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Original Article |

Endothelin-1 Levels in Severe Burn Injuries FREE

Gracey N. Onuoha, PhD; E. Kaya Alpar, FRCS; John Gowar, FRCS
[+] Author Affiliations

From the Department of Surgery, University of Birmingham, Birmingham, England (Drs Onuoha and Alpar), and the Burns and Plastic Unit, University Hospital NHS Trust, Selly Oak Hospital, Birmingham (Dr Gowar).


Arch Surg. 2000;135(12):1418-1421. doi:10.1001/archsurg.135.12.1418.
Text Size: A A A
Published online

Hypothesis  Most investigators have reported high levels of endothelin (ET)-1 in patients with thermal injury. We attempted to examine the hypothesis that ET-1 levels increase in patients with severe burn injury.

Patients and Methods  Plasma from 28 adult subjects, 14 of whom had thermal injuries with a median (range) percentage of total burn surface area of 22% (20%-76%), was assessed for ET-1 and tumor necrosis factor (TNF) α. Samples from closely age-matched patients were obtained on admission (day 1) and 24 hours postinjury (day 2). Samples were obtained before blood transfusion or surgical treatment occurred. Enzyme immunoassay techniques suitable for the measurements of the cytokines were used.

Results  Median (range) of TNF-α was higher in patients (day 1, 10.0 ng/L [1.2-35.0 ng/L]; day 2, 12.0 ng/L [0.4-39.0 ng/L]) than controls (0.8 ng/L [0.3-3.2 ng/L]) (P<.005) while ET-1 levels remained significantly unchanged in patients (mean [SD], day 1, 183.0 [42.2] ng/L; day 2, 204.7 [41.7] ng/L) compared with controls (170.0 [59.8] ng/L) (P>.05).

Conclusions  We observed no significantly raised levels of ET-1 in patients with thermal injury within 24 hours after burn injury. We found no significant correlation between the plasma levels of TNF-α and ET-1. Endothelin-1 levels did not seem to reflect severity of illness. The actual evaluation of ET-1 release in patients with thermal injury could enhance the pathophysiological study of human thermal injury.

THERMAL INJURY is generally associated with immunologic dysfunction resulting from alterations in cytokine responses and has been linked to the release of proinflammatory and anti-inflammatory mediators. The former group of mediators includes tumor necrosis factor (TNF)-α,1 while the latter includes endothelin (ET)-1.2 Immunological alterations of ET-1 increase the risk of development of infection, originating either from wounds or remote sites, and these can further increase the mediator release, alter hemodynamic status, and result in increased morbidity and mortality. Endothelin-1 is a powerful vasoconstrictor, a peptide with 21 amino acids, and is produced by ischemic or injured endothelial cells. Endothelin-1 affects pulmonary, hepatic, cardiac, and renal function.3 It also causes monocyte production of TNF-α2 and a substance that causes neutrophil production of superoxide.4 While plasma levels of ET-1 are one thousandth that of tissue levels of ET-1, they do seem to reflect ischemic or injury events in the macrovasculature.

Endothelin-1 is a candidate mediator for an important role in the genesis of the systemic response to burn injury and might also have a role in immune and inflammatory dysfunction. Endothelin-1 has been shown to increase after myocardial infarction,5 after perfusion that occurs after coronary thrombosis,6 in low-flow states,7 with pulmonary hypertension,8 in burns, and in sepsis.7 However, in our study there was no significantly raised level of ET-1 in these patients with thermal injuries. We also measured the release of TNF-α, one of the first cytokines shown to have diverse regulatory properties in immunity and inflammation.9 Systemic changes during inflammation such as increased acute-phase protein synthesis and fever probably represent action of this cytokine on the liver and hypothalamus. This cytokine acts in a paracrine fashion in the local environment to stimulate immune responses but also acts in an endocrinelike fashion on distant organs that participate in inflammatory responses. It increases in hemolysis, diabetes, preeclampsia, and in human graft-vs-host diseases. We attempted to learn the possible role of the cytokine in the immunological, inflammatory, and wound-healing characteristics in burns. Most researchers report high levels of ET-1 in patients with thermal injury, so an attempt was made to examine some of these reports.

