endothelin-1 and Hemorrhage

Topics: Animals; Blood Substitutes; Endothelin-1; Free Radical Scavengers; Hemoglobins; Hemorrhage; Humans; Nitric Oxide; Receptors, Adrenergic

During high intensity exercise, the very high pulmonary artery pressure (Ppa) experienced by Thoroughbred horses is considered a major factor in the aetiology of exercise-induced pulmonary haemorrhage (EIPH). Recently, endothelin-1 (ET-1), a potent vasoconstrictive hormone, has been found to increase Ppa in horses at rest via binding to its ET-1A receptor subtype. In addition, plasma concentrations of ET-1 are increased in horses during and after high intensity exercise.. If ET-1 increases Ppa during exercise in the horse, administration of a specific ET-1A antagonist would decrease Ppa and therefore EIPH.. Saline (CON) or an ET-1A receptor antagonist, TBC3214 (3 mg/kg bwt i.v.; ANTAG) was administered to horses 1 h prior to maximal incremental exercise on a high-speed treadmill. Gas exchange measurements were made breath-by-breath and blood samples collected during each 1 min stage to determine blood gases, acid-base status and cardiac output. EIPH was determined via bronchoalveolar lavage (BAL) approximately 30 min after exercise.. The time to fatigue, gas exchange and cardiovascular responses were not different between groups (P>0.05). Resting and peak Ppa did not differ significantly between treatments. Most importantly, ANTAG did not decrease EIPH.. These results do not support a deterministic role for ET-1 in the increased Ppa and therefore EIPH, during maximal exercise in the equine athlete.. Treatment with an ET-1A receptor antagonist does not appear to be a viable therapeutic intervention in the prevention of EIPH.

Topics: Animals; Blood Chemical Analysis; Blood Gas Analysis; Cross-Over Studies; Endothelin-1; Hemorrhage; Horse Diseases; Horses; Isoxazoles; Lung Diseases; Oxygen Consumption; Physical Conditioning, Animal; Pulmonary Wedge Pressure; Sulfonamides

Topics: Animals; Araliaceae; Blood Coagulation; Coagulants; Endothelin-1; Female; Hemorrhage; Male; Nitric Oxide Synthase Type III; Partial Thromboplastin Time; Prothrombin Time; Rats; Rats, Sprague-Dawley; Thromboxane B2

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 pathogenesis of the Crimean-Congo hemorrhagic fever (CCHF) and the cause of the hemorrhage are not yet fully understood. However, the endothelium plays a key role in the pathogenesis. The purpose of this study was to investigate endothelial dysfunction markers (asymmetrical dimethyl arginine [ADMA], endothelin 1[ET-1], thrombomodulin [TM], von Willebrand factor [vWf], and intercellular adhesion molecule [ICAM-1]) in serum in patients with CCHF and their associations with hemorrhage. Seventy-three patients with CCHF were included in the study. All patients' endothelial dysfunction markers were studied using routine biochemical and hematological tests. The data obtained were then subjected to statistical analysis. Statistically significant differences were determined between the patients and healthy control groups at time of presentation to hospital in terms of ADMA (P < 0.001), ET-1 (P < 0.001), TM (P = 0.039), vWf (P < 0.001), and ICAM-1 (P < 0.001) levels. Only the differences in TM and vWf were significant between the hemorrhagic and non-hemorrhagic groups (P < 0.05). Both serum ADMA and TM levels were significantly higher in the hemorrhage and non-hemorrhage CCHF groups on the 5th day compared to the 1st day (P < 0.05). Levels of endothelial dysfunction markers in CCHF vary in proportion to the damage occurring in the endothelium. ADMA and TM levels were lower in periods with mild endothelial injury. They were increased in line with severity endothelial injury. They may be an early marker in showing hemorrhage. Elevation in ADMA levels and low nitric oxide levels lead to endothelial injury and hemorrhage. Soluble TM that entered the circulation in line with the increased endothelial injury in hemorrhagic patients has been compromised the coagulation cascade.

