotes generation of inflammatory agents in HMEC-1 cells.. Oral treatment with Cur dampens cardiovasculopathy in acute Chagas mice. Cur impairs the Ca2+/NFATc1-regulated release of ET-1 from T. cruzi-infected vascular endothelium. These findings identify new perspectives for exploring the potential of Cur-based interventions to ameliorate Chagas heart disease.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Capillary Permeability; Cells, Cultured; Chagas Cardiomyopathy; Curcumin; Disease Progression; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Fluorescent Dyes; Interleukin-6; Male; Mice, Inbred C57BL; NFATC Transcription Factors; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Trypanosoma cruzi; Tumor Necrosis Factor-alpha

To investigate changes in the plasma concentrations of cardiac troponin I (CTnI), thromboxane A2 (TXA2), prostaglandin I2 (PGI2) and endothelin-1 (ET-1) in rabbits with massive pulmonary embolism (AMPE) and the impact of nitric oxide inhalation (NOI) on these indices.. A total of 30 Japanese rabbits were used to construct an MPE model and were divided into 3 groups equally (n=10), including an EXP group (undergoing modeling alone), an NOI group (receiving NOI 2 h post-modeling) and a CON group (receiving intravenous physiological saline).. In the model group, plasma concentration of CTnI peaked at 16 h following modeling (0.46±0.10 µg/ml) and significantly decreased following NOI. Plasma levels of TXB2, PGI2 and ET-1 peaked at 12, 16 and 8 h following modeling, respectively, and significantly decreased at different time points (0, 2, 4, 8, 12, 16, 20 and 24 h) following NOI. A significant correlation was observed between the peak plasma CTnI concentration and peak TXB2, 6-keto prostaglandin F1α and ET-1 concentrations in the model and NOI groups.. Increases in plasma TXA2, PGI2 and ET-1 levels causes myocardial damage in a rabbit model of AMPE; however, NOI effectively down regulates the plasma concentration of these molecules to produce a myocardial-protective effect.

Topics: Acute Disease; Administration, Inhalation; Animals; Bronchodilator Agents; Down-Regulation; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Epoprostenol; Female; Male; Nitric Oxide; Pulmonary Embolism; Rabbits; Random Allocation; Reference Values; Reproducibility of Results; Thromboxane A2; Time Factors; Treatment Outcome; Troponin I

Acute dyspnea is a frequent complaint in patients attending the emergency department (ED).. To evaluate the accuracy of PCT, MR-proANP, MR-proADM, copeptin and CT-proET1 for the risk-stratification of severe acute dyspnea patients presenting to the ED.. Multicenter prospective study in adult patients with a chief complaint of acute dyspnea. Pro-hormone type biomarkers concentrations were measured on arrival. Combined primary endpoint was a poor outcome.. Three hundred and ninety-four patients were included, 137 (35%) met the primary endpoint. MR-proADM was the only biomarker associated with the primary endpoint (odds ratio 1.43 [95%CI: 1.13-1.82], p = 0.003) as were the presence of paradoxical abdominal breathing (odds ratio 2.48 [95%CI: 1.31-4.68]) or cyanosis (odds ratio 3.18 [1.46-6.89]) Conclusions: In patients with severe acute dyspnea in the ED, pro-hormone type biomarkers measurements have a low added value to clinical signs for the prediction of poor outcome.

Topics: Acute Disease; Adrenomedullin; Atrial Natriuretic Factor; Biomarkers; Calcitonin; Dyspnea; Emergency Service, Hospital; Endothelin-1; Glycopeptides; Hormones; Humans; Peptide Fragments; Prognosis; Prospective Studies; Severity of Illness Index

Hypercalcaemia can occur under various pathological conditions, such as primary hyperparathyroidism, malignancy or granulomatosis, and it induces natriuresis and polyuria in various species via an unknown mechanism. A previous study demonstrated that hypercalcaemia induced by vitamin D in rats increased endothelin (ET)-1 expression in the distal nephron, which suggests the involvement of the ET system in hypercalcaemia-induced effects. In the present study, we demonstrate that, during vitamin D-induced hypercalcaemia, the activation of ET system by increased ET-1 is responsible for natriuresis but not for polyuria. Vitamin D-treated hypercalcaemic mice showed a blunted response to amiloride, suggesting that epithelial sodium channel function is inhibited. We have identified an original pathway that specifically mediates the effects of vitamin D-induced hypercalcaemia on sodium handling in the distal nephron without affecting water handling.. Acute hypercalcaemia increases urinary sodium and water excretion; however, the underlying molecular mechanism remains unclear. Because vitamin D-induced hypercalcaemia increases the renal expression of endothelin (ET)-1, we hypothesized that ET-1 mediates the effects of hypercalcaemia on renal sodium and water handling. Hypercalcaemia was induced in 8-week-old, parathyroid hormone-supplemented, male mice by oral administration of dihydrotachysterol (DHT) for 3 days. DHT-treated mice became hypercalcaemic and displayed increased urinary water and sodium excretion compared to controls. mRNA levels of ET-1 and the transcription factors CCAAT-enhancer binding protein β and δ were specifically increased in the distal convoluted tubule and downstream segments in DHT-treated mice. To examine the role of the ET system in hypercalcaemia-induced natriuresis and polyuria, mice were treated with the ET-1 receptor antagonist macitentan, with or without DHT. Mice treated with both macitentan and DHT displayed hypercalcaemia and polyuria similar to that in mice treated with DHT alone; however, no increase in urinary sodium excretion was observed. To identify the affected sodium transport mechanism, we assessed the response to various diuretics in control and DHT-treated hypercalcaemic mice. Amiloride, an inhibitor of the epithelial sodium channel (ENaC), increased sodium excretion to a lesser extent in DHT-treated mice compared to control mice. Mice treated with either macitentan+DHT or macitentan alone had a similar response to amiloride. In summary, vitamin D-induced hypercalcaemia increases the renal production of ET-1 and decreases ENaC activity, which is probably responsible for the rise in urinary sodium excretion but not for polyuria.

Topics: Acute Disease; Animals; Cell Line, Transformed; Endothelin-1; Hypercalcemia; Kidney Tubules; Male; Mice; Mice, Inbred C57BL; Natriuresis; Polyuria; Vitamin D

The purpose of this study was to investigate the correlation between flow-mediated dilatation of the brachial artery and serum endothelial biomarkers and to discuss the feasibility of sonographic evaluation of acute endothelial injury during cardiopulmonary bypass (CPB) surgery.. Sonography was applied to determine the percentage of change in the brachial artery size during flow-mediated dilatation. Meanwhile, the plasma concentrations of endothelial-derived biomarkers, such as endothelin 1, nitric oxide, and von Willebrand factor, were measured to monitor the changes in endothelial function. We analyzed the correlation between flow-mediated dilatation and biomarkers during the perioperative period of CPB in 27 patients.. All of the biomarkers changed dramatically, especially during the CPB period. There was a negative correlation between flow-mediated dilatation and von Willebrand factor (P = .001; R = -0.31).. A CPB event has a substantial impact on endothelial function, and sonographic assessment of the percentage of change in the brachial artery size during flow-mediated dilatation allows early detection of acute endothelial function injury in cardiac surgery.

Topics: Acute Disease; Biomarkers; Blood Flow Velocity; Brachial Artery; Cardiopulmonary Bypass; Endothelin-1; Endothelium, Vascular; Feasibility Studies; Female; Humans; Male; Middle Aged; Nitric Oxide; Ultrasonography; von Willebrand Factor

Endothelin-1 (ET-1) is an endogenous vasoconstrictor implicated in pulmonary and systemic hypertension, as well as ventricular dysfunction, through effects on vascular smooth muscle, the kidneys, and cardiomyocytes. We aimed to determine the association between serial ET-1 levels and acute heart failure patient outcomes.. We measured plasma ET-1 at baseline, 48-72 h, and 30 days in a cohort of 872 patients hospitalized with acute heart failure from the ASCEND-HF trial (randomized to nesiritide vs. placebo), and its association with 30-day mortality, 180-day mortality, in-hospital death or worsening heart failure, and 30-day mortality or rehospitalization. Median ET-1 was 7.6 [interquartile range (IQR) 5.9-10] pg/mL at baseline, 6.3 (IQR 4.9-8.1) pg/mL at 48-72 h, and 5.9 (IQR 4.7-7.9) pg/mL at 30 days (P < 0.001). Baseline and 48-72 h ET-1 were found to be independently associated with 180-day mortality in a multivariable analysis [hazard ratio (HR) 1.6, 95% confidence interval (CI) 1.3-2.0, P < 0.001 and HR 1.5, 95% CI 1.2-1.9, P = 0.001, respectively, log-transformed]. ET-1 that was measured at 48-72 h was also independently associated with death or worsening heart failure prior to discharge [odds ratio (OR) 1.6, 95% CI 1.03-2.4, P = 0.03]. These independent associations remained significant after including NT-proBNP in the multivariable analysis.. We observed an independent association between elevated ET-1 and short-term in-hospital clinical outcomes and 180-day mortality in hospitalized patients with acute heart failure ET-1 provided additional prognostic information which was incremental to that yielded by NT-proBNP.

Topics: Acute Disease; Aged; Biomarkers; Endothelin-1; Female; Heart Failure; Hospital Mortality; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Randomized Controlled Trials as Topic

Hypoxia induces an inflammatory response, which is enhanced by exercise. High altitude (HA) leads to endothelial activation and may be proinflammatory. The relationship between endothelial activation, inflammation, and acute mountain sickness (AMS) and its severity has never been examined.. Forty-eight trekkers were studied during a progressive trek at 3833, 4450, and 5129 m at rest postascent (exercise), and then again at rest 24 hours later. Twenty of the subjects were also tested at rest pre- and postexercise at sea level (SL) at 6 weeks preascent. We examined plasma levels of the interleukin 6 (IL-6), 17a (IL-17a), and endothelin-1 (ET-1) along with oxygen saturation (SpO2) and Lake Louise scores (LLS).. ET-1 (5.7 ± 2.1 vs. 4.3 ± 1.9 pg/mL; p < 0.001), IL-6 (3.3 ± 3.3 vs. 2.4 ± 2.3 pg/mL; p = 0.007), and IL-17a (1.3 ± 3.0 vs. 0.46 ± 0.4 pg/mL; p < 0.001) were all overall significantly higher at HA versus SL. There was a paired increase in ET-1 and IL-6 with exercise versus rest at SL, 3833, 4450, and 5129 m (p < 0.05). There was a negative correlation between LLS and SpO2 (r = -0.32; 95% confidence interval [CI] -0.21 to -0.42; p < 0.001) and a positive correlation between LLS and IL-6 (r = 0.16; 0.0-0.27; p = 0.007) and ET-1 levels (r = 0.29; 0.18-0.39; p < 0.001. Altitude, ET-1, IL-6, and SpO2 were all univariate predictors of AMS. On multivariate analysis, ET-1 (p = 0.002) and reducing SpO2 (p = 0.02) remained as the only independent predictors (overall r(2) = 0.16; p < 0.001) of AMS. ET-1 (p = 03) and SpO2 were (p = 0.01) also independent predictors of severe AMS (overall r(2) = 0.19; p < 0.001).. HA leads to endothelial activation and an inflammatory response. The rise in ET-1 and IL-6 is heavily influenced by the degree of exercise and hypoxia. ET-1 is an independent predictor of both AMS and its severity.

Topics: Acute Disease; Adult; Altitude; Altitude Sickness; Bolivia; Case-Control Studies; Endothelin-1; Female; Healthy Volunteers; Humans; Interleukin-17; Interleukin-6; Male; Middle Aged; Mountaineering; Rest

The role of endothelium in the progression of atheromasic disease has already been demonstrated. Endothelin-1 (ET-1) is released from endothelial cells during acute and chronic vascular damage and it appears to be the strongest vasoconstrictor agent known.The aim of this study is to investigate the amount of endothelial damage in patients with unstable angina (UA), as defined by serum levels of ET-1, to verify a possible correlation with increased ischaemic damage by evaluation of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and interleukin 8 (IL-8) levels.Serum levels of ET-1, IL-8 and NT-proBNP obtained from 10 patients affected by low-risk UA were compared to those belonging to eight healthy subjects. In order to compare the laboratory data pertaining to the two populations, a Student's t-test and a Mann-Whitney U test were performed.Levels of ET-1, IL-8 and NT-proBNP in samples of peripheral blood of patients affected by UA were significantly elevated, compared with those of the control group. The linear correlation analysis demonstrated a positive and significant correlation between levels of ET-1 and IL-8, between levels of ET-1 and NT-proBNP, and between levels of IL-8 and NT-proBNP in subjects affected by UA.Early elevated levels of ET-1, IL-8 and NT-proBNP in patients with UA show a coexistence between ischaemic insults and endothelial damages. A positive and significant linear correlation between levels of ET-1 and IL-8, between levels of ET-1 and NT-proBNP, and between levels of IL-8 and NT-proBNP confirms that an increased ischaemic insult is correlated to inflammation signs and endothelium damage signs.In patients with UA, ischaemia is always associated with a systemic immuno-mediated activity induced by acute endothelial damage. We suggest early administration of ET-1-selective receptor blockers and anti-inflammatory drugs.

Topics: Acute Disease; Adult; Angina, Unstable; Endothelial Cells; Endothelin-1; Endothelium; Female; Humans; Immunologic Factors; Inflammation; Interleukin-8; Male; Middle Aged; Myocardial Ischemia; Natriuretic Peptide, Brain; Peptide Fragments

The mechanisms underlying acute mountain sickness (AMS) and high-altitude pulmonary edema (HAPE) are not fully understood. We hypothesized that regulators of endothelial function, circulatory homeostasis, hypoxia and cell stress contribute to the pathobiology of AMS and HAPE.. We conducted a prospective case-control study of climbers developing altitude illness who were evacuated to the CIWEC clinic in Kathmandu, compared to healthy acclimatized climbers. ELISA was used to measure plasma biomarkers of the above pathways.. Of the 175 participants, there were 71 cases of HAPE, 54 cases of AMS and 50 acclimatized controls (ACs). Markers of endothelial function were associated with HAPE: circulating levels of endothelin-1 (ET-1) were significantly elevated and levels of sKDR (soluble kinase domain receptor) were significantly decreased in cases of HAPE compared to AC or AMS. ET-1 levels were associated with disease severity as indicated by oxygen saturation. Angiopoietin-like 4 (Angptl4) and resistin, a marker of cell stress, were associated with AMS and HAPE irrespective of severity. Corin and angiotensin converting enzyme, regulators of volume homeostasis, were significantly decreased in HAPE compared to AC.. Our findings indicate that regulators of endothelial function, vascular tone and cell stress are altered in altitude illness and may mechanistically contribute to the pathobiology of HAPE.

Topics: Acclimatization; Acute Disease; Adult; Altitude Sickness; Biomarkers; Case-Control Studies; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Hypoxia; Male; Middle Aged; Mountaineering; Nepal; Peptidyl-Dipeptidase A; Prospective Studies; Shock; Travel

Topics: Acute Disease; Altitude Sickness; Chronic Disease; Endothelin-1; Humans; Mountaineering

Biomarkers can help to identity acute heart failure (AHF) as the cause of symptoms in patients presenting to the emergency department (ED). Older patients may prove a diagnostic challenge due to co-morbidities. Therefore we prospectively investigated the diagnostic performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP) alone or in combination with other biomarkers for AHF upon admission at the ED.. 302 non-surgical patients aged ≥ 70 years were consecutively enrolled upon admission to the ED. In addition to NT-proBNP, mid-regional pro-adrenomedullin (MR-proADM), mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-endothelin-1 (CT-proET-1) and ultra-sensitive C-terminal pro-vasopressin (Copeptin-us) were measured at admission. Two cardiologists independently adjudicated the final diagnosis of AHF after reviewing all available baseline data excluding the biomarkers. We assessed changes in C-index, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) for the multimarker approach.. AHF was diagnosed in 120 (40%) patients (age 81±6 years, 64 men, 56 women). Adding MR-ADM to NT-proBNP levels improved C-index (0.84 versus 0.81; p=0.045), and yielded IDI (3.3%; p=0.002), NRI (17%, p<0.001) and continuous NRI (33.3%; p=0.002). Adding CT-proET-1 to NT-proBNP levels improved C index (0.86 versus 0.81, p=0.031), and yielded robust IDI (12.4%; p<0.001), NRI (31.3%, p<0.001) and continuous NRI (69.9%; p<0.001). No other dual or triple biomarker combination showed a significant improvement of both C-index and IDI.. In older patients presenting to the ED, the addition of CT-proET-1 or MR-proADM to NT-proBNP improves diagnostic accuracy of AHF. Both dual biomarker approaches offer significant risk reclassification improvement over NT-proBNP.

Topics: Academic Medical Centers; Acute Disease; Adrenomedullin; Aged; Aged, 80 and over; Aging; Atrial Natriuretic Factor; Biomarkers; Emergency Service, Hospital; Endothelin-1; Female; Glycopeptides; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prognosis; Prospective Studies; Protein Precursors; Reproducibility of Results; Sensitivity and Specificity; Severity of Illness Index

Altitude illness remains a major cause of mortality. Reduced chemosensitivity, irregular breathing leading to central apnoeas/hypopnoeas, and exaggerated pulmonary vasoconstriction may compromise oxygenation. All factors could enhance susceptibility to acute mountain sickness (AMS). We compared 12 AMS-susceptible individuals with recurrent and severe symptoms (AMS+) with 12 "AMS-nonsusceptible" subjects (AMS-), assessing sleep-breathing disorders in simulated altitude as well as chemoresponsive and pulmonary vasoconstrictive responses to hypoxia. During exposure to simulated altitude, mean blood oxygen saturation during sleep was lower in AMS+ subjects (81.6 ± 2.6 versus 86.0 ± 2.4%, p<0.01), associated with a lower central apnoea/hypopnoea index (18.2 ± 18.1 versus 33.4 ± 24.8 events · h(-1) in AMS+ and AMS- subjects, respectively; p=0.038). A lower hypoxic (isocapnic) chemoresponsiveness was observed in AMS+ subjects (0.40 ± 0.49 versus 0.97 ± 0.46 L · min(-1)·%; p<0.001). This represented the only significant and independent predictive factor for altitude intolerance, despite a higher increase in pulmonary artery systolic pressure in response to hypoxia, a lower lung diffusing capacity and a higher endothelin-1 level at baseline in AMS+ subjects (p<0.05). AMS+ subjects were more hypoxaemic whilst exhibiting fewer respiratory events during sleep owing to lower hypoxic (isocapnic) chemoresponsiveness. In conclusion, the reduction in peripheral hypoxic chemosensitivity appears to be a major causative factor for altitude intolerance.

Topics: Acute Disease; Adult; Altitude Sickness; Apnea; Endothelin-1; Female; Humans; Hypoxia; Male; Middle Aged; Oxygen; Pulmonary Artery; Pulmonary Diffusing Capacity; Severity of Illness Index; Sleep

To analyze gene expression profiles in an experimental pancreatitis and provide functional reversal of hypersensitivity with candidate gene endothelin-1 antagonists.. Dibutyltin dichloride (DBTC) is a chemical used as a polyvinyl carbonate stabilizer/catalyzer, biocide in agriculture, antifouling agent in paint and fabric. DBTC induces an acute pancreatitis flare through generation of reactive oxygen species. Lewis-inbred rats received a single i.v. injection with either DBTC or vehicle. Spinal cord and dorsal root ganglia (DRG) were taken at the peak of inflammation and processed for transcriptional profiling with a cDNA microarray biased for rat brain-specific genes. In a second study, groups of animals with DBTC-induced pancreatitis were treated with endothelin (ET) receptor antagonists [ET-A (BQ123) and ET-B BQ788)]. Spontaneous pain related mechanical and thermal hypersensitivity were measured. Immunohistochemical analysis was performed using anti-ET-A and ET-B antibodies on sections from pancreatic tissues and DRG of the T10-12 spinal segments.. Animals developed acute pancreatic inflammation persisting 7-10 d as confirmed by pathological studies (edema in parenchyma, loss of pancreatic architecture and islets, infiltration of inflammatory cells, neutrophil and mononuclear cells, degeneration, vacuolization and necrosis of acinar cells) and the pain-related behaviors (cutaneous secondary mechanical and thermal hypersensitivity). Gene expression profile was different in the spinal cord from animals with pancreatitis compared to the vehicle control group. Over 260 up-regulated and 60 down-regulated unique genes could be classified into 8 functional gene families: circulatory/acute phase/immunomodulatory; extracellular matrix; structural; channel/receptor/transporter; signaling transduction; transcription/translation-related; antioxidants/chaperones/heat shock; pancreatic and other enzymes. ET-1 was among the 52 candidate genes up-regulated greater than 2-fold in animals with pancreatic inflammation and visceral pain-related behavior. Treatments with the ET-A (BQ123) and ET-B (BQ-788) antagonists revealed significant protection against inflammatory pain related mechanical and thermal hypersensitivity behaviors in animals with pancreatitis (P < 0.05). Open field spontaneous behavioral activity (at baseline, day 6 and 30 min after drug treatments (BQ123, BQ788) showed overall stable activity levels indicating that the drugs produced no undesirable effects on normal exploratory behaviors, except for a trend toward reduction of the active time and increase in resting time at the highest dose (300 μmol/L). Immunocytochemical localization revealed that expression of ET-A and ET-B receptors increased in DRG from animals with pancreatitis. Endothelin receptor localization was combined in dual staining with neuronal marker NeuN, and glia marker, glial fibrillary acidic protein. ET-A was expressed in the cell bodies and occasional nuclei of DRG neurons in naïve animals. However, phenotypic expression of ET-A receptor was greatly increased in neurons of all sizes in animals with pancreatitis. Similarly, ET-B receptor was localized in neurons and in the satellite glia, as well as in the Schwann cell glial myelin sheaths surrounding the axons passing through the DRG.. Endothelin-receptor antagonists protect against inflammatory pain responses without interfering with normal exploratory behaviors. Candidate genes can serve as future biomarkers for diagnosis and/or targeted gene therapy.

Topics: Acute Disease; Animals; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Gene Expression Profiling; Gene Expression Regulation; Hyperalgesia; Male; Oligopeptides; Organotin Compounds; Pancreas; Pancreatitis; Peptides, Cyclic; Piperidines; Rats; Rats, Inbred Lew; Receptors, Endothelin; Spinal Cord

Endothelin-1 (ET-1), circulating endothelial cells (CEC) and endothelial progenitor cells (EPC) are well-known modulators of endothelial function with important cardiac effects after an acute myocardial infarction. However, the relationship between them has never been assessed. The objective of the present study was to establish the relationship between ET-1, CEC, and EPC concentrations after ST-elevation myocardial infarction (STEMI).. Endothelin-1, CEC, and EPC levels were measured in 61 patients presenting with a first STEMI. Samples were withdrawn acutely 6-24h and 1week after admission. Assessments included reperfusion outcomes (angiography), left ventricular ejection fraction (echocardiography), and 30-day mortality.. Mean age was 60.6±12.6years and 45 (74%) were males. Higher ET-1 plasma levels were associated with lower EPC count after 1week (7.45±2.53pg/ml if EPCs in the first quartile vs 5.72±1.49pg/ml if EPCs in the fourth quartile; P=0.04). In contrast with CEC and EPC count, higher ET-1 concentrations on admission were associated with Killip≥2 (9.92±2.01pg/ml vs 7.32±2.13pg/ml; P<0.001), post-reperfusion thrombolysis in myocardial infarction (TIMI) <3 (8.65±2.86pg/ml vs 5.87±1.93pg/ml; P=0.002), myocardial blush grade (MBG) <3 (7.46±2.48pg/ml vs 5.99±2.01pg/ml; P=0.004) and higher 30-day mortality (10.29±2.02pg/ml vs 6.57±2.20pg/ml; P=0.005).. In STEMI patients, high ET-1 levels on admission predict a lower EPC mobilization after 1week. Endothelin-1 provides better clinical, angiographic and echocardiographic information for prognosis than do CEC and EPC concentrations.

