endothelin-1 and Cerebral-Hemorrhage

Vascular damage caused by cerebral ischemia leads to edema, hemorrhage formation, and worsened outcomes in ischemic stroke patients. Therapeutic interventions need to be developed to provide vascular protection. The purpose of this review is to identify the pathophysiologic processes involved in vascular damage after ischemia, which may lead to strategies to provide vascular protection in ischemic stroke patients.. The pathologic processes caused by vascular injury after an occlusion of a cerebral artery can be separated into acute (hours), subacute (hours to days), and chronic (days to months). Targets for intervention can be identified for all 3 stages. Acutely, superoxide is the predominant mediator, followed by inflammatory mediators and proteases subacutely. In the chronic phase, proapoptotic gene products have been implicated.. Pharmacological agents designed to target specific pathologic and protective processes affecting the vasculature should be used in clinical trials of vascular protection after acute ischemic stroke.

Topics: Acute Disease; Angiopoietins; Angiotensin II; Antioxidants; Apoptosis; Blood-Brain Barrier; Brain Edema; Brain Ischemia; Cerebral Arteries; Cerebral Hemorrhage; Chronic Disease; Endothelin-1; Endothelium, Vascular; Humans; Inflammation Mediators; Matrix Metalloproteinases; Neuroprotective Agents; Neutrophils; Oxidative Stress; Reactive Oxygen Species; Vascular Endothelial Growth Factor A; Vasculitis

There is a growing body of evidence from clinical and epidemiologic studies that in utero exposure to infection plays an important role in the genesis of fetal or neonatal injury leading to cerebral palsy and chronic lung disease. Thus, after chorioamnionitis the incidence of immature neonates with periventricular white matter damage and periventricular or intraventricular hemorrhage is significantly elevated. Recent clinical and experimental data support the hypothesis that a fetal inflammatory response links antenatal infection with brain white matter damage and subsequent motor handicap. A variety of studies support the view that cytokines released during intrauterine infection directly cause injury to the immature brain. In this review, we provide evidence that in utero exposure to bacterial infection can severely alter fetal cardiovascular function, resulting in dysregulation of cerebral blood flow and subsequent hypoxic-ischemic brain injury.

Topics: Animals; Cardiovascular System; Cerebral Hemorrhage; Cerebral Palsy; Cytokines; Endothelin-1; Endotoxemia; Endotoxins; Female; Fetal Diseases; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Infant, Newborn, Diseases; Nitric Oxide; Pregnancy; Pregnancy Complications, Infectious

Neuroinflammation and secondary injury play a central role in the pathophysiology of intracerebral hemorrhage. The dual endothelin-1/VEGFsignal-peptide receptor (DEspR) has been reported to mediate the inflammatory response after acute brain injury in a rodent model. We performed a pilot study to assess the expression of DEspR on circulating leukocytes in patients who presented with spontaneous intracerebral hemorrhage (ICH).. We performed a prospective observational study of patients presenting to two academic medical centers with ICH. Normal healthy volunteers (NHV) were also recruited for sample analysis. Whole blood was obtained, and flow cytometry was performed to examine DEspR expression on neutrophils, monocytes, and lymphocytes.. A total of 19 patients were included in analysis. Median ICH volume was 39 cm. In this pilot study, DEspR is expressed on circulating neutrophils and monocytes in humans after ICH, with higher levels of expression in those with hypertension. Future work in larger cohorts should examine the relationship of DEspR expression with neuroinflammatory endpoints and long-term outcome.

Topics: Cerebral Hemorrhage; Endothelin-1; Humans; Hypertension; Pilot Projects; Receptors, Peptide

BACKGROUND The goal of the present study was to determine whether endothelin-1 (EDN1) variants are associated with intracerebral hemorrhage (ICH) risk among Chinese Han people. MATERIAL AND METHODS The genotyping of EDN1 rs5370 and rs6458155 polymorphisms were conducted in 154 ICH patients and 168 healthy controls using polymerase chain reaction (PCR) and sequencing. Deviation for genotype frequencies in controls from Hardy-Weinberg equilibrium (HWE) was assessed. The genotype and allele distribution of EDN1 polymorphisms was checked via χ² test between 2 groups. Strength of the association between EDN1 polymorphisms and ICH risk is presented by odds ratio (OR) and 95% confidence interval (95% CI). RESULTS Genotype distribution for rs5370 and rs6458155 polymorphisms in the control group both conformed to HWE (P>0.05). Only CC genotype and C allele frequencies of rs6458155 between ICH patients and healthy individuals were significantly different (P=0.025; P=0.043), indicating rs64581255 is associated with increased ICH onset (OR=2.214, 95% CI=1.009-4.461; OR=1.389, 95% CI=1.010-1.910). When adjusted by confounding factors, the significant correlations still existed between 2 groups (P=0.028, adjusted OR=2.217, 95% CI=1.092-4.500; P=0.046, adjusted OR=1.386, 95% CI=1.005-1.910). CONCLUSIONS EDN1 rs64581aEDN1 rs6458155 polymorphism may be a risk factor of ICH among Chinese Han people.55 polymorphism may be a risk factor of ICH among Chinese Han people.

