(Stroke. 2000;31:720.)
© 2000 American Heart Association, Inc.
Original Contributions |
Plasma Endothelin-1 Levels Neither Increase nor Correlate With Neurological Scores, Stroke Risk Factors, or Outcome in Patients With Ischemic Stroke
From the Department of Neurology (E.H., T.T., L.S., M.K.), Helsinki University Central Hospital, Helsinki, Finland; and Abbott Laboratories (K.H., C.L., T.J.O.), Abbott Park, Ill.
Correspondence to Dr Turgut Tatlisumak, Department of Neurology, Helsinki University Central Hospital, PO Box 300, 00029 HYKS Helsinki, Finland. E-mail turgut.tatlisumak{at}huch.fi
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Abstract |
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Background and Purpose—Endothelins (ETs) are potent vasoconstrictors and may play a role in the pathophysiology of several diseases. Limited and controversial data exist on their role in human ischemic stroke. We planned a prospective, observational, and longitudinal clinical study to test whether ET-1 levels increase in various phases of ischemic stroke and whether the ET-1 levels correlate with neurological scores, stroke etiology, stroke risk factors, or final outcome.
Methods—We measured plasma ET-1 levels with a sandwich-enzyme immunoassay method in 101 consecutive patients with ischemic stroke on admission and 1 week, 1 month, and 3 months after stroke and in 101 sex- and age-matched control subjects. At each sampling, the patients underwent a complete neurological evaluation. All stroke risk factors were recorded, an array of laboratory tests were performed, and the subtype of ischemic stroke was determined. The patients were contacted 3 years later for prognostic determination.
Results—ET-1 levels in patients (2.4±1.3 pg/mL on admission, 2.2±1.4 pg/mL at 1 week, 2.1±1.4 pg/mL at 1 month, and 2.1±1.2 pg/mL at 3 months) were not different from those of the control subjects (2.2±0.9 pg/mL) at any time point. No correlation was found between the ET-1 levels and stroke etiology, stroke risk factors, stroke recurrence risk, age, sex, or neurological scores, except that ET-1 levels correlated with the use of warfarin and with body mass index.
Conclusions—Plasma ET-1 levels were normal in patients with ischemic stroke. Our findings cannot exclude a role of ETs in the pathophysiology of ischemic stroke because plasma levels might not accurately reflect intracerebral concentrations, but they also do not support the occurrence of a major plasma ET-1 level increase at any phase of stroke. Our patient population is the largest ever reported in whom ET-1 levels were measured, but it consisted of mild and moderately ill patients with stroke due to the study design, of which the aim was long-term observation, which excludes severely ill patients.
Key Words: cerebral infarction • endothelins • prognosis • risk factors • stroke outcome
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Endothelins (ETs) are potent vasoconstrictors that are present in several species, including humans. ETs act through specific receptors with at least 2 distinct types: ETA and ETB. ETA receptors are present on vascular smooth muscle cells and mediate vasoconstriction, whereas ETB receptors are located on endothelial cells and mediate endothelium-dependent vasodilatation.1 ETs participate in the pathophysiology of a number of diseases, mainly as a result of potent vasoconstrictor effects.2 Increases in plasma ET levels occur in various animal models of global and focal ischemia,1 suggesting a role of ET in cerebral ischemia, but this issue is controversial.
Several studies in stroke patients have found elevated levels of ET-1 in various subtypes and phases of brain infarction,3 4 5 6 although contradictory results have also been presented.3 7 8 9 The relationship among plasma ET-1 levels, pathogenesis of stroke, recurrence of thromboembolic events, and death remains unclear. Several studies on ET-1 levels in ischemic stroke patients have been published, with a small number of patients (n=2,7 9,3 12,8 16,4 26,9 37,5 and 596 ), and the design of the studies has not encompassed the determination of ET-1 levels at the acute stage,4 6 8 nor have the studies included long-term follow-up4 5 8 9 or specific neurological assessment of the patients.6 8 In some studies, ET-1 levels were measured in cerebrospinal fluid (CSF),3 7 9 and in others, levels were measured in plasma.4 5 6 8 9 Some investigators used radioimmunoassay measurements,3 4 5 8 9 whereas others used the enzyme immunoassay method.6 7 We planned a prospective, observational, and longitudinal clinical study to describe the plasma ET-1 levels as measured with enzyme immunoassay in the acute and convalescent phases of 101 consecutive patients with ischemic stroke and of 101 sex- and age-matched volunteers. We also tried to determine whether age, sex, stroke risk factors, or etiology has an effect on ET-1 and whether any changes in the ET-1 levels may emerge as clinically useful for the diagnosis, prognosis, or prediction of thromboembolic recurrence in ischemic stroke patients.