Topics: Acute Disease; Aged; Angiography; Biomarkers; Echocardiography; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Myocardial Infarction; Myocardium; Risk Factors; Time Factors; Treatment Outcome

Hypoglycemia is associated with increased cardiovascular mortality, but the reason for this association is poorly understood. We tested the hypothesis that the myocardial blood flow reserve (MBFR) is decreased during hypoglycemia using myocardial contrast echocardiography in patients with type 1 diabetes mellitus (DM) and in healthy control subjects.. Twenty-eight volunteers with DM and 19 control subjects underwent hyperinsulinemic clamps with maintained sequential hyperinsulinemic euglycemia (plasma glucose, 90 mg/dL [5.0 mmol/L]) followed by hyperinsulinemic hypoglycemia (plasma glucose, 50 mg/dL [2.8 mmol/L]) for 60 minutes each. Low-power real-time myocardial contrast echocardiography was performed with flash impulse imaging using low-dose dipyridamole stress at baseline and during hyperinsulinemic euglycemia and hyperinsulinemic hypoglycemia. In control subjects, MBFR increased during hyperinsulinemic euglycemia by 0.57 U (22%) above baseline (B coefficient, 0.57; 95% confidence interval, 0.38 to 0.75; P<0.0001) and decreased during hyperinsulinemic hypoglycemia by 0.36 U (14%) below baseline values (B coefficient, -0.36; 95% confidence interval, -0.50 to -0.23; P<0.0001). Although MBFR was lower in patients with DM at baseline by 0.37 U (14%; B coefficient, -0.37; 95% confidence interval, -0.55 to -0.19; P=0.0002) compared with control subjects at baseline, the subsequent changes in MBFR during hyperinsulinemic euglycemia and hyperinsulinemic hypoglycemia in DM patients were similar to that observed in control subjects. Finally, the presence of microvascular complications in the patients with DM was associated with a reduction in MBFR of 0.52 U (24%; B coefficient, -0.52; 95% confidence interval, -0.70 to -0.34; P<0.0001).. Hypoglycemia decreases MBFR in both healthy humans and patients with DM. This finding may explain the association between hypoglycemia and increased cardiovascular mortality in susceptible individuals.

Topics: Acute Disease; Adult; Blood Glucose; C-Reactive Protein; Coronary Circulation; Diabetes Mellitus, Type 1; Echocardiography; Endothelin-1; Epinephrine; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Male; Microbubbles; Single-Blind Method; Young Adult

To explore the protecting effects and mechanisms of dexamethasone on spleen injury in rats with severe acute pancreatitis (SAP).. The rats were randomly divided into a model control group, treated group and sham-operated group. The contents of plasma endotoxin, serum NO, phospholipase A(2) enzyme (PLA(2)) and endothelin-1 (ET-1) were determined. The mortality rate, pathological changes and changes of Bax and Bcl-2 protein expression levels and apoptotic indexes in the spleen of rats were observed in all groups, respectively, at 3, 6 and 12 h after operation.. Although the survival rate was significantly higher in the treated group than in the model control group, there was no significantly different between them (P > 0.05). The expression levels of Bax and Bcl-2 proteins and apoptotic indexes were significantly higher in the treated group than in the model control group at different time points (P < 0.05 or P < 0.01) while other blood indexes contents and pathological severity scores of spleen were significantly lower in the treated group than in the model control group (P < 0.05, P < 0.01 or P < 0.001).. Dexamethasone can protect spleen from injury during SAP mainly by reducing the content of inflammatory mediators in blood.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Apoptosis; bcl-2-Associated X Protein; Dexamethasone; Disease Models, Animal; Endothelin-1; Endotoxins; Inflammation Mediators; Male; Nitric Oxide; Pancreatitis; Phospholipases A2; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Spleen; Splenic Diseases; Taurocholic Acid; Time Factors

Purpose. To investigate the effect of the endothelin(A) receptor inhibitor BQ-123 on the retinal arteriolar vasculature in minipig retinas in normal eyes and eyes with acute branch retinal vein occlusion (BRVO). Methods. Seven healthy eyes of seven minipigs and six eyes of six minipigs with experimental BRVO were evaluated under systemic anesthesia. An intravitreal juxta-arteriolar microinjection of 30 microL BQ-123 0.61 microg/mL (pH 7.4) was performed in all but one eye from each group, into which the physiologic saline vehicle alone was injected. Vessel-diameter changes were measured with a retinal vessel analyzer. Results. In healthy minipig retinas (n = 6), arteriolar diameter (+/-SD) increased 6.19% +/- 3.55% (P < 0.05), 25.98% +/- 2.37% (P < 0.001), 23.65% +/- 1.2% (P < 0.001), and 16.84% +/- 1.95% (P < 0.001), at 1, 5, 10, and 15 minutes, respectively, after BQ-123 microinjection. Two hours after experimental BRVO (n = 5), the retinal arteriolar diameter had decreased (13.07% +/- 5.7%; P < 0.01). One, 5, 10, and 15 minutes after BQ-123 microinjection, retinal arteriolar diameter had increased by 7.14% +/- 3.3% (P < 0.01), 26.74% +/- 7.63% (P < 0.001), 23.67% +/- 6.4% (P < 0.001), and 16.09% +/- 3.41% (P < 0.001), respectively. Vehicle only injection had no vasoactive effect on physiologic or BRVO retinas. Conclusions. A significant increase in retinal arteriolar diameter was demonstrated after juxta-arteriolar BQ-123 microinjection in healthy and in acute BRVO minipig retinas. The results suggest a role for endothelin-1 in maintaining retinal basal arteriolar tone. Reversing the BRVO-related vasoconstriction by juxta-arteriolar BQ-123 microinjection could bring a new perspective to the management of BRVO.

Topics: Acute Disease; Animals; Arterioles; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Microinjections; Muscle, Smooth, Vascular; Peptides, Cyclic; Retinal Artery; Retinal Vein Occlusion; Swine; Swine, Miniature; Vasodilation

Acute pulmonary embolism (PE) is a life-threatening disease, and several vasoconstrictors, including endothelin-1 (ET-1), play a key role in vasoconstriction and hypoxemia during the development of PE. Rho kinase is activated by various vasoconstrictors resulting in vascular contraction and remodeling. Recent evidence has revealed an important role of Rho kinase in the pathogenesis of systemic and pulmonary vascular diseases. However, contribution of Rho kinase in PE remains unclear. We thus investigated the role of Rho kinase in the PE rat model induced by intrajugular administration of polystyrene microspheres (mean diameter, 26 microm). At 6 h following the administration of microspheres (1.5 ml/kg), right ventricular systolic pressure (RVSP) was higher in the PE than in the control rats (15.8 +/- 1.6 vs. 32.9 +/- 7.5 mmHg). Arterial oxygen tension was lower (92.3 +/- 12.5 vs. 66.0 +/- 17.7 Torr), and alveolar-arterial difference in oxygen partial pressure was higher (3.9 +/- 3.8 vs. 36.5 +/- 26.9 Torr) in the PE rats. Western blotting analysis revealed upregulation and downregulation in expression of vascular cell adhesion molecule-1 and endothelial nitric oxide synthase in lungs from the PE rats, respectively, and radioimmunoassay demonstrated an increase in plasma ET-1 levels. Lung Rho kinase alpha expression was greater in the PE rats. At 5 h following administration of microspheres (0.75 ml/kg), intravenous Rho kinase inhibitors HA1077 and Y27632 (3 mg/kg each) attenuated elevation of RVSP (22.0 +/- 3.7, 17.1 +/- 3.2, 14.3 +/- 2.6 mmHg, PE, PE+HA1077, PE+Y27632) and the severity of hypoxemia (66.3 +/- 16.2, 94.9 +/- 23.0, 89.1 +/- 8.5 Torr, PE, PE+HA1077, PE+Y27632) in the PE rats. These results suggest that pulmonary endothelial dysfunction and activation of Rho kinase may contribute to the potentiation of vasoconstriction and hypoxemia in the PE rats.

Topics: Acute Disease; Animals; Blood Gas Analysis; Blood Pressure; Endothelin-1; Hemodynamics; Injections, Intravenous; Lung; Male; Microspheres; Nitric Oxide Synthase Type III; Polystyrenes; Protein Kinase Inhibitors; Pulmonary Artery; Pulmonary Embolism; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; Vascular Cell Adhesion Molecule-1

Severe acute pancreatitis (SAP) is a commonly seen acute abdominal syndrome characterized by sudden onset, rapid progression and high mortality rate. The damage in peripheral organs may be more severe than that in the pancreas, and can even lead to multiple organ dysfunction. It is critical to recognize early pathological changes in multiple organs. This study aimed to assess the early pathological features of damaged organs in a rat model of SAP.. Thirty clean grade healthy male Sprague-Dawley rats weighing 250-300 g were randomly divided into a model control group (n=15) and a sham-operated group (n=15). The SAP rat model was induced by sodium taurocholate. Samples of blood and from multiple organs were collected 3 hours after operation. We assessed the levels of IL-6, TNF-alpha, PLA2, NO, ET-1, MDA, amylases and endotoxin in blood and observed the early pathological changes in multiple damaged organs.. Levels of IL-6, TNF-alpha, PLA2, NO, ET-1 and MDA in serum and of amylase and endotoxin in plasma of the model control group rats were significantly higher than those of the sham-operated group (P<0.01). Different degrees of pathological change were observed in multiple damaged organs.. Multiple organ injury may occur at the early stage of SAP in rats.

Topics: Acute Disease; Animals; Cytokines; Disease Models, Animal; Edema; Endothelin-1; Hemorrhage; Kidney; Liver; Lung; Male; Malondialdehyde; Necrosis; Nitric Oxide; Pancreas; Pancreatitis; Rats; Rats, Sprague-Dawley

The aim of this study was to predict right ventricular dysfunction (RVD) using plasma concentration of D-dimer, pro-atrial natriuretic peptide (pro-ANP), brain natriuretic peptide (BNP), endothelin-1 (ET-1) and cardiac troponin I (TNI) in patients with pulmonary embolism (PE).. Patients suspected of PE had a ventilation/perfusion-single-photon emission-tomography (V/Q-SPECT), pulmonary multidetector computer tomography (MDCT) angiography, blood samples and ECG-gated cardiac CT performed the same day.. Pro-ANP, BNP and D-dimer are associated with significantly elevated levels in PE patients with RVD. ROC curves demonstrated that D-dimer, pro-ANP and BNP were accurate for detection of RVD.. Because measurements of cardiac biomarkers are inexpensive and easily obtained they may prove useful in the clinical diagnosis of RVD. However because of the small sample size, the results need to be confirmed in larger studies.

Topics: Acute Disease; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Denmark; Endothelin-1; Female; Fibrin Fibrinogen Degradation Products; Humans; Linear Models; Logistic Models; Male; Middle Aged; Natriuretic Peptide, Brain; Odds Ratio; Perfusion Imaging; Predictive Value of Tests; Prognosis; Prospective Studies; Pulmonary Embolism; ROC Curve; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; Troponin I; Up-Regulation; Ventricular Dysfunction, Right; Ventricular Function, Right

The underlying mechanisms for cerebral blood flow (CBF) abnormalities in acute bacterial meningitis (ABM) are largely unknown. Putative mediators include vasoactive peptides, e.g. calcitonin-gene related peptide (CGRP), vasoactive intestinal peptide (VIP), and endothelin-1 (ET-1), all of which may be affected by therapeutic interventions used in the intensive care unit. We measured arterial levels as well as the net cerebral flux of these peptides in patients with ABM, and in healthy volunteers undergoing interventions relevant to intensive care.. Seven patients with severe ABM and sepsis and fifteen healthy volunteers were included after informed consent. The net cerebral fluxes of vasoactive peptides were measured by the Kety-Schmidt technique in ABM patients (baseline study only), as well as in volunteers at baseline, during voluntary hyperventilation, after an intravenous injection of lipopolysaccharide (LPS), and during norepinephrine infusion.. The arterial levels of CGRP, but not of VIP or ET-1, were elevated in patients with ABM, but no net cerebral flux was present. CGRP levels decreased during hyperventilation and after LPS injection. No net cerebral flux of VIP occurred in any group at any time. A cerebral efflux of ET-1, which occurred in volunteers at baseline, was neither present in volunteers after LPS injection nor in patients with ABM.. The arterial concentration of the vasodilatory peptide, CGRP, but of neither VIP nor the vasoconstrictor ET-1, is elevated in patients with ABM and sepsis. A constitutive cerebral output of ET-1 appears to be present in healthy humans, but is abolished after LPS injection.

Topics: Acute Disease; Adult; Aged; Brain; Calcitonin Gene-Related Peptide; Critical Care; Endothelin-1; Female; Humans; Lipopolysaccharides; Male; Meningitis, Bacterial; Middle Aged; Vasoactive Intestinal Peptide

To investigate the effect of baicalin and octreotide on the expression levels of P-selectin protein in multiple organs of rats with severe acute pancreatitis and explore the underlying mechanism.. Rats were randomly divided into sham-operated, model control, baicalin-treated and octreotide-treated groups. At 3, 6 and 12 h after operation, the mortality rates of rats, the contents of plasma endotoxin as well as serum NO and ET-1, the pathological changes in multiple organs, and the expression levels of P-selectin protein in each group were observed.. At 12 h after operation, the mortality rates of rats in treated groups were significantly lower than that in the model control group (P < 0.05), and the pathological severity scores in multiple organs in treated groups were also significantly lower than those in the model control group (P < 0.05). The contents of plasma endotoxin, serum PLA(2) (at 6 and 12 h after operation), ET-1 and NO (at 3 and 12 h after operation) in treated groups were significantly lower than those in the model control group (P < 0.05, P < 0.01 or P < 0.001). In the baicalin-treated group, the expression levels of P-selectin protein in liver (at 3 h after operation), kidney (at 3 and 6 h after operation), pancreas, lung and spleen were significantly lower than those in the model control group (P < 0.01). In the octreotide-treated group, the expression levels of this protein in lung, intestinal mucosa (at 6 and 12 h after operation), lymph nodes (at 3 and 6 h after operation), spleen and thymus were significantly lower than those in the model control group (P < 0.05). Additionally, the products of the staining intensity and positive rate of P-selectin protein in pancreas, spleen (at 3 h after operation), intestinal mucosa (at 6 h after operation), thymus (at 6 h after operation) and lung (at 6 h after operation) in treated groups were significantly lower than those in the model control group (P < 0.05).. Both baicalin and octreotide can exert some protective effects on multiple organs and the former is superior to the latter in protecting pancreas. Furthermore, decreasing the expression levels of P-selectin protein in these organs is one of the possible mechanisms.

Topics: Acute Disease; Animals; Biomarkers; Disease Models, Animal; Endothelin-1; Endotoxins; Flavonoids; Immunohistochemistry; Male; Multiple Organ Failure; Nitric Oxide; Octreotide; P-Selectin; Pancreatitis; Phospholipases A2; Protective Agents; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Taurocholic Acid; Time Factors; Tissue Array Analysis

To study the influence and mechanisms of dexamethasone on mesenteric lymph node of rats with severe acute pancreatitis (SAP).. The SAP rats were assigned to model, treated or sham-operated groups. The mortality, pathological changes of mesenteric lymph nodes, expression levels of NF-kappa B, P-selectin, Bax, Bcl-2 and caspase-3 protein and changes in apoptotic indexes in lymph nodes were observed at 3, 6 and 12 h after operation. The blood levels of endotoxin, superoxide dismutase (SOD), malondialdehyde (MDA), and endothelin-1 (ET-1) in blood were determined.. SOD content, expression of Bax protein and apoptotic index were significantly higher in the treated group than in the model group at different time points (P < 0.05 or P < 0.01). Other blood-detecting indexes and histopathological scores of mesenteric lymph nodes were lower in the treated than in the model group (P < 0.05, P < 0.01 or P < 0.01). NF-kappa B protein expression was negative in all groups. Comparing P-selectin and caspase-3 expression levels among all three groups, there was no marked difference between the model and treated group.. Dexamethasone can protect mesenteric lymph nodes. The mechanism may be by reducing the content of inflammatory mediators in the blood and inducing lymphocyte apoptosis.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Dexamethasone; Disease Models, Animal; Endothelin-1; Lymph Nodes; Male; Malondialdehyde; Mesentery; NF-kappa B; P-Selectin; Pancreatitis; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Superoxide Dismutase

Aristolochic acid nephropathy (AAN) is a progressive tubulointerstitial renal disease caused by aristolochic acid intake. To determine the contribution of renal ischemia to the pathogenesis of AAN, we characterized changes in the expression of angiogenic factors and vasoactive substances, and then we evaluated the expression of a marker of hypoxia in an acute AAN rat model. Rats were orally administrated either a decoction of Aristolochiae manshuriensis that contained 20 mg/kg of aristolochic acid-I or an equal volume of distilled water (control group) once daily for 4 days or 7 days. Renal histology and serum creatinine were assessed. Expression of endothelin-1 (ET-1) and hypoxia inducible factor-1 alpha (HIF-1alpha) mRNA within renal cortex were determined by semiquantitative reverse-transcription polymerase chain reaction. Levels of ET-1, nitric oxide (NO), vascular endothelial growth factor (VEGF), and HIF-1alpha in kidneys were determined by radioimmunoassay, Griess method, Western blot, and immunohistochemistry, respectively. Tubular injury scores and ET-1 mRNA expression were increased in the AA-treated rats at both days 4 and 8, whereas serum creatinine level and ET-1 protein expression was increased only at day 4. In contrast, NO production in AA-treated rats was decreased at day 8 compared with the control group. Similarly, VEGF protein expression was reduced in the AA-treated rats at both days 4 and 8. A dramatic increase in nuclear staining for HIF-1alpha was observed mainly in the tubular cells of tubulointerstitial damage area in the AA-treated rats at day 8. The observed increase in HIF-1alpha protein expression, decrease in VEGF protein expression, and imbalance of vasoactive substances after induction of acute kidney injury by AA suggests that ischemic injury contributes to the pathogenesis of AAN.

Topics: Acute Disease; Animals; Aristolochia; Aristolochic Acids; Blotting, Western; Cell Nucleus; Creatinine; Disease Models, Animal; Endothelin-1; Gene Expression Regulation; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Ischemia; Kidney; Male; Nitric Oxide; Quality Control; Radioimmunoassay; Random Allocation; Rats; Rats, Wistar; RNA, Messenger; Time Factors; Vascular Endothelial Growth Factor A

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.

Topics: Action Potentials; Acute Disease; Animals; Balloon Occlusion; Biomarkers; Coronary Angiography; Endothelin-1; Endothelin-2; Endothelin-3; Gene Expression Regulation; Myocardial Ischemia; Predictive Value of Tests; Swine; Time Factors; Ventricular Fibrillation; Ventricular Premature Complexes

The current study examined the role of endothelin-1 (ET-1) in mediating acute lung inflammation induced by short-term cigarette smoke exposure. Hamsters received intraperitoneal injections of ET-1, followed by a 2-hour period of smoke exposure, for 3 consecutive days. The lungs were then evaluated for inflammatory changes, using the following parameters: (1) lung histopathology, (2) neutrophil content of bronchoalveolar lavage fluid (BALF), (3) percent tumor necrosis factor receptor 1 (TNFR1)-labeled BALF macrophages, and (4) alveolar septal cell apoptosis. Results indicate that ET-1 significantly amplified the effect of smoke on each of these inflammatory markers and that these responses could be blocked by pretreatment with a novel endothelin receptor A antagonist, HJP272. In particular, exogenous ET-1 induced a marked increase in BALF neutrophils, consistent with a role for this mediator as an inflammatory cell "gatekeeper."

Topics: Acute Disease; Animals; Apoptosis; Cricetinae; Endothelin-1; Hydroxyquinolines; Lung; Mesocricetus; Pneumonia; Receptors, Tumor Necrosis Factor, Type I; Tobacco Smoke Pollution

The present study was conducted to investigate whether hydroxysafflor yellow A (HSYA) has a protective effect on acute and chronic heart failure (AHF/CHF) induced by ligation of the left anterior descending coronary artery for 3 h and 8 weeks, respectively. The rats were divided into the following groups: sham operation, coronary artery ligation (CAL), CAL+HSYA (100 mg kg(-1) by gavage) and CAL+diltiazem (20 mg kg(-1) by gavage). In the AHF model, heart function, as determined by haemodynamic studies and echocardiography, was improved significantly by pretreatment with HSYA or diltiazem. Significant reductions in elevated serum creatine phosphokinase, lactate dehydrogenase, malondialdehyde (MDA), glutamic oxalacetic transaminase, glutamic pyruvic transaminase and blood viscosity were observed, and the activity of serum superoxide dismutase (SOD) was enhanced (all P<0.01). In the CHF model, HSYA and diltiazem restored abnormal heart function, and completely suppressed the elevated plasma atrial natriuretic polypeptide (ANP) and endothelin-1 (ET-1), serum and left-ventricular tissue inducible nitric oxide (NO) synthase (iNOS), NO and MDA, and improved the decrease in SOD. HSYA and diltiazem improved cardiac performance in AHF and reduced cardiac remodelling in CHF by reducing tissue weight indices: left ventricular weight/body weight (BW), right ventricular weight/BW, kidney weight/BW and lung weight/BW, and attenuating increases in infarct size, inner diameter of the left ventricle and collagen volume fraction in non-infarcted areas, and the decrease in mean wall thickness of infarcted myocardium. These results suggest that HSYA exerted beneficial actions in cardiac performance in models of both AHF and CHF, mainly by suppressing ET-1, iNOS and oxidative stress in infarcted tissue.

Topics: Acute Disease; Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Viscosity; Cardiotonic Agents; Chalcone; Chronic Disease; Coronary Vessels; Creatine Kinase; Diltiazem; Disease Models, Animal; Echocardiography; Endothelin-1; Heart Failure; Hemodynamics; L-Lactate Dehydrogenase; Ligation; Malondialdehyde; Nitric Oxide Synthase; Oxidative Stress; Quinones; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

To assess plasma endothelin-1 (ET-1), C-reactive protein (CRP) and fibrinogen (FIB) levels in acute ischemic stroke (AIS) and explore the potential association among them.. In 23 consecutive patients with AIS diagnosed clinically and confirmed by CT brain scan, we measured plasma levels of ET-1 by radioimmunoassay, and CRP and FIB on the first and fifth days after the onset of AIS and we compared them with the levels of ten healthy volunteers in the control group.. The mean plasma levels of ET-1 in AIS patients on the first and fifth days were respectively 19.93+/-6.72 and 16.47+/-26.3 pmol/l (p<0.001) compared with 3.68+/-1.2 pmol/l in the control group (p<0.001 versus mean values on the first and fifth days). The mean plasma levels of CRP in the patients on the first and fifth days were respectively 2.7+/-4.7 and 3.0+/-4.4 mg/dl (p>0.05) compared with 0.2+/-0.1 mg/dl in the control group (p<0.05 versus mean values on the first and fifth days). The mean plasma levels of FIB in the patients on the first and fifth days were respectively 361+/-98.89 and 392.7+/-144.89 mg/dl, while in the control group, it was 330.5+/-90.28 mg/dl (p>0.05 versus mean values on the first and fifth days). A positive association was found between the plasma levels of ET-1 and CRP on the fifth day (p<0.05).. ET-1 was found to be significantly elevated in the plasma in the AIS. There is association between ET-1 and CRP on the fifth day after AIS. Plasma levels of ET-1 and its association with CRP levels may be used as additional biomarkers for AIS.

