endothelin-1 and Pulmonary-Edema

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

The seriousness of scorpion envenomation results essentially from left cardiac function with pulmonary oedema and/or a state of shock. Adrenergic myocarditis, toxic myocarditis and myocardial ischemia are the 3 mechanisms that explain the cardiac dysfunction. Myocardial ischemia is not only due to the release of catecolamines but also the effect of the cytokines and/or neuropeptide Y on the coronary vessels. The cardiac damage can be due or enhanced by the depressive effect of the cytokines on the myocardial cells. The frequently observed hyperglycaemia only enhances the state of the already damaged myocardium.

Topics: Acidosis; Animals; beta-Thromboglobulin; Blood Platelets; Catecholamines; Cytokines; Endothelin-1; Humans; Hyperglycemia; Myocardial Ischemia; Myocarditis; Myocardium; Neuropeptide Y; Pulmonary Edema; Scorpion Stings; Scorpion Venoms; Scorpions; Shock, Cardiogenic; Stress, Physiological

High-altitude pulmonary edema (HAPE) is the predominant cause of death due to high-altitude illness. At first sight, the observation that mountaineers regularly consume red wine in order to "feel better" seems to be paradoxical because, especially at higher altitudes, alcohol consumption could be detrimental. In this article, we review the potential mechanisms by which the components of red wine may beneficially affect the development of HAPE.. The underlying cause of HAPE is the altitude-related reduction in barometric pressure, which leads to a decrease in partial pressure of oxygen in the alveolae and subsequently in the pulmonary capillaries and arterial system. Two cellular mechanisms have been described, both of which increase pulmonary vascular tone: enhanced endothelin 1 production and the increased generation of reactive oxygen species. Recent evidence has indicated that some of the compounds of red wine suppress endothelin 1 gene expression, and the anti-oxidative properties of red wine have been previously reported.. This article briefly summarises the pathophysiological cellular events leading to HAPE and describes the potential mechanisms by which the ingredients of red wine may have a beneficial effect.

Topics: Altitude; Altitude Sickness; Blood Pressure; Endothelin-1; Humans; Nitric Oxide; Pressure; Pulmonary Edema; Reactive Oxygen Species; Wine

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

High-altitude pulmonary edema (HAPE) is characterized by excessive pulmonary vasoconstriction and is associated with decreased concentrations of nitric oxide (NO) in the lung.. We hypothesized that individuals susceptible to HAPE (HAPE-S) would also have dysfunction of the vascular NO vasodilator pathway during hypoxia in the systemic vasculature.. During normoxia (FI(O(2)) = 0.21) and 4 hours of normobaric hypoxia (FI(O(2)) = 0.12, corresponding to an altitude of 4,500 m above sea level) endothelium-dependent and endothelium-independent vasodilator responses to intraarterial infusion of acetylcholine (ACh) and sodium nitroprusside, respectively, were measured by forearm venous occlusion plethysmography in nine HAPE-S subjects and in nine HAPE-resistant control subjects.. Pulmonary artery systolic pressure increased from 22 +/- 3 to 33 +/- 6 mm Hg (p < 0.001) during hypoxia in control subjects, and from 25 +/- 4 to 50 +/- 9 mm Hg in HAPE-S subjects (p < 0.001). Despite similar responses during normoxia in both groups, ACh-induced changes in forearm blood flow markedly decreased during hypoxia in HAPE-S subjects (p = 0.01) but not in control subjects. The attenuated vascular response to ACh infusion during hypoxia inversely correlated with increased pulmonary artery systolic pressure (p = 0.04) and decreased plasma nitrite correlated with attenuated ACh-induced vasodilation in HAPE-S subjects (p = 0.02).. Hypoxia markedly impairs vascular endothelial function in the systemic circulation in HAPE-S subjects due to a decreased bioavailability of NO. Impairment of the NO pathway could contribute to the enhanced hypoxic pulmonary vasoconstriction that is central to the pathogenesis of HAPE.

Topics: Acetylcholine; Adult; Altitude Sickness; Blood Pressure; Disease Susceptibility; Endothelin-1; Endothelium, Vascular; Female; Forearm; Hemodynamics; Humans; Hypoxia; Male; Middle Aged; Nitrates; Nitrites; Nitroprusside; Pulmonary Artery; Pulmonary Edema; Pulmonary Gas Exchange; Regional Blood Flow; Single-Blind Method; Vasodilation; Vasodilator Agents

We investigated the effects of nasal continuous positive airway pressure (CPAP) on plasma endothelin-1 (ET-1) concentrations in patients with cardiogenic pulmonary edema. Thirty patients were randomly assigned to two groups: 15 patients who received oxygen plus nasal CPAP (CPAP group), and 15 patients who received only oxygen by face mask (oxygen group). The heart rate and the mean pulmonary artery pressure decreased significantly in the CPAP group. The PaO2/ fraction of inspired oxygen (FIO2) ratio increased in the CPAP group (163 +/- 70 to 332 +/- 104, P < 0.01) after 6 h and was significantly higher than that in the oxygen group. Arterial plasma ET-1 concentrations decreased from 6.2 +/- 2.0 pg/mL to 4.8 +/- 1.7 pg/mL (P < 0.05) after 6 h and to 3.3 +/- 0.7 pg/mL (P < 0.01) after 24 h in the CPAP group. Arterial plasma ET-1 concentrations in the CPAP group compared with the oxygen group were significantly lower at 24 h. There was a correlation between the arterial plasma ET-1 concentrations and mean pulmonary artery pressure (r = 0.62, P < 0.001), and PaO2/FIO2 (r = -0.46, P < 0.01). Nasal CPAP led to an early decrease in plasma ET-1 concentrations, and improvement in oxygenation and hemodynamics.