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Subjects and Methods |
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One hundred one consecutive patients with clinically and radiologically proved brain infarction who were admitted to Helsinki University Central Hospital in 1994 were included in the study. All subjects gave informed consent. The study was approved by the Ethics Committee and was carried out according to the principles of the Declaration of Helsinki and the institutional guidelines. Patients who were unable to give informed consent or who refused to participate and those who were unlikely to survive were excluded. Probability of survival was decided on clinical grounds. Three patients died during the 3-month study period and are excluded from the study. An equal number of control subjects matched for sex and age were selected from patients referred to the Outpatient Clinic of the Department of Neurology; individuals were excluded who had a history suggestive of atherothrombotic or hematological disease. The patients underwent a neurological examination on admission (within 2 days after the stroke) and at 1 week (7±1 days), 1 month (30±3 days), and 3 months (90±7 days). The National Institutes of Health Stroke Score, Scandinavian Stroke Scale, and Glasgow Coma Scale (GCS) were performed at each time point, and the Barthel Index, Modified Rankin Score, and Mini-Mental State Examination were performed at 3 months only. Risk factors for stroke were elicited from the patient‘s history, physical examination, previous hospital records, laboratory tests, and family members’ reports. Classification of cerebral infarction was made according to the Trial of Org 10172 in Acute Stroke Treatment criteria.10 The 3-year follow-up was conducted by telephone, and in case of a recurrent thromboembolism, hospital records were reviewed.
Fasting blood samples were collected without venous stasis from an antecubital vein via a 19-gauge scalp vein needle on admission (within 2 days after the stroke) and at 1 week (7±1 days), 1 month (30±3 days), and 3 months (90±7 days). Sex- and age-matched (±4 years) control subjects underwent blood sampling once. All blood samples were collected between 8 and 10 AM to overcome any possible circadian effects. The ET-1 concentration of human plasma samples was quantified with the use of a commercially available sandwich-enzyme immunoassay kit (R and D Systems) after extraction as described previously.11 The ET-1 molecule has 2 termini: 1 N terminus with a rigid structure with 2 disulfide bonds and a C-terminal hexapeptide consisting of relatively hydrophobic amino acids. It is predictable from the amino acid sequences of ETs and big ETs that an antibody to the N-terminal portion of ET-1 will cross-react with big ET-1 and possibly with ET-2 and that an antibody to the C-terminal portion of ET-1 will cross-react with ET-2 and ET-3. When 2 antibodies are used (1 for each terminus), the method allows for recognition of a specific molecule with much higher accuracy. Because sandwich-enzyme immunoassays consist of 2 antibodies, they have higher specificity than conventional radioimmunoassays.12 Plasma samples were thoroughly mixed with 1.5 volumes of acetone/water/1 mol/L HCl (40:5:1 [v/v/v]) and centrifuged at 3000 rpm for 20 minutes. The supernatant was decanted and dried down under reduced pressure in a centrifugal evaporator (Savant Instruments). The pellet was reconstituted in one fourth the initial plasma volume of a diluent buffer and allowed to redissolve overnight at 4°C. The samples, which included standards in buffer and reconstituted extracts of the quality control and test samples and an enzyme (horseradish peroxidase)-labeled second anti–ET-1 antibody, were sequentially added to a 96-well microplate precoated with an anti–ET-1 antibody. After 6 hours of incubation at 4°C and the removal of unbound materials, the amount of enzyme-conjugated tracer bound to the wells was detected through reaction with a substrate specific for the enzyme. The reaction product was measured by reading the absorbance at 450 nm with a correction wavelength of 650 nm. The assay is sensitive to detect as little as 0.2 pg/well ET-1 (C. Lanni, unpublished observation). A standard curve was determined with the use of the mean absorbance values of the included ET-1 standards, and the ET-1 concentration in all unknown plasma samples was then calculated with linear regression. All standards and samples were tested in duplicate. The standard (calibrator) curves for our batches ranged from 96% to 100% of theory over the range of 0.9 to 60 pg/mL, allowing virtually 100% of the human ET-1 measured in the samples. Blood glucose, total cholesterol, HDL-cholesterol, and triglyceride levels were determined in serum 3 months after stroke.