Topics: Acute Disease; Aged; Aged, 80 and over; Biomarkers; Brain; Brain Ischemia; C-Reactive Protein; Endothelin-1; Female; Fibrinogen; Humans; Male; Predictive Value of Tests; Radioimmunoassay; Tomography, X-Ray Computed; Up-Regulation

Chagas' disease, caused by the protozoan Trypanosoma cruzi, is a major cause of cardiovascular disability in countries where it is endemic. Damage to the heart microvasculature has been proposed to be an important factor in the pathogenesis of heart dysfunction. Endothelin-1 (ET-1) is a potent vasoconstrictor and exerts its effects via specific ET A and ET B receptors. A few studies have suggested a role for ET-1 and its receptors in the pathogenesis of Chagas' disease. We investigated the effects of treatment with bosentan, an ET A/ET B receptor antagonist, on the course of T. cruzi infection (Y strain) in C57Bl/6 mice. Treatment with bosentan (100 mg kg-1 day-1) was given per os starting day 0 after infection until sacrifice. Bosentan significantly increased myocardial inflammation, with no effects on parasitemia. Although the total number of nests was similar, a lower number of intact amastigote nests was found in the heart of bosentan-treated animals. Bosentan failed to affect the infection-associated increase in the cardiac levels of the cytokines IFN-g and TNF-a and the chemokines CCL2/MCP-1, CCL3/MIP-1a and CCL5/RANTES. In vitro, pre-incubation with ET-1 (0.1 microM) 4 h before infection enhanced the uptake of the parasites by peritoneal macrophages, and this effect was abrogated when macrophages were pre-treated with bosentan (1 microM) 15 min before incubation with ET-1. However, ET-1 did not alter killing of intracellular parasites after 48 h of in vitro infection. Our data suggest that bosentan-treated mice have a delay in controlling parasitism which is compensated for exacerbated inflammation. Infection is eventually controlled in these animals and lethality is unchanged, demonstrating that ET-1 plays a minor role in the protection against acute murine T. cruzi infection.

Topics: Acute Disease; Animals; Bosentan; Chagas Cardiomyopathy; Cytokines; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Male; Mice; Mice, Inbred C57BL; Parasitemia; Sulfonamides; Trypanosoma cruzi

There is evidence that endothelin (ET) 1 affect neutrophil functions and that patients with severe acute pancreatitis have increased plasma levels of ETs. Under appropriate conditions, neutrophils are able to injure the endothelium. In the present study, we compared healthy donors with acute pancreatitis patients for neutrophil degranulation and its ability to injure the endothelium and the contribution of ET-1 to this injury.. Injury was evaluated by measuring the detachment of endothelial cells (ECV-304) growing in monolayer in coculture with human neutrophils for 4 hours. Neutrophil degranulation was assessed by myeloperoxidase (MPO) activity in coculture supernatants. In some experiments, neutrophils were pretreated with the antagonist of ET(A) receptor (BQ-123, 10(-6) M), which has high affinity for ET-1.. Neutrophils from both healthy donors and acute pancreatitis patients caused detachment of endothelial cells, and levels of MPO activity were increased in coculture supernatants. Neutrophils from acute pancreatitis patients caused significantly higher levels of detachment and MPO in the supernatants. Pretreatment of neutrophils with BQ-123 inhibited the detachment caused by neutrophils from healthy donors but not by neutrophils from acute pancreatitis patients.. These results show that neutrophils taken from healthy donors damage the endothelium by a mechanism dependent on ETs acting via ET(A) receptor, whereas neutrophils from acute pancreatitis patients cause more severe damage that is not dependent on ETs in the in vitro system used.

Topics: Acute Disease; Adult; Antihypertensive Agents; Cell Degranulation; Cells, Cultured; Endothelial Cells; Endothelin A Receptor Antagonists; Endothelin-1; Humans; In Vitro Techniques; Neutrophils; Pancreatitis; Peptides, Cyclic; Peroxidase; Receptor, Endothelin A; Severity of Illness Index

Acute hypoxia causes pulmonary vasoconstriction and coronary vasodilation. The divergent effects of hypoxia on pulmonary and coronary vascular smooth muscle cells suggest that the mechanisms involved in oxygen sensing and downstream effectors are different in these two types of cells. Since production of reactive oxygen species (ROS) is regulated by oxygen tension, ROS have been hypothesized to be a signaling mechanism in hypoxia-induced pulmonary vasoconstriction and vascular remodeling. Furthermore, an increased ROS production is also implicated in arteriosclerosis. In this study, we determined and compared the effects of hypoxia on ROS levels in human pulmonary arterial smooth muscle cells (PASMC) and coronary arterial smooth muscle cells (CASMC). Our results indicated that acute exposure to hypoxia (Po(2) = 25-30 mmHg for 5-10 min) significantly and rapidly decreased ROS levels in both PASMC and CASMC. However, chronic exposure to hypoxia (Po(2) = 30 mmHg for 48 h) markedly increased ROS levels in PASMC, but decreased ROS production in CASMC. Furthermore, chronic treatment with endothelin-1, a potent vasoconstrictor and mitogen, caused a significant increase in ROS production in both PASMC and CASMC. The inhibitory effect of acute hypoxia on ROS production in PASMC was also accelerated in cells chronically treated with endothelin-1. While the decreased ROS in PASMC and CASMC after acute exposure to hypoxia may reflect the lower level of oxygen substrate available for ROS production, the increased ROS production in PASMC during chronic hypoxia may reflect a pathophysiological response unique to the pulmonary vasculature that contributes to the development of pulmonary vascular remodeling in patients with hypoxia-associated pulmonary hypertension.

Topics: Acute Disease; Cells, Cultured; Chronic Disease; Coronary Vessels; Drug Administration Schedule; Endothelin-1; Humans; Hypoxia; Mitogens; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Pulmonary Artery; Reactive Oxygen Species; Superoxides; Vasoconstrictor Agents

To establish an ideal model of multiple organ injury of rats with severe acute pancreatitis (SAP).. SAP models were induced by retrograde injection of 0.1 mL/100 g 3.5% sodium taurocholate into the biliopancreatic duct of Sprague-Dawley rats. The plasma and samples of multiple organ tissues of rats were collected at 3, 6 and 12 h after modeling. The ascites volume, ascites/body weight ratio, and contents of amylase, endotoxin, endothelin-1 (ET-1), nitrogen monoxidum (NO), phospholipase A(2) (PLA(2)), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) in plasma were determined. The histological changes of multiple organs were observed under light microscope.. The ascites volume, ascites/body weight ratio, and contents of various inflammatory mediators in blood were higher in the model group than in the sham operation group at all time points [2.38 (1.10), 2.58 (0.70), 2.54 (0.71) vs 0.20 (0.04), 0.30 (0.30), 0.22 (0.10) at 3, 6 and 12 h in ascites/body weight ratio; 1582 (284), 1769 (362), 1618 (302) (U/L) vs 5303 (1373), 6276 (1029), 7538 (2934) (U/L) at 3, 6 and 12 h in Amylase; 0.016 (0.005), 0.016 (0.010), 0.014 (0.015) (EU/mL) vs 0.053 (0.029), 0.059 (0.037), 0.060 (0.022) (EU/mL) at 3, 6 and 12 h in Endotoxin; 3.900 (3.200), 4.000 (1.700), 5.300 (3.000) (ng/L) vs 41.438 (37.721), 92.151 (23.119), 65.016 (26.806) (ng/L) at 3, 6 and 12 h in TNF-alpha, all P < 0.01]. Visible congestion, edema and lamellar necrosis and massive leukocytic infiltration were found in the pancreas of rats of model group. There were also pathological changes of lung, liver, kidney, spleen, ileum, lymphonode, thymus, myocardium and brain.. This rat model features reliability, convenience and a high achievement ratio. Complicated with multiple organ injury, it is an ideal animal model of SAP.

Topics: Acute Disease; Amylases; Animals; Ascitic Fluid; Body Weight; Brain; Disease Models, Animal; Endothelin-1; Endotoxins; Feasibility Studies; Ileum; Interleukin-6; Kidney; Liver; Lymph Nodes; Male; Multiple Organ Failure; Myocardium; Nitric Oxide; Pancreas; Pancreatitis; Phospholipases A; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Severity of Illness Index; Taurocholic Acid; Thymus Gland; Time Factors; Tumor Necrosis Factor-alpha

To investigate the protective effects and mechanisms of Baicalin and octreotide on renal injury of rats with severe acute pancreatitis (SAP).. One hundred and eighty SD rats were randomly assigned to the model group, Baicalin-treated group, octreotide-treated group and sham operation group. The mortality, plasma endotoxin level, contents of blood urea nitrogen (BUN), creatinine (CREA), phospholipase A2 (PLA2), nitrogen monoxide (NO), tumor necrosis factor (TNF)-alpha, IL-6 and endothelin-1 (ET-1) in serum, expression levels of renal Bax and Bcl-2 protein, apoptotic indexes and pathological changes of kidney were observed at 3, 6 and 12 h after operation.. The renal pathological changes were milder in treated group than in model group. The survival at 12 h and renal apoptotic indexes at 6 h were significantly (P<0.05) higher in treated group than in model group [66.67% vs 100%; 0.00 (0.02)% and 0.00 (0.04)% vs 0.00 (0.00)%, respectively]. The serum CREA content was markedly lower in octreotide-treated group than in model group at 3 h and 6 h (P<0.01, 29.200+/-5.710 micromol/L vs 38.400+/-11.344 micromol/L; P<0.05, 33.533+/-10.106 micromol/L vs 45.154+/-17.435 micromol/L, respectively). The expression level of renal Bax protein was not significantly different between model group and treated groups at all time points. The expression level of renal Bcl-2 protein was lower in Baicalin-treated group than in model group at 6 h [P<0.001, 0.00 (0.00) grade score vs 3.00 (3.00) grade score]. The Bcl-2 expression level was lower in octreotide-treated group than in model group at 6 h and 12 h [P<0.05, 0.00 (0.00) grade score vs 3.00 (3.00) grade score; 0.00 (0.00) grade score vs 0.00 (1.25) grade score, respectively]. The serum NO contents were lower in treated groups than in model group at 3 h and 12 h [P<0.05, 57.50 (22.50) and 52.50 (15.00) micromol/L vs 65.00 (7.50) micromol/L; P<0.01, 57.50 (27.50) and 45.00 (12.50) micromol/L vs 74.10 (26.15) micromol/L, respectively]. The plasma endotoxin content and serum BUN content (at 6 h and 12 h) were lower in treated groups than in model group. The contents of IL-6, ET-1, TNF-alpha (at 6 h) and PLA2 (at 6 h and 12 h) were lower in treated groups than in model group [P<0.001, 3.031 (0.870) and 2.646 (1.373) pg/mL vs 5.437 (1.025) pg/mL; 2.882 (1.392) and 3.076 (1.205) pg/mL vs 6.817 (0.810) pg/mL; 2.832 (0.597) and 2.462 (1.353) pg/mL vs 5.356 (0.747) pg/mL; 16.226 (3.174) and 14.855 (5.747) pg/mL vs 25.625 (7.973) pg/mL; 18.625 (5.780) and 15.185 (1.761) pg/mL vs 24.725 (3.759) pg/mL; 65.10 (27.51) and 47.60 (16.50) pg/mL vs 92.15 (23.12) pg/mL; 67.91+/-20.61 and 66.86+/-22.10 U/mL, 63.13+/-26.31 and 53.63+/-12.28 U/mL vs 101.46+/-14.67 and 105.33+/-18.10 U/mL, respectively].. Both Baicalin and octreotide can protect the kidney of rats with severe acute pancreatitis. The therapeutic mechanisms of Baicalin and octreotide might be related to their inhibition of inflammatory mediators and induction of apoptosis. Baicalin might be a promising therapeutic tool for severe acute pancreatitis.

Topics: Acute Disease; Animals; Anti-Infective Agents; Apoptosis; bcl-2-Associated X Protein; Creatinine; Dose-Response Relationship, Drug; Endothelin-1; Flavonoids; Gastrointestinal Agents; Interleukin-6; Kidney Diseases; Kidney Tubules; Male; Nitric Oxide; Octreotide; Pancreatitis; Phospholipases A2; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Alleviation of microcirculation disorders in severe acute pancreatitis (SAP) can improve survival rates, and low molecular weight heparin (LMWH) is well known to have potent ameliorative effect on microcirculation disorders caused by anti-coagulant activity. The aim of this study was to investigate the effects of LMWH on pancreatic microcirculation in SAP in rats.. SD rats were randomly divided into 3 groups: sham operation (S) group, SAP group, and LMWH treatment (LT) group. The concentrations of serum amylase, tumor necrosis factor-alpha (TNF-alpha), endothelin-1 (ET-1), pancreatic ultrastructure were examined at 24 hours after the models were set up in each group.. Compared with S group, the concentration of serum amylase, ET-1, and TNF-alpha in SAP group were significantly increased (P < 0.001); After LMWH treatment, the concentration of serum amylase, ET-1, TNF-alpha were decreased significantly compared with SAP group (P < 0.001, 0.01, 0.001, respectively). On electron microscopy, the microthrombosis in LT group was significantly less than that in SAP group. The 3-day survival rate in SAP group (25.0%) was significantly lower than that in S group (100.0%, P < 0.05) and in LT group (87.5%, P < 0.05).. The disorder of pancreatic microcirculation may be involved in the inflammatory response of rats with SAP. LMWH can effectively improve the survival rate of SAP, and alleviate the severity of microcirculation disorders through its antithrombin effects and down-regulate the levels of serum ET-1 and TNF-alpha.

Topics: Acute Disease; Animals; Anticoagulants; Disease Models, Animal; Endothelin-1; Heparin, Low-Molecular-Weight; Microcirculation; Microscopy, Electron; Pancreas; Pancreatitis; Rats; Rats, Sprague-Dawley; Survival Rate; Tumor Necrosis Factor-alpha

Chagas' disease caused by the parasite, Trypanosoma cruzi, is accompanied by an acute myocarditis which can be fatal. Mice (A/J strain) infected with T. cruzi (Tulahuen strain) develop an acute myocarditis associated with high parasitemia and uniform mortality. Examination of the myocardium demonstrated myonecrosis, vasculitis and parasite pseudocysts. Immunoblot analysis and quantitative real time PCR of heart lysates demonstrated an increased expression of cell cycle regulatory proteins such as cyclins B1, D1, A1 and E1 and an increased expression of cdk2 when compared with uninfected controls. Extracellular signal-regulated kinase (ERK) was activated. Proliferating cell nuclear antigen (PCNA), endothelin-1, endothelin receptor type A (ET(A)) and endothelin receptor type B (ET(B)) expression were increased. Caveolin-1 is important in the regulation of ERK and cyclin D1. The expression of caveolin-1 as well as caveolin-2 and caveolin-3 was reduced. These data suggest that acute fatal T. cruzi myocarditis is accompanied by changes in cell cycle proteins such as the cyclins and caveolin and that the upregulation of the endothelin pathway may be important in the myocardial abnormalities and mortality observed in this mouse model.

Topics: Acute Disease; Animals; Caveolin 1; Chagas Disease; Cyclins; Disease Models, Animal; Endothelin-1; Gene Expression Regulation; Male; Mice; Myocarditis; RNA, Messenger; Trypanosoma cruzi

Elevated plasma and tissue endothelin (ET)-1 levels in patients with critical limb ischemia (CLI) has been described. Here the effect of a period of acute ischemia and subsequent reperfusion on plasma ET-1 and tissue ET-1/ET receptors in skeletal muscle biopsies from CLI patients undergoing femoro-distal bypass surgery was studied. Peripheral and "local" blood and muscle biopsies were obtained from patients undergoing femoro-distal bypass surgery, at the start of the procedure (control), after a period of vascular clamping (ischemia), and after clamp release (reperfusion). Plasma ET-1 was determined by enzyme-linked immunosorbent assay. Tissue ET-1 was assessed by counting ET-1 immunostaining cells per unit area, and ET(A)/ET(B) receptors were identified on sections by in vitro autoradiography in which binding was quantitatively assessed by densitometry. There was no significant effect of ischemia or reperfusion on plasma ET-1 levels or on ET(A)/ET(B) receptor binding. However, tissue ET-1 increased during both acute ischemia and reperfusion (P < 0.05). A high proportion of positive ET-1 immunostaining was associated with microvessels and also exhibited a similar distribution to macrophages. Previously, it has been shown that both plasma ET-1 and tissue ET-1/ET receptors are increased in CLI patients compared with atherosclerotic controls. Also, increased muscle ET-1 levels have been described in acute ischemia caused by tourniquet application in nonischemic patients undergoing total knee replacement. In CLI patients, in whom ET-1 is already upregulated, this further increase may exacerbate existing pathologic processes and contribute to ischemia-reperfusion injury. ET-1 antagonists may therefore be useful adjuncts in CLI and other surgical procedures in which ischemia-reperfusion damage occurs.

Topics: Acute Disease; Chronic Disease; Endothelin-1; Humans; Immunohistochemistry; Ischemia; Leg; Receptor, Endothelin A; Receptor, Endothelin B; Reperfusion

Inhalation of endothelin (ET)-A receptor antagonists has been shown to improve gas exchange in experimental acute lung injury (ALI) but may induce side effects by increasing circulating ET-1 levels. We investigated whether the inhaled ET(A) receptor antagonist, LU-135252, at low doses, improves gas exchange without affecting ET-1 plasma concentrations and lung injury in an animal model of ALI. Twenty-two piglets were examined in a prospective, randomized, controlled study. In anesthetized animals, ALI was induced by surfactant depletion. Animals received either LU-135252 at a dose of 0.3 mg/kg during 20 mins (LU group; n = 11), or nebulization of saline buffer (control group; n = 11). The Mann-Whitney U test was used to compare groups (P < 0.05). In the LU group, arterial partial pressure of oxygen (PaO2) and mean pulmonary artery pressure (MPAP) improved compared with the control group (PaO2, 319 +/- 44 mm Hg vs. 57 +/- 3 mm Hg; MPAP, 32 +/- 2 mm Hg vs. 41 +/- 2 mm Hg; values at 6 hrs after induction of ALI; P < 0.05). Mean arterial pressure and cardiac output were not different between groups. ET-1 plasma concentrations increased from 0.96 +/- 0.06 fmol/ml after induction of ALI to a maximum of 1.17 +/- 0.09 fmol/ml at 3 hrs after ALI onset in the LU group and did not differ significantly from the control group (1.21 +/- 0.08 fmol/ml, not significant). On histologic examination, we found no differences in total lung injury score between groups. However, the LU group revealed significantly reduced interstitial inflammation and hemorrhage (P < 0.05 vs. control group). In this animal model of ALI, inhalation of LU-135252 at a dose of 0.3 mg/kg induced a significant and sustained improvement in gas exchange, whereas there were no changes in ET-1 plasma concentrations. Furthermore, our data indicate a trend toward decreased pulmonary inflammation in the group receiving the inhaled ET(A) receptor antagonist.

Topics: Acute Disease; Administration, Inhalation; Animals; Blood Pressure; Cardiac Output; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin-1; Inflammation; Lung Diseases; Phenylpropionates; Prospective Studies; Pulmonary Gas Exchange; Pyrimidines; Random Allocation; Swine

Beneficial effects of inhaled nitric oxide (iNO) on arterial oxygenation in acute lung injury (ALI) suggest the presence of vasoconstriction in ventilated lung regions and this may be influenced by endothelin-1 (ET-1). We studied a possible interaction between ET-1 and iNO in experimental ALI. Sixteen piglets were anesthetized and mechanically ventilated (inspired O2 fraction, 1.0). After induction of ALI by surfactant depletion, animals were randomly assigned to either inhale 30 ppm NO (iNO group, n = 8), or to receive no further intervention (controls, n = 8). Measurements were performed during the following 4 hrs. In all animals, induction of ALI significantly decreased arterial oxygen tension (PaO2) from 569 +/- 15 (prelavage) to 58 +/- 3 mm Hg. Inhaled NO significantly increased PaO2 when compared with controls (iNO group: 265 +/- 51 mm Hg; controls: 50 +/- 4 mm Hg, values at 4 hrs, P < 0.01). Prelavage ET-1 plasma levels were comparable between groups (iNO: 0.74 +/- 0.03, controls: 0.71 +/- 0.03 fmol/ml, NS). During the protocol, the ET-1 levels increased and were different at 3 hrs (iNO: 0.93 +/- 0.06, controls: 1.25 +/- 0.09 fmol/ml; P < 0.05). PaO2 changes induced by iNO revealed a moderate and significant correlation with ET-1 plasma levels (R = 0.548, P = 0.001). Our data suggest that endogenous ET-1 production influences the efficacy of iNO in ALI. Furthermore, iNO reduced ET-1 plasma levels, possibly indicating anti-inflammatory properties of iNO in the early phase of ALI.

Topics: Acute Disease; Administration, Inhalation; Animals; Disease Models, Animal; Endothelin-1; Lung; Lung Injury; Nitric Oxide; Pulmonary Gas Exchange; Random Allocation; Swine

Although Mycoplasma pneumoniae infection is known to be associated with acute wheezing and the exacerbation of asthma, the mechanism by which this pathogen contributes to the development of wheeze-related symptoms is not fully understood. The aim of our study was to examine serum endothelin (ET)-1 and other cytokines in acute M. pneumoniae pneumonia and investigate if there is any relation between these inflammatory mediators and the occurrence of wheezing. We studied 53 patients, aged 3-13 yr, who admitted with pneumonia. These patients were divided into three groups: M. pneumoniae pneumonia with wheeze (n=23) and without wheeze (n=19), and the patients without the evidence of M. pneumoniae infection (n=11). Age-matched controls (n=10) were also studied. The serum concentrations of ET-1, interleukin (IL)-5 and IL-18 were measured using ELISA kits in patient groups and controls. The patients with M. pneumoniae pneumonia had significantly higher serum ET-1 than those without evidence of M. pneumoniae infection. In the presence of M. pneumoniae pneumonia, ET-1 concentrations were significantly higher in the patients with wheeze than those without wheeze. IL-5 and IL-18 in each patient group were higher compared to controls. However, no significant between-group difference was observed. Total serum IgE levels were significantly higher in the patients with M. pneumoniae pneumonia and wheeze than in those without wheeze. A positive correlation was observed between serum ET-1 and total IgE in the patients with M. pneumoniae pneumonia and wheeze. Our results may suggest a role of ET-1 in the occurrence of acute wheezing or exacerbation of asthma associated with M. pneumoniae pneumonia.