PATIENTS

Fourteen adult patients (mean age, 52.6 years; lower and upper quartile ranges, 29-94 years; 10 men) with thermal injury were resuscitated with a modified Parkland formula to a urine output of about 30 mL per hour. These patients were compared with 14 healthy closely age-matched control subjects (mean age, 51.4 years; lower and upper quartile ranges, 24-86 years; 7 men). Mean (SD) percentage of total burn surface area (%TBSA) was 35.0 (23.1).

Ninety one percent of patients had burns on the upper extremities, including hand, neck, thorax, and upper back; 7 (50%) had burns on the lower extremities, including abdomen and lower back, some with mixed burns; and 10 (71%) of patients survived. Patient's demographic details are given in Table 1. Plasma was drawn immediately on admission (day 1) and 24 hours after admission (day 2). Samples were obtained from subjects through a venipuncture and into EDTA aprotinin bottles in a protocol approved by the institutional review committee for University of Birmingham, Birmingham, England. Samples were obtained from patients before blood transfusion or surgical intervention. Immediately on arrival to the laboratory and within one-half hour after sampling, the venous blood samples were centrifuged for 15 minutes at 5000 rpm at 0°C. Aliquots of plasma were placed in polypropylene tubes stored at −80°C until the tests were performed. The Ethics Committee of University of Birmingham approved this study, and informed consent was obtained from all subjects or care givers.

LABORATORY ANALYSIS
Enzyme Immunoassay

The levels of ET-1 and TNF-α were measured using commercially available enzyme immunoassay kits (ET-1, EIA 6901 [host, rabbit] and TNF-α, ACCUCYTE; both from Peninsula Laboratories, Merceyside, England) as per instructions. The plasma analysis of ET-1 required extraction using separation-column buffer containing 200 mg of C-18 (catalogue number RIK-SEPCOLI; Peninsula Laboratories), equilibrated once with 1 mL of 100% acetonitrile. This was followed by washing 3 times with 3 mL of Buffer A (1% trifluoroacetic acid in 99% distilled water) (catalogue number BUF-A1; Peninsula Laboratories). The plasma was acidified with an equal amount of Buffer A to plasma and clarified by centrifugation at 10,000 rpm for 20 minutes at 4°C, and the supernatant passed through the pretreated cartridges. After washing the column slowly 3 times with 3 mL of Buffer A, the peptide was then slowly eluted into a polypropylene tube, and the eluant evaporated to dryness in a centrifugal concentrator.

The dried extract was reconstituted with assay buffer prior to assay analysis. No extraction was required for TNF-α. During analysis, known amounts of ET-1 and TNF-α were incubated with their specific antibodies, and these samples subsequently were incubated with biotinylated-labeled peptides. After removing unbound biotinylated peptide by washing, streptavidin-conjugated horseradish peroxidase was added. After washing away excess streptavidin-conjugated horseradish peroxidase, tetramethyl benzidine dihydrochloride was allowed to react with bound horseradish peroxidase. All samples were performed in duplicates and absorbance read with a spectrophotometer at 450 nm for ET-1 and at 492 nm for TNF-α. These numbers were then fitted to the standard curve to derive numeric values.

Endothelin-1

The lowest detectable concentration of ET-1 was 0.04 to 0.06 ng/mL of the plasma sample (tracer, biotinylated ET-1). There was 100% cross reactivity with ET-1 (human); 7%, ET-2 (human, canine); 0.005%, ET-3 (human, rat, porcine, rabbit); 17%, big ET-1 (human); and 0%, big ET-22-38 (human), vasoactive intestinal peptide, and brain natriuretic peptide-32 (human). Intra-assay and interassay coefficients of variation were 5% and 14%, respectively.

Human TNF-α

The lowest detectable concentration of TNF-α was 0.195 ng/mL of the plasma sample. The tracer was biotinylated TNF-α. Intra-assay and interassay variations for human TNF-α were 6.5% and 11.7%, respectively.

Statistics

Results are expressed as median (lower and upper quartile range) in nanograms of the peptide per liter of plasma sample. Nonparametric statistic (Wilcoxon rank sum test) was used. Mean and SD were calculated to describe continuous variables. The degree of correlation between peptide scores and %TBSA was calculated using a Spearman rank correlation coefficient. P<.05 was considered significant, statistically.