Statistical Analysis
The values given are median and mean±SD. ET-1 levels for the
patients at different time points and for the control subjects were
compared by Wilcoxon’s matched pairs signed rank sum test,
with correction for multiple comparison. Correlation between the ET-1
levels and the neurological scores was calculated by Spearman’s rank
correlation. Patients with and without a particular risk factor, as
well as patients with and without a recurrent thromboembolic disease,
were compared with the Mann-Whitney U test. Patients
categorized by different causes of stroke were compared with
Kruskal-Wallis ANOVA. Significant findings in Kruskal-Wallis
analysis were studied further with ANCOVA. A 2-tailed value of
P<0.05 was considered statistically significant.
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Results |
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Of the 101 patients (age 63.1±12.2 years), 64 were men (63.3±11.2, range 28.0 to 88.0 years) and 37 were women (62.6±14.0, range 27.0 to 83.0 years). In the control group (101 subjects, age 64.3±12.3 years), the age distribution was 65.1±11.4 years for men (range 32.0 to 85.0 years) and 63.0±13.7 years for women (range 26.0 to 81.0 years). All patients completed the study protocol. All patients received either antithrombotic drugs or warfarin after the stroke. Twenty-nine thromboembolic episodes occurred in 29 patients during the next 3 years. The neurological scores are summarized in Table 1
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ET-1 levels of the stroke patients at 4 different time points and of
the control subjects are given in Table 2
(P>0.05 for all time points). Among the factors that have
potential to correlate with ET-1 level (sex; age; cause of brain
infarction; body mass index [BMI]; serum triglyceride,
serum total cholesterol, LDL-cholesterol, and
HDL-cholesterol levels; presence of diabetes, hypertension,
or sleep apnea; and smoking), only HDL-cholesterol and BMI
appeared to be significant. BMI showed a positive correlation with ET-1
level (P=0.05, 0.02, 0.4, and 0.06), and
HDL-cholesterol showed a positive correlation with ET-1
level only at 3 months (P=0.05). These data are summarized
in Table 2. Patients receiving anticoagulant treatment
(warfarin) had significantly higher ET-1 levels at 1 and 3 months
(P=0.1, 0.3, 0.009, and 0.03, respectively). We found a
significant positive correlation between the ET-1 level and GCS only on
admission (P=0.05), but no correlation was found between the
ET-1 levels and the other neurological scores (National Institutes of
Health Stroke Score, Scandinavian Stroke Scale, and GCS at any time
point and Barthel Index, Modified Rankin Score, and Mini-Mental State
Examination at 3 months) (data not shown). ET-1 level at 3 months after
stroke did not predict recurrent thromboembolic events; it was 2.0±1.3
pg/mL (median 2.3, range 0.0 to 4.8 pg/mL) in patients with recurrent
thromboembolic events (n=29) versus 2.1±1.2 pg/mL (median 2.3, range
0.0 to 4.4 pg/mL) in patients without a recurrence (n=72,
P>0.05).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Since the description of ETs by Yanagisawa et al,13 ETs have been shown to be potent constrictors of arteries. ET-1 could be involved in the pathogenesis of cerebrovascular diseases because of its strong and long-lasting vasoconstrictor effect. Even though we could not demonstrate an increase in plasma ET-1 levels in the acute phase of ischemic stroke, 3 studies reported beneficial effects of various ET-1 antagonists in cat and rat models of focal cerebral ischemia.14 15 16 These results suggest a deleterious role for ET-1 in ischemic stroke mediated by its vasoconstrictor or by other effects, at least in experimental stroke.