Topics: Acute Disease; Adolescent; Child; Child, Preschool; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoglobulin E; Interleukin-18; Interleukin-5; Male; Pneumonia, Mycoplasma; Respiratory Sounds

To assess the role of serum endothelin-1 (ET-1) in the pathogenesis of central serous chorioretinopathy (CSC).. Prospective, case control study.. The serum ET-1 levels of 21 otherwise healthy patients who received a diagnosis of acute CSC (group 1) were measured with the enzyme-linked immunosorbent assay (ELISA) method at the initial visit, at the one month follow-up examination, and after complete angiographic resolution of the leakage. Nine patients with a previous diagnosis of CSC (group 2), 10 patients from the outpatient clinic (group 3), and 14 hospital employees (group 4) were also included.. The serum ET-1 levels in group 1 revealed neither correlation with the disease activity nor significant difference from the levels in groups 2 and 4. However, serum ET-1 levels in group 3 were statistically higher than the levels in groups 1 and 4.. These findings suggest no role of serum ET-1 in pathogenesis of CSC in otherwise healthy subjects.

Topics: Acute Disease; Case-Control Studies; Choroid Diseases; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Humans; Prospective Studies; Retinal Diseases

Clinical studies have documented an abrupt rise in plasma endothelin-1 (ET-1) coincident with an increase in mean arterial pressure (MAP) during the response to acute stress. We therefore examined the ET(A) and ET(B) receptor-dependent effects of ET-1 on the pressor response to acute environmental stress in ET-1-dependent hypertension. Stress was induced by administration of air jet pulses (3 min) in ET(B) receptor-deficient (ET(B) sl/sl) rats fed normal salt (NS; 0.8% NaCl), high salt (HS; 8% NaCl), and HS plus the ET(A) receptor antagonist ABT-627 (5 mg.kg(-1).day(-1)) on successive weeks. MAP was chronically monitored by telemetry. Total pressor response (area under the curve) was significantly reduced in ET(B) sl/sl rats maintained on a HS vs. NS diet [-6.8 mmHg (SD 18.7) vs. 29.3 mmHg (SD 8.1) x 3 min, P < 0.05]. Conversely, the total pressor response was augmented in both wild-type [34.2 mmHg (SD 29.2) x 3 min, P < 0.05 vs. NS] and ET(B) sl/sl rats [49.1 mmHg (SD 11.8) x 3 min, P < 0.05 vs. NS] by ABT-627. Blockade of ET(B) receptors in Sprague-Dawley rats caused an increase in basal MAP that was enhanced by HS and lowered by mixed ET(A)/ET(B) receptor antagonism; none of these treatments, however, had any effect on the pressor response. These data demonstrate that increasing endogenous ET-1 suppresses the pressor response to acute stress through ET(A) receptor activation in a genetic model of ET-1-dependent hypertension. These results are consistent with reports that ET-1 can attenuate sympathetically mediated responses.

Topics: Acute Disease; Air Movements; Animals; Endothelin-1; Hypertension; Male; Rats; Rats, Inbred Dahl; Rats, Mutant Strains; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Sodium Chloride, Dietary; Stress, Physiological; Sympathetic Nervous System

Endothelin-1 (ET-1) exists in endothelial cells as well as a variety of other cell types. The presence of ET-1 and its receptors in neurons suggests its possible role as a neurotransmitter and/or neuromodulator. Studies utilizing exogenous ET-1 have suggested that ET-1 affects pain transmission. This study was designed to examine the possible role(s) of neuronal ET-1 in pain processing. We produced neuron-specific ET-1 knockout mice using the Cre/loxP system with a synapsin I promoter and examined the effects produced by the lack of neuronal ET-1 on pain behavior using common pain models and a model of stress-induced analgesia. In acute nociceptive pain models, paw withdrawal thresholds to radiant heat and mechanical stimuli applied with von Frey hairs were significantly lower in the knockout mice compared with control. This indicated that the absence of neuronal ET-1 leads to greater sensitivity to acute nociceptive stimuli. After inflammation was produced by intraplantar injection of carrageenan, there was a significantly greater degree of thermal hyperalgesia and mechanical allodynia in the knockout mice even after the difference in baseline values was compensated. Furthermore, in a neuropathic pain model produced by spinal nerve ligation, there was also a greater degree of mechanical allodynia in the knockout mice. Finally, in a swim-stress model, the magnitude of stress-induced analgesia was less in the knockout mice, indicating the involvement of neuronal ET-1 in stress-induced analgesia. The results suggest that there is a basal release of ET-1 from neurons that affect baseline pain thresholds as well as an additional release during persistent pain states that acts to suppress the pain. The involvement of neuronal ET-1 in stress-induced analgesia further suggests its role in endogenous pain inhibitory systems. To confirm that ET-1 is released in persistent pain states and to determine which part of the CNS is involved, we measured the concentrations of ET-1 before and after inducing peripheral inflammation in different parts of the CNS involved in endogenous pain inhibitory systems in normal mice. We found that ET-1 was increased in the hypothalamus while no significant increase was observed in the midbrain, medulla and spinal cord. The results of the present study suggest that neuronal ET-1 is involved in endogenous pain inhibitory control likely via pathways through the hypothalamus.

Topics: Acute Disease; Animals; Disease Models, Animal; Endothelin-1; Hyperalgesia; Hypothalamus; Mice; Mice, Knockout; Neural Inhibition; Neural Pathways; Neurons; Pain; Pain Measurement; Pain Threshold; Pain, Intractable; Peripheral Nervous System Diseases; Physical Stimulation; Promoter Regions, Genetic; Reaction Time; Stress, Physiological; Synapsins

Ischaemia-reperfusion (IR)-associated microcirculatory changes play a major role in acute post-transplantation pancreatitis. The pathophysiological role of platelets in these events is unknown. The aim of this study was to examine platelet adhesion and function during early reperfusion after pancreatic ischaemia.. Rats were subjected to warm pancreatic ischaemia by cross-clamping of the pancreatic vessels for 1 h. After 1 h of reperfusion, platelet-endothelium interaction was evaluated after platelet separation and staining by fluorescence microscopy. Amylase levels and pancreatic histology were evaluated 24 h after reperfusion. Animals treated according to an identical protocol, but without ischaemia, served as controls.. Mild pancreatitis had developed by 24 h after IR; serum amylase levels were significantly higher than those in control animals. The numbers of adherent platelets in capillaries and venules were significantly increased, and platelet velocity in capillaries was significantly decreased, in the IR group compared with controls. There was significantly more oedema and inflammation in pancreatic tissue after IR.. Warm ischaemia for 1 h followed by reperfusion for 24 h caused mild pancreatitis in this experimental model. The pancreatic microcirculation was characterized by pronounced platelet-endothelium interaction in capillaries and venules. These results suggest that platelet activation may play an important role in acute post-transplantation pancreatitis.

Topics: Acute Disease; Animals; Blood Platelets; Constriction; Endothelin-1; Male; Pancreas; Pancreatitis; Platelet Adhesiveness; Rats; Rats, Wistar; Reperfusion Injury; Thromboxane A2

Coronary effects of endothelin-1 and vasopressin during acute hypotension, and the role of NO and prostanoids in these effects were examined in anesthetized goats. Left circumflex coronary artery flow was measured electromagnetically, and hypotension was induced by constriction of the caudal vena cava in animals non-treated (7 goats) or treated with the inhibitor of NO synthesis N(w)-nitro-L-arginine methyl esther (L-NAME, 5 goats), the cyclooxygenase inhibitor meclofenamate (5 goats) or both drugs (5 goats). Under normotension (22 goats), mean arterial pressure averaged 93 +/- 3 mm Hg and coronary vascular conductance (CVC) 0.37 +/- 0.025 ml/min/mm Hg. Endothelin-1 (0.01-0.3 nmol) and vasopressin (0.03-1 nmol), intracoronarily injected, dose-dependently decreased CVC by up to 56% for endothelin-1 and 40% for vasopressin. During hypotension in every condition tested, mean arterial pressure decreased to approximately 60 mm Hg, and CVC only decreased during hypotension pretreated with L-NAME (23%) or L-NAME + meclofenamate (34%). Under non-treated hypotension, the decreases in CVC by endothelin-1 were augmented approximately 1.5 fold, and those by vasopressin were not modified. This increase in CVR by endothelin-1 was not affected by L-NAME and was reversed by meclofenamate or L-NAME + meclofenamate. The coronary effects of vasopressin were not modified by any of these treatments. Therefore, acute hypotension increases the coronary vasoconstriction in response to endothelin-1 but not to vasopressin. This increased response to endothelin-1 may be related to both inhibition of NO release and release of vasoconstrictor prostanoids.

Topics: Acute Disease; Anesthesia; Animals; Blood Pressure; Coronary Circulation; Cyclooxygenase Inhibitors; Disease Models, Animal; Endothelin-1; Female; Goats; Hypotension; Meclofenamic Acid; NG-Nitroarginine Methyl Ester; Nitric Oxide; Vasoconstriction; Vasopressins

Severe sepsis is associated with increased total peripheral resistance (TPR) and decreased organ blood flow, in which endothelin-1 (ET-1) plays an important role. Plasma levels of ghrelin, a newly-identified endogenous ligand for growth hormone secretagogue receptor and a potent vasodilatory peptide, are significantly reduced in sepsis. Ghrelin downregulation heralds the hypodynamic response in severe sepsis. Therefore, we hypothesized that the administration of exogenous ghrelin improves organ blood flow by downregulation of ET-1 under such conditions.. Male adult Sprague-Dawley rats were subjected to sepsis by cecal ligation and puncture (CLP). At 5 h post-CLP, a bolus intravenous injection of 2 nmol ghrelin was followed by a continuous infusion of 12 nmol ghrelin via a primed mini-pump over 15 h. At 20 h post-CLP (i.e., severe sepsis), cardiac output (CO), stroke volume (SV), TPR, and organ blood flow were measured using (141)Ce-microspheres. Plasma ET-1 levels and preproET-1 gene expression in the liver, small intestine, and kidneys were measured by ELISA and RT-PCR, respectively. The direct effect of ghrelin on ET-1 production was studied using cultured human umbilical vein endothelial cells (HUVECs) treated with tumor necrosis factor-alpha (TNF-alpha).. Ghrelin administration reduced TPR, increased CO, SV, and organ blood flow, downregulated preproET-1 gene expression, and decreased plasma levels of ET-1 in sepsis. Ghrelin inhibited TNF-alpha-induced ET-1 release from HUVECs in a dose-dependent manner. Moreover, ghrelin inhibited TNF-alpha-induced activation of nuclear factor-kappaB (NF-kappaB) in HUVECs.. The improvement of tissue perfusion by ghrelin in severe sepsis appears to be mediated by downregulation of ET-1 involving a NF-kappaB-dependent pathway.

Topics: Acute Disease; Animals; Cells, Cultured; Colonic Diseases; Down-Regulation; Endothelial Cells; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Ghrelin; Infusions, Intravenous; Intestine, Small; Kidney; Liver; Male; Microspheres; NF-kappa B; Peptide Hormones; Perfusion; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Reverse Transcriptase Polymerase Chain Reaction; Sepsis; Tumor Necrosis Factor-alpha

To compare the accuracy of biomarkers for identifying acute chest syndrome (ACS) in patients with sickle cell disease presenting to a pediatric emergency department (ED).. We conducted a 13-month-long (2002-2003) cohort study with nested case-control in patients with sickle cell disease presenting to the pediatric ED with vaso-occlusive crises or fever in which we compared levels of secretory phospholipase A2 (sPLA2), endothelin-1, interleukin-6 (IL-6), and peripheral white blood cell count (WBC) in cases that were complicated by ACS and in control subjects with uncomplicated illnesses. For diagnosis, a test was considered to be accurate when the area under its receiver operator characteristic curve (AUC) was >0.70. Laboratory tests with AUC values > or =0.70 were entered into a binary recursive partitioning model for diagnosis.. For the period of study, samples from 72 visits were obtained from 51 patients who presented with vaso-occlusive crises (range: 1-4 visits per patient; 15 were enrolled more than once). ACS complicated 19 of 72 visits (26%, 95% confidence interval: 17%-38%). At an AUC value of 0.79, only the sPLA2 test was accurate for diagnosing ACS. AUC values for peripheral WBC, endothelin-1, and IL-6 were 0.68, 0.51, and 0.52, respectively. Binary recursive partitioning retained only sPLA2 at a cutoff of 13.7 ng/mL to be accurate for diagnosis. This cutoff had a sensitivity of 74% (14 of 19), a specificity of 87% (46 of 53), a positive likelihood ratio of 5.6, and a negative likelihood ratio of 0.18.. Secretory phospholipase A2 but not endothelin-1, IL-6, or WBC is an accurate test for identifying present or incipient ACS in young patients who present to the ED with sickle cell pain crises.

Topics: Acute Disease; Adolescent; Anemia, Sickle Cell; Area Under Curve; Biomarkers; Chest Pain; Child; Endothelin-1; Female; Humans; Interleukin-6; Leukocyte Count; Lung Diseases; Male; Phospholipases A; Phospholipases A2; Sensitivity and Specificity; Syndrome

To assess effects of NF-kappaB activation inhibitor (pyrrolidine dithiocarbamate--PDTC) alone or with endothelins (ET-1, ET-2, ET-3) in early course of cerulein-induced acute pancreatitis (AP) in rats.. After 4 h of AP in Wistar rats, treated with PDTC 10 or 40 mg/kg or with PDTC 10 mg/kg and ET-1, ET-2 or ET-3, 0.5 or 1.0 nmol/kg twice i.p. in 1 h interval, free active trypsin (FAT), total potential trypsin (TPT) and lipase in 12000 x g supernatants of pancreatic homogenates, plasma alpha-amylase and histological changes were assayed. %FAT/TPT was an index of trypsinogen activation.. %FAT/TPT significantly increased to 12.42 +/- 2.14%, lipase to 5.51 +/- 0.84 U/mg protein and alpha-amylase to 28.5 +/- 5.61 U/mL in AP vs 1.96 +/- 0.31%, 1.29 +/- 0.11 U/mg and 5.80 +/- 1.38 U/ml in healthy control. Higher dose PDTC attenuated trypsinogen activation to 3.01 +/- 0.53% and alpha-amylase to 15.3 +/- 1.38. PDTC and ET-1 attenuated %FAT/TPT to 2.55 +/- 0.18% with lower and 2.34 +/- 0.44% with higher dose. ET-3 was less effective than ET-1: 6.76 +/- 0.46% with lower dose. Lower doses of ET-1 and ET-2 with PDTC, diminished lipase activity to 2.60 +/- 0.36 and 2.94 +/- 0.33.. Cumulative attenuation of trypsinogen activation after lower dose of PDTC and ET-1 approximated the effect of higher dose of PDTC. Additional effect of ET-3 was weaker than ET-1, and ET-2 was ineffective in this respect. The combination of this NF-kappaB activation inhibitor and ET-1 could be beneficial in early course of edematous AP by attenuating of trypsinogen activation. However, it should be treated with caution because of some unfavorable effects on histological scores of pancreatic injury.

Topics: Acute Disease; alpha-Amylases; Animals; Antioxidants; Ceruletide; Endothelin-1; Endothelin-2; Endothelin-3; Enzyme Activation; Lipase; Male; NF-kappa B; Pancreatitis; Pyrrolidines; Rats; Rats, Wistar; Thiocarbamates; Trypsinogen

Pulmonary intralobar arteries express heme oxygenase (HO)-1 and -2 and release carbon monoxide (CO) during incubation in Krebs buffer. Acute hypoxia elicits isometric tension development (0.77 +/- 0.06 mN/mm) in pulmonary vascular rings treated with 15 micromol/l chromium mesoporphyrin (CrMP), an inhibitor of HO-dependent CO synthesis, but has no effect in untreated vessels. Acute hypoxia also induces contraction of pulmonary vessels taken from rats injected with HO-2 antisense oligodeoxynucleotides (ODN), which decrease pulmonary HO-2 vascular expression and CO release. Hypoxia-induced contraction of vessels treated with CrMP is attenuated (P < 0.05) by endothelium removal, by CO (1-100 micromol/l) in the bathing buffer, and by endothelin-1 (ET-1) receptor blockade with L-754142 (10 micromol/l). CrMP increases ET-1 levels in pulmonary intralobar arteries, particularly during incubation in hypooxygenated media. CrMP also causes a leftward shift in the concentration-response curve to ET-1, which is offset by exogenous CO. In anesthetized rats, pretreatment with CrMP (40 micromol/kg iv) intensifies the elevation of pulmonary artery pressure elicited by breathing a hypoxic gas mixture. However, acute hypoxia does not elicit augmentation of pulmonary arterial pressure in rats pretreated concurrently with CrMP and the ET-1 receptor antagonist L-745142 (15 mg/kg iv). These data suggest that a product of HO activity, most likely CO, inhibits hypoxia-induced pulmonary vasoconstriction by reducing ET-1 vascular levels and sensitivity.

Topics: Acute Disease; Animals; Carbon Monoxide; Endothelin-1; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Hypoxia; Male; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; Vasoconstriction

To evaluate the effect of tumor necrosis factor (TNF), endothelin (ET) and nitric oxide (NO) on hyperdynamic circulation (HC) of rats with acute and chronic portal hypertension (PHT).. Chronic portal hypertension was induced in Wistar rats by injection of carbon tetrachloride. After two weeks of cirrhosis formation, L-NMMA (25 mg/kg) was injected into one group of cirrhotic rats via femoral vein and the experiment was begun immediately. Another group of cirrhotic rats was injected with anti-rat TNFalpha (300 mg/kg) via abdominal cavity twice within 48 h and the experiment was performed 24 h after the second injection. The blood concentrations of TNFalpha, ET-1 and NO in portal vein and the nitric oxide synthase (NOS) activity in hepatic tissue were determined pre-and post-injection of anti-rat TNFalpha or L-NMMA. Stroke volume (SV), cardiac output (CO), portal pressure (PP), superior mesenteric artery blood flow (SMA flow) and iliac artery blood flow (IAflow) were measured simultaneously. Acute portal hypertension was established in Wistar rats by partial portal-vein ligation (PVL). The parameters mentioned above were determined at 0.5 h, 24 h, 48 h, 72 h and 120 h after PVL. After the formation of stable PHT, the PVL rats were injected with anti-rat TNFalpha or L-NMMA according to different groups, the parameters mentioned above were also determined.. In cirrhotic rats, the blood levels of TNFalpha, NO in portal vein and the liver NOS activity were significantly increased (P<0.05) while the blood level of ET-1 was not statistically different (P>0.05) from the control animals (477.67+/-83.81 pg/mL vs 48.87+/-32.79 pg/mL, 278.41+/-20.11 micromol/L vs 113.28+/-14.51 micromol/L, 1.81+/-0.06 u/mg.prot vs 0.87+/-0.03 u/mg.prot and 14.33+/-4.42 pg/mL vs 8.72+/-0.79 pg/mL, respectively). After injection of anti-rat TNFalpha, the blood level of TNFalpha was lower than that in controls (15.17+/-18.79 pg/mL vs 48.87+/-32.79 pg/mL). The blood level of NO and the liver NOS activity were significantly decreased, but still higher than those of the controls. The blood level of ET-1 was not significantly changed. PP, SV, CO, SMAflow and IAflow were ameliorated. After injection of L-NMMA, the blood level of NO and the liver NOS activity were recovered to those of the controls. PP and CO were also recovered to those of the controls. SV, SMAflow and IAflow were ameliorated. In PVL rats, the blood levels of TNFalpha, NO in portal vein and the liver NOS activity were gradually increased and reached the highest levels at 48 h after PVL. The blood level of ET-1 among different staged animals was not significantly different from the control animals. PP among different staged animals (2.4+/-0.18 kPa at 0.5 h, 1.56+/-0.08 kPa at 24 h, 1.74+/-0.1 kPa at 48 h, 2.38+/-0.05 kPa at 72 h, 2.39+/-0.16 kPa at 120 h) was significantly higher than that in controls (0.9+/-0.16 kPa). After injection of anti-rat TNFalpha in 72 h PVL rats, the blood level of TNFalpha was lower than that in controls (14+/-14 pg/mL vs 48.87+/-32.79 pg/mL). The blood level of NO and the liver NOS activity were significantly decreased, but still higher than those of the controls. The blood level of ET-1 was not significantly changed. PP was decreased from 2.38+/-0.05 kPa to 1.68+/-0.12 kPa, but significantly higher than that in controls. SV, CO, SMAflow and IAflow were ameliorated. After injection of L-NMMA in 72 h PVL rats, the blood level of NO and the liver NOS activity were recovered to those of the controls. PP, SV, CO, SMAflow and IAflow were also recovered to those of the controls.. NO plays a critical role in the development and maintenance of HC in acute PHT and is a key factor for maintenance of HC in chronic PHT. TNFalpha may not participate in the hemodynamic changes of HC directly, while play an indirect role by inducing the production of NO through activating NOS. No evidence that circulating ET-1 plays a role in both models of portal hypertension has been found.

Topics: Acute Disease; Animals; Antineoplastic Agents; Chronic Disease; Endothelin-1; Enzyme Inhibitors; Hypertension, Portal; Liver; Liver Circulation; Male; Nitric Oxide; Nitric Oxide Synthase; omega-N-Methylarginine; Portal Vein; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Atrium and B-type natriuretic peptides (ANP and BNP) and big endothelin (ET)-1 are markers for severity of heart failure and may be used in the quality assessment of donor hearts. Elevated cardiac troponins predict early graft failure after heart transplantation. This study evaluated the effects of acute brain death (BD) on the release of ANP, BNP, big ET-1, and cardiac troponins in an animal model.. Pigs were randomized into a BD group (n=5) and a control group (n=5). In the first group, acute BD was induced, and anesthesia was stopped. In the control animals, a sham operation was performed, and anesthesia was continued. Parameters were measured at baseline and for 13 hours postoperatively.. After acute BD, there were significant hemodynamic changes. In the control group, the BNP level was higher than in the BD group and decreased over time (P =0.016). There was no significant change in BNP release in the BD group up to 13 hours (P =0.1). ANP release remained stable over time in the control group (P =0.35) but decreased in the BD group (P =0.043). The big ET-1 levels were not different between groups. Cardiac troponin I was elevated in the BD group 5 hours after BD (P< 0.05) but remained under 1.5 mg/L throughout the study.. Acute BD did not lead to an increase of BNP and ANP levels. Moreover, intact brain function seems to augment the release of natriuretic peptides from the myocardium. Further clinical evaluation of prognostic values of natriuretic peptides for the assessment of donor hearts is necessary. Cardiac troponins are a useful additional tool in the evaluation of donor hearts.

Topics: Acute Disease; Animals; Atrial Natriuretic Factor; Brain Death; Endothelin-1; Female; Male; Models, Animal; Natriuretic Peptide, Brain; Swine; Troponin I

Vascular occlusive diseases are usually seen in the elderly but can occur even in younger patients without arteriosclerosis. We assume a vascular dysregulation as a underlying pathogenetic mechanism.. In a prospective study we analysed the clinical findings of six patients under 55 years of age, three men with retinal vein occlusions and three women with branch retinal arterial obstructions. They were examined for signs of a vascular dysregulation and the endothelin-1 (ET-1) plasma level was measured.. In all patients the ET-1 plasma level was markedly elevated. The mean value (3.72 +/- 0.8 pg/ml) was significantly increased compared to normal values for that age (1.52 +/- 0.24 pg/ml; p < 0.001). In all cases an increased tendency for vascular dysregulation could be demonstrated in nailfold capillaroscopy. Furthermore, frequent coldness of the extremities was mentioned by every patient and migraine was mentioned by four patients whereas neither changes of the vessels in carotis and ophthalmica region nor disturbances in the haemostasis and fibrinolysis could be found.. All six patients with vascular occlusive diseases occurring before the age of 55 had a vascular dysregulation and increased ET-1 plasma levels. A relationship between the vascular dysregulation and the vascular occlusive diseases is therefore likely.