Topics: Adult; Aged; Arginine; Biomarkers; Cytokines; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Hemorrhage; Hemorrhagic Fever Virus, Crimean-Congo; Hemorrhagic Fever, Crimean; Humans; Kinetics; Male; Middle Aged; Prognosis; Prospective Studies; ROC Curve; Thrombomodulin; Turkey; von Willebrand Factor

Predicting the likely success of primary PCI to salvage potential infarcted myocardium is desirable. We compared early invasive parameters of coronary microcirculation function with the levels of circulating endothelin (ET-1) and 6-month ejection fraction after STEMI.. Forty-four STEMI patients underwent assessment of coronary flow reserve (CFR) and index of myocardial resistance (IMR) on completion of PPCI and one day later. Cardiac magnetic resonance (CMR) at 24 h and 6 months assessed ejection fraction, oedema, late gadolinium enhancement, and salvage. In patients with depressed EF, there was no difference in IMR or CFR measured immediately after PPCI compared with those with preserved EF. However, by Day 1, CFR was significantly lower in those with depressed EF [2.0(1.5-2.3) vs. 2.6(2.1-3.3), P = 0.008]. In multivariable models, higher CFR post-PPCI [EST: +8.9 (SE 3.7) per 1 CFR unit, P = 0.03] and greater increase in CFR between post-PPCI and Day 1 [EST: +8.5 (SE 3.4) per 1 CFR unit, P = 0.01] were associated with higher salvage index. Circulating endothelin levels were significantly elevated in the low EF group at both 6 and 24 h, and 24 h levels correlated with CFR.. Changes of the coronary microcirculation in the first day after PPCI are associated with 6-month ejection fraction and myocardial salvage. Depressed CFR at 24 h is associated with CMR imaging indices of MVO and haemorrhage and elevated endothelin levels.

Topics: Coronary Circulation; Coronary Occlusion; Coronary Vessels; Endothelin-1; Female; Hemorrhage; Humans; Magnetic Resonance Angiography; Male; Microcirculation; Microvessels; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Prospective Studies; Recovery of Function; Stroke Volume; Vascular Resistance

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

To test the compensatory role of endothelin-1 when acute blood loss is superimposed on anaesthesia, by characterizing the effect of systemic endothelin receptor subtype A (ET(A)) blockade on the haemodynamic and hormonal responses to haemorrhage in dogs anaesthetized with xenon/remifentanil (X/R) or isoflurane/remifentanil (I/R).. Prospective experimental randomized controlled study.. Six female Beagle dogs, 13.4 +/- 1.3 kg.. Animals were anaesthetized with remifentanil 0.5 microg kg(-1) minute(-1) plus either 0.8% isoflurane (I/R) or 63% xenon (X/R), with and without (Control) the systemic intravenous endothelin receptor subtype A antagonist atrasentan (four groups, n = 6 each). After 60 minutes of baseline anaesthesia, the dogs were bled (20 mL kg(-1)) over 5 minutes and hypovolemia was maintained for 1 hour. Continuous haemodynamic monitoring was performed via femoral and pulmonary artery catheters; vasoactive hormones were measured before and after haemorrhage.. In Controls, systemic vascular resistance (SVR), vasopressin and catecholamine plasma concentrations were higher with X/R than with I/R anaesthesia at pre-haemorrhage baseline. The peak increase after haemorrhage was higher during X/R than during I/R anaesthesia (SVR 7420 +/- 867 versus 5423 +/- 547 dyne seconds cm(-5); vasopressin 104 +/- 23 versus 44 +/- 6 pg mL(-1); epinephrine 2956 +/- 310 versus 177 +/- 99 pg mL(-1); norepinephrine 862 +/- 117 versus 195 +/- 33 pg mL(-1), p < 0.05). Haemorrhage reduced central venous pressure from 3 +/- 1 to 1 +/- 1 cm H(2)O (I/R, ns) and from 8 +/- 1 to 5 +/- 1 cm H(2)O (X/R, p < 0.05), but did not reduce mean arterial pressure, nor cardiac output. Atrasentan did not alter the haemodynamic and hormonal response to haemorrhage during either anaesthetic protocol.. Selective ET(A) receptor blockade with atrasentan did not impair the haemodynamic and hormonal compensation of acute haemorrhage during X/R or I/R anaesthesia in dogs.