This study focused on those patients with an early tissue injury during the time before burn wound sepsis or systemic sepsis occurs. No patient had cardiac disease, experienced shock, or had multiple system organ failure. None of the patients received anticoagulants, steroids, blood transfusion, or surgical treatment within the time of blood sampling. As a criterion for the work, only adult patients (>16 years) were accepted for the study to complement the age of the control subjects.

In the control group, the median (lower-upper quartile range) values were 198 ng/L (72-229 ng/L) for ET-1 and 0.8 ng/L (0.25-3.20 ng/L) for TNF-α. There was no significantly raised level of ET-1 between patients at admission (198 ng/L [117-229 ng/L]) or 24 hours postinjury (207 ng/L [117-270 ng/L]) compared with controls (P>.05). The TNF-α levels were significantly raised in patients (day 1, 10.0 ng/L [1.2-35.0 ng/L]; day 2, 12.0 ng/L [0.4-39.0 ng/L]) compared with controls (P<.005). The release of TNF-α in patients was at least 10 times higher than that in control subjects. A higher level of TNF-α was obtained at day 2 of our study; however, this variation did not correlate with any differences in %TBSA, ET-1 release, or presence of a pulmonary injury. Table 2 summarizes the results.

Table Graphic Jump LocationTable 2. Biochemical Data of 14 Patients and 14 Controls*

In this study the effect of tissue injury on circulating levels of ET-1 and TNF-α has been evaluated and compared in patients with thermal injury and age-matched healthy controls. Basal levels of ET-1 were not significantly changed while TNF-α levels increased in patients with thermal injury and in the concentrations maintained within 24 hours after thermal injury. Several cytokines, monokines, enzymes, and lipids have been identified that change dramatically in burn injury and may have a role in either the local or systemic response to thermal injury or wound healing.10,11 However, whether any single mediator or factor can be identified and changed to improve outcome remains uncertain. Endothelin-1 is a 21 amino acid peptide formed in the endothelial cells and produced by injured or ischemic vascular endothelium.3 While originally identified as a potent vasoconstrictor, it was shown to be a potent bronchoconstrictor, visceral smooth muscle contractor, and a secretogogue and growth factor for many cells.

At least 6 endothelins (big ET-1,12 ET-1,13 big ET-2,14 ET-2,15 big ET-3,16 and ET-317) have been identified in the human genome. Of those, only ET-1 has been studied thoroughly. Endothelin-1 is a bronchoconstrictor4 and pulmonary vasoconstrictor,3 has both negative and positive cardiac inotropic effects,3,18 stimulates hepatic Kupffer cells19 and hepatocellular glycogenesis,19 and inhibits bile flow.20 It is a renal vasoconstrictor,21 gut mucosal ulceragen, neuroendocrine stimulant,22 and leukocyte activator; it stimulates proliferation of smooth muscle cells23 and causes TNF-α release.24 Thus, ET-1 is a candidate mediator in the systemic response to burn injury and a potential stimulus to activation of the immune response and inflammatory mechanisms. Endothelin-1 is also known to cause monocyte production of transforming growth factor and basic fibroblast growth factor, suggesting that this neuropeptide may have a role in wound healing. However, the measurement of the specific isoform remains difficult.

The levels of ET-1 in patients with thermal injuries has been inconsistent in terms of its actual release or measured levels. While some reports suggest increased levels of the peptides in the peripheral blood samples of patients with burn injury,11 others observed reduced levels of the cytokine.25 In this study, using commercially available ET-1 kits, our results show insignificant differences in levels between patients and age-matched controls. Although many studies describe moderate elevation of plasma ET levels in patients with thermal injuries, including severe burns,11,26,27 it remains unclear if this elevation is that of the biologically active peptide ET-1 or of its precursor, big ET.