Topics: Aged; Blood Pressure; Endothelin-1; Female; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Oxygen Inhalation Therapy; Positive-Pressure Respiration; Pulmonary Artery; Pulmonary Edema

Neurogenic pulmonary edema (NPE) is a fatal complication in children with enterovirus 71 (EV71) encephalitis. Endothelin 1 (ET-1), a potent vasoconstrictor, can induce pulmonary edema in rats via intrathecal injections. Thus, it was hypothesized that ET-1 in the central nervous system may correlate with NPE in children with EV71 encephalitis.. Clinical data and ET-1 in the cerebrospinal fluid (CSF) were compared between three groups: (1) EV71 encephalitis with NPE; (2) EV71 encephalitis without NPE; and (3) non-EV71 aseptic meningitis. ET-1 immunostaining was performed on the brainstem of autopsy patients.. The EV71 with NPE group showed significantly increased CSF levels of ET-1 compared to the EV71 without NPE and the non-EV71 aseptic meningitis groups (both p<0.01). The optimum cut-off point of ET-1 to predict NPE in EV71 patients, based on the receiver operating characteristic curve, was 0.5 pg/ml (sensitivity 83%, specificity 100%). Immunostaining in the brainstem showed increased ET-1 expression, mainly in the oligodendrocytes, in EV71 with NPE patients compared with control patients.. ET-1 in the central nervous system may play a role in the development of NPE in children with EV71 infection and could be used as a biomarker or therapeutic target for NPE in EV71 encephalitis.

Topics: Animals; Brain Stem; Child, Preschool; Encephalitis, Viral; Endothelin-1; Enterovirus A, Human; Enterovirus Infections; Female; Humans; Infant; Male; Meningitis, Aseptic; Pulmonary Edema; Rats

Vascular leakage and oedema formation are key components in sepsis. In septic patients, plasma levels of the vasoconstrictive and pro-inflammatory peptide endothelin-1 (ET-1) correlate with mortality. During sepsis, neutrophils release heparin-binding protein (HBP) known to increase vascular permeability and to be a promising biomarker of human sepsis. As disruption of ET-signalling in endotoxemia attenuates formation of oedema, we hypothesized that this effect could be related to decreased levels of HBP. To investigate this, we studied the effects of ET-receptor antagonism on plasma HBP and oedema formation in a porcine model of sepsis. In addition, to further characterize a potential endothelin/HBP interaction, we investigated the effects of graded ET-receptor agonist infusions.. Sixteen anesthetized pigs were subjected to 5 h of endotoxemia and were randomized to receive either the ET-receptor antagonist tezosentan or vehicle after 2 h. Haemodynamics, gas-exchange and lung water were monitored. In separate experiments, plasma HBP was measured in eight non-endotoxemic animals exposed to graded infusion of ET-1 or sarafotoxin 6c.. Endotoxemia increased plasma ET-1, plasma HBP, and extravascular lung water. Tezosentan-treatment markedly attenuated plasma HBP and extravascular lung water, and these parameters correlated significantly. Tezosentan decreased pulmonary vascular resistance and increased respiratory compliance. In non-endotoxemic pigs graded ET-1 and sarafotoxin 6c infusions caused a dose-dependent increase in plasma HBP.. ET-receptor antagonism reduces porcine endotoxin-induced pulmonary oedema and plasma levels of the oedema-promoting protein HBP. Moreover, direct ET-receptor stimulation distinctively increases plasma HBP. Together, these results suggest a novel mechanism by which ET-1 contributes to formation of oedema during experimental sepsis.

Topics: Animals; Antimicrobial Cationic Peptides; Blood Proteins; Capillary Leak Syndrome; Carrier Proteins; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endotoxemia; Endotoxins; Extravascular Lung Water; Female; Hemodynamics; Inflammation; Infusions, Intravenous; Leukocyte Count; Male; Neutrophil Activation; Pulmonary Edema; Pyridines; Random Allocation; Receptor, Endothelin B; Sus scrofa; Swine; Tetrazoles; Viper Venoms