Topics: Anesthesia; Anesthesia, Inhalation; Anesthesia, Intravenous; Anesthetics, Inhalation; Anesthetics, Intravenous; Animals; Atrasentan; Blood Loss, Surgical; Catecholamines; Dog Diseases; Dogs; Endothelin A Receptor Antagonists; Endothelin-1; Epinephrine; Female; Hemodynamics; Hemorrhage; Isoflurane; Norepinephrine; Piperidines; Pyrrolidines; Remifentanil; Time Factors; Vascular Resistance; Vasopressins; Xenon

The effects of endothelin receptor subtype A (ETA) blockade on hemodynamics and hormonal adaptation during hemorrhage were studied in xenon/remifentanil-anesthetized dogs (n=6) pretreated with an angiotensin II type 1 (AT1)-receptor blocker.. after a baseline awake period, anesthesia was induced in the dogs with propofol and maintained with xenon/remifentanil (baseline anesthesia). Sixty minutes later, 20 mL x kg(-1) of blood was withdrawn within 5 min and the dogs observed for another hour (hemorrhage). AT1 group followed the same protocol as controls except the AT1-receptor blocker losartan (i.v. 100 microg x kg(-1) x min(-1)) was started at the beginning of the experiment. AT1+ETA group was the same as AT1 group but with the addition of the ETA-receptor blocker atrasentan (i.v. 1 mg x kg(-1), then 0.01 mg x kg(-1) x min(-1)). In controls, mean arterial pressure (MAP) remained unchanged during baseline anesthesia, whereas systemic vascular resistance (SVR) increased from 3282+/-281 to 7321+/-803 dyn.s.cm-5, heart rate (HR) decreased from 86+/-4 to 40+/-3 beats x min(-1), and cardiac output (CO) decreased from 2.3+/-0.2 to 0.9+/-0.1 L x min(-1) (p<0.05), with no further changes after hemorrhage. In AT1-inhibited dogs, MAP (71+/-6 mm Hg) and SVR (5939+/-611 dyn x s x cm(-5)) were lower during baseline anesthesia and after hemorrhage, but greater than those in AT1+ETA (66+/-7 mm Hg, 5034+/-658 dyn x s x cm(-5)) (p<0.05). HR and CO were not different between groups. Plasma concentration of vasopressin was highest with AT1+ETA inhibition after hemorrhage. Combined AT1+ETA-receptor blockade impaired vasoconstriction more than did AT1-receptor blockade alone, both during baseline xenon anesthesia and after hemorrhage. Even a large increase in vasoconstrictor hormones could not prevent the decrease in blood pressure and the smaller increase in SVR. Thus, endothelin is an important vasoconstrictor during hemorrhage, and both endothelin and angiotensin II are essential hormones for cardiovascular stabilization after hemorrhage.

Topics: Anesthesia; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Atrasentan; Blood Pressure; Dogs; Endothelin A Receptor Antagonists; Endothelin-1; Female; Hemodynamics; Hemorrhage; Losartan; Pyrrolidines; Vascular Resistance; Vasoconstriction; Vasopressins; Xenon

Although endothelin-1 (ET-1)-induced organ hypoperfusion after trauma-hemorrhage is improved by estrogen administration, it remains unclear whether estrogen receptor (ER) subtypes play any role in the attenuation of ET-1-induced vasoconstriction in any specific organ bed. To investigate this, isolated perfusion experiments in the heart, liver, small intestine, kidney, and lung were carried out in sham, at the time of maximum bleedout (MBO; i.e., 5-cm midline incision, with removal of 60% of circulating blood volume over 45 min to maintain a mean blood pressure of 40 mmHg), and 2 h after trauma-hemorrhage and resuscitation (T-H/R). Organ-specific ET-1-induced vasoconstriction was evaluated, and the effects of 17beta-estradiol (E2) and ER-specific agonists propylpyrazole triol (PPT; ERalpha agonist) and diarylpropionitrile (DPN; ERbeta agonist) were determined. ET-1 induced the greatest vasoconstriction in sham animals, with the strongest response in the kidneys, followed by the small intestine and liver. ET-1-induced responses were weakest in the heart and lungs. ET-1-induced vasoconstriction was evident at the time of MBO but was significantly decreased at 2 h after T-H/R. ERbeta plays an important role in cardiac performance, as evidenced by improved heart performance (+dP/dt) in the presence of DPN. DPN also induced a greater effect than PPT in the reduction of ET-1-induced vasoconstriction in the kidneys and lungs. In contrast, PPT attenuated ET-1-induced vasoconstriction in the liver, whereas both DPN and PPT were equally effective in the small intestine. The increased +dP/dt values induced by E2, DPN, or PPT were evident at the time of MBO but were significantly decreased at 2 h after T-H/R. These data indicate that the effects of ET-1 on vasoconstriction and the role of ER subtypes in estrogen-induced vasorelaxation are organ specific and temporally specific after trauma-hemorrhage.

