(Stroke. 1997;28:1951-1955.)
© 1997 American Heart Association, Inc.
Articles |
Endothelin in Cerebrospinal Fluid and Plasma of Patients in the Early Stage of Ischemic Stroke
From the Department of Neurology (Y.L., R. Gilad, I.S.-P.), E. Wolfson Medical Center, Holon, affiliated with the faculty of medicine, Tel Aviv University; the Department of Molecular Microbiology and Biotechnology (G.F.); and the Department of Neurobiochemistry (R. Galron, M.S.), The George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Correspondence to Yair Lampl, MD, Department of Neurology, Edith Wolfson Medical Center, Holon 58100, Israel.
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Abstract |
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Background and Purpose Endothelin 1 (ET-1), a highly potent endogenous vasoactive peptide, exerts a sustained vasoconstrictive effect on cerebral vessels. Elevation of ET-1 in plasma has been reported 1 to 3 days after ischemic stroke. Since we assumed that a much faster and more intense response may be observed in the cerebrospinal fluid (CSF) and since an increase in concentration of ET-1 in the CSF may cause constriction of cerebral vessels and eventually influence the neurological outcome, we measured ET-1 values in the CSF within 18 hours of stroke onset and compared the values with those in the plasma.
Methods Twenty-six consecutive patients with acute stroke were clinically evaluated according to the modified Matthew Scale and underwent two repeat CT scans. Within 5 to 18 hours of stroke onset, lumbar puncture and blood samples were concomitantly obtained and tested; ET-1 levels in CSF and plasma of these patients were analyzed by radioimmunoassay and compared with the levels of a control group of patients with no neurological disease.
Results The mean CSF concentration of ET-1 in the CSF of stroke patients was 16.06±4.9 pg/mL, compared with 5.51±1.47 pg/mL in the control group (P<.001). It was significantly higher in cortical infarcts (mean, 17.7±4.1 pg/mL) than in subcortical lesions (mean, 10.77±4.1 pg/mL) (P<.001) and significantly correlated with the volume of the lesion (P=.003). The correlation between ET-1 levels in the CSF and the Matthew Scale score was less significant (P=.05). Plasma ET-1 level was not elevated in any group.
Conclusions ET-1 is found to be significantly elevated in the CSF of stroke patients during the 18 hours after stroke. No elevation was demonstrated in plasma at this time period. ET-1 may be used as an additional indicator of ischemic vascular events in the early diagnosis of stroke. The dissimilarity between the CSF and plasma ET-1 concentrations may lead also to an hypothesis that there is a vasoconstrictive effect on the cerebral vessels or a neuronal effect caused by ET-1 in the mechanism of the progression of brain ischemia.
Key Words: endothelins • stroke, acute • cerebrospinal fluid • diagnosis
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Introduction |
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Endothelin-1 (ET-1), a 21–amino acid peptide present in mammalian endothelial cells, is among the most potent vasoconstrictive substances known. It exists in three different isopeptides, ET-1, ET-2, and ET-3, of which ET-1 is the most powerful, and is characterized by a long-acting vasoconstrictor activity.1 2
The vasoconstrictor effect of ET on blood vessels of the brain, regional blood flow, and cerebral microvascular pressure was demonstrated in the choroid plexus of the rabbit,3 as well as in the large cerebral arteries of cats.4 The vasoconstrictive effect on cerebral microvessels was found to be dose-dependent in response to ET-1 but not to ET-35 and lasted for 24- to 2 hours.6 7 ET-mediated vasoconstriction aggravated the ischemic effect of an existing cerebral lesion and was associated with an increased ET-1 concentration in brain tissue and plasma.8 The ET-1–mediated ischemic effect and the neurodestructive mechanisms could be reversed by specific ET-receptor blocking,9 as well as by N-methyl-D-aspartate antagonists.10 It was suggested that a balance between a cerebral vasoconstriction induced by ET and a powerful vasodilator mechanism mediated by nitric oxide comprises the basic system for normal regulation of the cerebral blood flow.11 A factor that decreases ET-1 levels in the endothelial cell microvessels was found to be released from cultured astrocytes.12 In addition, it was also suggested that astrocytes may be involved in a regulatory loop of ET-1 production at the level of the blood-brain barrier.13 ET-1 and ET-3 were both detected in astrocytes after focal or global ischemia, especially in damaged hippocampal tissue.14
In vivo studies with animal models have shown that administration of ET-1 into the cerebrospinal fluid (CSF)–containing space, either intracisternally or intraventricularly, is followed by severe and sustained vasospasm lasting for up to 72 hours.6 7 Intraventricular administration of ET-1 reduced cerebral blood flow and led to the development of brain infarction.15 Injection of ET-1 into the lateral ventricles of conscious rats induced hypometabolism of various brain structures16 ; this effect could be completely reversed by intraventricular ET-1–receptor antagonists.9
Increased ET-1 concentrations have been demonstrated in the CSF and plasma of patients with subarachnoid hemorrhage17 18 19 and in the serum of individuals with acute vascular headache.20 Most authors assume that ET-1 plays a key role in vasospasm after subarachnoid hemorrhage, although circulating plasma ET-1 levels could not be correlated with the severity of the local vasoconstrictive effect on cerebral arteries.21 In patients with ischemic stroke, plasma ET-1 levels were examined at various stages after the event and were found to be elevated.22 23 24
The present study was performed to find out whether the ET-1 concentration in CSF and plasma may help in anticipating the effects of a stroke, both clinically and neuroradiologically, and whether there is a possibility of using these findings as an indicator for stroke in the very early stages of cerebrovascular brain ischemia.