Ischaemia/reperfusion (I/R) injury of the lungs contributes to pulmonary dysfunction after cardiac surgery with cardiopulmonary bypass (CPB), leading to increased morbidity and mortality of patients. This study investigated the value of controlled lung reperfusion strategies on lung ischaemia-reperfusion injury in a porcine CPB model.. Pigs were subjected to routine CPB for 120 min with 60 min of blood cardioplegic cardiac arrest (CCA). Following CCA, the uncontrolled reperfusion (UR, n = 6) group was conventionally weaned from CPB. Two groups underwent controlled lung reperfusion strategies (CR group: controlled reperfusion conditions, n = 6; MR group: controlled reperfusion conditions and modified reperfusate, n = 6) via the pulmonary artery before CPB weaning. Sham-operated pigs (n = 7) served as controls. Animals were followed up until 4 h after CPB. Pulmonary function, haemodynamics, markers of inflammation, endothelial injury and oxidative stress as well as morphological lung alterations were analysed.. CPB (UR group) induced deterioration of pulmonary function (lung mechanics, oxygenation index and lung oedema). Also, controlled lung reperfusion groups (CR and MR) presented with pulmonary dysfunction after CPB. However, compared with UR, controlled lung reperfusion strategies (CR and MR) improved lung mechanics and reduced markers of oxidative stress, but without alteration of haemodynamics, oxygenation, inflammation, endothelial injury and lung morphology. Both controlled reperfusion groups were similar without relevant differences.. Controlled lung reperfusion strategies attenuated a decrease in lung mechanics and an increase in oxidative stress, indicating an influence on CPB-related pulmonary injury. However, they failed to avoid completely CPB-related lung injury, implying the need for additional strategies given the multifactorial pathophysiology of postoperative pulmonary dysfunction.

Topics: Animals; Biomarkers; Cardiopulmonary Bypass; Disease Models, Animal; Endothelin-1; Hemodynamics; Inflammation Mediators; Interleukin-6; Lung; Lung Injury; Malondialdehyde; Oxidative Stress; Perfusion; Pulmonary Edema; Reperfusion Injury; Respiratory Mechanics; Swine; Time Factors

The aim of the present study is to determine the effects of the BAY 11-7082, a nuclear factor-kappaB (NF-κB) inhibitor, on endothelin-1 (ET-1) induced lung edema, the level of reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF-α) in the lungs. Experiments were carried out on adult male Wistar-Kyoto rats. The animals were divided into 4 groups: Group I: saline-treated control; Group II: saline followed by ET-1 (12.5 μg/kg b.w., i.v.); Group III: BAY 11-7082 (10 mg/kg b.w., i.v.) administered one hour before saline; Group IV: BAY 11-7082 (10 mg/kg b.w., i.v.) administered 1 hour before ET-1 (12.5 μg/kg b.w., i.v.). Injection of ET-1 alone showed a significant (P<0.001) increase in thiobarbituric acid reactive substances (TBARS) and hydrogen peroxide (H(2)O(2)) level as well as a decrease (P<0.01) in GSH level and GSH/GSSG ratio (P<0.02). BAY 11-7082 significantly decreased TBARS (P<0.01) and H(2)O(2) (P<0.05) level as well as improved the redox status (P<0.02) in the lungs. BAY 11-7082 also prevented ET-1 induced lung edema (P<0.05). The concentration of TNF-α (P<0.02) and p65 subunit of NF-κB signaling compound (P<0.001) was increased in the presence of ET-1, while BAY 11-7082 decreased both TNF-α level (P<0.05) and p65 subunit concentration (P<0.01). Our results indicate that BAY 11-7082 plays a protective role in ET-1 induced oxidative lung injury. It successfully prevents lung edema as well as ROS and TNF-α overproduction. Our results also highlight the important role of the NF-κB pathway in ET-1 induced lung injury and ROS overproduction.

Topics: Animals; Endothelin-1; Male; NF-kappa B; Nitriles; Oxidative Stress; Pulmonary Edema; Random Allocation; Rats; Rats, Inbred WKY; Reactive Oxygen Species; Sulfones

Endothelin-1 (ET-1) is thought to play a pivotal role in pulmonary edema formation. The underlying mechanisms remain uncertain but may include alterations in capillary pressure and vascular permeability. There are no studies investigating whether ET-1 also affects alveolar fluid clearance which is the primary mechanism for the resolution of pulmonary edema. Therefore, we performed this study to clarify effects of ET-1 on alveolar reabsorption and fluid balance in the rat lung.. Alveolar fluid clearance was measured in fluid instilled rat lungs using a 5% albumin solution with or without ET-1 (10(-7) M) and/or amiloride (100 microM). Net alveolar fluid balance, time course of edema formation, pulmonary capillary pressure, and alveolar permeability to albumin were measured in the isolated, ventilated, constant pressure perfused rat lung with or without ET-1 (0.8 nM) added to the perfusate.. In the fluid-instilled lung, ET-1 reduced alveolar fluid clearance by about 65%, an effect that was related to a decrease in amiloride-sensitive transepithelial Na(+) transport (P < 0.001). The ET-1-induced inhibition was completely prevented by the endothelin B receptor antagonist BQ788 (P = 0.006), whereas the endothelin A receptor antagonist BQ123 had no effect (P = 0.663). In the isolated, ventilated, perfused rat lung ET-1 caused a net accumulation of alveolar fluid by about 20% (P = 0.011 vs control), whereas lungs of control rats cleared about 20% of the instilled fluid. ET-1 increased pulmonary capillary pressure (+9.4 cm H(2)O), decreased perfusate flow (-81%), accelerated lung weight gain and reduced lung survival time (P < 0.001). Permeability to albumin was not significantly affected by ET-1 (P = 0.24).. ET-1 inhibits alveolar fluid clearance of anesthetized rats by inhibition of amiloride-sensitive epithelial Na(+) channels. The inhibitory effect of ET-1 results from activation of the endothelin B receptor. These findings suggest a mechanism by which ET-1, in addition to increasing capillary pressure, contributes to pulmonary edema formation.