Topics: Animals; Blood Circulation; Blood Pressure; Coronary Circulation; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Hemorrhage; Intestine, Small; Liver Circulation; Male; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Renal Circulation; Resuscitation; Time Factors; Vasodilation; Vasodilator Agents

Although endothelin-1 (ET-1) induces vasoconstriction, it remains unknown whether 17beta-estradiol (E(2)) treatment following trauma-hemorrhage alters these ET-1-induced vasoconstrictive effects. In addition, the role of the specific estrogen receptor (ER) subtypes (ER-alpha and ER-beta) and the endothelium-localized downstream mechanisms of actions of E(2) remain unclear. We hypothesized that E(2) attenuates increased ET-1-induced vasoconstriction following trauma-hemorrhage via an ER-beta-mediated pathway. To study this, aortic rings were isolated from male Sprague-Dawley rats following trauma-hemorrhage with or without E(2) treatment, and alterations in tension were determined in vitro. Dose-response curves to ET-1 were determined, and the vasoactive properties of E(2), propylpyrazole triol (PPT, ER-alpha agonist), and diarylpropionitrile (DPN, ER-beta agonist) were determined. The results showed that trauma-hemorrhage significantly increased ET-1-induced vasoconstriction; however, administration of E(2) normalized ET-1-induced vasoconstriction in trauma-hemorrhage vessels to the sham-operated control level. The ER-beta agonist DPN counteracted ET-1-induced vasoconstriction, whereas the ER-alpha agonist PPT was ineffective. Moreover, the vasorelaxing effects of E(2) were not observed in endothelium-denuded aortic rings or by pretreatment of the rings with a nitric oxide (NO) synthase inhibitor. Cyclooxygenase inhibition with indomethacin had no effect on the action of E(2). Thus, E(2) administration attenuates ET-1-induced vasoconstriction following trauma-hemorrhage via an ER-beta-mediated pathway that is dependent on endothelium-derived NO synthesis.

Topics: Animals; Aorta; Dose-Response Relationship, Drug; Drug Combinations; Endothelin-1; Estradiol; Hemorrhage; Male; Rats; Rats, Sprague-Dawley; Vasoconstriction; Wounds, Penetrating

Severe traumatic brain injury (TBI) is characterized by a high mortality and poor outcome. The pathomechanisms involved are cytokine-mediated proinflammatory and anti-inflammatory reactions and significant cerebral microcirculatory disorders. The role of endothelin 1 (ET-1), a very potent vasoconstrictive peptide, in the deterioration of cerebral perfusion after trauma is still unclear. The presented study investigated the changes in ET-1 in the cerebrospinal fluid (CSF) and plasma after TBI in humans, with special regard to the presence of subarachnoid hemorrhage (SAH) and clinical outcome. Twenty patients with TBI were consecutively enrolled into the study, 10 patients without SAH (TBI group) and 10 patients with SAH (TBI-H group). Paired samples of plasma and CSF were collected for 10 days after trauma. Analysis of the ET-1 concentrations showed that TBI is associated with initially increased ET-1 values in plasma (TBI, day 1; TBI-H, days 2-3) and significantly increased (P < 0.05, vs. control) CSF concentrations (TBI, days 1-2; TBI-H, days 1-3) in the first days after trauma. In the further time course, ET-1 values declined in both groups, reaching reference values in plasma. The CSF values remained significantly (P < 0.05 vs. control) elevated. Both groups showed a second peak on the beginning of the second week after trauma in plasma and CSF. Whereas plasma concentrations failed to reach significance, CSF values showed a significant peak on day 7 in both groups. The TBI-H patients had significantly (P < 0.05) higher values in the secondary peak compared with patients of the TBI group. The kinetics of traumatic SAH-dependent ET-1 needs to be assessed in further investigations.

Topics: Adolescent; Adult; Aged, 80 and over; Brain Injuries; Endothelin-1; Female; Glasgow Coma Scale; Hemorrhage; Humans; Male; Microcirculation; Middle Aged; Peptides; Treatment Outcome