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Subjects and Methods |
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Patients
The study population consisted of 26 consecutive patients, 16 men and 10 women, with acute stroke. Their mean age was 64 years (range, 38 to 98 years). Excluded from the study were patients for whom the medical history or neuroradiological imaging studies revealed evidence of intracerebral hemorrhage, hemorrhagic infarction, brain tumors, demyelinating disease, vascular headache, acute or chronic infection, inflammatory disease of the central nervous system, systemic metabolic disorders, or systemic vasculitis.
This study was approved by the hospital ethics committee.
Each patient was clinically examined by two neurologists. All of the patients underwent brain CT scan on admission to exclude intracerebral or subarachnoid hemorrhage or brain tumor; a second CT scan was performed 7 days later. The clinical neurological status was evaluated according to the modified Matthew Scale.25
Within 18 hours of stroke onset (mean time, 7.3±3.1 hours), well established criteria26 were followed to avoid any contraindications or complications and to ensure proper techniques were used for patient evaluation and examination. Lumbar puncture was performed at the level of L3-L4 or L4-L5 interspaces. A period of 18 hours was chosen as the upper time limit for inclusion into the study in order to examine the ET-1 in the three-quarter time period when brain ischemia is known to progress into persistent stroke deficit or to be transient. The exact time of stroke onset was confirmed by additional family members. Biochemical analyses of the CSF cell counts were performed immediately after the lumbar puncture. Acetic acid (500 µg/mL) and aprotinin (5 µg/mL) were added to the CSF specimen, which was centrifuged at 3000 rpm for 20 minutes at 4°C. Blood-brain barrier function was assessed using the Q albumin value method, with a Q albumin value of 9.0 defined as the upper limit of the normal range.24 Albumin and IgG concentrations were determined by the electroimmunoassay technique. A venous blood specimen withdrawn at the time of the lumbar puncture was treated with acetic acid and aprotinin. The blood was taken from the brachial vein, centrifuged, and separated; then the plasma was examined in the same way as for the CSF specimens. The control group consisted of 11 patients with a mean age of 61 years (range, 32 to 67 years) whose presenting complaints were acute vertigo (5 patients), acute headache of nonvascular origin (4 patients), or cervical pain (2 patients). Neuroradiological examination of these patients was normal, and none of them is known to have a clinical neurological deficit. Lumbar puncture was performed in these patients as part of the neurological evaluation to exclude subarachnoid bleeding or an infectious disease. The procedure was performed in as nonstressful an environment as possible to avoid an undesirable influence in the activation of the sympathetic nervous system by mental stress.28
Neuroradiological Examination
Brain CT scans were obtained using an Elite Elcint 2001 CT
scanning apparatus and were evaluated by a
neuroradiologist. The site of the lesion was located, and the lesions
were classified as cortical or subcortical. The volume of infarction
was measured using the addition of the calculated infarction areas in
each CT slice with a width of 10 mm. The relative diameter of the
infarct was calculated as the ratio of the maximal diameter of the
infarct to the maximal diameter of brain. The smallest distance between
the infarct and the subarachnoid space or the ventricle was
also measured. These parameters were determined from the CT
scan obtained on admission as well as from the control CT scan obtained
7 days later.