Topics: Albumins; Amiloride; Animals; Blood Pressure; Bronchoalveolar Lavage Fluid; Capillaries; Capillary Permeability; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Epithelial Sodium Channel Blockers; Epithelial Sodium Channels; Extravascular Lung Water; Hydrostatic Pressure; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Pulmonary Alveoli; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Sodium Channel Blockers; Time Factors; Vasoconstriction

Contact of blood with artificial surfaces and air as well as ischemia/reperfusion injury to the heart and lungs mediate systemic and local inflammation during cardiopulmonary bypass (CPB). Activation of complement and coagulation cascades leads to and accompanies endothelial cell damage. Therefore, endothelial-targeted cytoprotection with the complement inhibitor and endothelial protectant dextran sulfate (DXS, MW 5000) may attenuate CBP-associated myocardial and pulmonary injury.. Eighteen pigs (DXS, n=10; phosphate buffered saline [PBS], n=8) underwent standard cardiopulmonary bypass. After aortic cross-clamping, cardiac arrest was initiated with modified Buckberg blood cardioplegia (BCP), repeated after 30 and 60 min with BCP containing either DXS (300 mg/10 ml, equivalent to 5mg/kg) or 10 ml of PBS. Following 30 min reperfusion, pigs were weaned from CPB. During 2h of observation, cardiac function was monitored by echocardiography and invasive pressure measurements. Inflammatory and coagulation markers were assessed regularly. Animals were then sacrificed and heart and lungs analyzed.. DXS significantly reduced CK-MB levels (43.4+/-14.8 ng/ml PBS, 35.9+/-11.1 ng/ml DXS, p=0.042) and significantly diminished cytokine release: TNFalpha (1507.6+/-269.2 pg/ml PBS, 222.1+/-125.6 pg/ml DXS, p=0.0071), IL1beta (1081.8+/-203.0 pg/ml PBS, 110.7+/-79.4 pg/ml DXS, p=0.0071), IL-6 (173.0+/-91.5 pg/ml PBS, 40.8+/-19.4 pg/ml DXS, p=0.002) and IL-8 (304.6+/-81.3 pg/ml PBS, 25.4+/-14.2 pg/ml DXS, p=0.0071). Tissue endothelin-1 levels were significantly reduced (6.29+/-1.90 pg/100mg PBS, 3.55+/-1.15 pg/100mg DXS p=0.030) as well as thrombin-anti-thrombin formation (20.7+/-1.0 microg/ml PBS, 12.8+/-4.1 microg/ml DXS, p=0.043). Also DXS reduced cardiac and pulmonary complement deposition, neutrophil infiltration, hemorrhage and pulmonary edema (measured as lung water content, 81+/-3% vs 78+/-3%, p=0.047), indicative of attenuated myocardial and pulmonary CPB-injury. Diastolic left ventricular function (measured as dp/dt(min)), pulmonary artery pressure (21+/-3 mmHg PBS, 19+/-3 mmHg DXS, p=0.002) and right ventricular pressure (21+/-1 mmHg PBS, 19+/-3 mmHg DXS p=0.021) were significantly improved with the use of DXS.. Addition of DXS to the BCP solution ameliorates post-CPB injury and to a certain extent improves cardiopulmonary function. Endothelial protection in addition to myocyte protection may improve post-CPB outcome and recovery.

Topics: Animals; Blood Coagulation; Cardiopulmonary Bypass; Complement Hemolytic Activity Assay; Dextran Sulfate; Disease Models, Animal; Drug Evaluation, Preclinical; Endothelin-1; Heart Arrest, Induced; Hemodynamics; Inflammation Mediators; Lung Diseases; Myocardial Reperfusion Injury; Pulmonary Edema; Reperfusion Injury; Sus scrofa

Endothelin 1 (ET-1) is a potent pulmonary vasoconstrictor and mediator of lung diseases. Antagonism of the ET-1-mediated effects has become an important therapeutic approach. ET-1 (A and B) receptors are differentially distributed in the lung vasculature. Whereas the ET(A) receptors mainly mediate vasoconstriction, the endothelial ET(B) receptor seems to have vasodilative properties. We sought to determine if antagonism of ET receptors can be achieved by inhalation of specific blockers in a model of ET-1-mediated pulmonary hypertension.