At the acute stage, ET-1 levels were reported as either elevated3 4 5 6 or normal.7 8 9 In the chronic phase, the ET-1 levels were increased.6 In our patients, plasma ET-1 levels were not significantly elevated at any time point after stroke. Our results are in disagreement with several previous studies.4 5 6 17 It was found18 that ET-1 acts in cerebral vessels from the adventitial but not from the luminal side. ET-1 activity is likely to be much higher at the interface of the endothelium and smooth muscle than in plasma.19 It is possible that increased local production of ET-1 may not be correctly detected in peripheral blood. This is consistent with the hypothesis that ET-1 is a local regulating factor.20
There is 1 study that demonstrated a significant correlation between plasma ET activity and age,6 whereas several others did not show any difference by age.19 21 22 Sex hormones may modify ET-1 activity, as determined in several studies.20 23 24 25 In the present study, ET-1 level did not show significant correlation with sex. The fact that 64 of 101 patients were males and that most female patients were postmenopausal in our study was a mere coincidence. The relationship between ET-1 activity and known risk factors for stroke has been addressed in numerous studies. Significant positive correlation was reported between cholesterol and ET-1 levels.20 26 The elevation of plasma ET-1 activity observed in hypercholesterolemic patients even without atherosclerotic lesions may reflect an endothelial dysfunction.26 In the present study, low HDL-cholesterol level showed a significant positive correlation with ET-1 level at 3 months only, which probably was a coincidence. Arterial hypertension is a central risk factor for stroke and correlated with ET-1 levels in earlier studies,27 28 29 30 although perfectly normal ET-1 levels were also observed.20 31 32 An association of ET-1 level with diabetes was considered positive and strong,22 33 but in other studies,21 34 no correlation was observed at all. It is possible that the release of ET-1 may be stimulated by insulin in a concentration-dependent manner.35 In general, the type and duration of diabetes, as well as the efficiency of antidiabetic treatment, may represent a confounder. Diabetes is usually aggressively treated in the Helsinki region, which might explain the lack of significant correlation between plasma ET-1 levels and diabetes. In addition, body weight is equivocally associated with ET-1 level.22 35 36 37 The mechanisms responsible for elevated plasma ET-1 levels in obese subjects remain unknown; this may be related to insulin resistance and hyperinsulinemia.38 In our study, ET-1 level showed a significant positive correlation with BMI on admission and at 1 week and a slight correlation at 3 months. The positive relationship between the effect of current cigarette smoking and ET-1 levels has been proposed to reflect the damage to the endothelial cells.39 40 The ET-1 level in patients with sleep apnea was investigated recently41 ; elevated ET-1 levels were found in patients with sleep apnea who did not have any other disease that may be associated with elevated ET-1 levels. It is possible that elevated ET-1 levels are caused by endothelial dysfunction in pulmonary and systematic vasculature. In our study, ET-1 level did not correlate with sleep apnea.
Pathogenetic mechanisms may differ in various stroke subtypes. Lampl et al9 found that ET-1 levels were significantly higher in the CSF of patients with large cortical infarctions than in patients with smaller subcortical lesions. Patients with acute cardiogenic cerebral embolism also had significantly higher plasma ET-1 levels than others.6 These findings are in disagreement with the data reported by Estrada et al,5 who did not find a correlation between plasma ET-1 levels and the cause of stroke. Our results did not indicate any relationship between plasma ET-1 levels and cause of stroke. The higher plasma ET-1 levels in patients with cardioembolic stroke reported in previous reports may be explained by warfarin use, as was shown to occur in the present study.
Plasma ET-1 level is an independent prognostic indicator of cardiovascular mortality rates and is strongly related to long-term outcome after myocardial infarction.42 43 Ziv et al4 reported that ET-1 level in stroke patients with more severe neurological impairment tended to be higher than that in the patients with a milder disorder. Hamann et al8 found a significant correlation between a poor clinical outcome and a high ET level. Estrada et al5 suggested that ET-1 level could be considered as a marker of disease severity in acute ischemic stroke. In our study, no correlation was found with stroke severity, stroke outcome, or risk of thromboembolic recurrence.