Although gender differences in intestinal perfusion exist following trauma-hemorrhage (T-H), it remains unknown whether endothelin-1 (ET-1) plays any role in these dimorphic responses. To study this, male, proestrus female (female), and 17 beta-estradiol (E2)-treated male rats underwent midline laparotomy, hemorrhagic shock (blood pressure 40 mmHg, 90 min), and resuscitation (Ringer lactate, 4X shed blood volume, 1 h). Two hours thereafter, intestinal perfusion flow (IPF) was measured using isolated intestinal perfusion. The IPF in sham-operated males was significantly lower than those in other groups and decreased markedly following T-H. In contrast, no significant decrease in IPF was observed in females and E2 males following T-H. The lower IPF in sham-operated males was significantly elevated by ET(A) receptor antagonist (BQ-123) administration and was similar to that seen in sham-operated females. The decreased IPF in males after T-H was also attenuated by BQ-123 administration. The intestinal ET-1 levels in sham-operated males were significantly higher than in other groups. Although plasma and intestinal ET-1 levels increased significantly after T-H in all groups, they were highest in males. Plasma E2 levels in females and E2 males were significantly higher than in males; however, they were not affected by T-H. There was a negative correlation between plasma ET-1 and E2 following T-H. Thus ET-1 appears to play an important role in intestinal perfusion failure following T-H in males. Because E2 can modulate this vasoconstrictor effect of ET-1, these findings may partially explain the previously observed salutary effect of estrogen in improving intestinal perfusion following T-H in males.

Topics: Animals; Endothelin Receptor Antagonists; Endothelin-1; Estradiol; Female; Gene Expression; Hemorrhage; Intestine, Small; Male; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Sex Factors; Shock, Hemorrhagic

A recent study suggested that administration of androstenediol (Adiol) after trauma-hemorrhage (T-H) improves hepatic functions; however, the mechanism responsible for the salutary effect of Adiol remains unknown. Although studies indicate similarities and association between the anti-inflammatory properties of Adiol and peroxisome proliferator-activated receptor gamma (PPARgamma), whether the salutary effects of Adiol are mediated via upregulation of PPARgamma remains unclear.. Male Sprague-Dawley rats underwent laparotomy and approximately 90 minutes of hemorrhagic shock (40 mm Hg), followed by resuscitation with 4 times the shed blood volume in the form of Ringer's lactate. Adiol (1 mg per kilogram of body weight, iv) was administered at the end of resuscitation. An additional group of rats were treated with PPARgamma antagonist (GW9662, 1 mg/kg ip) along with Adiol and the rats were sacrificed 5 hours thereafter.. Hepatic functions were markedly depressed and plasma tumor necrosis factor-alpha, C-reactive protein and endothelin-1 were markedly increased after T-H. DNA-binding activity of nuclear factor kappa B and AP-1, and gene expressions of inducible nitric oxide synthase and endothelin-1 in the liver also increased significantly. These parameters were attenuated by Adiol treatment. These effects were accompanied an increased DNA-binding activity of PPARgamma in T-H-Adiol-treated rats. Treatment of rats with GW9662 prevented the salutary effects of Adiol after T-H.. Since blockade of PPARgamma prevented the salutary effects of Adiol on hepatic functions and proinflammatory factors, this finding suggests that Adiol mediated its salutary effects after T-H via the PPARgamma-related pathways.

Topics: Anabolic Agents; Androstenediol; Anilides; Animals; C-Reactive Protein; Endothelin-1; Gene Expression; Hemorrhage; Liver; Male; NF-kappa B; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; PPAR gamma; Rats; Rats, Sprague-Dawley; Transcription Factor AP-1; Tumor Necrosis Factor-alpha; Wounds and Injuries

This study investigates angiotensin II and endothelin-1 mediated mechanisms involved in the haemodynamic, hormonal, and renal response towards acute hypotensive haemorrhage.. Conscious dogs were pre-treated with angiotensin II type 1 (AT1) and/or endothelin-A (ETA) receptor blockers or not. Protocol 1: After a 60-min baseline period, 25% of the dog's blood was rapidly withdrawn. The blood was retransfused 60 min later and data recorded for another hour. Protocol 2: Likewise, but preceded by AT1 blockade with i.v. Losartan. Protocol 3: Likewise, but preceded by ETA blockade with i.v. ABT-627. Protocol 4: Likewise, but with combined AT1 plus ETA blockade.. In controls, haemorrhage decreased mean arterial pressure (MAP) by approximately 25%, cardiac output by approximately 40%, and urine volume by approximately 60%, increased angiotensin II (3.1-fold), endothelin-1 (1.13-fold), vasopressin (116-fold), and adrenaline concentrations (3.2-fold). Glomerular filtration rate and noradrenaline concentrations remained unchanged. During AT1 blockade, the MAP decrease was exaggerated (-40%) and glomerular filtration rate fell. During ETA blockade, noradrenaline increased after haemorrhage instead of adrenaline, and the MAP recovery after retransfusion was blunted. The decrease in cardiac output was similar in all protocols.. Angiotensin II is more important than endothelin-1 for the short-term regulation of MAP and glomerular filtration rate after haemorrhage, whereas endothelin-1 seems necessary for complete MAP recovery after retransfusion. After haemorrhage, endothelin-1 seems to facilitate adrenaline release and to blunt noradrenaline release. Haemorrhage-induced compensatory mechanisms maintain blood flow more effectively than blood pressure, as the decrease in cardiac output--but not MAP--was similar in all protocols.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Atrasentan; Blood Pressure; Blood Transfusion; Cardiac Output; Dogs; Endothelin-1; Epinephrine; Female; Glomerular Filtration Rate; Hemodynamics; Hemorrhage; Losartan; Norepinephrine; Pyrrolidines; Receptor, Endothelin A; Stroke Volume; Urine; Vascular Resistance; Vasopressins