Topics: Administration, Inhalation; Antihypertensive Agents; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Oligopeptides; Peptides, Cyclic; Piperidines; Pulmonary Artery; Pulmonary Edema; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

Topics: Adult; Altitude Sickness; Endothelin-1; Gene Deletion; Genetic Predisposition to Disease; Humans; Mutagenesis, Insertional; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Pulmonary Edema

To investigate the role of endothelin-1 in the pathogenesis of neurogenetic pulmonary edema.. The levels of endothelin-1 in plasma and lung were measured in rats which suffered from diffuse brain injury on Marmarous' model. The changes of endothelin-1 in the lungs were also detected using an immunohistochemical method.. After heavy diffuse brain injury in rats, the levels of endothelin-1 in plasma and lung began increasing at 1 hour, and peaked at 6 hour. Though a little declining at 24 hour, it maintained a higher level within 48 hours (P < 0.05). Pulmonary pathology showed that after brain injury there were congestion, swelling in pulmonary microvessels with broadened pulmonary interstitial tissue, and leucocyte infiltration was dominated by neutrophils and monocytes from 1 hour on, which peaked at 6 hour. More serious congestion, swelling and protein effusion in pulmonary alveoli were observed at both 24 h and 48 h. Immunohistochemically, endothelin-1 had more significant expression and higher levels of OD in the experimental groups than that in the control's, the most significance of which was at 6 hour.. The inflammatory injury mechanism caused by endothelin-1 may play an important role in neurogenic pulmonary edema.

Topics: Animals; Endothelin-1; Lung; Male; Pulmonary Alveoli; Pulmonary Edema; Rats; Rats, Wistar

Sepsis-induced acute lung injury is still associated with high morbidity and mortality. The pathophysiology is complex, and markers of injury include increased extravascular lung water. To evaluate the effects of the novel dual endothelin receptor antagonist tezosentan on endotoxin-induced changes in extravascular lung water and gas exchange, 16 pigs were anaesthetized and catheterized. Twelve animals were subjected to 5 h of endotoxemia. After 2 h, six of these animals received a bolus of tezosentan 1 mg kg(-1) followed by a continuous infusion of 1 mg kg(-1) h(-1) to the end of the experiment at 5 h. Conventional pulmonary and hemodynamic parameters were measured. Extravascular lung water was determined in these pigs after 5 h of endotoxemia, as well as in the four additional nonendotoxemic sham animals. Tezosentan in the current dosage counteracted the deterioration of lung function caused by endotoxin, as measured by dead space, venous admixture, and compliance. In addition, pulmonary hypertension was attenuated. Tezosentan had a marked effect on the endotoxin-induced increase in extravascular lung water that was reduced to levels observed in nonendotoxemic sham animals. These results suggest that endothelin is involved in endotoxin-induced lung injury and the development of pulmonary edema. Dual endothelin receptor antagonism may be of value in the treatment of sepsis-related acute lung injury.

Topics: Acid-Base Equilibrium; Animals; Endothelin Receptor Antagonists; Endothelin-1; Endotoxins; Female; Hemodynamics; Hemoglobins; Male; Pulmonary Edema; Pulmonary Gas Exchange; Pyridines; Sus scrofa; Tetrazoles

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

Ischemia-reperfusion (I/R) injury of the lung involves increased pulmonary vascular resistance. Prostaglandins are thought to have a beneficial effect in lung transplantation, but their mechanism in I/R injury is unknown. We investigated whether iloprost, a stable prostacyclin analogue, prevents I/R-associated pulmonary vascular dysfunction and whether it affects endothelin-1 (ET-1) balance.. In an isolated blood-perfusion model, we subjected lungs of Lewis rats to 45 minutes of ischemia at 37 degrees C and randomly allocated the lungs to 3 groups (n = 6 each): iloprost (33.3 nmol/liter) added to the perfusate before ischemia and reperfusion (ILO+IR), iloprost (33.3 nmol/liter) given only before reperfusion (ILO+R), and controls without iloprost treatment (ILO-).. Reperfusion induced marked pulmonary edema in non-treated controls (ILO-), which was attenuated in ILO+R lungs and completely prevented in ILO+IR lungs. At 60 minutes reperfusion, arterial oxygen tension was significantly greater in both ILO+R and ILO+IR lungs compared with ILO- controls. Mean pulmonary artery pressure and pulmonary vascular resistance were slightly decreased in the ILO+R and significantly decreased in the ILO+IR group compared with the ILO- controls. Plasma levels of big ET-1, measured in both afferent and efferent blood, showed that I/R results in increased pulmonary venous levels of big ET-1. Interestingly, the increased venoarterial ET-1 gradient in ILO- lungs decreased significantly in the ILO+IR group.. We demonstrated in an isolated lung perfusion model that iloprost ameliorates post-ischemic lung reperfusion injury and maintains an appropriate pulmonary ET-1 balance.

Topics: Animals; Body Weight; Disease Models, Animal; Endothelin-1; Iloprost; Lung; Male; Models, Cardiovascular; Oxygen; Pulmonary Circulation; Pulmonary Edema; Pulmonary Gas Exchange; Pulmonary Wedge Pressure; Rats; Rats, Inbred Lew; Reperfusion Injury; Respiratory Distress Syndrome; Severity of Illness Index; Statistics as Topic; Vascular Resistance; Vasodilator Agents

In a group of 124 patients the authors investigated the importance of assessment of plasma levels of big endothelin and endothelin 1 in patients with chronic heart failure as compared with other currently used non-invasive parameters. A six fold increase of plasma levels of both substances was found in patients in functional class NYHA IV as compared with patients in class NYHA II-III. But even patients in the milder stage of NYHA had twice as high values as compared with the standard of the healthy population. Similarly patients with interstitial pulmonary oedema had a twice as high level of both parameters as compared with patients who had a normal finding on X-ray or merely a redistribution of the pulmonary vascularization. The sensitivity of assessment of plasma levels is such that this examination could become part of the basic diagnosis.