We originally expected much higher ET-1 concentrations in the plasma of our patients, but why ET-1 levels in stroke patients were not different from those of the control subjects may be due to the following factors: the first blood samples were usually taken between 24 to 48 hours after the stroke, thus missing the hyperacute phase. In subarachnoidal hemorrhage, the ET-1 levels reached their maximal levels several days after the insult,44 but the temporal sequence of plasma and CSF ET-1 level changes in ischemic stroke is not yet established. The patients included to this study were in better condition than average stroke patients (to ensure long-time survival), introducing a bias toward normality. Most of our patients had small to medium-sized infarctions. ET levels may be higher in patients with severe strokes associated with extensive brain tissue necrosis.5 8 Coincidentally, the study population was male dominant. However, our work is the largest, most detailed, and most uniform study to measure plasma ET-1 levels in ischemic stroke patients. ET-1 is released to the abluminal side of the vasculature; consequently, plasma ET-1 levels probably do not accurately reflect the true magnitude of ET-1 level increase. Measurement from the CSF during the hyperacute phase may deliver more accurate results, but such an approach raises ethical questions and would not be universally suitable in clinical practice.
Despite these limitations, we can conclude that plasma ET-1 levels do not correlate significantly with neurological scores, with the cause of stroke, or with the risk factors for stroke, and they do not predict recurrence of thromboembolic events. Warfarin use may have a significant effect on ET-1 levels, but the mechanisms underlying this possible relationship remain unclear. Clinically, the measurement of plasma ET-1 levels did not yield useful information for the evaluation of stroke patients in this study, such as suggesting a cause, estimating the risk of recurrence, or guiding secondary prevention. Our results, however, should be interpreted with caution and cannot completely exclude a role for ETs in the pathophysiology of ischemic stroke.
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Acknowledgments |
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Drs Tatlisumak and Soinne were supported in part by The Maire Taponen Foundation, Helsinki, Finland.
Received September 15, 1999; revision received December 3, 1999; accepted December 3, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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1. Barone FC, Willette RN, Yue T-L, Feuerstein G. Therapeutic effects of endothelin receptor antagonists in stroke. Neurol Res. 1995;17:259–264.[Medline] [Order article via Infotrieve]
2. Rubanyi GM, Polokoff MA. Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev. 1994;46:325–415.[Medline] [Order article via Infotrieve]
3. Hirata Y, Matsunaga T, Ando K, Furukawa T, Tsukagoshi H, Maruma F. Presence of endothelin-1-like immunoreactivity in human cerebrospinal fluid. Biochem Biophys Res Commun. 1990;166:1274–1278.[Medline] [Order article via Infotrieve]
4.
Ziv I, Fleminger G, Archiron A, Melamed E, Sokolovski
M. Increased plasma endothelin-1 in acute ischemic stroke.
Stroke. 1992;23:1014–1016.
5. Estrada V, Téllez MJ, Moya J, Fernández-Durango R, Egido J, Cruz AF. High plasma levels of endothelin-1 and atrial natriuretic peptide in patients with acute ischemic stroke. Am J Hypertens. 1994;7:1085–1089.[Medline] [Order article via Infotrieve]
6. Anwaar I, Gottsäter A, Lindgärde F, Mattiasson I. Increasing plasma neopterin and persistent plasma endothelin during follow-up after acute cerebral ischemia. Angiology. 1999;50:1–8.
7. Suzuki H, Sato S, Suzuki Y, Oka M, Tsuchiya T, Iino I, Yamanaka T, Ishihara N, Shimoda S. Endothelin immunoreactivity in CSF of patients with subarachnoid hemorrhage. Ann Med. 1990;22:233–236.[Medline] [Order article via Infotrieve]
8. Hamann GF, Isenberg E, Strittmatter M, Moili R, Schimrigk K. Big-endothelin in acute ischemic stroke. J Stroke Cerebrovasc Dis. 1993;3:256–260.
9.
Lampl Y, Fleminger G, Gilad R, Galtron R,
Sarova-Pinhas I, Sokolovski M. Endothelin in cerebrospinal fluid and
plasma of patients in the early stage of ischemic stroke.
Stroke. 1997;28:1951–1955.
10.
Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB,
Gordon DL, Marsh EE III, and the TOAST investigators. Classification of
subtype of acute ischemic stroke. Stroke. 1993;24:35–41.