Topics: Acute Disease; Adult; Endothelin-1; Endothelium, Vascular; Female; Homeostasis; Humans; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Retinal Artery Occlusion; Retinal Vein Occlusion; Risk Factors; Skin Temperature; Vascular Resistance

To investigate the hemodynamic effects of tezosentan in the intact lamb both at rest and during acute and chronic pulmonary hypertension.. Prospective, randomized experimental study.. University-based research laboratory.. Lambs with and without pulmonary hypertension.. Six newborn lambs were instrumented to measure vascular pressures and left pulmonary blood flow. The hemodynamic effects of tezosentan (0.5, 1.0, 5.0 mg/kg, intravenously) were studied at rest and during U46619-induced pulmonary hypertension. Following in utero placement of an aortopulmonary vascular graft, nine additional lambs with increased pulmonary blood flow and chronic pulmonary hypertension (shunt) were also studied at 1 wk (n = 5) and 8 wks (n = 4) of age.. At rest, tezosentan had no significant effect on any of the variables. During acute U46619-induced pulmonary hypertension, tezosentan caused a dose-dependent decrease in pulmonary arterial pressure (from 5.9% +/- 4.7 to 16.0% +/- 10.7; p < .05) and pulmonary vascular resistance (from 6.2% +/- 8.0 to 21% +/- 8.8; p < .05). Mean systemic arterial pressure was unchanged. In 1- and 8-wk-old shunt lambs with increased pulmonary blood flow, tezosentan (1 mg/kg) produced potent nonselective pulmonary vasodilation.. Tezosentan, a combined endothelin receptor antagonist optimized for parenteral use, induces potent selective pulmonary vasodilation during acute U46619-induced pulmonary hypertension and potent nonselective vasodilation in chronic pulmonary hypertension secondary to increased pulmonary blood flow. In general, the hemodynamic effects of bolus doses of tezosentan occurred within 60 secs of administration and lasted approximately 5-10 mins. The hemodynamic profile of intravenous tezosentan may make it a useful adjunct therapy for acute pulmonary hypertensive disorders and warrants further study.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acute Disease; Animals; Animals, Newborn; Chronic Disease; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Hypertension, Pulmonary; Injections, Intra-Arterial; Pulmonary Circulation; Pyridines; Random Allocation; Sheep; Tetrazoles; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

To investigate in rats the role of endothelin (ET)-1 gene expression in the development and progression of acute gastric mucosal lesions (AGML) induced by stress, and the effect of BQ-123 (a special ETA receptor antagonist) on the AGML.. A rat model of gastric ulcer induced by cold-restraint-stress (CRS) was used. ET-1 concentrations in the plasma and gastric mucosa were determined by radioimmunoassay (RIA), gastric mucosa blood flow (GMBF) was measured with a laser Doppler flow meter, the ulcer index (UI) was used to estimate the degree of gastric mucosa damage and the expression levels of ET-1 mRNA in the gastric mucosa were measured using dot blot and reverse transcription polymerase chain reaction (RT-PCR). Different doses of BQ-123 were administered via the left femoral vein prior to the stress in order to observe the effects of BQ-123 on the ET-1 concentrations in the plasma and gastric mucosa, the GMBF and the UI.. Compared with the normal controls, the ET-1 concentrations in the plasma and gastric mucosa of the stressed rats were increased significantly (P < 0.05), the GMBF was decreased markedly (P < 0.01), and the UI increased dramatically (P < 0.01). There was a significant positive correlation between the gastric mucosal EF-1 concentration and the UI (r = 0.98, P < 0.01), and a significant negative correlation between the gastric mucosal ET-1 concentration and GMBF (r = -0.89, P < 0.01) and also between the UI and GMBF (r = -0.98, P < 0.01). The expression level of ET-1 mRNA in the gastric mucosa of the stressed rats increased significantly compared with that of the normal controls (P < 0.01), and there was a positive correlation between the expression of ET-1 mRNA and the ET-1 concentration in the gastric mucosa (r = 0.93, P < 0.01). Compared with the untreated animals, the GMBF was increased (P < 0.01) and the UI decreased significantly (P < 0.01) in the BQ-123-treated rats, and the dose of BQ-123 correlated with the degree of change in the GMBF and UI; however, the ET-1 concentrations of either the plasma or the gastric mucosa did not change markedly in the BQ-123-treated animals (P > 0.05).. The present study showed that the level of expression of ET-1 mRNA and the synthesis of ET-1 in the gastric mucosa both increased significantly, which suggests that the increased concentration of endogenous ET-1 may be involved in the development and progression of stress ulcer (acute gastric mucosa lesion). The mechanism of action may be associated with a reduction of GMBF induced by ETAR-mediated vasoconstriction. BQ-123 can dose-dependently attenuate significantly the degree of damage to the gastric mucosa induced by stress, and may have therapeutic benefits for stress ulcer.

Topics: Acute Disease; Animals; Cold Temperature; Endothelin Receptor Antagonists; Endothelin-1; Gastric Mucosa; Gene Expression; Male; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Restraint, Physical; RNA, Messenger; Stomach Ulcer; Stress, Physiological

To assess the effect of endothelins: ET-1, ET-2 and ET-3 on trypsinogen activation, lipase activity and histological changes in the pancreas in early (4 hrs) cerulein acute pancreatitis (AP) in rats.. In 45 Wistar rats with cerulein induced AP (2 x 40 microg/kg i.p. at 1 hour interval, the effect of endothelins at the dose 2 x 0.5 or 2 x 1.0 nmol/kg i.p. was assessed vs untreated AP; 6 healthy rats were control (C). Free active trypsin (FAT), total potential trypsin after activation with enterokinase (TPT), lipase in 12000 xg supernatants of pancreatic homogenates and the plasma alpha-amylase were assayed. The %FAT/TPT was an index of trypsinogen activation.. %FAT/TPT increased from 3.0 +/- 0.6 in C to 16.2 +/- 3.1 in AP (p < 0.01). ET-1 decreased this index to 4.8 +/- 1.1 after higher dose (p < 0.01); the effect of lower dose was insignificant. Attenuating effect of ET-2 was significant: 7.3 +/- 1.7 after higher dose (p < 0.05) and 6.1 +/- 0.9 after lower dose (p < 0.01). ET-3 diminished this index to 4.5 +/- 1.5 (p < 0.01) and to 6.3 +/- 2.2 (p < 0.05) respectively. Lipase activity in supernatant increased from 4.1 +/- 0.6 in C to 6.3 +/- 0.7 U/mg protein in untreated AP (p < 0.05) and plasma alpha-amylase from 7.0 +/- 0.6 in C to 25.9 +/- 4.3 U/ml in AP (p < 0.001), without essential changes in treated groups vs untreated AP. Higher doses of endothelins decreased inflammatory cell infiltration score in AP.. The exogenous endothelins, especially ET-2 and ET-3 and to lesser extent ET-1 exerted some protective effect in early, edematous acute pancreatitis by the attenuation of trypsinogen activation and inflammatory cell infiltration in the pancreas.

Topics: Acute Disease; alpha-Amylases; Animals; Ceruletide; Endothelin-1; Endothelin-2; Endothelin-3; Endothelins; Enzyme Activation; Lipase; Male; Pancreatitis; Rats; Rats, Wistar; Time Factors; Trypsinogen

The role of endothelin-1 (ET-1) and of its receptor A (ETA) blockade in oedematous acute pancreatitis (AP) remains unclear. In 40 male Wistar rats with i.p. cerulein-induced AP, lasting 4 hours, ET-1 2x0.5 nmol/kg and 2x1.0 nmol/kg or selective ETA antagonist LU 302146, 10 mg/kg and 20 mg/kg was given i.p. simultaneously with cerulein. Histological and ultrastructural studies of pancreatic specimens were done. ET-1 decreased the inflammatory infiltration, but not the mean scores of necrosis and vacuolization in AP. The ultrastructural damage of acinar cells was less evident after ET-1 than in untreated AP. Selective ETA antagonist slightly aggravated the vacuolization and necrosis of acinar cells and some ultrastructural alterations in AP. In conclusion, ET-1, in contrast to selective ETA antagonist, exerts some protective effect in the early course of oedematous cerulein-induced acute pancreatitis in rats.

Topics: Acute Disease; Animals; Cytoplasmic Granules; Endothelin-1; Male; Pancreas; Pancreatitis; Rats; Rats, Wistar; Receptor, Endothelin A; Vacuoles

Wistar rats were deeply anesthetized and perfused by Hanks' solution bubbled with either 95% air and 5% CO2 (normoxic group) or 95% N2 and 5% CO2 (hypoxic group) from the thoracic aorta for 30 minutes. The isolated abdominal aortas were used for electron microscopy, immunocytochemistry of endothelin-1 (ET-1) and endothelin-converting enzyme-1 (ECE-1), and in situ hybridization of preproendothelin-1 mRNA. A remarkable increase in the number of Weibel-Palade bodies, storage sites of ET-1 and ECE-1, occurred in the hypoxic group when compared with the normoxic group. Immunoreactivities for ET-1 and ECE-1, and signals for preproendothelin-1 mRNA were seen along the endothelia of both groups, but the intensities were significantly elevated in the hypoxic group. The increase in the number of ECE-1 immunoreactive gold particles was noticed in Weibel-Palade bodies in the hypoxic group. These findings indicate the enhancement of preproendothelin-1 synthesis in the rat aortic endothelial cells and the acceleration of ET-1 processing in Weibel-Palade bodies of such cells in an acute hypoxic condition.

Topics: Acute Disease; Animals; Aorta, Abdominal; Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-Converting Enzymes; Hypoxia; Immunohistochemistry; In Situ Hybridization; Male; Metalloendopeptidases; Microscopy, Immunoelectron; Protein Precursors; Rats; Rats, Wistar; RNA, Messenger; Up-Regulation; Weibel-Palade Bodies

Endothelin-1 (ET-1), the most potent vasoconstrictor peptide, is known to play a role in arterial hypertension. In patients with acute poststreptococcal glomerulonephritis (APSGN) an increase in the production of ET-1 is suspected due to damaged endothelium, platelet activation and increased thrombin production in the glomeruli. The aim of the present study was to investigate whether the levels of plasma ET-1 are elevated in children with APSGN. Furthermore, we examined the association between plasma ET-1 levels and blood pressure levels in the same children.. We studied 18 children (14 boys) with APSGN (mean age 7.44 to approximately 2.82 years). Fourteen healthy children served as controls. The following parameters were evaluated: plasma ET-1, plasma atrial natriuretic peptide (ANP), plasma renin (Rn), serum aldosterone (Aldo), creatinine clearance (Ccr) and fractional excretion of sodium (FENa).. The mean plasma ET-1 concentrations were higher in patients with APSGN (3.39 to approximately 1.86 pg/mL) compared to controls (1.40 to approximately 0.15 pg/mL; P=0.0001). Patients with APSGN also had higher plasma ANP concentrations (41.67 to approximately 27.99 pg/mL) than the controls (22.80 to approximately 4.24 pg/mL; P=0.011). Plasma Rn concentrations were lower in patients (24.54 to approximately 16.34 microU/mL) compared to controls (56.76 to approximately 32.36 microU/mL; P=0.027). A positive correlation was found between ET-1 plasma concentrations and the height of systolic or diastolic blood pressure (r=0.57, P=0.013 and r=0.53, P=0.023, respectively).. Our results suggest that increased plasma ET-1 concentrations may play an important role in the pathogenesis of hypertension in children with acute poststreptococcal glomerulonephritis.

Topics: Acute Disease; Child; Endothelin-1; Female; Glomerulonephritis; Humans; Hypertension; Male; Streptococcal Infections

Severe acute pancreatitis is occasionally associated with pancreatic and intestinal necrosis. Mesenteric vasoconstriction is one of the most probable types of pathogenesis of these complications.. To investigate the involvement of endothelin-1 (ET-1), a potent vasoconstrictor.. Plasma ET-1 concentrations were extremely high in patients with pancreatic and/or diffuse intestinal necrosis. ET-1 mRNA was demonstrated in the rat pancreas, and the production of ET-1 protein by human umbilical vein endothelial cells was enhanced by tumor necrosis factor-alpha, thrombin, and protease-activated receptor-2-activating peptide. Administration of ET-1 in vivo induced mesenteric arterial spasm and decreased pancreatic and intestinal blood flow.. These results suggest the following: ET-1 is produced in and around the pancreas, mainly by endothelial cells, in severe acute pancreatitis; in the inflammatory setting, cytokines, activated thrombin and trypsin, may stimulate ET-1 production in a paracrine fashion; produced ET-1 may exaggerate the splanchnic microcirculation; and progressive ischemia may lead to necrosis of the pancreas and intestine.

Topics: Acute Disease; Adolescent; Adult; Aged; Animals; Endothelin-1; Female; Humans; Intestines; Ischemia; Male; Mesenteric Arteries; Middle Aged; Necrosis; Pancreas; Pancreatitis; Rats; Rats, Wistar; RNA, Messenger; Vasoconstriction

To inquire into effects of cytokines and other inflammatory media, and peptide hormones during multiple organ dysfunction syndrome (MODS) subsequent to acute abdominal diseases.. In 19 patients with MODS due to acute abdominal diseases, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), thromboxane B(2) (TXB(2)), 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)), endotoxin, gene-related peptide(CGRP), endothelin-1 (ET-1) and substance P (SP) in plasma, and lipid peroxide (LPO) and nitric oxide (NO) in serum were determined dynamically.. Both TNF-alpha and IL-6 at increased significantly in MODS patients; IL-6 on day 0 in patients without treatment of endoscopic retrograde bile duct drainage (ERBD) were higher than that in patients with correspondent treatment, IL-6 in severe acute cholangitis patients was higher than that in patients with acute necrotic pancreatitis, it approached 24,000 ng/L during toxic shock. TNF-alpha and IL-6 during early stage of MODS were higher than that during systemic inflammatory response syndrome (SIRS) respectively. Endotoxin and LPO levels in MODS patients increased significantly. The levels of NO in emergency patients with MODS was elevated, but lowered in patients with acute necrotic pancreatitis, hepatocarcinoma, advanced age's patients with long time fever due to hepatic abscess. TXB(2) and 6-keto-PGF(1alpha) during early stage rose significantly, both decreased after treatment. ET-1 and CGRP during early stage increased significantly, SP peaked on day 0.. The level of IL-6 persistently higher than 300 ng/L suggests the diagnosis of MODS. The levels of IL-6 and TNF-alpha could be taken as an indication of the degree of SIRS. NO maybe either increased or decreased, ET-1, CGRP, TXB(2), 6-keto-PGF(1alpha), endotoxin, and LPO are found to be increased MODS.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Cytokines; Digestive System Diseases; Endothelin-1; Female; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Multiple Organ Failure; Peptide Hormones; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor-alpha

Topics: Acute Disease; Aged; Aged, 80 and over; C-Reactive Protein; E-Selectin; Endothelin-1; Female; Heart Failure; Humans; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-6; Male; Middle Aged; Myocardial Ischemia; Natriuretic Peptide, Brain; Neurotransmitter Agents; Norepinephrine; P-Selectin; Pulmonary Edema; Sympathomimetics; Tumor Necrosis Factor-alpha

Acute pulmonary air embolism (APAE) was induced in nine piglets by repeated intravenous bolus injection of room air into a large bore central venous catheter at time=0 min so that the mean pulmonary artery pressure (MPAP) was maintained at two times the baseline value for 4 h. Another five animals served as controls. At time=0, 30, 60, 120, 240 min, circulating arterial plasma levels of endothelin-1 (ET-1), its precursor big ET-1, and thromboxane (Tx), were measured by RIA and EIA, respectively, along with hemodynamics and blood gases. The data showed that following APAE, there was a rapid increase in MPAP and a persistent decrease in Pa(O(2)), while the mean arterial blood pressure and cardiac output remained comparable. Plasma levels of ET-1, big ET-1 and Tx were also increased steadily in these first 4 h. These results showed that during APAE, the resulted changes in the pulmonary vascular and airway tones mediated by these potent mediators could explain the observed pulmonary hypertension and the deterioration of gas exchange.

Topics: Acute Disease; Animals; Disease Models, Animal; Embolism, Air; Endothelin-1; Hemodynamics; Pulmonary Embolism; Random Allocation; Swine; Thromboxanes

Endothelin (ET)-1 is causatively involved in ischemia-reperfusion induced acute inflammatory reactions and microcirculatory disturbances in many organs. We investigated the role of endothelin-1 in the microcirculatory consequences of ischemia-reperfusion of the bladder using intravital fluorescence videomicroscopy.. Male Sprague-Dawley rats were used in the experiments. The animals were randomly assigned to a sham operated group or to 1 of 2 ischemia-reperfusion groups that underwent 60 minutes of ischemia followed by 30 minutes of bladder reperfusion. In 1 ischemia-reperfusion group the animals were pretreated with BQ 610, a specific ET-A receptor blocker. The bladder was placed on an especially designed stage for intravital fluorescence videomicroscopy measurements. Venular red blood cell velocity, functional capillary density, venular and arteriolar diameter, venular and arteriolar macromolecular leakage, and leukocyte-endothelial cell interactions in postcapillary venules were determined using a computer assisted analyzing system.. Functional capillary density, red blood cell velocity, venular and arteriolar diameter were significantly decreased and macromolecular leakage was significantly enhanced after bladder ischemia-reperfusion. The number of rolling and adherent leukocytes was significantly increased in postcapillary venules. Pretreatment with BQ 610 was effective for attenuating the effects of ischemia-reperfusion induced inflammation but could not completely prevent microcirculatory failure.. Ischemia-reperfusion induced cystitis leads to significant impairment of the microcirculation and ET-1 is suggested to have an important role in this process. Pretreatment with an ET-A receptor antagonist reduces ischemia-reperfusion related microvascular disturbances in the bladder.

Topics: Acute Disease; Animals; Cystitis; Endothelin Receptor Antagonists; Endothelin-1; Male; Microcirculation; Oligopeptides; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Reperfusion Injury; Urinary Bladder

Chagas' disease is caused by the intracellular protozoan Trypanosoma cruzi. Here we have investigated the role of endothelin-1 in T. cruzi acute infection in rats, using the orally active ET(A) receptor antagonist BSF-461314. Treatment with BSF-461314 markedly increased parasitaemia, but animals managed to control the infection by day 15. Histopathological analysis of heart tissue at the end of the acute phase showed greater numbers of parasite nests in BSF-461314-treated animals. The perfusion of isolated rat hearts from infected animals with bradykinin failed to induce an increase, and actually reduced, coronary blood flow. Pretreatment with BSF-461314 prevented changes in coronary flow induced by T. cruzi infection. Together these results demonstrate that endothelin-1, through ET(A) receptor activation, contributes to the protective immune response against acute T. cruzi infection. Moreover, these data suggest that endothelin-1 is a mediator of impaired endothelium-dependent vasomotion in the coronary microcirculation associated with acute T. cruzi infection.

Topics: Acute Disease; Animals; Bradykinin; Chagas Cardiomyopathy; Endothelin Receptor Antagonists; Endothelin-1; Heart; Male; Models, Animal; Parasitemia; Perfusion; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Vasodilator Agents

This study aims to investigate the role of endothelin-1 (ET-1) in the genesis of acute ischaemic arrhythmias. In anaesthetized cats and rats receiving continuous monitor of electrocardiogram and arterial blood pressure, the ischaemic arrhythmias during 60-min myocardial ischaemia elicited by the occlusion of the left anterior descending coronary artery (LAD) were analysed. To prevent the putative arrhythmic effects of endogenous ET-1, ET(A) receptor antagonist BQ610 (1.5-6.0 nmol/kg) was intracoronary injected just before LAD occlusion in cats, and preproET-1 mRNA antisense oligodeoxynucleotide (AS-ODN; 30-90 nmol/kg) was intravenously injected 2 h before LAD occlusion in rats. The results showed that BQ610 dose-dependently decreased the incidences of ventricular tachycardia (VT) and ventricular fibrillation (VF), and the numbers of ventricular ectopic beats (VEBs). At the dose of 6.0 nmol/kg, the incidence of VT decreased significantly from 33.3% in normal saline (NS) control group to zero (P<0.01), and total VEBs decreased significantly from 831+/-162 to 158+/-51 (P<0.05). In rats receiving ET-1 AS-ODN, plasma ET-1 decreased significantly after 2 h, and remained stable at 30 min of LAD occlusion. However, in rats receiving the control, NS or sense ODN, plasma ET-1 remained unchanged after administration, but increased significantly during LAD occlusion. The ischaemic arrhythmias were dose-dependently suppressed in the presence of ET-1 AS-ODN. At the dose of 90 nmol/kg, the incidence of VT decreased significantly from 100% in both the control groups to 30%. The numbers of single VEBs, consecutive VEBs, VT and total VEBs were also significantly decreased, from 60+/-15 in NS group to 19+/-12, 11+/-3 to 2+/-2, 155+/-41 to 11+/-11, and 239+/-49 to 35+/-25 respectively. In the present cat and rat models of coronary artery occlusion, antagonism of either ET(A) receptors or endogenous ET-1 synthesis prevented the ischaemic arrhythmias, indicating that ET-1 is possibly an important promotive factor in the genesis of acute ischaemic arrhythmias.