Topics: Biomarkers; Endothelin-1; Endothelins; Female; Heart Failure; Humans; Male; Middle Aged; Protein Precursors; Pulmonary Edema; Sensitivity and Specificity

To investigate the changes of antioxidative capacity and endothelial function among patients with high altitude pulmonary edema (HAPE).. The serum levels of SOD, MDA, GSH, NO, NOS and ET-1 were measured before and after treatment among 34 cases of patients with HAPE, and 20 local healthy volunteers served as control.. The serum levels of SOD, GSH, NO and NOS were lower in patient-group before treatment than after treatment and those in control-group significantly (P < 0.01), while the concentration of MDA and ET-1 were higher in patient-group before treatment than after treatment and those in the control-group significantly (P < 0.01). The serum levels of SOD, MDA, GSH, NO, NOS and ET-1 were not different between patient-group after treatment and the control-group (P > 0.05).. The results indicated that changes of SOD, MDA, GSH, NO, NOS and ET-1 may participate in the course of HAPE.

Topics: Adolescent; Adult; Altitude Sickness; Antioxidants; Endothelin-1; Endothelium, Vascular; Female; Glutathione; Humans; Male; Nitric Oxide; Nitric Oxide Synthase; Pulmonary Edema; Superoxide Dismutase

Nitric oxide (NO) seems to play an important role in tissue injury during reperfusion of the lung. FK409 is the first spontaneous NO donor that increases plasma guanosine 3':5'-cyclic monophosphate. It is reported that FK409 prevented myocardial infarction following occlusion and reperfusion in rat coronary arteries. In this study, we evaluated the effects of FK409 on pulmonary ischemia-reperfusion injury in an in situ warm ischemia model of rats.. Animals were divided into 2 groups: the FK409 study group that was administered FK409 (0.4 mg/kg) before reperfusion and the control group, administered a saline vehicle only. Following a thoracotomy, the bronchus, pulmonary artery and vein were separately clamped for 1 hour. Arterial oxygen tension (PaO2), arterial oxygen saturation (SaO2), and endothelin-I (ET-I) were measured after 2 hours of reperfusion. Histologic and immunohistochemical studies were performed; polymorphonuclear neutrophils (PMNs) were counted after 2 hours of reperfusion.. PaO2, SaO2, ET-I after 2 hours of reperfusion and the 7-day survival rate were significantly (p < 0.05) better in the FK409 group than the control group. Histologic damage was reduced in the FK409 group compared with the control group. PMN infiltration was also significantly (p < 0.05) lower in the FK409 group than in the control group.. FK409 seems to protect against ischemia-reperfusion injury of the lung. This effect may be related to a homeostatic effect on pulmonary vascular beds and prevention of PMN sequestration.

Topics: Animals; Endothelin-1; Immunohistochemistry; Lung; Lung Transplantation; Male; Nitric Oxide Donors; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitro Compounds; Oxygen; Pulmonary Edema; Rats; Rats, Wistar; Reperfusion Injury

Exaggerated pulmonary hypertension is thought to play an important part in the pathogenesis of high-altitude pulmonary edema (HAPE). Endothelin-1 is a potent pulmonary vasoconstrictor peptide that also augments microvascular permeability.. We measured endothelin-1 plasma levels and pulmonary artery pressure in 16 mountaineers prone to HAPE and in 16 mountaineers resistant to this condition at low (580 m) and high (4559 m) altitudes. At high altitude, in mountaineers prone to HAPE, mean (+/-SE) endothelin-1 plasma levels were approximately 33% higher than in HAPE-resistant mountaineers (22.2+/-1.1 versus 16.8+/-1.1 pg/mL, P<0.01). There was a direct relationship between the changes from low to high altitude in endothelin-1 plasma levels and systolic pulmonary artery pressure (r=0.82, P<0.01) and between endothelin-1 plasma levels and pulmonary artery pressure measured at high altitude (r=0.35, P=0.05).. These findings suggest that in HAPE-susceptible mountaineers, an augmented release of the potent pulmonary vasoconstrictor peptide endothelin-1 and/or its reduced pulmonary clearance could represent one of the mechanisms contributing to exaggerated pulmonary hypertension at high altitude.