Endothelin Extraction Procedure
Duplicate samples of 0.5 mL of CSF were acidified by 4 mL of 4%
acetic acid in water and applied to a C18 Sep-Pak cartridge (Waters
Chromatography Division). After washing the cartridge
with 5 mL of 4% acetic acid, ET was eluted with 2.5 mL of 60%
acetonitrile containing 0.5% ammonium acetate. The samples were dried
by evaporation in a Speed Vac apparatus (Savant). Dried
fractions were reconstituted with 0.25 mL of radioimmunoassay buffer,
and 100 µL were assayed and duplicated.
Two experiments were performed to test the efficiency of the ET extraction procedure. First, I-125–labeled ET-1 (13 000 cpm) was mixed with increasing amounts of unlabeled ET-1 (128 pg in 3 mL fractions of 4% acetic acid). Each fraction was then applied to a C18 Sep-Pak cartridge. The cartridge was washed with the same buffer, and ET-1 was eluted with 2.5 mL of 60% acetonitrile containing 0.5% ammonium acetate. The amount of radioactive material recovered was found to be 75±5% (mean±SD). In the second experiment, ET-1 (56 pg) was added to a sample of control CSF (1 mL), which was then processed according to a standard extraction procedure. After removal of the acetonitrile by evaporation, the amount of ET-1 was determined in duplicate samples. In a representative assay, 30 and 28 pg were detected in a pair of duplicate samples. Assuming an endogenous level of 5 pg ET-1 per tube, the above figures represent a recovery of exogenous ET-1 of about 90%. The 6-assay coefficient of variation for the extraction was 8%.
Radioimmunoassay Procedure
Radioimmunoassay was performed with Amersham International RIA
Kit (Code RPA545). Duplicate samples of 0.1 mL were assayed according
to the manufacturer's instructions. Cross-reactivities of the assay
(according to the manufacturer's specifications) for ET-1, ET-2, ET-3,
and big ET are 100%, 7%, 7%, and 17%, respectively.
Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS, Inc). Two group comparison was done with unpaired Student's t test. Bonferroni's correction test was used to compare the various groups.
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Results |
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The mean level of ET-1 in the CSF of stroke patients was significantly higher than in the control group (Fig 1
) (16.06±3.5 pg/mL versus
5.1±1.47 pg/mL, P<.001). Among the stroke patients
themselves, the mean ET-1 level in the CSF was significantly higher in
cortical infarcts than in subcortical infarcts (Fig 2) (17.70±3.5 versus 10.77±4.1
pg/mL, P<.001), and each of these was significantly
higher than in the control group (P<.001 and
P<.01, respectively).
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Blood-brain barrier function, as indicated by Q albumin values, was normal in all CSF samples (range, 3.5 to 7.8).
The mean levels of ET-1 in the plasma of the stroke patients during 18 hours from the onset and the control group were 5.51±1.47 and 4.66±0.63 pg/mL, respectively. Among the stroke patients, mean ET-1 levels in cortical and subcortical infarcts were 5.00±0.89 and 4.98±0.67 pg/mL, respectively, indicating that plasma ET-1 levels in the control group did not differ significantly from those of the stroke patients as a group or of the cortical or subcortical infarct subgroups.
No correlation was found between ET-1 levels in the CSF and in the plasma (P=.98, r=.005).
Fifteen patients (9 men, 6 women) had cortical infarcts and 11 (7 men, 4 women) had subcortical infarctions. The mean volumes of the cortical and subcortical infarcts as measured neuroradiologically were 20.55±20.20 and 8.77±15.74 cm3, respectively. The size of the lesion was found to be directly correlated with ET-1 levels in the CSF (P=.003, r=.805) but not in the plasma. There was no correlation between the distance of the infarct from the subarachnoid space and the level of ET-1 in the CSF or in the plasma.
A small direct positive correlation was found between patients' clinical scores on the Matthew Scale and their levels of ET-1 in the CSF (P=.05, r=.101).