Topics: Acute Disease; Animals; Arrhythmias, Cardiac; Blood Pressure; Cats; Electrocardiography; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Male; Myocardial Ischemia; Oligonucleotides, Antisense; Oligopeptides; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A

This study compares the haemodynamic and hormonal responses during haemorrhage of conscious dogs pre-treated with an endothelin-A (ET-A) receptor inhibitor. The dogs were studied in two different randomized groups: the control group and a group that was given the ET-A receptor antagonist ABT-627 (as a bolus of 1 mg x kg of body weight(-1) followed by 0.01 mg x kg body weight(-1) x min(-1) intravenously). The time-course was the same for both groups: after a 1 h baseline period (pre-haemorrhage), blood (25 ml x kg of body weight(-1)) was withdrawn within 5 min. Haemodynamics were continuously recorded and hormone levels measured after 1 h (post-haemorrhage). Thereafter, the blood withdrawn was retransfused within 5 min and haemodynamics again observed for 1 h (post-retransfusion). In ABT-627-treated dogs, the decrease in mean arterial pressure from 87+/-3 to 64+/-3 mmHg (P<0.05 versus pre-haemorrhage), and cardiac output from 2.1+/-0.1 to 1.3+/-0.1 l x min(-1) (P<0.05 versus pre-haemorrhage) and the increase in systemic vascular resistance from 3286+/-174 to 4211+/-230 dyn.s.cm(-5) (P<0.05 versus pre-haemorrhage) during acute haemorrhage are comparable with controls. During haemorrhage in controls, vasopressin levels increased from 0+/-0 to 13+/-2 pg x ml(-1) (P<0.05 versus pre-haemorrhage), angiotensin II levels increased from 9+/-1 to 28+/-9 pg x ml(-1) (P<0.05 versus pre-haemorrhage) and adrenaline levels increased from 134+/-22 to 426+/-74 pg x ml(-1) (P<0.05 versus pre-haemorrhage) whereas noradrenaline levels did not change (approx. 200 pg x ml(-1)). In ABT-627-treated dogs, vasopressin levels increased from 0.2+/-0.0 to 22.2+/-6.1 pg x ml(-1) (P<0.05 versus pre-haemorrhage and P<0.05 versus control), angiotensin II levels increased from 8+/-1 to 37+/-8 pg x ml(-1) (P<0.05 versus pre-haemorrhage), noradrenaline levels increased from 147+/-16 to 405+/-116 pg x ml(-1) (P<0.05 versus pre-haemorrhage) and adrenaline levels did not change (200 pg x ml(-1)) during haemorrhage. We conclude from our results that dogs receiving the selective ET-A inhibitor ABT-627 seem to show a different hormonal response after haemorrhage compared with controls, displaying considerably higher noradrenaline concentrations. Independent of ET-A receptor inhibition, cardiac output during haemorrhage was maintained within the control range. This may indicate that the organism is defending blood flow (cardiac output) over blood pressure during haemorrhage, and that this defence s

Topics: Action Potentials; Acute Disease; Angiotensin II; Animals; Atrasentan; Blood Pressure; Cardiac Output; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Hemorrhage; Norepinephrine; Pyrrolidines; Random Allocation; Receptor, Endothelin A; Vascular Resistance; Vasodilator Agents; Vasopressins

Acute pulmonary air embolism (APAE) injures the vascular endothelium in the lung and results in pulmonary hypertension (PH). Endothelins (ETs), a family of potent vasoactive peptides, are known to be associated with PH of various aetiologies. We evaluated the effects of ABT-627, a selective ET(A) receptor (ET(A)-R) antagonist in a rat model of APAE over 3 h. APAE rats developed a higher right ventricular systolic pressure (RVSP), lower mean arterial blood pressure (MABP), and had lower PaO(2). At 3 h, arterial plasma levels of ET-1 were increased. ABT-627-treated controls showed no effects. However, ABT-627 significantly lowered RVSP during APAE, abolished the short recovery phase (within 10-25 min) of MABP without affecting the subsequent lowering of MABP, and improved oxygen saturation in APAE rats. These results show that ET(A)-R subtype is involved in the pathogenesis of APAE since a blockade of this receptor subtype attenuated the cardiopulmonary deterioration and improved blood gas exchanges in rats with this disease.

Topics: Acute Disease; Animals; Atrasentan; Embolism, Air; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-3; Gene Expression; Lung; Male; Models, Animal; Oxygen; Pulmonary Embolism; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin

The coronary effects of endothelin-1 (ET-1) during acute hypertension were examined in anesthetized goats, where the left circumflex coronary artery flow was electromagnetically measured and hypertension was induced by constriction of the thoracic aorta. In six non-treated goats, aortic constriction increased arterial pressure (mean arterial pressure=128+/-5 mmHg) and coronary flow (by 34%) without changing coronary vascular conductance. In this case, ET-1 (0.01-0.3 nmol) when injected intracoronarily, decreased coronary vascular conductance, which was similar in hypertension and in normotension. In eight N(G)-nitro-L-arginine methyl ester-treated goats, aortic constriction increased arterial pressure (mean arterial pressure=131+/-5 mmHg) and coronary flow (by 26%) and decreased coronary vascular conductance (by 17%). In this case, ET-1 (0.01-0.3 nmol) also decreased coronary vascular conductance, which was similar in N(G)-nitro-L-arginine methyl ester-treated hypertension that observed in normotension. Therefore, acute hypertension attenuates the coronary vasoconstriction caused by ET-1, and this attenuation might be related to mechanisms other than changes in NO release.

Topics: Acute Disease; Animals; Coronary Circulation; Endothelin-1; Enzyme Inhibitors; Female; Goats; Hypertension; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Vascular Resistance; Vasoconstrictor Agents

The effects of endothelin (ET) agonists on airway mechanics and bronchial blood flow were studied as well as the effects of mixed ET-receptor antagonist bosentan on allergen-induced airway reactions in the pig. ET agonists [ET-1, ET-3, and the ET(B) receptor-selective agonist Sarafotoxin 6c (Sf6c)] were given as intravenous injections (0.4-200 pmol/kg) to eight anesthetized pigs. Bosentan (10 mg/kg iv) was then administered, and the injections were repeated. Only Sf6c caused a significant increase in airway resistance, and this response was blocked by bosentan. Sf6c and ET-1 (200 and 400 pmol/kg, respectively) were also given as aerosols to five pigs. Sf6c, but not ET-1, caused bronchoconstriction via this route. All agonists (intravenous) caused increases in bronchial vascular conductance, an effect that was blocked by an NO-synthase inhibitor (N(G)-nitro-L-arginine) but unaffected by a cyxlooxygenase inhibitor (diclofenac). Fourteen pigs were sensitized with ascaris suum antigen. Under anesthesia, eight pigs were pretreated with bosentan, and six pigs were controls. They were all challenged with allergen aerosol resulting in acute bronchoconstriction and elevation of ET-1 in bronchoalveolar lavage fluid. Bosentan did not affect the maximal acute airway obstruction but markedly increased baseline bronchial vascular conductance, suggesting a basal vascular tone regulated by ETs. In conclusion, ETs induce bronchoconstriction primarily via the ET(B) receptor in the pig. However, ETs are probably not involved in the allergen-induced acute bronchoconstriction in this model.

Topics: Acute Disease; Airway Resistance; Animals; Ascaris suum; Bosentan; Bronchi; Bronchoconstriction; Bronchoconstrictor Agents; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Hypersensitivity; Pulmonary Circulation; Sulfonamides; Swine; Viper Venoms

Renal failure occurs in approximately 55% of patients with acute liver failure. We have previously shown that plasma endothelin 1 concentrations are elevated in patients with acute liver failure and the hepatorenal syndrome. There are few reported satisfactory animal models of liver failure together with functional renal failure. In this study, a rat model of acute liver failure induced by galactosamine that also develops renal failure was first characterised. This model was used to investigate the hypothesis that endothelin 1 is an important mediator involved in the pathogenesis of renal impairment that occurs in acute liver failure.. Acute liver failure was induced in male Sprague-Dawley rats by intraperitoneal injection of galactosamine together with treatment with the endothelin receptor antagonist Bosentan. Twenty four hour urine collections were made using a metabolic cage. Renal blood flow was measured in anaesthetised animals.. This model developed renal failure and liver failure in the absence of any significant renal pathology, and with an accompanying fall in renal blood flow. Plasma concentrations of endothelin 1 were increased twofold following the onset of liver and renal failure (p<0.05), and there was significant upregulation of the endothelin receptor A (ET(A)) in the renal cortex (p<0.05). Administration of Bosentan prevented the development of renal failure when given before or 24 hours after the onset of liver injury (p<0.05) but had no effect on liver injury itself, or on renal blood flow.. This study demonstrates that this animal model has many of the features needed to be regarded as a model of renal failure that occurs in acute liver failure. The observation that plasma levels of endothelin 1 and ET(A) receptors are increased and upregulated, and that renal failure is prevented by an endothelin antagonist supports the hypothesis originally put forward that ET(A) is important in the pathogenesis of renal failure that occurs in patients with acute liver failure.

Topics: Acute Disease; Analysis of Variance; Animals; Antihypertensive Agents; Biomarkers; Bosentan; Cells, Cultured; Endothelin Receptor Antagonists; Endothelin-1; Galactosamine; Hepatorenal Syndrome; Male; Microscopy, Electron; Osmolar Concentration; Rats; Rats, Sprague-Dawley; Renal Circulation; Statistics, Nonparametric; Sulfonamides; Up-Regulation

Deeply anesthetized male Wistar rats were perfused by Hanks' balanced salt solution bubbled with either 95%air and 5%CO2 (normoxic group) or 95%N2 and 5%CO2 (hypoxic group) from the thoracic aorta for 30 min, and the isolated abdominal aortae from both groups were used for electron microscopy, immunocytochemistry of endothelin (ET)-1 and ET-converting enzyme (ECE)-1, and in situ hybridization of preproET-1 mRNA. A remarkable increase in the number of Weibel-Palade (WP) bodies, storage sites of ET-1 and ECE-1, occurred in the hypoxic group when compared to the normoxic group. Immunoreactivities for ET-1 and ECE-1, and signals for preproET-1 mRNA were seen along the endothelia of both groups, but the intensities were significantly elevated in the hypoxic group. The increase in the number of ECE-1 immunoreactive gold particles was noticed especially in WP bodies in the hypoxic group. These findings indicate the enhancement of preproET-1 synthesis in the aortic endothelial cells as well as the acceleration of ET-1 processing in increased WP bodies in such cells in an experimentally hypoxic condition of the rat aortae.

Topics: Acute Disease; Animals; Aorta, Thoracic; Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Hypoxia; Immunohistochemistry; In Situ Hybridization; Male; Metalloendopeptidases; Microscopy, Electron; Microscopy, Immunoelectron; Protein Precursors; Rats; Rats, Wistar; RNA, Messenger; Signal Transduction; Vasoconstriction; Weibel-Palade Bodies

Endothelin-1 (ET-1) has been formerly demonstrated to have potent vasocontractile as well as bronchoconstrictor effects in vitro. This followup study was aimed to evaluate the possible changes in ET-1 levels in the plasma of asthmatic children, according to disease activity and severity.. Plasma ET-1 was estimated by enzyme-linked immunoadsorbent assay in 30 asthmatic patients (6 to 12 years old) during and after remission of an acute attack. Thirty age- and sex-matched healthy children were included as a control group.. Plasma ET-1 immunoreactivity was significantly increased in the asthmatic children during the attacks (17.2+/-6.9 pg/mL) in comparison to the levels during quiescence of symptoms (0.9+/-1.13 pg/mL). Further, both values were significantly higher than the control value (0.22+/-0.29 pg/mL). The severity of attacks as judged clinically and by peak expiratory flow rate measurement did not influence the plasma endothelin status; neither did the family history of atopy nor the absolute eosinophil count. However, serum total IgE levels could be positively correlated to the plasma endothelin concentrations measured after remission of the asthmatic attacks (P < 0.05).. Our findings reinforce the concept that ET-1 may be implicated in the pathogenesis of bronchoconstriction. This may encourage further studies on the value of ET-1 antagonism among alternative therapeutic modalities of childhood asthma.

Topics: Acute Disease; Asthma; Bronchial Spasm; Bronchoconstriction; Capillary Leak Syndrome; Case-Control Studies; Child; Convalescence; Endothelin-1; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Female; Fibronectins; Humans; Hypersensitivity, Immediate; Immunoglobulin E; Male; Phospholipases A; Severity of Illness Index

Filariasis, a mosquito-borne parasitic disease, is a worldwide health problem. There is still, some controversial concerning the diagnosis of acute and chronic infections. The serum levels of endothelin-1 (ET-1), interleukin-2 (IL-2) and amino-terminal propeptide Type III (PIII NP) was measured in patients with acute and chronic filariasis as compared with controls. The ET-1, IL-2 and PIII NP levels were significantly high in chronic cases than in acute. On the other hand, the serum levels of IL-2 and PIII NP were significantly high in acute cases than in the controls. These three immuno-mediators play role in the pathogenesis of filariasis particularly. The chronic cases. So, these mediators can be used as markers for diagnosis of human cases infected with chronic and acute filariasis.

Topics: Acute Disease; Adult; Animals; Chronic Disease; Endothelin-1; Female; Filariasis; Humans; Interleukin-2; Male; Peptide Fragments; Procollagen; Wuchereria bancrofti

The present study sought to determine whether increases in arterial blood pressure inhibited drinking behavior evoked by ANG II, hyperosmolality, or hypovolemia in rats. Cumulative water intakes in 60- or 90-min tests and latency to the first lick were recorded as indexes of thirst. During intravenous infusions of 100 ng. kg(-1). min(-1) ANG II, attenuation of the induced increases in arterial pressure with the arteriolar vasodilator diazoxide resulted in greater water intakes and shorter latencies to drink. Drinking behavior stimulated by intravenous infusion of hypertonic saline was significantly inhibited by increases in arterial pressure caused by intravenous infusion of phenylephrine or endothelin-1, and this inhibition of drinking was proportional to the induced increase in pressure. Upon termination of the phenylephrine infusion, mean arterial pressure returned to basal values, and drinking was restored. Phenylephrine-induced increases in arterial pressure also inhibited drinking behavior in response to hypovolemia that could not be explained by differences in plasma renin activity, plasma protein concentration, or plasma osmolality. Thus increases in arterial pressure inhibit water drinking behavior in response to each of these three thirst stimuli in rats.

Topics: Acute Disease; Angiotensin II; Animals; Blood Pressure; Drinking; Drinking Behavior; Endothelin-1; Hypertension; Hypovolemia; Infusions, Intravenous; Male; Osmotic Pressure; Phenylephrine; Polyethylene Glycols; Potassium; Pressoreceptors; Rats; Rats, Sprague-Dawley; Saline Solution, Hypertonic; Sodium; Solvents; Thirst; Urine; Vasoconstrictor Agents

Endothelin-1 has been shown to reduce pancreatic blood flow and cause focal acinar cell necrosis similar to those seen in acute pancreatitis (AP), whereas therapy with endothelin receptor antagonists enhanced pancreatic capillary blood flow (PCBF) and decreased mortality rates. The current study evaluated the role of endothelin in the development of severe AP. Trypsinogen activation peptides, acinar cell necrosis, and PCBF were used as local indicators of disease severity, fluid sequestration, cardiorespiratory and renal parameters, and colonic capillary blood flow as systemic disease indicators. The following groups of animals were examined: 1) rats with mild edematous AP and 2) severe necrotizing AP treated with and without endothelin, 3) transgenic rats overexpressing endothelin with severe AP, and 4) rats with severe AP prophylactically treated with endothelin receptor antagonists. The following observations were made: endothelin superimposed on mild AP caused hemoconcentration, a decrease in PCBF, and necrosis and ascites not seen in this model without endothelin exposure. Endothelin superimposed on severe AP had no significant effects. After induction of severe AP, less PCBF and more acinar cell necrosis were observed in transgenic rats than in their normal littermates. Prophylactic endothelin receptor antagonists improved local (acinar necrosis, PCBF) and systemic parameters (ascites, urine production, colonic capillary blood flow) of disease severity in animals with severe AP. These observations underscore the role of endothelin as a mediator of disease severity in AP and suggest that endothelin receptor blockade may become a promising therapeutic tool in this disease.

Topics: Acute Disease; Animals; Animals, Genetically Modified; Blood Pressure; Capillaries; Ceruletide; Edema; Endothelin-1; Gene Expression; Hematocrit; Male; Pancreas; Pancreatitis; Pancreatitis, Acute Necrotizing; Rats; Rats, Sprague-Dawley

Circulating and urinary levels of endothelin (ET), an endothelium-derived vasoconstrictive and mitogenic peptide have been reported to increase in patients with chronic obstructive pulmonary disease (COPD), but the mechanisms of these abnormalities are not fully understood. Our study objectives were to evaluate pulmonary and renal ET clearance in COPD patients during an acute exacerbation. Our participants included nine consecutive patients with moderate to severe COPD without signs of right heart failure admitted for acute exacerbation and ten healthy volunteers (HV) as controls. ET was detected by radioimmunoassay in venous and arterial blood as well as in a timed urine specimen. For each subject, arterial/venous immunoreactive ET ratio (ir-ETart/ir-ETven) was evaluated as an index of its pulmonary clearance. Creatinine clearance was employed in each case to obtain a corrected renal ir-ET clearance. Glomerular filtration rate (GFR) was also assessed by dynamic(99m)Tc-diethylenetriamine pentaacetic acid renal scintigraphy in six COPD patients during acute exacerbation and at recovery. The ratio ir-ETart/ir-ETven was comparable in COPD patients (0.75+/-0.12) and in HV (0.82+/-0.09). A significant difference was found with respect to 24 h ir-ET urinary excretion between COPD patients during exacerbation as well as at recovery (respectively 142.1+/-12.8 ng/24 h and 89.0+/-15.1 ng/24 h) and HV (65.1+/-10.1 ng/24 h). ET renal clearance was higher in COPD patients than in HV (29.2+/-5.2 ml min(-1)in COPD during exacerbation; 17.5+/-3.9 ml min(-1)at recovery and 13.6+/-2.4 ml min(-1)in HV, P<0.001). GFR was 69.4+/-10.0 ml min(-1)in COPD patients during exacerbation and it significantly increased at the recovery (95.5+/-20.9 ml min(-1)P<0.001). Corrected renal clearance of the peptide was significantly correlated to GFR values during the exacerbation (r=-0.81, P<0.05). Furthermore change in renal ET production resulted associated with changes in paCO(2)(r=0.83, P<0.001) and in paO(2)(r=-0.73, P<0.05). Acute exacerbation in COPD patients causes an increase in renal ET production which is partially reversible at the recovery, in the absence of significant changes in ET-1 circulating levels. ET might contribute to the renal response to hypoxaemia and hypercapnia in COPD.

Topics: Acute Disease; Aged; Endothelin-1; Glomerular Filtration Rate; Humans; Hypercapnia; Hypoxia; Kidney; Lung Diseases, Obstructive; Male; Middle Aged

Topics: Acute Disease; Adult; Endothelin-1; Female; Humans; Male; Middle Aged; Osmolar Concentration; Prognosis; Subarachnoid Hemorrhage; Vasospasm, Intracranial

Topics: Acute Disease; Biomarkers; Endothelin-1; Humans; Lung Diseases, Obstructive; Sputum

The plasma endothelin-1 (ET-1) level is elevated in patients with acute pulmonary thromboembolism (APE). Whether ET-1 is a pathogenic mediator or a simple marker of APE is not known. We investigated the role of ET-1 in hemodynamic dysfunction in APE through evaluating the effects of ET(A) receptor antagonist in an experimental APE model. We also examined ET-1 expression in embolized lungs. In a canine autologous blood clot pulmonary embolism model, ET(A) receptor antagonist ZD2574 (10 mg/kg, intravenous; ZD2574 group; n = 6) or vehicle (control group; n = 5) was administered. Hemodynamic and gas exchange parameters and plasma levels of ET-1 were serially measured. Prepro-ET-1 mRNA expression and the distribution of ET-1 peptide in lung tissues were also examined. With ZD2574 pulmonary arterial pressure and pulmonary vascular resistance significantly decreased, and were lower compared with the control group. The decrease in cardiac output was also less in the ZD2574 group. Plasma ET-1 levels increased after embolization. Prepro-ET-1 mRNA expression increased in embolized lungs and ET-1 peptide expression also increased in embolized lungs, particularly in the muscular pulmonary arteries, compared with normal lungs. These findings suggest that ET-1 partially contributes to hemodynamic derangements of APE, and that ET(A) receptor antagonists might constitute a useful therapeutic tool for APE.

Topics: Acute Disease; Animals; Dogs; Endothelin-1; Hemodynamics; Pulmonary Embolism

Topics: Acute Disease; Antihypertensive Agents; Bosentan; Chronic Disease; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endothelin-1; Exercise Tolerance; Heart Failure; Hemodynamics; Humans; Phenylpropionates; Pyridines; Pyrimidines; Sulfonamides; Tetrazoles; Treatment Outcome; Vasodilator Agents

A role of the potent and long-acting vasoconstrictor peptide endothelin (ET)- I in the pathophysiology of chronic human heart failure has been postulated, based upon indirect evidence such as elevated plasma ET-1 levels and their relationship to the degree of haemodynamic impairment. Acute heart failure shares many features of chronic heart failure, albeit in an exaggerated fashion. As both the mixed ETA/ETB-receptor antagonist bosentan and the selective ETA receptor antagonist BQ 123 acutely improved the haemodynamics of chronic heart failure patients, there seems to be good reason to believe that ET-1 receptor antagonism may also be of benefit in the setting of acute heart failure. However, appropriate trials will have to be performed to document the clinical benefit of such an approach. Finally, the question remains open as to whether mixed ET-1 receptor antagonists like bosentan will prove better, worse or equal to antagonists that block the ETA, receptor only.

Topics: Acute Disease; Animals; Antihypertensive Agents; Bosentan; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Peptides, Cyclic; Receptor, Endothelin A; Receptor, Endothelin B; Sulfonamides

Blacks exhibit greater vasoconstriction-mediated blood pressure (BP) increases in response to stress than do whites. Endothelin-1 (ET-1), a potent vasoconstrictive peptide, has been proposed as having a role in racial differences in stress reactivity. We evaluated the hemodynamic and plasma ET-1 levels of 41 (23 whites, 18 blacks, mean age 18.6 years) normotensive adolescent males at rest and in response to a video game challenge and forehead cold stimulation. Measurements were performed at catheter insertion and before and immediately after the 2 stressors, which were separated by 20-minute rest periods. Blacks exhibited higher absolute levels of diastolic blood pressure, total peripheral resistance index, or both in response to catheter insertion and to the video game challenge and during recovery from video game challenge and cold stimulation (P<0. 05 for all). Blacks exhibited higher absolute levels of ET-1 at every evaluation point (P<0.05 for all) and greater increases in ET-1 in response to both stressors (ps<0.05). These findings suggest that altered endothelial function may be involved in racial differences in hemodynamic reactivity to stress and possibly in the development of essential hypertension.

Topics: Acute Disease; Adolescent; Analysis of Variance; Black People; Blood Pressure; Cold Temperature; Endothelin-1; Humans; Hypertension; Longitudinal Studies; Male; Rest; Stress, Physiological; Video Games; White People

Helicobacter pylori is recognized as a primary etiologic factor in the development of gastric disease and the product of particular significance to the virulent action of the bacterium is its cell wall lipopolysaccharide. We applied the animal model of H. pylori lipopolysaccharide-induced acute gastritis to study the effect of antiulcer agents, omeprazole and sucralfate, on the course of mucosal inflammatory responses by analyzing the interplay between the extent of epithelial cell apoptosis and the mucosal expression of endothelin-1 (ET-1), tumor necrosis factor-alpha (TNF-alpha), and the activity of constitutive (cNOS) and inducible (NOS-2) nitric oxide synthase.. Rats pretreated twice daily for 3 consecutive days with omeprazole at 40 mg/kg, sucralfate at 100 mg/kg or the vehicle, were subjected to intragastric application of H. pylori lipopolysaccharide at 50 microg/animal, and after 2, 4, and 10 additional days on the antiulcer drug or vehicle regimen their mucosal tissue used for histologic and biochemical assessment.. In the absence of antiulcer agents, H. pylori lipopolysaccharide elicited within 2 days a pattern of acute mucosal inflammatory responses accompanied by a massive epithelial cell apoptosis, a 2.9-fold increase in the mucosal expression of ET-1, an 11.7-fold enhancement in TNF-alpha, and a 9.3-fold increase in NOS-2, while cNOS activity showed a 5.5-fold decrease. The extent of mucosal inflammatory involvement reached a maximum by the 4th day and showed a decline by the 10th day. This was reflected in a marked reduction in epithelial cell apoptosis, decrease in the mucosal expression of ET-1, TNF-alpha and NOS-2, and the recovery in cNOS activity. Comparing to the vehicle controls, treatment with proton pump inhibitor, omeprazole, led at the end of a 10 day period to a 48.3% reduction in the extent of mucosal inflammatory involvement elicited by H. pylori lipopolysaccharide, while a 74.2% reduction in the mucosal inflammatory involvement was achieved with gastroprotective agent, sucralfate. Moreover, this advantage of sucralfate over omeprazole in countering the lipopolysaccharide-induced changes was reflected at the end of 10 day treatment period in a 20.4% greater decrease in apoptosis, a 47.5% greater reduction in TNF-alpha and a 50.7% greater reduction in ET-1. However, both agents exerted similar influence on the restoration of gastric mucosal cNOS activity and showed a comparable effect at the end of a 10 day treatment in countering the lipopolysaccharide-induced increase in the expression of NOS-2.. The findings suggest that an increase in the mucosal ET-1 level elicited by H. pylori lipopolysaccharide, combined with a decline in cNOS may be responsible for the induction of TNF-alpha and triggering the inflammatory process. We also show that sucralfate exhibits greater efficacy than omeprazole in suppressing the H. pylori-induced mucosal inflammatory responses. This property of sucralfate may well be due to its ability to suppress the mucosal rise in ET-1.