Topics: Adult; Altitude; Blood Pressure; Disease Susceptibility; Endothelin-1; Female; Humans; Male; Middle Aged; Mountaineering; Pulmonary Artery; Pulmonary Edema; Systole

In the process of developing a model of Escherichia coli endotoxin-induced acute lung injury and shock in specific pathogen-free pigs, the effects of pretreatment with metyrapone (a cortisol-synthesis inhibitor) were examined. Metyrapone was administered 1.5 h before start of endotoxin infusion at t = 0 h (MET-ETOX group, n = 6). At the end of the experiments (t = 4 h) a bronchoalveolar lavage (BAL) was performed. Control animals received only endotoxin (CON-ETOX group, n = 6) or metyrapone (MET-CON group, n = 4). The following results are presented as means +/- SEM. It was found that metyrapone successfully blocked endogenous cortisol synthesis (plasma cortisol levels were 41.0 +/- 5.9 nM in MET-ETOX vs. 339.0 +/- 37.7 nM in CON-ETOX at t = 4 h, P <0.01). At t = 4 h the MET-ETOX animals had substantially increased systemic hypotension compared to the CON-ETOX group (mean arterial pressure 26.7 +/- 4.3 vs. 77.7 +/- 12.2 mmHg, P <0.01), decreased dynamic lung compliance (10.9 +/- 0.7 vs. 13.7 +/- 0.6 ml/cmH2O, P <0.01), increased percentage of BAL neutrophils (28.4 +/- 6.5 vs. 6.6 +/-1.8, P <0.01), pulmonary edema (BAL total protein 0.82 +/- 0.21 vs. 0.42 +/- 0.09 mg/mL, P <0.05), elevated levels of interleukin-8 (1924 +/- 275 vs. 324 +/- 131 pg/mL, P <0.01) and acidosis (pH 7.11 +/- 0.03 vs. 7.23 +/- 0.06, P <0.05). The MET-ETOX group also showed an increased pulmonary hypertension between 2 and 3 h after start of endotoxin infusion and a trend toward significantly increased levels of plasma interleukin-8 (P = 0.052). Arterial pCO2, pO2/FiO2, plasma endothelin-1, plasma TNFalpha, and blood leukocytes were not markedly influenced by the plasma cortisol levels. Nitric oxide production did not seem to be altered by endotoxin infusion in this model, in contrast to other animal studies; this discrepancy could be thought to be due to endotoxin-dosage differences or species differences. It is concluded that if endogenous cortisol production is blocked by metyrapone, the reactions occurring as a result of the endotoxin-induced acute lung injury and shock are greatly enhanced and that therefore pretreatment with metyrapone might be an important addition to this model with specific pathogen-free pigs.

Topics: Acid-Base Imbalance; Animals; Blood Gas Analysis; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Endothelin-1; Endotoxins; Female; Hydrocortisone; Hypotension; Interleukin-8; Leukocytes; Male; Metyrapone; Neutrophils; Nitric Oxide; Nitrites; Peroxidase; Proteins; Pulmonary Edema; Respiratory Distress Syndrome; Respiratory Function Tests; Shock; Specific Pathogen-Free Organisms; Swine; Tumor Necrosis Factor-alpha

FK409 is the first spontaneous nitric oxide (NO) donor known to increase plasma cyclic guanosine 3',5'monophosphate levels. In this study, we evaluated the effect of FK409 on pulmonary ischemia-reperfusion injury in an in situ warm ischemia canine model. Fourteen dogs were divided into two groups, and the FK409-treated group was given 5 micrograms/kg per min FK409. Warm ischemia was induced for 3 h. The arterial partial pressure of oxygen (PaO2), arterial oxygen saturation (SaO2), cardiac output (CO), left pulmonary vascular resistance (L-PVR), and endothelin-I (ET-I) were measured. A histologic study was performed, and polymorphonuclear neutrophils (PMNs) were also counted. The PaO2, SaO2, and L-PVR levels and PMNs after 30 min of reperfusion, ET-I after 2 h of reperfusion, and the 7-day survival rate were significantly (P < 0.05) better in the FK409-treated group than in the control group. The histologic damage was reduced in the FK409-treated group compared to the control group. FK409 appears to have a protective effect in ischemia-reperfusion injury of the lung.

Topics: Animals; Cardiac Output; Cyclic GMP; Dogs; Drug Evaluation, Preclinical; Endothelin-1; Ischemia; Lung; Nitric Oxide Donors; Nitro Compounds; Oxygen; Partial Pressure; Pulmonary Edema; Reperfusion Injury

The intrathecal (i.t.) injection of endothelins to conscious rats was found to cause respiratory arrest. To gain some insights into this central phenomenon, peripheral vascular permeability and lung oedema were measured after i.t. and i.v. injections of these peptides. When injected at T-8 spinal cord level, endothelin-1 (65 and 650 pmol) and endothelin-3 (650 pmol) enhanced vascular permeability in the lungs by 22-fold and 7-fold, respectively, and caused sudden death at the highest dose. Less prominent increases (between 1.4- and 2.2-fold) of vascular permeability were observed in other tissues (trachea, kidney, ears, skin of hind paws and back skin) with endothelin-1. Endothelin-1 (650 pmol) caused a similar increase (27-fold) in lung vascular permeability when injected at T-2, although the response was significantly less (P < 0.05) if injected at the L-4 (15-fold) spinal cord level. Only endothelin-1 produced lung oedema when injected at the T-2 or T-8 level. In contrast, intravenous injection of endothelins-1 and -3 (650 pmol) did not produce lung oedema and the lung vascular permeability was increased by only 1.4-1.6-fold and all rats survived. The prior i.t. injection of 6.5 nmol BQ-123 (cyclo[D-Trp, D-Asp, L-Pro, D-Val, L-Leu]), a selective endothelin ET(A) receptor antagonist, prevented the increases of lung vascular permeability and oedema and the mortality induced by i.t. endothelin-1 (650 pmol). Whereas i.v. treatment with phentolamine (2 mg/kg) or pentolinium (25 mg/kg + 50 mg/kg per h x 15 min) abolished the lung vascular permeability changes evoked by endothelin-1 (650) pmol), atropine (1 mg/kg), NG-nitro-L-arginine (50 mg/kg) or indomethacin (5 mg/kg) had no effect. Moreover, the effects of endothelin-1 were attenuated in capsaicin pretreated rats (125 mg/kg, 10 days earlier) and almost abolished in rats subjected to sympathectomy with 6-hydroxydopamine (100 mg/kg, 24-48 h earlier). All these treatments except atropine and NG-nitro-L-arginine prevented the endothelin-1-induced lung oedema and reduced the lethality by around 50%. These results suggest that the increases of pulmonary vascular permeability and oedema induced by i.t. endothelin-1 are due to an intense pulmonary vasoconstriction mediated by alpha-adrenoceptors following the release of catecholamines in response to the activation of endothelin ET(A) receptor in the spinal cord. This central phenomenon seems to be reflexogenic, including the involvement of primary afferent C-fibe