11. Suzuki N, Matsumoto H, Kitada C, Masaki T, Fujino M. A sensitive sandwich-enzyme immunoassay for human endothelin. J Immunol Methods. 1989;118:245–250.[Medline] [Order article via Infotrieve]
12. Suzuki N, Matsumoto H, Miyauchi T, Kitada C, Tsuda M, Goto K, Masaki T, Fujino M. Sandwich-enzyme immunoassays for endothelin family peptides. J Cardiovasc Pharm. 1991;17(suppl 7):S420–S422.
13. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Lobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potential vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;322:411–415.
14. Patel TR, Galbraith S, Graham DI, Hallak H, Doherty AM, McCulloch J. Endothelin receptor antagonist increases cerebral perfusion and reduces ischaemic damage in feline focal cerebral ischemia. J Cereb Blood Flow Metab. 1996;16:950–958.[Medline] [Order article via Infotrieve]
15.
Tatlisumak T, Carano RAD, Takano K, Opgenorth TJ, Sotak
CH, Fisher M. A novel endothelin antagonist, A-127722,
attenuates ischemic lesion size in rats with temporary middle
cerebral artery occlusion: a diffusion and perfusion MRI study.
Stroke. 1998;29:850–857.
16. Dawson DA, Hallenbeck JM, Spatz M. The endothelin antagonist RO61-1790 attenuates focal cerebral ischemic injury. Stroke. 1998;29:323. Abstract.
17. Wei GZ, Zhang J, Sheng SL. Increased plasma endothelin 1 concentration in acute cerebral infarction and its clinical significance. Chung Hua Nei Ko Tsa Chih. 1994;33:388–390.
18. Shigeno T, Mima T, Takakura K, Yanagisawa M, Saito A, Goto K, Masaki T. Endothelin-1 acts in cerebral arteries from the adventitial but not from the luminal side. J Cardiovasc Pharmacol. 1989;13:174–176.
19. Lerman A, Edwards BS, Hallet JW, Heublein DM, Sandberg SM, Burnett JC. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med. 1991;325:997–1001.[Abstract]
20. Wilcox JG, Hatch IE, Gentzschein E, Stanczyk FZ, Lobo RA. Endothelin levels decrease after oral and nonoral estrogen in postmenopausal women with increased cardiovascular risk factors. Fertil Steril. 1997;67:273–277.[Medline] [Order article via Infotrieve]
21. Güvener N, Aytemir K, Aksöyek S, Gedik O. Plasma endothelin-1 levels in non-insulin dependent diabetes mellitus patients with macrovascular disease. Cor Art Dis. 1997;8:253–258.
22. Perfetto F, Tarquini R, Tapparini L, Tarquini B. Influence of non-insulin-dependent diabetes mellitus on plasma endothelin-1 levels in patients with advanced atherosclerosis. J Diabetes Complications. 1998;12:187–192.[Medline] [Order article via Infotrieve]
23. Thiemermann C, Lidbury PS, Thomas GR, Vane JR. Endothelin-1 releases prostacyclin and inhibits ex vivo platelet aggregation in the anesthetized rabbit. J Cardiovasc Pharmacol. 1989;13(suppl):138–141.
24.
Polderman KH, Stehouwer CDA, van Kamp GJ, Dekker GA,
Verheugt FWA, Gooren LJG. Influence of sex hormones on plasma
endothelin levels. Ann Intern Med. 1993;118:429–432.
25.
Richard V, Hogie M, Clozel M, Loffler B-M, Thuillez C.
In vivo evidence of an endothelin-induced vasopressor tone after
inhibition of nitric oxide synthesis in rats. Circulation. 1995;91:771–775.
26. Mangiafico RA, Malatino LS, Santonocito M, Spada RS, Polizzi G, Tamburino G. Raised plasma endothelin-1 concentrations in patients with primary hypercholesterolemia without evidence of atherosclerosis. Int Angiol. 1996;15:240–244.[Medline] [Order article via Infotrieve]
27. Saito Y, Nakao K, Mukoyama M, Imura H. Increased plasma endothelin level in patients with essential hypertension. N Engl J Med. 1990;322:205. Letter.[Medline] [Order article via Infotrieve]
28.