Topics: Acute Disease; Animals; Anti-Ulcer Agents; Apoptosis; Endothelin-1; Gastric Mucosa; Gastritis; Helicobacter pylori; Lipopolysaccharides; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Omeprazole; Rats; Rats, Sprague-Dawley; Sucralfate; Tumor Necrosis Factor-alpha; Up-Regulation

We describe the pharmacological characteristics of SM-19712 (4-chloro-N-[[(4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl)amino]carbonyl] benzenesulfonamide, monosodium salt). SM-19712 inhibited endothelin converting enzyme (ECE) solubilized from rat lung microsomes with an IC50 value of 42 nM and, at 10 - 100 microM, had no effect on other metalloproteases such as neutral endopeptidase 24.11 and angiotensin converting enzyme, showing a high specificity for ECE. In cultured porcine aortic endothelial cells, SM-19712 at 1 - 100 microM concentration-dependently inhibited the endogenous conversion of big endothelin-1 (ET-1) to ET-1 with an IC50 value of 31 microM. In anesthetized rats, either intravenous (1-30 mg/kg) or oral (10-30 mg/kg) administration of SM-19712 dose-dependently suppressed the pressor responses induced by big ET-1. In acute myocardial infarction of rabbits subjected to coronary occlusion and reperfusion, SM-19712 reduced the infarct size, the increase in serum concentration of ET-1 and the serum activity of creatinine phosphokinase. The present study demonstrates that SM-19712 is a structurally novel, nonpeptide, potent and selective inhibitor of ECE, and SM-19712 is a valuable new tool for elucidating the pathophysiological role of ECE.

Topics: Acute Disease; Animals; Aspartic Acid Endopeptidases; Disease Models, Animal; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Inhibitors; Glycopeptides; Lung; Male; Metalloendopeptidases; Myocardial Infarction; Pressoreceptors; Rabbits; Rats; Rats, Sprague-Dawley; Substrate Specificity; Sulfonamides; Sulfonylurea Compounds; Swine

In the present work we evaluated the role of circulating endothelin-1 (ET-1) in haemodynamics and the adrenal medulla responses to stress using PD-142893, a mixed endothelin-A- and -B- (ET(A)/ET(B)) receptor antagonist. Male Wistar rats were chronically instrumented with arterial and venous catheters and a microdialysis probe placed into the adrenal medulla. Stress was induced by a 1 h period of immobilization. PD-142893 was infused (20 microg/kg/min) for 90 min starting 30 min before stress onset. Concentrations of norepinephrine and epinephrine in dialysate samples were measured by high-performance liquid chromatography (HPLC). At rest animals displayed a stable level of norepinephrine (85 +/- 34 pg/ml) and epinephrine (176 +/- 57 pg/ml) in adrenal perfusate and constant haemodynamic parameters. Stress increased adrenal secretion (norepinephrine 206 +/- 50%, epinephrine 202 +/- 45%) associated with hypertension (peak 141 +/- 3 mmHg) and tachycardia (peak 505 +/- 5 bpm). No significant changes in haemodynamics or of plasma catecholamine levels were observed during infusion of PD-142893. The antagonist did not significantly change the stress-induced increase in catecholamine secretion, tachycardia or hypertension. Thus, in Wistar rats, circulating ET-1 seems not to be essential for blood pressure control or adrenal catecholamine secretion during acute stress.

Topics: Acute Disease; Animals; Catecholamines; Endothelin Receptor Antagonists; Endothelin-1; Hemodynamics; Male; Oligopeptides; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Stress, Physiological

To investigate the effects of hypoxemia, hypercapnia, and cardiovascular hormones (norepinephrine, endothelin-1, and atrial natriuretic factor) on blood pressure during acute respiratory failure.. Patients with chronic obstructive pulmonary disease and acute respiratory failure were divided into four groups of 10 patients each: hypoxemia-normocapnia, hypoxemia-hypercapnia, hypoxemia-hypocapnia, and normoxemia-hypercapnia. Plasma norepinephrine levels were determined by high-performance liquid chromatography with electrochemical detection. Plasma endothelin-1 and atrial natriuretic factor levels were radioimmunoassayed after chromatographic preextraction.. Systolic blood pressure and cardiovascular hormone levels were greater in patients with hypercapnia (whether or not they also had hypoxemia) than in those with normocapnia and hypoxemia. For example, in patients with hypercapnia and normoxemia, the mean (+/- SD) systolic blood pressure was 183+/-31 mm Hg and the mean norepinephrine level was 494+/-107 pg/mL, as compared with 150+/- 6 mm Hg and 243+/-58 pg/mL in those with normocapnia and hypoxemia (both P<0.05). Similar results were seen for endothelin-1 and atrial natriuretic factor levels, and for the comparisons of hypoxemic patients who were hypercapnic with those who were normocapnic.. These results suggest that blood carbon dioxide levels, rather than oxygen levels, are responsible for hypertension during acute respiratory failure, perhaps as a result of enhanced sympatho-adrenergic activity.

Topics: Acute Disease; Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Carbon Dioxide; Endothelin-1; Female; Heart Rate; Humans; Hypercapnia; Hypertension; Hypocapnia; Hypoxia; Lung Diseases, Obstructive; Male; Middle Aged; Norepinephrine; Oxygen; Respiratory Insufficiency; Severity of Illness Index

Liver failure represents a major therapeutic challenge, and yet basic pathophysiological questions about hepatic perfusion and oxygenation in this condition have been poorly investigated. In this study, hepatic blood flow (HBF) and splanchnic oxygen delivery (DO2, sp) and oxygen consumption (VO2,sp) were assessed in patients with liver failure defined as hepatic encephalopathy grade II or more. Measurements were repeated after high-volume plasmapheresis (HVP) with exchange of 8 to 10 L of plasma. HBF was estimated by use of constant infusion of D-sorbitol and calculated according to Fick's principle from peripheral artery and hepatic vein concentrations. In 14 patients with acute liver failure (ALF), HBF (1.78 +/- 0.78 L/min) and VO2,sp (3.9 +/- 0.9 mmol/min) were higher than in 11 patients without liver disease (1.07 +/- 0.19 L/min, P <.01) and (2.3 +/- 0.7 mmol/min, P <.001). In 9 patients with acute on chronic liver disease (AOCLD), HBF (1.96 +/- 1.19 L/min) and VO2,sp (3.9 +/- 2.3 mmol/min) were higher than in 18 patients with stable cirrhosis (1.00 +/- 0.36 L/min, P <.005; and 2.0 +/- 0.6 mmol/min, P <.005). During HVP, HBF increased from 1.67 +/- 0.72 to 2.07 +/- 1.11 L/min (n=11) in ALF, and from 1.89 +/- 1.32 to 2.34 +/- 1.54 L/min (n=7) in AOCLD, P <.05 in both cases. In patients with ALF, cardiac output (thermodilution) was unchanged (6.7 +/- 2.5 vs. 6.6 +/- 2.2 L/min, NS) during HVP. Blood flow was redirected to the liver as the systemic vascular resistance index increased (1,587 +/- 650 vs. 2, 020 +/- 806 Dyne. s. cm-5. m2, P <.01) whereas splanchnic vascular resistance was unchanged. In AOCLD, neither systemic nor splanchnic vascular resistance was affected by HVP, but as cardiac output increased from 9.1 +/- 2.8 to 10.1 +/- 2.9 L/min (P <.01) more blood was directed to the splanchnic region. In all liver failure patients treated with HVP (n=18), DO2,sp increased by 15% (P <.05) whereas VO2,sp was unchanged. Endothelin-1 (ET-1) and ET-3 were determined before and after HVP. Changes of ET-1 were positively correlated with changes in HBF (P <.005) and VO2,sp (P <.05), indicating a role for ET-1 in splanchnic circulation and oxygenation. ET-3 was negatively correlated with systemic vascular resistance index before HVP (P <.05) but changes during HVP did not correlate. Our data suggest that liver failure is associated with increased HBF and VO2, sp. HVP further increased HBF and DO2,sp but VO2,sp was unchanged, indicating that splanchnic hypoxia

Topics: Acute Disease; Adult; Blood Flow Velocity; Chronic Disease; Endothelin-1; Endothelin-3; Female; Hepatic Encephalopathy; Humans; Liver Circulation; Liver Diseases; Liver Failure; Liver Failure, Acute; Male; Middle Aged; Oxygen Consumption; Plasmapheresis; Splanchnic Circulation

Release of inflammatory mediators from leukocytes and endothelial release of vasoactive factors are both important in the pathogenesis of atherosclerosis. To evaluate the concentrations of a specific marker for macrophage activation, neopterin, and the potent endothelial derived vasoconstrictive peptide endothelin-1 (ET-1), during the acute and chronic stages of cerebral ischemia, plasma concentrations of neopterin and ET-1 were measured in 59 patients with acute cerebral infarction or transient ischemic attack (median age 73 years, range 43-93, 27 men) and after a 1-year follow-up in 57/59 (97%) of patients. Plasma neopterin was higher at follow-up (6.3 nmol/L [3.7-21.6] vs 5.6 nmol/L [3.5-17.2]; p < 0.05) than at the acute stage, whereas the plasma ET-1 concentration was unchanged. Plasma concentrations of both neopterin and ET-1 correlated directly with age both in the acute stage (r = 0.42 and r = 0.35, respectively; p < 0.01) and after follow-up (r = 0.34; p < 0.05 and r = 0.27; p = 0.05, respectively). In conclusion, plasma neopterin increased after acute cerebral ischemia, indicating chronic inflammatory activity and continuous macrophage activation in ischemic cerebrovascular diseases.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Brain Ischemia; Endothelin-1; Female; Follow-Up Studies; Humans; Ischemic Attack, Transient; Male; Middle Aged; Neopterin; Time Factors

Acute lung injury produces pulmonary hypertension, altered vascular reactivity, and endothelial injury. To determine whether acute lung injury impairs the endothelium-dependent regulation of pulmonary vascular tone, 16 lambs were studied during U46619-induced pulmonary hypertension without acute lung injury, or air embolization-induced pulmonary hypertension with acute lung injury. The hemodynamic responses to endothelium-dependent (acetylcholine, ATP, ET-1, and 4 Ala ET-1 [an ETb receptor agonist]) and endothelium-independent (nitroprusside and isoproterenol) vasodilators were compared. During U46619-induced pulmonary hypertension, all vasodilators decreased pulmonary arterial pressure and vascular resistance (P < 0.05). During air embolization-induced pulmonary hypertension, the pulmonary vasodilating effects of acetylcholine, ATP, and 4 Ala ET-1 were attenuated (P < 0.05); the pulmonary vasodilating effects of nitroprusside and isoproterenol were unchanged; and the pulmonary vasodilating effects of ET-1 were reversed, producing pulmonary vasoconstriction (P < 0.05). During air embolization, the pulmonary vasoconstricting effects of ET-1 were blocked by BQ 123, an ETa receptor antagonist. The systemic effects of the vasoactive drugs were similar during both conditions. We conclude that pulmonary hypertension with acute lung injury induced by air embolization results in endothelial dysfunction; there is selective impairment of endothelium-dependent pulmonary vasodilation and an altered response to ET-1 from pulmonary vasodilation to vasoconstriction. This altered response to ET-1 is associated with decreased ETb receptor-mediated vasodilation and increased ETa receptor-mediated vasoconstriction. Endothelial injury and dysfunction account, in part, for the altered regulation of pulmonary vascular tone during pulmonary hypertension with acute lung injury.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acute Disease; Animals; Disease Models, Animal; Embolism, Air; Endothelin-1; Endothelium, Vascular; Hemodynamics; Hypertension, Pulmonary; Lung; Lung Injury; Nitric Oxide; Pulmonary Circulation; Random Allocation; Reference Values; Respiration, Artificial; Sheep; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents

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.

Topics: Acute Disease; Endothelin-1; Female; Gastrointestinal Motility; Gastrointestinal Transit; Humans; Male; Middle Aged; Pancreatitis

Acute pulmonary hypertension occurring after cardiopulmonary bypass can be a cause of post-operative morbidity and mortality. The purpose of this study was to investigate whether bosentan, a non-peptidic mixed endothelin antagonist affected the pulmonary hypertension induced by experimental cardiopulmonary bypass.. Pigs were anesthetized and instrumented to determine hemodynamic measurements. Pigs were randomized to receive either 3 mg/kg bolus + 7 mg/kg per h bosentan (n = 8) or saline (n = 7). All pigs underwent 90 min of cardiopulmonary bypass and were further observed for a 120-min period.. In the control group, cardiopulmonary bypass induced a dramatic pulmonary hypertension (+78 +/- 13%, P < 0.005) and accompanied an increase of pulmonary vascular resistance (+228 +/- 50%, P < 0.005), whereas, in the treated group, bosentan completely prevented these deleterious effects of cardiopulmonary bypass with only a moderate decrease of systemic vascular resistance (-19 +/- 14.6%, P < 0.05).. The present findings support the hypothesis that endogenous endothelin is a mediator of acute pulmonary hypertension occurring after cardiopulmonary bypass. Bosentan, a mixed endothelin antagonist completely prevented pulmonary hypertension after cardiopulmonary bypass and may, therefore, have therapeutic applications in the management of patients following cardiac surgery.

Topics: Acute Disease; Animals; Antihypertensive Agents; Bosentan; Cardiopulmonary Bypass; Endothelin-1; Hemodynamics; Hypertension, Pulmonary; Sulfonamides; Swine

Biosynthesis of endothelin-1 (ET-1), the most potent endogenous vasoconstrictor yet identified, is increased following myocardial infarction (MI) in man. Pathological events which occur in the connective tissues of the equine hoof during laminitis are similar in some respects, to changes occurring in the myocardial connective tissues following MI in man. The objective of this study was to determine whether ET-1 expression in connective tissues obtained from the hoof of laminitic horses is increased compared with tissues obtained from healthy horses. Expression of ET-1 in connective tissues of the equine hoof was measured following tissue extraction from 3 groups of horses: horses in which acute laminitis had been induced by the administration of starch; chronically foundered horses; nonlaminitic horses. The concentration of ET-1 in laminar connective tissues obtained from all laminitic horses (1573.0 +/- 392.8 pg/g of tissue; n = 10) was increased when compared with tissues obtained from nonlaminitic horses (392.5 +/- 117.4 pg/g of tissue; n = 5) (P<0.05). The concentration of ET-1 in laminar connective tissues obtained from the experimentally induced, acute laminitic horses (1043.6 +/- 254.4 pg/g of tissue; n = 7) and from the spontaneously affected, chronic laminitic horses (2808.3 +/- 878.6 pg/g of tissue; n = 3) was increased compared with the control group (P<0.05, P<0.01, respectively). The concentration of ET-1 in laminar connective tissues obtained from the chronic laminitic horses was greater than that of the experimentally induced, acute laminitic group (P<0.05). It is suggested that the data provide a strong argument that increased ET-1 expression in the connective tissues of the equine hoof represent a potentially important and hitherto unrecognised component of the pathophysiology of equine laminitis. Further studies are needed to determine whether inhibitors of ET-1 converting enzyme or antagonists of ET-1 receptors might be useful in the treatment and prevention of laminitis in horses.

Topics: Acute Disease; Animals; Chronic Disease; Connective Tissue; Endothelin-1; Female; Foot Diseases; Hoof and Claw; Horse Diseases; Horses; Inflammation; Male

Insulin stimulates the production of endothelin-1 (ET-1) and nitric oxide (NO) by isolated endothelial cells. Additionally, insulin-dependent glucose transport and insulin-mediated NO production partially share common elements in signal transduction. There are discordant data on plasma ET-1 levels during acute euglycemic systemic hyperinsulinemia in normotensive men and men with essential hypertension (EH) (known to be insulin-resistant), as well as on the relations between insulin sensitivity and vascular function. Our aim was to assess the response of approximate measures of whole-body generation of NO and ET-1 to acute euglycemic hyperinsulinemia in EH patients and controls. We studied 17 newly diagnosed untreated men with uncomplicated EH and 10 normotensive controls. Plasma ET-1 and urinary excretion of nitrite plus nitrate, stable NO metabolites (Uno(x)), were measured before and during a 3-hour hyperinsulinemic-euglycemic clamp. Both in hypertensives and normotensives, plasma ET-1 levels were reduced after 2 hours of the clamp (EH: baseline, 3.1+/-1.9 pg/mL; 2 hours, 1.9+/-1.2 pg/mL, P = .04 v baseline; controls: baseline, 4.2+/-2.6 pg/mL; 2 hours, 2.8+/-1.4 pg/mL, P = .04 v baseline). No significant changes in Uno(x) during the clamp were observed. Changes in Uno(x) during the clamp (deltaUno(x)) and differences in plasma ET-1 measured before the end and before the beginning of the clamp (deltaET-1) were correlated in the controls (r = .75, P = .01) but not in EH (r = -.01, P = .97). No parameter of glucose metabolism correlated with basal Uno(x), basal plasma ET-1, deltaUno(x), and deltaET-1, whether absolute or percent values, in either group. Thus, acute euglycemic hyperinsulinemia produces a decrease in plasma ET-1 in both EH patients and controls. The lack of correlation between deltaUno(x) and deltaET-1 under these conditions in EH may suggest an impairment of systems governing interactions between the NO-dependent pathway and ET-1. In addition, insulin actions on glucose metabolism and on the endothelial mediators appear dissociated.

Topics: Acute Disease; Adult; Blood Glucose; Endothelin-1; Humans; Hyperinsulinism; Hypertension; Male; Middle Aged; Nitrates; Nitrites; Reference Values

Using in vivo microscopy red blood cell (RBC) velocities, functional capillary density (FCD) and capillary diameters were estimated after inducing acute pancreatitis by intraductal infusion of sodium taurocholate (0.8 ml; 4%) or after topical superfusion of the pancreas with ET-1 (100 pmol). Sodium taurocholate mediated a significant decrease in RBC velocities between 50 and 70%, transient decrease in capillary diameters by 10%, and a sustained decrease in FCD between 60 and 70% paralleled by a dramatic heterogeneity in blood flow. Topical superfusion of the exteriorized pancreas with ET-1 caused a significant decrease in RBC velocities between 65 and 75%, a sustained decrease in capillary diameters by 10%, and a decrease in FCD by 45% accompanied by an increase in flow heterogeneity. Following sodium taurocholate infusion pancreas histology revealed a severe edema and sublobular acinar cell necrosis, while topical ET-1 application displayed a severe edema of the pancreas with focal acinar cell necrosis. Thus, ET-1 mediated a deterioration of the pancreatic microcirculation, which is similar to the microcirculatory failure found in sodium taurocholate-induced experimental pancreatitis and was associated with focal acinar cell necrosis. We are thus inclined to hypothesize that endothelin released by injured endothelial cells during acute biliary pancreatitis promotes microcirculatory failure and ischemia in acute pancreatitis, eventually leading to acinar cell necrosis.

Topics: Acute Disease; Administration, Topical; Animals; Blood Flow Velocity; Capillaries; Endothelin-1; Male; Microcirculation; Pancreas; Pancreatitis; Rats; Rats, Inbred Lew; Regional Blood Flow; Taurocholic Acid

This study was performed to integratively investigate the vasoregulatory response during standardized splanchnic hypoperfusion in pigs. Splanchnic perfusion was reduced to 50% of baseline by: haemorrhage by 20 and 40% of the estimated total blood volume; femoral venous infusion of live E. coli to establish sepsis of systemic origin; portal venous infusion of live E. coli to establish sepsis of splanchnic origin. Invasive haemodynamic monitoring and radioimmunoassay analyses of arterial plasma concentrations of angiotensin II, endothelin-1 and atrial natriuretic peptide were carried out. Acute hypovolaemia reduced systemic and splanchnic vascular resistances following transient increases and increased angiotensin II levels (+587%), whereas endothelin-1 and atrial natriuretic peptide levels did not change significantly. Systemic sepsis following femoral venous infusion of E. coli resulted in increased splanchnic vascular resistance and increased levels of angiotensin II (+274%), endothelin-1 (+134%) and atrial natriuretic peptide (+185%). Infusion of E. coli via the portal venous route induced an increase in splanchnic vascular resistance associated with particularly elevated levels of angiotensin II (+1770%) as well as increased endothelin-1 (+201%) and atrial natriuretic peptide (+229%) concentrations. Hypovolaemia and sepsis, although standardized with a predefined level of splanchnic hypoperfusion, elicited differentiated cardiovascular and vasopeptidergic responses. Sepsis, particularly of portal origin, notably increased splanchnic vascular resistance related to increased production of the vasoconstrictors angiotensin II and endothelin-1. The role of atrial natriuretic peptide as a vasodilator seems to be of subordinate importance in hypovolaemia and sepsis.

Topics: Acute Disease; Anesthesia; Angiotensin II; Animals; Atrial Natriuretic Factor; Endothelin-1; Escherichia coli Infections; Female; Femoral Vein; Hemorrhage; Hypovolemia; Male; Neuropeptides; Portal Vein; Sepsis; Splanchnic Circulation; Swine; Vasoconstrictor Agents

The aim of the study was to evaluate concentrations of atrial natriuretic peptide (ANP) and endothelin in blood serum of the patients with nonatopic bronchial asthma in the exacerbation phase and during non-symptomatic period. The study included 20 patients with nonatopic bronchial asthma (10 women and 10 men, mean age 34.2) treated in the Allergological Outpatient Clinic in Zabrze (Poland). A control group consisted of 5 healthy volunteers without atopy. The study consisted of evaluation of the ANP and endothelin in blood serum by radioimmunoassay and by functional respiratory tests. It was shown that ANP concentrations during bronchial asthma exacerbation were two times lower than in the same group examined in the remission phase (7.8-13.7 pmol/ml, p < 0.05). At the time of bronchospastic symptoms occurrence, the concentrations of endothelin were statistically significant and higher than in the non-symptomatic group (11.6-6.9 pmol/ml, p < 0.05). In the examined group the reverse proportion relation between concentrations of the studied peptides in blood serum was observed r = -0.56, p < 0.05 according to Spearman test.