Topics: Animals; Capillary Permeability; Endothelin-1; Endothelin-3; Endothelins; Injections, Spinal; Male; Pulmonary Edema; Rats; Rats, Wistar; Spinal Cord

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

We present a case of high altitude pulmonary oedema (HAPE) with pulmonary hypertension and polymorphonuclear leucocyte (PMN) accumulation in bronchoalveolar lavage fluid (BALF), which occurred in a 21 year old man. Plasma endothelin-1 (ET-1) and interleukin-8 (IL-8) concentration in BALF were elevated on admission, and returned to normal level at recovery, when the pulmonary artery pressure and the PMN counts in BALF were normal. In addition, E-selectin and intercellular adhesion molecule-1 (ICAM-1) in BALF were also slightly increased on admission. These findings suggest that endothelin-1 is a vasoconstrictor which contributes to the pulmonary hypertension in high altitude pulmonary oedema, and that some of the inflammatory mediators play an important role in chemotaxis and accumulation of polymorphonuclear leucocytes in the development of high altitude pulmonary oedema.

Topics: Adult; Altitude Sickness; Bronchoalveolar Lavage Fluid; Chemotaxis, Leukocyte; E-Selectin; Endothelin-1; Humans; Hypertension, Pulmonary; Intercellular Adhesion Molecule-1; Interleukin-8; Leukocyte Count; Male; Mountaineering; Neutrophils; Pulmonary Edema; Pulmonary Wedge Pressure; Vasoconstrictor Agents

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

Alpha-naphthylthiourea when injected intraperitoneally to rats (10 mg kg-1 i.p.) produced lung oedema as indicated by an increase in lung weight/body ratio and pleural effusion reaching a maximum within 4 hours. Prior intravenous single bolus injection of endothelin-1 elicited a significant and dose-dependent inhibition in both parameters. However, prior i.v. injection of angiotensin II using relatively higher doses did not alter the oedema-producing effect of alpha-naphthylthiourea indicating a characteristic for endothelin-1. The inhibitory effect of endothelin-1 on pleural effusion is more prominent than lung weight/body weight ratio. The resolution of lung oedema by single bolus i.v. injection of endothelin-1 is probably due to the acute long-lasting and potent vasoconstrictor effect of the peptide and its large accumulation in lung tissue. Phosphoramidon, an inhibitor of endothelin converting enzyme, did not alter the oedema producing effect of alpha-naphthylthiourea indicating the lack of the participation of endothelin-peptide cascade to this pathological event. Bosentan, a non-selective receptor blocker of endothelin-1, did not inhibit the preventive effect of the peptide against alpha-naphthylthiourea-induced lung oedema. Possible mechanisms of the acute effect of endothelin-1 on lung oedema are discussed.

Topics: Angiotensin II; Animals; Aspartic Acid Endopeptidases; Body Weight; Bosentan; Endothelin-1; Endothelin-Converting Enzymes; Glycopeptides; Male; Metalloendopeptidases; Organ Size; Pleural Effusion; Protease Inhibitors; Pulmonary Edema; Rats; Sulfonamides; Thiourea

To investigate the machanisms of ET-1-induced lung edema.. Different doses of ET-1 were added to isolate rat lungs perfused by Ringer's solution containing albumin to explore the mechanisms of ET-1 induced pulmonary edema. The lung weight gain, pulmonary vascular permeability to water (Wf) and albumin (Ps) were observed.. It was found that low dose ET-1 increased lung weight gain, pulmonary artery pressure, pulmonary capillary pressure, pulmonary vascular post-resistance and total resistance, but no significant changes of vascular permeability were observed.. The mechanisms of lung edema induced by ET-1 are different. Low dose ET-1 may induce lung edema by increasing pulmonary vascular permeability while large dose ET-1 by increasing pulmonary vascular pressure.

Topics: Animals; Capillary Permeability; Endothelin-1; In Vitro Techniques; Lung; Male; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Vascular Resistance