Endothelin-1 is a member of a family of peptides arising from preendothelial and proendothelial species, which after proteolysis yields 3 isoforms termed ET-1, ET-2, and ET-3. Big ET may be the main circulating form of ET in man.28 The report by Huribal et al26 for instance, indicates that the elevations of plasma ET levels in severe burns is primarily related to elevated circulating ET-1. Their study revealed the presence of ET of similar activity without any big ET activity, thus suggesting that thermal injuries might not be the main cause of raised circulating ET concentrations. Furthermore, it is not clear if such increases in patients is associated with elevated tissue ET levels. Most of these non–age-matching patient and control groups do not provide evidence of the stimulus for its release.27 Possible sources could include microvascular injury from the burn, underperfused tissues for local or systemic reasons, sepsis, increased ET-1 production by monocytes activated by injury, or decreased clearance of the peptide by local or hepatic metabolic mechanisms.

In some of these studies, there was no mention of the specificity or cross reactivity of the peptide to its different isoforms,11,25 and often the ET-1 was not extracted from the assay matrix.26,27 The extraction procedure not only allows for the concentration of the sample but also serves to separate peptides from potentially interfering substances. A measurement of ET-1 in plasma is difficult because of the presence of the 3 different isoforms and of precursors such as big ETs. Assays frequently measure both bioactive fragments and precursor, or cross react, between isoforms, and in some cases the cross reactivity could be as much as 100%.29 This suggests that the high levels reported in some results could be owing to the cross reactions of different isoforms other than ET-1 itself. Our assay has less than 20% cross reactivity between ET-1 and big ET-1. Therefore, although previous studies have indicated a modest elevation of circulating ET-1 levels in patients with thermal injuries, the failure to do so here could relate to methodological differences. Our findings are in agreement with the reports of Areta et al.30

We also measured the release of TNF-α. Significantly high TNF-α levels were observed in patients with thermal injury, and these levels were maintained within the time of the study. Tumor necrosis factor α is crucial in the initiation of humoral and cellular immune responses and stimulates systemic changes during inflammation, including synthesis of acute-phase proteins and the induction of fever. Tumor necrosis factor α was among the first monocyte-derived cytokines shown to have diverse regulatory properties in immunity and inflammation. It may also induce tissue destruction in chronic inflammatory disease.9 This monocyte causes physiological31 and pathological alteration in the host.32

One of the biological effects of ET is its ability to cause the proliferation of smooth muscle cells,15 thus in these thermally injured patients, ET-1 may play an important role in the healing of wounds. The strong, characteristically long-lasting vasoconstrictor activity of ET-1 may also be important in the control of systemic blood pressure and/or local blood flow; hence, disturbance in the control of ET-1 production could affect wound healing in patients with thermal injuries.

An attempt has been made in this study to confirm the peripheral release levels of ET-1 in closely age-matched patients and controls. We observed no significant changes in ET-1 release in this nonseptic group of patients within 24 hours postinjury. The peripheral levels of ET-1 in patients with thermal injury have been inconsistent. The actual evaluation of ET-1 in patients with thermal wounds could enhance the pathophysiological study of human burns, opening doors to greater useful clinical information about flame injuries.

We are grateful to other members of staff of Selly Oak Hospital, Burns and Plastic Unit, particularly Rob Williams, FRCS, for help in obtaining suitable blood samples and patient care. We thank Louise Hiller, PhD, for the statistical analysis.

Reprints: Gracey N. Onuoha, PhD, Department of Trauma/Surgery, Selly Oak Hospital, Raddlebarn Rd, Birmingham B29 6JD, England.