Topics: Adult; Asian People; Case-Control Studies; Cerebral Hemorrhage; China; Cohort Studies; Endothelin-1; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors

BACKGROUND This study investigated the correlations between acute cerebral hemorrhage complicated with stress ulcer bleeding and corresponding indexes, including the Acute Physiology and Chronic Health Evaluation (APACHE) II score, vascular endothelin-1 (ET-1), tumor necrosis factor-alpha (TNF-α), and blood lipid factors. MATERIAL AND METHODS A total of 53 patients with acute cerebral hemorrhage complicated with stress ulcer bleeding were selected as the observation group and 50 patients with simple acute cerebral hemorrhage were selected as the control group. The APACHE II score and the levels of ET-1, TNF-α, and blood lipid factors, including total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and malondialdehyde (MDA), were detected and the correlations of were analyzed between the 2 groups of patients. RESULTS The blood lipid index TG, APACHE II score, ET-1, TNF-a, renal function indexes [blood urea nitrogen (BUN) and creatinine (Cr)], mortality rate, hemoglobin, and MDA in the observation group were significantly higher than those in the control group, while HDL-C in the observation group was obviously lower than in the control group (p<0.05). The APACHEII score had positive correlations with TG and TNF-α (r=0.8960, r=0.8563, respectively), while it was negatively correlated with TC, HDL-C, LDL-C, and ET-1 (r=-0.909, r=-0.9292, r=-0.8543, and r=-0.8899, respectively) (p<0.001 in all comparisons). APACHEII score, BUN, and Cr were all risk factors. CONCLUSIONS Stress ulcer in patients with acute cerebral hemorrhage is associated with blood lipid changes and inflammation, which provides clues for the diagnosis and treatment of acute cerebral hemorrhage.

Topics: Adult; APACHE; Cerebral Hemorrhage; Cholesterol, HDL; Cholesterol, LDL; Endothelin-1; Female; Humans; Lipids; Male; Middle Aged; Peptic Ulcer; Risk Factors; Stress, Psychological; Triglycerides; Tumor Necrosis Factor-alpha

To determine the effects of minimally invasive surgery (MIS) at various stages after intracerebral hemorrhage (ICH) on perihematomal endothelin (ET)-1 levels and neurological functioning.. Sixty rabbits were randomly distributed into a model control group (MC group, 30 rabbits) or a MIS group (MI group, 30 rabbits). An ICH model was established in all animals. In the MI group, ICH was evacuated by MIS at 6, 12, 18, 24, and 48 hours (six rabbits at each time point) after the ICH was established. The animals in the MC group underwent the same procedures for ICH evacuation, but with a sham operation without hematoma aspiration. All the animals were sacrificed 7 days after the ICH was established. Neurological deficit scores were determined, and the perihematomal brain tissue was removed to determine the ET-1 levels, blood-brain barrier (BBB) permeability, and brain water content (BWC).. The neurological deficit scores, perihematomal ET-1 levels, BBB permeability, and BWC all decreased significantly in the MI group compared to the MC group. Performing the MIS for evacuating the ICH at 6 hours resulted in the most remarkable decreases in these indices, followed by a significant difference observed at 12 hours within the MI subgroups.. Performing MIS at 6-12 hours after ICH resulted in the most significant decreases in neurological deficit scores, ET-1 levels, BBB permeability, and brain edema. The optimal time window for performing MIS for ICH evacuation might be within 6-12 hours after hemorrhage.