To observe the phenomenon of pulmonary hemorrhage (PH) induced by exogenous endothelin-1 (exET-1) and the antagonizing effect of exogenous calcitonin gene-related peptide (exCGRP) in newborn rats.. (1) To study the exET-1 induced PH: 100 newborn Wistar rats were randomly assigned into control group (group A, n = 10) and experiment groups (20 rats in each of groups B, C, D and E and 10 in group F). Thirty microl of normal saline and different concentrations of exET-1 in saline (ranged from 2 x 10(-6) mol/L to 10 x 10(-6) mol/L) were dripped into the rats' trachea through intubation for control group and the experiment groups, respectively. (2) To study the antagonizing effect of calcitonin gene-related peptide against endothelin: 50 rats were randomly assigned into control group (group D(1), n = 10) and experiment groups D(2), D(3), D(4) and D(5) (10 rats in each group), and were treated with 30 microl of normal saline as control and 4 x 10(-6) mol/L exET-1 via tracheal dripping. Twenty microl of exCGRP (concentrations ranged from 6.7 x 10(-8) mol/L to 6.7 x 10(-6) mol/L) were given by dripping to rats in groups D(3) to D(5) 30 minutes after the administration of exET-1. (3) The rats were sacrificed 3 hours after the first tracheal dripping and the gross anatomical and histological (HE staining) changes in lungs were observed.. (1) Following the treatment with exET-1, the rats showed cyanosis and dyspnea rapidly. The severity of respiratory symptoms varied in a dose dependent fashion with the concentrations of exET-1. The symptoms were relieved in the survived rats in about 30 minutes. The rats of all exET-1 treated groups presented with different degree of PH and group D (treated with 4 x 10(-6) mol/L of exET-1) had the highest incidence (diffuse PH 30%, focal PH 25%, spotty PH 25% and 80% in total), with a mortality of 20%. Rats in group E and F had lower incidence of PH (50% and 20%) but higher mortality (35% and 60%). (2) After the administration of different concentrations of exCGRP, the skin of the exET-1 treated rats turned ruddy rapidly with a significantly decreased incidence of PH and all the rats survived. The best protective effect was observed with the concentration of 6.7 x 10(-6) mol/L, and the incidence of PH was reduced to 20% (focal PH 10%, spotty PH 10%).. A significant increase of the endogenous ET-1 in hemorrhagic lung tissue caused by rewarming and reoxygenation following hypothermia and hypoxia had been confirmed. Administration of intratracheal exET-1 could induce pulmonary hemorrhage. This suggests that a significant increase of endogenous ET-1 in lung tissue may be one of the mechanisms in pathogenesis of PH caused by rewarming and reoxygenation following hypothermia and hypoxia. Endotracheal administration of exCGRP showed protective antagonizing effect against PH induced by exET-1. The authors speculate that the exCGRP has the potential to treat or even prevent PH caused by a significant increase of the endogenous ET-1.