De Bandt  JChollet-Martin  SHernvann  A  et al.  Cytokine response to burn injury: relationship with protein metabolism. J Trauma. 1994;36624
Link to Article
Takayama  TKMiller  CSzabo  G Elevated tumor necrosis factor alpha production concomitant to elevated postglandin E2 production by trauma patients' monocytes. Arch Surg. 1990;12529- 35
Link to Article
McMillen  MHuribal  MKumar  RSumpio  BE Endothelin-stimulated human monocytes produce prostaglandin E2 but not leukotriene B4. J Surg Res. 1993;54331- 335
Link to Article
Huribal  MMcMillen  MAKumar  R  et al.  Endothelin-stimulated monocyte supernatants enhance neutrophil superoxide production. Shock. 1994;1184- 187
Link to Article
Miyauchi  TYanagisawa  MTomizawa  A  et al.  Increased plasma levels of endothelin-1 and big endothelin-1 in acute myocardial infarction [letter]. Lancet. 1989;253- 54
Link to Article
Lechleitner  PGenser  NMair  J  et al.  Plasma immunoreactive endothelin in the acute and subacute phases of myocardial infarction in patients undergoing fibrinolysis. Clin Chem. 1993;39955- 959
Pittet  JFMorel  DRHemsen  A  et al.  Elevated plasma endothelin-1 concentrations are associated with the severity of illness in patients with sepsis. Ann Surg. 1991;213261- 265
Link to Article
Allen  SWChatfield  BAKoppenhafer  SA  et al.  Circulating immunoreactive endothelin-1 in children with pulmonary hypertension. Am Rev Respir Dis. 1993;148519- 522
Link to Article
Le  JVilcek  J Tumor necrosis factor and interleukin 1: cytokines with multiple overlapping biological activities. Lab Invest. 1987;56234- 248
Onuoha  GNAlpar  EKGowar  J Plasma levels of atrial natriuretic peptide in severe burn injury. Burns. 2000;26449- 453
Link to Article
McMillen  MAHuribal  MCunningham  ME  et al.  Endothelin-1, interleukin-6, and interleukin-8 levels increase in patients with burns. J Burn Care Rehabil. 1996;17384- 389
Link to Article
Kashiwabara  TInagaki  YOhta  H  et al.  Putative precursors of endothelin have less vasoconstrictor activity in vitro but a potent pressor effect in vivo. FEBS Lett. 1989;24773- 76
Link to Article
Itoh  YYanagisawa  MOhkubo  S  et al.  Cloning and sequence analysis of cDNA encoding the precursor of a human endothelin-derived vasoconstrictor peptide, endothelin: identity of human and porcine endothelin. FEBS Lett. 1988;231440- 444
Link to Article
Gratton  JPRae  GABkaily  GD'Orleans-Juste  P ET(B) receptor blockage potentiates the pressor response to big endothelin-1 but not big endothelin-2 in the anesthetized rabbit. Hypertension. 2000;35726- 731
Link to Article
Inoue  AYanagisawa  MKimura  S  et al.  The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci U S A. 1989;862863- 2867
Link to Article
Bloch  KDEddy  RLShows  TBQuertermous  T cDNA cloning and chromosomal assignment of the gene encoding endothelin 3. J Biol Chem. 1989;26418156- 18161
Watanabe  TXKumagaya  SNishio  HNakajima  KKimura  TSakakibara  S Effects of endothelin-1 and endothelin-3 on blood pressure in conscious hypertensive rats [abstract]. J Cardiovasc Pharmacol. 1989;13S207- S208
Link to Article
Vigne  PLazdunski  MFrelin  C The inotropic effect of endothelin-1 on rat atria involves hydrolysis of phosphatidylinositol. FEBS Lett. 1989;249143- 146
Link to Article
Gandhi  CRStephenson  KOlson  MS Endothelin, a potent peptide agonist in the liver. J Biol Chem. 1990;26517432- 17435
Isales  CMNathanson  MHBruck  R Endothelin-1 induces cholestasis which is mediated by an increase in portal pressure. Biochem Biophys Res Commun. 1993;1911244- 1251
Link to Article
Badr  KFMurray  JJBreyere  MD  et al.  Mesangial cell, glomerular, and renal vascular response to endothelin in the rat kidney. J Clin Invest. 1989;83336- 342
Link to Article
Stokjilkovic  SSMerelli  FIida  T  et al.  Endothelin stimulation of cytosolic calcium and gonadotropin secretion in anterior pituitary cells. Science. 1990;2481663- 1666
Link to Article
Nakaki  TNakayama  MYamamoto  SKato  R Endothelin-mediated stimulation of DNA synthesis in vascular smooth muscle cells. Biochem Biophys Res Commun. 1989;158880- 883
Link to Article
Ohta  KHirata  YImai  T  et al.  Cytokine-induced release of endothelin-1 from porcine renal epithelial cell line. Biochem Biophys Res Comm. 1990;169578- 584
Link to Article
Wakisaka  NKubota  TAndo  KAihara  MInoue  HIshida  H Endothelin-1 kinetics in plasma, urine, and blister fluid in burn patients. Ann Plast Surg. 1996;37305- 309
Link to Article
Huribal  MCunningham  MED'Aiuto  MLPlebn  WEMcMillen  MA Endothelin levels in patients with burns covering more than 20% body surface area. J Burn Care Rehabil. 1995;1623- 26
Link to Article
Nakae  HEndo  SInada  KYamada  YTakakuwa  TYoshida  M Plasma levels of endothelin-1 and thrombomodulin in burn patients. Burns. 1996;22594- 597
Link to Article
Wei  CMLerman  ARodeheffer  RJ  et al.  Endothelin in human congestive heart failure. Circulation. 1994;891580- 1586
Link to Article
Not Available, Tools for Protein and Peptide Research.  Belmont, Calif Peninsula Laboratories1996-1997;225- 227
Koweal-Vern  AWalenga  JMSharp-Pucci  M  et al.  Post edema and related changes in interluekin-2, leukocytes, platelet activation, endothelin-1 and C1esterase inhibitor. J Burn Care Rehabil. 1997;1899- 103
Link to Article
Evans  RDArgiles  JMWilliamson  DH Metabolic effects of tumor necrosis factor-alpha (cachectin) and interleukin-1. Clin Sci (Lond). 1989;77357- 364
Cunningham  MEHuribal  MBala  RJ  et al.  Endothelin-1 and endothelin-4 stimulate monocyte production of cytokines. Crit Care Med. 1997;25958- 964
Link to Article