Topics: Acute Disease; Adolescent; Adult; Analysis of Variance; Asthma; Atrial Natriuretic Factor; Endothelin-1; Female; Humans; Male; Middle Aged

Endothelin-1 (ET-1) is a potent vasoconstrictor with vasopressor and mitogenic effects. Blood samples were collected from 21 renal transplant patients undergoing acute rejection at the time of diagnostic kidney biopsy: there were 20 men and one woman, mean age 35.6 years. All patients were on triple immunosuppressive therapy with cyclosporine A, azathioprine and methylprednisolone. Twenty living kidney donors pre-uninephrectomy (11 men and nine women, mean age 34 years) served as controls. Control kidney was obtained from fresh autopsy material and normal kidney tissue from nephrectomies for malignancy. Mean plasma ET-1 was significantly increased at 1.56 +/- 0.2 pg ml(-1) during acute rejection compared to 0.74 +/- 0.06 pg ml(-1) in donors (p = 0.0009 unpaired t-test). ET(A) receptor immunolabelling was visualised in distal tubules and collecting ducts with minimal labelling in the glomeruli and blood vessels of control kidney tissue ET(A) receptor labelling was similar in kidney biopsies with acute rejection. ET(B) receptor immunolabelling was significantly increased in glomeruli (p = 0.002) and decreased in distal tubules (p = 0.004) in kidneys with acute rejection compared to control kidney tissue. While these findings may account for the oedema and hypertension observed during acute rejection, the exact significance needs to be studied further.

Topics: Acute Disease; Adolescent; Adult; Endothelin-1; Female; Graft Rejection; Humans; Image Cytometry; Immunohistochemistry; Kidney Transplantation; Male; Middle Aged; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin

We have reported previously that cerulein-induced edematous pancreatitis would transform into hemorrhagic pancreatitis by administration of endothelin-1 in rats. In the present study, we tried to protect rat model from developing into hemorrhagic pancreatitis with BQ123 (an ETA receptor antagonist).. The rat model was made by 5-hour restraint water-immersion stress and two intraperitoneal injections of cerulein (40 micrograms/kg) at hourly interval. BQ123 (3 or 6 mg/kg) was administered intravenously 30 minutes before and 2 hours after the first cerulein injection.. Acute hemorrhagic pancreatitis was induced in all rats treated with cerulin + stress. The score for pancreatic hemorrhage was 2.4 +/- 0.2 in this group. In the rats pretreated with BQ123, the score was reduced to 1.0 +/- 0.0, pancreas wet weight and serum amylase activity were significantly reduced, and histologic alterations in the pancreas lightened, also the local pancreatic blood flow improved without affecting the systemic blood pressure.. These results suggest that endothelin-1 should play a role in aggravating the development of acute hemorrhagic pancreatitis, through its action on the pancreatic microcirculation.

Topics: Acute Disease; Animals; Ceruletide; Endothelin Receptor Antagonists; Endothelin-1; Male; Pancreatitis; Peptides, Cyclic; Rats; Rats, Sprague-Dawley

To investigate the possible involvement of endogenous nitric oxide (NO) in acute hypotension during maintenance hemodialysis, we measured the plasma concentration of the nitrate anion NO3-, a stable metabolite of NO, in 19 patients undergoing hemodialysis. We analyzed heart rate variability to estimate the relationship between autonomic nervous activity and NO production, low-frequency/high-frequency components (L/H) as a parameter of cardiac sympathetic activity, and high-frequency power as a parameter of cardiac vagal activity. Six patients developed severe hypotension (a change in mean blood pressure during dialysis > or = 20 mm Hg), four patients developed mild hypotension (a change in mean blood pressure < or = 19 mm Hg and > or = 1 mm Hg), and nine patients did not develop hypotension. The plasma levels of NO3- before dialysis were markedly elevated in the severely hypotensive group compared with the patients who showed no hypotension (566+/-122 micromol/L v 133+/-38 micromol/L; P < 0.01), and this difference disappeared midhemodialysis and after hemodialysis. The plasma concentration of NO3- before dialysis was significantly associated with both the change in mean blood pressure during dialysis (r= -0.735; P = 0.003) and the mean blood pressure after dialysis (r = -0.675; P = 0.0015). The L/H ratio was inhibited before or after dialysis in the severely hypotensive group compared with the nonhypotensive group, and hypotension during dialysis was correlated with the inhibited L/H ratio before (r = 0.784; P = 0.001) or after (r = 0.822; P = 0.001) dialysis. Plasma NO3- concentrations were correlated with the L/H ratio before (r = -0.553; P = .014) or after (r = -0.546; P = 0.015) dialysis. These results suggest that inhibited sympathetic activity is one of the causes of acute hypotension during dialysis, and the enhanced production of NO is involved in this inhibition of the sympathetic activity in patients having a hypotensive episode during dialysis. The plasma concentration of NO3- before dialysis may be a predictor of the risk of hypotension during dialysis in patients with end-stage renal disease.

Topics: Acute Disease; Anions; Blood Pressure; Cyclic GMP; Endothelin-1; Female; Heart Rate; Humans; Hypotension; Kidney Failure, Chronic; Male; Middle Aged; Nitrates; Nitric Oxide; Renal Dialysis; Sympathetic Nervous System

Topics: Acute Disease; Brain Ischemia; Cerebrovascular Disorders; Endothelin-1; Humans

The abundance of endothelial cells in bone marrow and the proximity of these cells to osteoclasts and osteoblasts suggest a role for endothelin-1 (ET-1) on bone metabolism. In vitro, the direct contact with bone endothelial cells induces osteoclastic progenitors to differentiate into mature elements. Recently it has been reported that ET-1 inhibits osteoclastic bone resorption and cell mobility through a specific receptor on osteoclasts; other authors demonstrated that ET-1 exerts a mitogenic activity on osteoblast-like cells (MC3T3) by stimulating tyrosin phosphorylation. We measured ET-1 circulating levels in patients with active Paget's bone disease, a condition with accelerated bone turnover. For the study we recruited 11 patients with Paget's bone disease (5F, 6M; mean age 68.2 +/- 3.6) in the acute stage of the disease; 10 healthy subjects (7F, 3M; mean age 66.5 +/- 3.9) were also enrolled as controls. Plasma ET-1 levels were measured with RIA kits provided by Nichols Institute. Patients showed significantly (P < 0.01) higher ET-1 circulating levels than controls (6.35 +/- 1.9 versus 3.4 +/- 1.2 pg/ml) with a positive correlation (r = 0.63; P = 0.038) with serum alkaline phosphatase (ALP), but not with urinary hydroxyproline. The higher levels of ET-1 in our patients suggest a physiopathological role for this peptide in the disease and, could perhaps represent a new useful marker of Paget's bone disease activity.

Topics: Acute Disease; Aged; Alkaline Phosphatase; Biomarkers; Endothelin-1; Female; Humans; Hydroxyproline; Male; Osteitis Deformans

We examined whether endothelin-1 (ET-1), a potent vasoconstrictive peptide secreted in high concentration by metastatic prostate cancer cells, produces endothelin receptor-dependent pain behavior when applied to rat sciatic nerve. ET-1 (200-800 microM) applied to the epineurial surface of rat sciatic nerve produced reliable, robust, unilateral hindpaw flinching lasting 60 min. Pre-emptive systemic morphine completely blocked this effect in a naloxone-reversible manner, suggesting that this behavior was pain-related. Equipotent doses of epineurially applied epinephrine had no effect, suggesting that ET-1 effects are on tissue sites other than sciatic nerve microvessels. Prior and co-administration of BQ-123, an endothelin-A (ET(A)) receptor antagonist, also blocked ET-1-induced hindpaw flinching establishing that pain behavior induced by ET-1 application to rat sciatic nerve is ET(A) receptor mediated.

Topics: Acute Disease; Administration, Topical; Adrenergic alpha-Agonists; Analgesics, Opioid; Animals; Behavior, Animal; Drug Interactions; Endothelin-1; Epinephrine; Male; Microcirculation; Morphine; Naloxone; Narcotic Antagonists; Pain; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Endothelin; Sciatic Nerve

The effects of endothelin 1 (ET-1) on hemodynamics and acute liver damage were studied using perfused livers of rats treated with D-galactosamine. In control liver perfused in situ with constant pressure, infusion of ET-1 into the portal vein at a concentration of 0.1 nmol/L decreased the flow rate without a significant leakage of lactate dehydrogenase (LDH) or aspartate transaminase (AST) into the effluent. In contrast, in similarly perfused liver 24 hours after treatment with D-galactosamine (800 mg/kg intraperitoneally), ET-1 caused rapid and remarkable increases in the leakage of LDH and AST from the liver accompanied by the reduction of perfusion flow to the extent similar to that observed in control livers. In addition, ET-1 decreased oxygen uptake and bile secretion in galactosamine-treated livers. The potentiating effects of ET-1 on enzyme leakage were also observed under constant flow conditions. Moreover, infusion of the thromboxane A2 analogue at a concentration of 10 nmol/L decreased the flow rate markedly, yet the rapid increases in enzyme leakage were not observed. Infusion of ET-3 induced the responses of flow reduction and the potentiation of rapid enzyme leakage similar to those obtained with ET-1. Neither the endothelin A-receptor antagonist BQ485 nor the endothelin B-receptor antagonist BQ788 could inhibit the acute liver damage caused by ET-1; instead they exaggerated its effects. The combination of both antagonists together, however, almost completely suppressed the flow reduction and the potentiation of enzyme leakage caused by ET-1. These results indicate that ET-1 is capable of aggravating acute liver damage not merely through reduction of the flow rate but through direct action on liver cells. They also suggest that both the endothelin A and endothelin B receptors are involved in this action of ET-1.

Topics: Acute Disease; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-3; Galactosamine; Hemodynamics; L-Lactate Dehydrogenase; Liver; Liver Circulation; Liver Diseases; Male; Perfusion; Rats; Rats, Sprague-Dawley; Thromboxane A2

Cocaine-associated vascular events are not completely explained by adrenergic stimulation. The purposes of this study were to investigate whether vasoconstrictive endothelin-1 is released by cocaine and to elucidate the mechanisms involved.. Endothelin-1 was measured by radioimmunoassay and high-performance liquid chromatography (1) in the supernatant of porcine aortic endothelial cells after treatment with cocaine (10(-7) to 10(-4) mol/L) and a sigma-receptor antagonist, haloperidol (10(-6) mol/L) or ditolylguanidine (10(-5) mol/L) and (2) in plasma and urine of 12 cocaine-intoxicated patients and 13 healthy control subjects. Radioligand binding assays were performed on endothelial membrane preparations. In cell culture, cocaine significantly increased endothelin accumulation above baseline at 3 to 24 hours; endothelin release rates per hour increased dose-dependently, reaching a plateau of 175+/-23% of control at hour 4 to 5. Coincubation of cocaine with haloperidol or ditolylguanidine abolished or reduced cocaine-induced endothelin release. Endothelial membrane preparations specifically and displaceably bound the highly selective sigma-ligand [3H]ditolylguanidine (25x10(-9) mol/L), with 1400 binding sites estimated per cell. Endothelin-1 levels in plasma (22.7+/-5.6 versus 7.3+/-0.8 pmol/L) and urine (41.5+/-10.1 versus 12.7+/-3.8 pmol/L) of cocaine-intoxicated patients were significantly increased compared with control values.. The data suggest that cocaine increases the endothelin-1 release in vitro and in vivo. The cocaine-induced vasoconstriction/vasospasm may therefore be facilitated by the release of endothelin-1. Cocaine appears to be an exogenous stimulator at endothelial sigma-receptors. The endogenous ligands of this antiopioid system may prove to play a role in vasospastic angina, acute myocardial infarction, and sudden cardiac death.

Topics: Acute Disease; Adolescent; Adult; Animals; Cells, Cultured; Cocaine; Cocaine-Related Disorders; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Female; Humans; Male; Receptors, sigma; Swine; Time Factors; Vasoconstrictor Agents

The relative contributions of microvascular inflammation and vasomotor dysregulation to the development of acute vaso-occlusive crisis in sickle cell disease have been intensely studied. The present observational study was designed to examine the levels of circulating proinflammatory cytokines, anti-inflammatory cytokines, and vasoactive mediators during and after acute painful crisis. In symptomatic sickle cell patients, plasma levels of endothelin-1 and prostaglandin E2 were elevated during crises compared with healthy African-American controls. These levels had decreased, but not normalized, when patients were seen 1 to 3 weeks after discharge from hospital. Other mediators (tumor necrosis factor alpha [TNFalpha], interleukin-1beta [IL-1beta], IL-6, IL-8, and IL-10) were neither elevated in asymptomatic sickle cell disease nor in acute vaso-occlusive crisis. As a potent long-acting mediator of vasoconstriction and inflammation, endothelin-1 may play a key role in the cycle of ischemia and inflammation that initiates and sustains pain of crisis. The downregulatory effects of prostaglandin E2 on immune cell function may contribute to the increased susceptibility to infection observed in patients with sickle cell disease.

Topics: Acute Disease; Adult; Anemia, Sickle Cell; Cell Adhesion Molecules; Cytokines; Dinoprostone; Endothelin-1; Humans; Ischemia; Microcirculation; Middle Aged; Monocytes; Pain; Vascular Diseases; Vasculitis; Vasoconstriction

Topics: Acute Disease; Anemia, Sickle Cell; Endothelin-1; Endothelium, Vascular; Humans

This study was designed to assess which cells in transplanted lungs express endothelin-1 (ET-1) and if expression of the peptide can be used to discriminate between rejection and infection in transplanted lungs.. Transbronchial biopsies (n=104) from 29 human lung transplant recipients were stained immunohistochemically for ET-1. Cells expressing ET-1 (pneumocytes, endothelial cells, airway epithelial cells, lymphocytes, and macrophages) were quantified and correlated with clinical histopathology findings.. ET-1 was expressed in airway epithelial cells (93% of the biopsies), infiltrating macrophages (86%), and lymphocytes (19%) but not in endothelial cells or pneumocytes. ET-1 expression did not vary with rejection, obliterative bronchiolitis, or infection. ET-1 expression did not correlate with age, grade of rejection, pulmonary function, or time after transplantation.. In transplanted human lungs, ET-1 is expressed in airway epithelial cells and infiltrating macrophages, and expression does not vary with pathological processes. Therefore, immunostaining for ET-1 probably cannot be used to discriminate between rejection and infection in transplanted lungs.

Topics: Acute Disease; Adult; Aged; Bronchiolitis Obliterans; Diagnosis, Differential; Endothelin-1; Epithelial Cells; Female; Graft Rejection; Humans; Lung; Lung Transplantation; Male; Middle Aged; Tissue Distribution

We examined the possibility of the involvement of endothelin (ET)-1, a potent vasoactive peptide, in the process of astrocyte proliferation after brain injury. Acute brain damage in rats was induced by cold-injury. Astrocytes changed from a differentiated state to an immature, RC-1-positive state immediately after the injury. In the injured site, the level of ET-1-like immunoreactivity in the tissue was significantly increased on the first postoperative day and was sustained at a high level for 5 days. ET(B) receptor mRNA was markedly but transiently down-regulated only on the first day after the injury. Brain extracts (BE) were prepared from the injured tissues, and their effects on the proliferative characteristics of astrocytes were examined in primary culture of astrocytes. The flat morphology, which was observed in association with cell proliferation, and DNA synthesis of astrocytes were enhanced by treatment with each of the BE from 1 (D1-BE), 3 and 5 days after the injury. A monoclonal antibody that recognizes the C-terminus of rat ET-1 and ET-3 inhibited the DNA synthesis of astrocytes induced by D1-BE. These results provide experimental evidence that ET-1 may participate in the initiation of gliosis in the acute phase of brain damage.

Topics: Acute Disease; Animals; Antibodies, Monoclonal; Astrocytes; Brain; Brain Injuries; Cells, Cultured; Cold Temperature; DNA; Down-Regulation; Endothelin-1; Male; Rats; Rats, Wistar; Receptor, Endothelin B; Receptors, Endothelin; Thymidine; Time Factors; Tissue Extracts

To investigate the role of the endothelial-derived vasoactive mediator endothelin (ET-1) in the acute chest syndrome (ACS), we incubated bovine pulmonary artery endothelial cells (BPAEC) with red blood cells (equivalent to a hematocrit of 20%) and/or autologous plasma (1:10 dilution) from two patients during ACS and during routine clinic visits. Cellular RNA was analyzed for ET-1 transcripts by Northern analysis and ET-1 protein levels in BPAEC supernatants and in plasma measured by radioimmunoassay. ET-1 mRNA expression and protein levels increased in BPAEC exposed to plasma obtained during ACS; in contrast, exposure to plasma obtained during routine clinic visits did not alter BPAEC ET-1 mRNA expression or protein levels. Plasma ET-1 level was elevated during ACS, decreased during resolution, and remained slightly elevated during routine clinic visits. Plasma obtained from one patient 4 d prior to hospitalization for vasoocclusive crisis contained the highest ET-1 level and markedly increased BPAEC ET-1 mRNA expression and protein levels. In both patients, BPAEC ET-1 mRNA and protein expression in vitro and plasma ET-1 levels in vivo correlated with stage of disease and occurred in the absence of direct erythrocyte contact in vitro. These observations suggest that ET-1 production contributes to development of ACS.

Topics: Acute Disease; Adult; Anemia, Sickle Cell; Animals; Cattle; Endothelin-1; Female; Humans; Lung Diseases; Pulmonary Artery; RNA; RNA, Messenger

We have previously shown that high altitude pulmonary edema-susceptible subjects (HAPE-S) have an accentuated pulmonary vascular response to hypoxia. In this study, we investigated the relationship between plasma endothelin-1 (ET-1) levels and the acute hypoxic pulmonary vascular response in HAPE-S and control subjects. In six HAPE-S and seven healthy subjects, we evaluated acceleration time/right ventricular ejection time (AcT/RVET) using Doppler echocardiography, and measured plasma ET-1 levels by radioimmunoassay (RIA) before and after 5 minutes of breathing 10% oxygen. The HAPE-S showed a significantly increased pulmonary vascular response to hypoxia compared with healthy subjects. However, no statistically significant changes of plasma ET-1 levels were observed before and after hypoxia in both groups. We conclude that the increased pulmonary vascular response to acute hypoxia in HAPE-S may not be related to ET-1 release.

Topics: Acute Disease; Adult; Altitude Sickness; Case-Control Studies; Endothelin-1; Female; Humans; Hypoxia; Male; Middle Aged; Pulmonary Circulation; Pulmonary Edema

Experimental studies have provided evidence that, during acute pulmonary allograft rejection, endothelial dysfunction occurs not only in the transplanted lung but also in arteries of organs native to the transplant recipient. We therefore tested the hypothesis that allograft rejection leads to the release of factors into the circulation that could affect the endothelial function in lung transplant recipients.. Acetylcholine (10, 30, and 60 micrograms/min) and sodium nitroprusside (1, 3, and 6 micrograms/min) were infused into the brachial artery in nine transplant recipients (five single lung, one double lung, three heart-lung) 2 to 37 weeks after transplantation, during both acute rejection and rejection-free episodes. Changes in forearm blood flow were assessed with venous occlusion plethysmography. Plasma levels of interleukin-2, -6, and -8, endothelin-1, L-arginine, and asymmetric dimethylarginine were measured and correlated to rejection episodes.. The vasodilatory response to acetylcholine was significantly reduced during acute rejection compared with rejection-free episodes (percentage increase from basal flow: 156% +/- 21%, 395% +/- 65%, and 585% +/- 87% during rejection versus 272% +/- 75%, 633% +/- 113%, and 933% +/- 158% during absence of rejection, p < 0.05). No statistically significant difference was found between vasodilatory responses to nitroprusside during acute rejection and rejection-free episodes. Plasma levels of L-arginine, asymmetric dimethylarginine, interleukin-6, and endothelin-1 were not significantly altered during lung rejection.. These data indicate that a reversible peripheral decrease in endothelium-dependent vasodilatation occurs during acute rejection in lung transplant recipients. This result may be due to interactions among circulating cytokines and leukocytes activated by the rejection process and the endothelium.

Topics: Acetylcholine; Acute Disease; Adolescent; Adult; Arginine; Blood Flow Velocity; Brachial Artery; Cytokines; Endothelin-1; Endothelium, Vascular; Female; Forearm; Graft Rejection; Humans; Infusions, Intra-Arterial; Lung Transplantation; Male; Middle Aged; Nitroprusside; Plethysmography; Retrospective Studies; Transplantation, Homologous; Vasodilation; Vasodilator Agents

The purpose of this study was to investigate whether endogenous endothelin-1 (ET-1) production in coronary circulation is associated with acute coronary thrombotic events in vivo. To achieve this goal, we have designed a new experimental canine model of coronary thrombosis.. In vivo occlusive thrombus was induced by the intracoronary application of radiofrequency energy (660 kHz, 50 W) in closed-chest dogs. Pathological and immunohistochemical examinations of thrombosed coronary artery were performed. In 12 dogs, plasminogen activator was administered intravenously and serial measurements of ET-1, thromboxane B2 (TXB2) and thrombin-antithrombin III complex (TAT) levels in plasma from the coronary sinus, aortic root and inferior vena cava were examined.. Occlusive platelet-rich thrombi were attached to the deeply injured intimal surface. TAT and TXB2 increased rapidly soon after the intimal injury and declined after successful thrombolysis. In contrast, ET-1 in the coronary sinus was elevated after reperfusion and was significantly higher than in the aorta. Net ET-1 production in the coronary circulation showed a significant positive correlation with the peak TAT levels (r = 0.69, P < 0.05), but not with TXB2 or total occlusion time as an index of ischemic severity.. Deep intimal injury leads to occlusive coronary thrombus. Thrombus formation and its subsequent lysis is associated with the activation and deactivation, respectively, of the coagulation cascade and platelets. Thrombin generation may stimulate ET-1 production in the coronary endothelium in acute coronary thrombotic events.

Topics: Acute Disease; Animals; Coronary Angiography; Coronary Circulation; Coronary Thrombosis; Coronary Vessels; Disease Models, Animal; Dogs; Endothelin-1; Radio Waves

We studied whether endothelin-1 (ET-1) and leukotoxin (Lx), which have a different effects on vascular tone in isolated perfused rat lungs, also have different effects on mitochondrial function in edematous lung injury. Lung mitochondria were extracted from isolated perfused rat lungs exposed to each mediator. In lungs exposed to 0.5 nmol of ET-1, lung wet weight increased with a markedly elevated perfusion pressure but with no increase in the release of lactate dehydrogenase (LDH), an index of cell damage, into the perfusate. Neither mitochondrial respiration rate no ATP content in the lung tissue differed from those of untreated lungs. In contrast, in lungs treated with 30 mumol of Lx, lung wet weight markedly increased despite a small elevation of perfusion pressure; release of LDH into the perfusate increased, and the mitochondrial respiration rate in state 3 adn 4 significantly decreased while the ATP content in the lung tissue was less than in untreated lungs. We also examined cellular and mitochondrial damage in hydrostatic lung edema caused by raising an outflow reservoir. Mitochondrial respiration was not suppressed, and perfusate LDH activity was not increased, although lung wet weight increased as much as it did after the treatment described above. These results indicate that lung mitochondrial function is differentially affected by ET-1 and Lx, and they suggest that abnormalities in energy production by lung mitochondria are related to permeability edema.

Topics: Acute Disease; Adenosine Triphosphate; Animals; Endothelin-1; Energy Metabolism; Exotoxins; In Vitro Techniques; Inflammation Mediators; L-Lactate Dehydrogenase; Lung; Male; Mitochondria; Organ Size; Oxygen Consumption; Pulmonary Edema; Rats; Rats, Sprague-Dawley