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Discussion |
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The results of this study show that the levels of ET-1 in the CSF of patients suffering from acute ischemic stroke were significantly higher than those of the control group. The corresponding elevation of ET-1 levels in the plasma of stroke patients was much less pronounced and was not statistically significant, raising the possibility that ET-1 in the CSF and in the plasma originate from different sources. The difference in ET-1 concentrations in CSF and plasma could, however, also be explained in terms of a "spill phenomenon" of ET-1 after stroke and different dilution capacities of the plasma and CSF compartments. The possibility that the release of ET into the CSF and plasma is of a different characteristic, and speed was taken into consideration. The normal function of the blood-brain barrier in all of our patients, as indicated by normal Q albumin ratios, may suggest that ET-1 in the CSF is of central nervous system origin, since an intact functioning blood-brain barrier is believed to be the main factor preventing a vasoconstrictive effect of circulating ET-1.29 The elevation of ET level in neural tissue after focal ischemia and in the extracellular fluid in global ischemia was already demonstrated.30 Nevertheless, it must be mentioned that albumin is much larger in diameter than ET-1, so that the assumption that the blood-brain barrier function, displayed according to the Q albumin method, can be involved in the transfer of ET-1 through the blood-brain barrier has only some limited value.
Previous studies have demonstrated an elevation of plasma ET-1 between the day 1 and day 7 after an ischemic cerebrovascular event.22 23 24 ET-1 levels in the CSF were not examined in those patients. Others have reported that ET-1 concentration in the plasma is correlated with the clinical status on admission and the final outcome, but not with the size of the infarction.23 A possible explanation for the discrepancy between the normal plasma ET level found in our study and the elevated ET concentration in previous reports may be the very early stage of measurement in our patient. The mean time of sample collection was 7.3 hours in our patients, with an upper limit of only 18 hours. In rat models, the elevation of ET in the CSF was shown to be more rapid and significant than in plasma after an acute stress maneuver. The decrease in the CSF level was rapid as well.31 Another explanation was the presence of an abnormally high ET-1 level in the control group caused by an increase of the sympathetic activity induced by the various complaints of the control group patients.28 Nevertheless, since the ET values were similar to those of other control groups in ET stroke studies22 and since in none of the subgroup patients, especially the vertigo complaining patients, did the ET-1 levels differ from the other subgroups, the possibility was rejected. We found that ET-1 levels were significantly higher in the CSF of patients with large cortical infarcts compared with smaller subcortical lesions. Moreover, we found that CSF levels of ET-1 were correlated with the volume of the cortical infarct and to some extent also with the degree of clinical neurological deficits. The ratio of CSF–ET-1 contraction between stroke patients and the control group was higher than 3:1. Previous studies that examined the ET-1 concentration in the CSF of subarachnoid stroke patients during the stage of vasospasm found similar data.32 These findings support a direct relationship between ET-1 elevation in CSF and the brain infarction.
The presence of a highly potent vasoconstrictive agent such as ET-1 at high concentrations in the CSF after stroke may be expected to eventually exert a vasconstrictive effect on the large cerebral vessels located in the CSF. A major part of the ET-A receptors are located on the external surface of the cerebral vessels, allowing free access to these vessels by substances present in the CSF.33 Evidence that ET-1 causes vasoconstriction if applied from the adventitial side33 may explain the mechanism of such a physiological reaction. However, in those stroke patients with alteration of the blood-brain barrier, ET-1 may eventually have access also to the vascular smooth muscle cells and thus induce an additional contraction mechanism.
Studies with animal models have demonstrated the onset of sustained vasospasm as a result of increased levels of ET-16 7 15 16 and complete reversibility of the vasoconstrictive effect after injection of ET-A receptor antagonists.7 These findings support the possibility that a similar vasoconstrictive effect is caused by the high concentration of ET-1 in the CSF during the first hours after stroke onset. This may have a deleterious effect on the development of the infarction and of the neurological deficit. Current trends in therapy seem to advocate an administration of combined ET-A and ET-B blockers for protection against the development of stroke.34 35 36 It seems that both receptors are present and only by actions on both can an effective blockage be achieved.
The demonstrated correlation between the size of the tissue lesion and ET-1 levels in the CSF within only a few hours of infarction may serve as a basis for a rapid and accurate method for the estimation of the severity and prediction of the final outcome of a cerebrovascular event soon after its onset, especially in the case of large cortical lesions. It may also be used to differentiate between the onset of a cerebrovascular event and of other nonvascular incidents presenting a similar clinical picture. Determination of ET-1 levels in the CSF may be a useful method, especially in those many cases when the neuroradiological picture remains unclear for several days after the onset of ischemic stroke.
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Acknowledgments |
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We are thankful to Judy Brandt for her skillful editing and word processing expertise and contributions and to Dikla Geva, MS, for her statistical work and analysis.
Received April 21, 1997; revision received June 11, 1997; accepted June 12, 1997.
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References |
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