Figures

Tables

Table Graphic Jump LocationTable 2. Biochemical Data of 14 Patients and 14 Controls*

References

De Bandt  JChollet-Martin  SHernvann  A  et al.  Cytokine response to burn injury: relationship with protein metabolism. J Trauma. 1994;36624
Link to Article
Takayama  TKMiller  CSzabo  G Elevated tumor necrosis factor alpha production concomitant to elevated postglandin E2 production by trauma patients' monocytes. Arch Surg. 1990;12529- 35
Link to Article
McMillen  MHuribal  MKumar  RSumpio  BE Endothelin-stimulated human monocytes produce prostaglandin E2 but not leukotriene B4. J Surg Res. 1993;54331- 335
Link to Article
Huribal  MMcMillen  MAKumar  R  et al.  Endothelin-stimulated monocyte supernatants enhance neutrophil superoxide production. Shock. 1994;1184- 187
Link to Article
Miyauchi  TYanagisawa  MTomizawa  A  et al.  Increased plasma levels of endothelin-1 and big endothelin-1 in acute myocardial infarction [letter]. Lancet. 1989;253- 54
Link to Article
Lechleitner  PGenser  NMair  J  et al.  Plasma immunoreactive endothelin in the acute and subacute phases of myocardial infarction in patients undergoing fibrinolysis. Clin Chem. 1993;39955- 959
Pittet  JFMorel  DRHemsen  A  et al.  Elevated plasma endothelin-1 concentrations are associated with the severity of illness in patients with sepsis. Ann Surg. 1991;213261- 265
Link to Article
Allen  SWChatfield  BAKoppenhafer  SA  et al.  Circulating immunoreactive endothelin-1 in children with pulmonary hypertension. Am Rev Respir Dis. 1993;148519- 522
Link to Article
Le  JVilcek  J Tumor necrosis factor and interleukin 1: cytokines with multiple overlapping biological activities. Lab Invest. 1987;56234- 248
Onuoha  GNAlpar  EKGowar  J Plasma levels of atrial natriuretic peptide in severe burn injury. Burns. 2000;26449- 453
Link to Article
McMillen  MAHuribal  MCunningham  ME  et al.  Endothelin-1, interleukin-6, and interleukin-8 levels increase in patients with burns. J Burn Care Rehabil. 1996;17384- 389
Link to Article
Kashiwabara  TInagaki  YOhta  H  et al.  Putative precursors of endothelin have less vasoconstrictor activity in vitro but a potent pressor effect in vivo. FEBS Lett. 1989;24773- 76
Link to Article
Itoh  YYanagisawa  MOhkubo  S  et al.  Cloning and sequence analysis of cDNA encoding the precursor of a human endothelin-derived vasoconstrictor peptide, endothelin: identity of human and porcine endothelin. FEBS Lett. 1988;231440- 444
Link to Article
Gratton  JPRae  GABkaily  GD'Orleans-Juste  P ET(B) receptor blockage potentiates the pressor response to big endothelin-1 but not big endothelin-2 in the anesthetized rabbit. Hypertension. 2000;35726- 731
Link to Article
Inoue  AYanagisawa  MKimura  S  et al.  The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci U S A. 1989;862863- 2867
Link to Article
Bloch  KDEddy  RLShows  TBQuertermous  T cDNA cloning and chromosomal assignment of the gene encoding endothelin 3. J Biol Chem. 1989;26418156- 18161