Topics: Animals; Animals, Newborn; Calcitonin Gene-Related Peptide; Dose-Response Relationship, Drug; Endothelin-1; Female; Hemorrhage; Lung; Lung Diseases; Male; Random Allocation; Rats; Rats, Wistar

In the present study, we examined cardiac and regional haemodynamic effects of endothelin-1 (ET-1), a potent vasoconstrictive factor, in a rat model of pressure-controlled irreversible haemorrhagic shock resulting in the death of all control animals within 30 min. Experiments were carried out in male ethylurethane-anaesthetised Wistar rats subjected to hypotension of 20-25 mmHg, which resulted in bradycardia, an extreme decrease in cardiac index (CI) and an increase in total peripheral resistance index (TPRI), with reductions in renal (RBF), hindquarters (HBF) and mesenteric blood flow (MBF). ET-1 (50, 200 pmol/kg) administered intravenously at 5 min of critical hypotension produced increases in mean arterial pressure (MAP) and heart rate (HR), which were significantly higher than those in normotensive animals, and a 100% survival at 2 h after treatment. The effects were accompanied by a rise in CI, a decrease in TPRI, with increases in RBF and HBF and persistently lowered MBF, and an increase in circulating blood volume 20 min after treatment. The cardiovascular effects of ET-1 were inhibited by the ETA receptor antagonist BQ-123 (1 mg/kg), while the ETB receptor antagonist BQ-788 (3 mg/kg) had no effect. In conclusion, ET-1 acting via ETA receptors produces reversal of haemorrhagic hypotension in rats due to the mobilisation of blood from venous reservoirs, with the improvements in cardiac function and the perfusion of peripheral tissues.

Topics: Animals; Blood Pressure; Bradycardia; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hemodynamics; Hemorrhage; Hindlimb; Hypotension; Injections, Intravenous; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Wistar; Receptor, Endothelin A; Renal Circulation; Shock, Hemorrhagic; Sodium Chloride; Splanchnic Circulation; Time Factors; Vascular Resistance

Thromboxane A2 (TXA2) and endothelin-1 (ET-1) have been proposed as the important vasoconstrictors that increase portal venous resistance in paracrine or autocrine fashion. We hypothesized that the hepatic damage following trauma-hemorrhage (T-H) is induced by the impaired hepatic circulation due to the increased production of vasoconstrictors such as ET-1 and TXA2 by the liver. To test this, male Sprague-Dawley rats (n = 6/group) were subjected to trauma (i.e., midline laparotomy) and hemorrhage (35-40 mmHg for 90 min followed by fluid resuscitation) or sham operation. At 2 or 5 h after the end of resuscitation, the liver was isolated and perfused and portal inflow pressure, bile flow, and release of ET-1 and thromboxane B2 (TXB2; a stable metabolite of TXA2) into the perfusate were measured. The level of portal pressure was higher at 5 h following T-H compared with 2 h after T-H and sham. The portal pressure was inversely correlated to the amount of bile production. Furthermore, the bile flow was significantly correlated to the hepatic damage as evidenced by release of lactate dehydrogenase into the perfusate. The level of ET-1 at 5 h following T-H in the perfusate after 30 min of recirculation did not show any difference from sham. However, the levels of TXB2 in the T-H group were significantly higher than those in sham at that interval. These results indicate that the increased release of TXA2 but not ET-1 following T-H might be responsible for producing the increased portal resistance, decreased bile production, and hepatic damage.

Topics: Abdominal Injuries; Alanine Transaminase; Animals; Bile; Endothelin-1; Hemorrhage; Hypertension, Portal; In Vitro Techniques; L-Lactate Dehydrogenase; Liver; Male; Perfusion; Portal Vein; Rats; Rats, Sprague-Dawley; Thromboxane A2; Thromboxane B2; Venous Pressure; Wounds, Penetrating

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

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

This study was designed to examine the preventive effect of a novel endothelin (ET)-receptor antagonist TA-0201 on the cerebral vasospasm in a canine double-hemorrhage model. TA-0201 (10(-9)-10(-7) M) inhibited ET-1-induced vasoconstriction in the isolated canine basilar artery without endothelium in a concentration-dependent manner. Its pA2 value was 9.2 (ET(A) antagonism). In a canine double-hemorrhage model, intravenous treatment with TA-0201 (3 mg/kg, twice a day for 7 days) ameliorated the basilar artery narrowing significantly on day 7 compared with that in nontreated dogs. The reductions of the basilar artery diameter were 26.1+/-3.9% and 40.5+/-4.1% with and without TA-0201 treatment, respectively (p<0.05). Histologic study on day 7 indicated that treatment with TA-0201 inhibited vessel-wall damage such as disintegration of endothelium architecture and degeneration of medial smooth-muscle cells. We conclude that intravenous treatment with TA-0201 prevents the development of cerebral vasospasm and accompanying pathologic changes of the vessel wall, probably through blockade of ET(A) receptors.