Douglas SA, Gellai M, Ezekial M, Feuerstein GZ, Elliot
JD, Ohlstein EH. Antihypertensive actions of the novel nonpeptide ET
receptor antagonist SB 209670. Hypertension. 1955;25:818–822.
29. Ferri C, Bellini C, Desideri G, Baldoncini R, De Siati L, Santucci A. Elevated plasma endothelin-1 levels as an additional risk factor in non-obese essential hypertensive patients with metabolic abnormalities. Diabetologia. 1997;40:100–102.[Medline] [Order article via Infotrieve]
30. Cottone S, Vadalà A, Vella MC, Mulé G, Contorno A, Cerasola G. Comparison of tumor necrosis factor and endothelin-1 between essential and renal hypertensive patients. J Hum Hypertens. 1998;12:351–354.[Medline] [Order article via Infotrieve]
31. Schffrin EL, Thibault G. Plasma endothelin in human essential hypertension. Am J Hypertens. 1991;4:303–308.[Medline] [Order article via Infotrieve]
32. Cassone R, Moroni C, Parlapiano C, Bondanini F, Blefari T, Affricano C. Endothelin-1 plasma levels in essential hypertension: increased levels with coronary artery disease. Am Heart J. 1996;132:1048–1049.[Medline] [Order article via Infotrieve]
33. Donatelli M, Hoffmann E, Coletti I, Andolina G, Russo V, Bucalo ML, Valenti TML, Compagno V, Cataldo MG, Morici ML. Circulating endothelin-1 levels in type 2 diabetic patients with ischemic heart disease. Acta Diabetol. 1996;33:246–248.[Medline] [Order article via Infotrieve]
34. Kanno K, Hirata Y, Shichiri M, Marumo F. Plasma endothelin levels in patients with diabetes mellitus with or without vascular complication. J Cardiovasc Pharmacol. 1991;17(suppl 7):475–476.
35. Ferri C, De-Mattia G. The effect of insulin on endothelin-1 (ET-1) secretion in human cultured endothelial cells. Metabolism. 1995;44:689–690.[Medline] [Order article via Infotrieve]
36. Wolpert HA, Steen SN, Istfan NW, Simonson DC. Insulin modulates circulating endothelin-1 levels in human. Metab Clin Exp. 1993;8:1027–1030.
37. Parrinello G, Scaglione R, Pinto A, Corrao S, Cecala M, Di Silvestre G, Amato P, Licata A, Licata G. Central obesity and hypertension. Am J Hypertens. 1996;9:1186–1191.[Medline] [Order article via Infotrieve]
38. Ferri C, Piccoli A, Properzi G, Bellini C, Pittoni V, Valesini G, Santuccci A. Insulin induces endothelin-1 release from human cultured endothelial cells. J Hypertens. 1994;12(suppl):S127. Abstract.
39. Haak T, Jungmann E, Raab C, Usadel KH. Elevated endothelin-1 levels after cigarette smoking. Metabolism. 1994;43:267–269.[Medline] [Order article via Infotrieve]
40. Gambaro G, Verlato F, Casara ABD, Saladini G, Del Prete D, Masiero GBM, Checchetto S, Baggio B. Renal impairment in chronic cigarette smokers. J Am Soc Nephrol. 1998;9:562–567.[Abstract]
41. Saarelainen S, Seppälä E, Laasonen K, Hasan J. Circulating endothelin-1 in obstructive sleep apnea. Endothelium. 1997;5:115–118.[Medline] [Order article via Infotrieve]
42.
Omland T, Lie RT, Aakvaag A, Aarsland T, Dickstein K.
Plasma endothelin determination as a prognostic indicator of 1-year
mortality after acute myocardial infarction. Circulation. 1994;89:1573–1579.
43. Omland T, Bonarjee V, Lie RT, Caidahl K. Neurohumoral measurements as indicators of long-term prognosis after acute myocardial infarction. Am J Cardiol. 1995;76:230–235.[Medline] [Order article via Infotrieve]
44. Fujimori A, Yanagisawa M, Saito A, Goto K, Masaki T, Mima T, Takakura K, Shigeno T. Endothelin in plasma and cerebral fluid of patients with subarachnoid hemorrhage. Lancet. 1990;336:633. Letter.
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