Watanabe  TXKumagaya  SNishio  HNakajima  KKimura  TSakakibara  S Effects of endothelin-1 and endothelin-3 on blood pressure in conscious hypertensive rats [abstract]. J Cardiovasc Pharmacol. 1989;13S207- S208
Link to Article
Vigne  PLazdunski  MFrelin  C The inotropic effect of endothelin-1 on rat atria involves hydrolysis of phosphatidylinositol. FEBS Lett. 1989;249143- 146
Link to Article
Gandhi  CRStephenson  KOlson  MS Endothelin, a potent peptide agonist in the liver. J Biol Chem. 1990;26517432- 17435
Isales  CMNathanson  MHBruck  R Endothelin-1 induces cholestasis which is mediated by an increase in portal pressure. Biochem Biophys Res Commun. 1993;1911244- 1251
Link to Article
Badr  KFMurray  JJBreyere  MD  et al.  Mesangial cell, glomerular, and renal vascular response to endothelin in the rat kidney. J Clin Invest. 1989;83336- 342
Link to Article
Stokjilkovic  SSMerelli  FIida  T  et al.  Endothelin stimulation of cytosolic calcium and gonadotropin secretion in anterior pituitary cells. Science. 1990;2481663- 1666
Link to Article
Nakaki  TNakayama  MYamamoto  SKato  R Endothelin-mediated stimulation of DNA synthesis in vascular smooth muscle cells. Biochem Biophys Res Commun. 1989;158880- 883
Link to Article
Ohta  KHirata  YImai  T  et al.  Cytokine-induced release of endothelin-1 from porcine renal epithelial cell line. Biochem Biophys Res Comm. 1990;169578- 584
Link to Article
Wakisaka  NKubota  TAndo  KAihara  MInoue  HIshida  H Endothelin-1 kinetics in plasma, urine, and blister fluid in burn patients. Ann Plast Surg. 1996;37305- 309
Link to Article
Huribal  MCunningham  MED'Aiuto  MLPlebn  WEMcMillen  MA Endothelin levels in patients with burns covering more than 20% body surface area. J Burn Care Rehabil. 1995;1623- 26
Link to Article
Nakae  HEndo  SInada  KYamada  YTakakuwa  TYoshida  M Plasma levels of endothelin-1 and thrombomodulin in burn patients. Burns. 1996;22594- 597
Link to Article
Wei  CMLerman  ARodeheffer  RJ  et al.  Endothelin in human congestive heart failure. Circulation. 1994;891580- 1586
Link to Article
Not Available, Tools for Protein and Peptide Research.  Belmont, Calif Peninsula Laboratories1996-1997;225- 227
Koweal-Vern  AWalenga  JMSharp-Pucci  M  et al.  Post edema and related changes in interluekin-2, leukocytes, platelet activation, endothelin-1 and C1esterase inhibitor. J Burn Care Rehabil. 1997;1899- 103
Link to Article
Evans  RDArgiles  JMWilliamson  DH Metabolic effects of tumor necrosis factor-alpha (cachectin) and interleukin-1. Clin Sci (Lond). 1989;77357- 364
Cunningham  MEHuribal  MBala  RJ  et al.  Endothelin-1 and endothelin-4 stimulate monocyte production of cytokines. Crit Care Med. 1997;25958- 964
Link to Article

Correspondence

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The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
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