Topics: Animals; Basilar Artery; Blood Pressure; Disease Models, Animal; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Hemorrhage; Male; Microscopy, Electron; Pyrimidines; Receptor, Endothelin A; Sulfonamides; Vasoconstriction; Vasospasm, Intracranial

Diaspirin cross-linked hemoglobin (DCLHb) is a hemoglobin-based therapeutic agent that produces significant cardiovascular effects, possibly due to its actions on vasoactive substances, such as endothelin (ET) and nitric oxide (NO). We have studied the modulation of cardiovascular effects of DCLHb by an NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), and an ETA-receptor antagonist, FR-139317, in hemorrhaged rats. Control rats resuscitated with vehicle [Ringer lactate (RL), 4 ml/kg iv] did not show any improvement in O2 consumption, base deficit, systemic hemodynamics, or regional blood flow after hemorrhage, and the rats survived for < 70 min. Administration of DCLHb (400 mg/kg iv) significantly improved O2 consumption, base deficit, systemic hemodynamics, and regional blood circulation after resuscitation, and the rats survived for > 120 min after hemorrhage. Plasma ET-1 and guanosine 3',5'-cyclic monophosphate (cGMP) concentrations increased after hemorrhage. DCLHb produced an increase in ET-1 and decreased cGMP concentrations in plasma. Pretreatment with L-NAME (10 mg/kg iv) or FR-139317 (4 mg/kg iv) attenuated the DCLHb-induced improvement in survival time, base deficit, systemic hemodynamics, and regional blood circulation. L-NAME (10 mg/kg iv) per se did not produce any resuscitative effect; therefore the NO mechanism may not be contributing toward the efficacy of DCLHb in hemorrhaged rats. However, FR-139317 attenuated the efficacy of DCLHb; therefore an increase in plasma ET-1 concentration by DCLHb may be contributing toward the efficacy of DCLHb in hemorrhage. Hemorrhage-induced increase in cGMP levels could be attenuated by L-NAME, but L-NAME was not effective in resuscitation of hemorrhaged rats, indicating a lack of role of NO in resuscitation. It is concluded that the ET mechanism is more important in the beneficial effect of DCLHb than the NO mechanism in hemorrhage.

Topics: Animals; Aspirin; Blood Substitutes; Cyclic GMP; Endothelin-1; Endothelins; Enzyme Inhibitors; Gases; Hemodynamics; Hemoglobins; Hemorrhage; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oxygen; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Resuscitation; Survival Analysis

This study investigated the effects of intraventricular/periventricular blood on cerebral cAMP production and cortical cerebrovascular reactivity. Under halothane and N2O anesthesia, 3 mL of either autologous blood or artificial cerebrospinal fluid (CSF) were injected into the left caudate nucleus; volume was adequate to result in extrusion of fluid or blood into the lateral ventricles of 1-2-d-old piglets. Twenty-four hours later, a closed cranial window was implanted over the left parietal cortex. Pial arteriolar responses to vasodilator and vasoconstrictor stimuli were monitored. Before the application of vasoactive agents, cortical periarachioid CSF was collected for cAMP measurement. Pial arteriolar responses to topical application of endothelin-1 (10(-9) and 10(-8) M) and to leukotriene C4 (10(-10) and 10(-9) M) were similar between the two groups. However, pial arteriolar responses to topical application of cAMP-mediated vasodilators, prostaglandin E2 (10(-6) and 10(-5) M), and histamine (10(-6) and 10(-5) M), respectively, were markedly reduced in the blood group when compared with the artificial CSF (control) group. Mean CSF cAMP level in the blood group was significantly lower than the control group (199 +/- 31 versus 1092 +/- 238 fmol/mL, p = 0.0006). We conclude that in newborn pigs intraventricular/periventricular blood results in a marked reduction of CSF cAMP concentration and attenuation of the cerebrovascular responses to cAMP-mediated vasodilators on the cortical surface remote from the site of blood or hematoma.

Topics: Animals; Animals, Newborn; Arteries; Blood Coagulation; Blood Physiological Phenomena; Blood Pressure; Blood Volume; Carbon Dioxide; Cerebral Ventricles; Cerebrospinal Fluid; Cerebrovascular Circulation; Cyclic AMP; Dinoprostone; Endothelin-1; Hemorrhage; Histamine; Hydrogen-Ion Concentration; Leukotrienes; Oxygen; Partial Pressure; Swine; Vasoconstrictor Agents; Vasodilator Agents