Topics: Animals; Blood-Brain Barrier; Brain; Brain Edema; Cerebral Hemorrhage; Disease Models, Animal; Endothelin-1; Hematoma; Male; Minimally Invasive Surgical Procedures; Neurosurgical Procedures; Permeability; Rabbits; Recovery of Function; RNA, Messenger

Endothelin-1 (ET-1) has deleterious effects on water homeostasis, cerebral edema, and blood-brain barrier (BBB) integrity. Highly expressed ET-1 was observed after intracerebral hemorrhage (ICH); however, ET-1 changes and their relationship with BBB disruption within 24 hours of ICH have not been thoroughly investigated. The aim of the present study was to observe the changes in perihematomal ET-1 levels in various phases of ICH and their correlation with the BBB integrity in a rabbit model of ICH.. Twenty-five rabbits (3.2-4.3 kg body weight) were randomly divided into a normal control group (five rabbits) and a model group (20 rabbits). Animals in the model group were equally divided into four subgroups (five rabbits each to be sacrificed at 6, 12, 18, and 24 hours following ICH establishment). An ICH model was prepared in the model group by infusing autologous arterial blood into the rabbit brain. ET-1 expression in perihematomal brain tissues was determined using immunohistochemistry and color image analysis, and the permeability of the BBB was assayed using the Evan's Blue (EB) method. A repeated measures analysis of variance was used to make comparisons of the ET-1 and EB content across the entire time series.. The number of perihematomal endothelial cells with ET-1 positive expressions following 6, 12, 18, and 24 hours ICH model establishment was 9.32, 13.05, 15.90, and 20.44, respectively, but as low as 6.67 in the control group. The average transmittance of ET-1-positive cell bodies at 6, 12, 18, and 24 hours after ICH was 99.10, 97.40, 85.70, and 80.80, respectively, but 100.12 in the control group. These data reveal that the expression of ET-1 was significantly increased at 6, 12, 18, and 24 hours after ICH compared with the control group, and a marked decrease in the average transmittance of ET-1-positive cell bodies was noted (P < 0.05). Similarly, the perihematomal EB content at 6, 12, 18, and 24 hours after ICH was 29.39 ± 1.16, 32.20 ± 0.73, 33.63 ± 1.08, and 35.26 ± 1.12, respectively, in the model group and 28.06 ± 0.80 in the control group. The results indicate that a significant increase in the EB content in the model group was observed compared with that of the control group (P < 0.05). Moreover, a positive correlation between the number of ET-1-positive endothelial cells and BBB permeability was observed (r = 0.883, P < 0.05).. High levels of ET-1 are closely associated with BBB disruption. ET-1 may play an important role in the pathogenesis of secondary brain injury after ICH.

Topics: Animals; Blood-Brain Barrier; Brain; Cerebral Hemorrhage; Disease Models, Animal; Endothelin-1; Immunohistochemistry; Male; Rabbits

Ischaemic stroke induces endothelial progenitor cell (EPC) mobilisation from bone marrow into peripheral blood. Circulating EPCs play an important role in post-injury regeneration of vasculature, whereas endothelial cells (ECs) have been shown to reflect endothelial damage and may be responsible for increased Endothelin-1 (ET-1) expression. We investigated herein the association between numbers of circulating ECs and EPCs, the levels of soluble factors regulating their migration and function, and the clinical outcome in patients with haemorrhagic (HS) or ischaemic stroke (IS). Sixteen patients with HS and eighteen with IS were assessed during the first 24h, day 3, and day 7 after stroke and compared them with twenty-three control subjects. We found elevated EPC and EC concentrations using flow cytometry and increase in VEGF, SDF-1, HGF, and ET-1 plasma levels by ELISA in the HS patients, while ET-1 mRNA expression in peripheral blood cells was elevated in the IS patients. Significant correlations were observed between EPCs or ECs and Big ET-1 protein or mRNA levels in HS but not in the IS patients. We suggest that ET-1 may play a role in pathophysiology of stroke and subsequent EPC mobilisation; however, further studies aimed at the precise elucidation of this issue are required.

Topics: Aged; Aged, 80 and over; Biomarkers; Brain Ischemia; Cerebral Hemorrhage; Endothelial Cells; Endothelin-1; Female; Humans; Male; Middle Aged; Stem Cells; Stroke; Up-Regulation

Bradykinesia in upper extremities is associated with a wide variety of motor disorders; however, there are few tasks that assay forelimb movement speed in rodent models. This study describes the bradykinesia assessment task, a novel method to quantitatively measure forelimb speed in rats. Rats were trained to reach out through a narrow slot in the cage and rapidly press a lever twice within a predefined time window to receive a food reward. The task provides measurement of multiple parameters of forelimb function, including inter-press interval, number of presses per trial, and success rate. The bradykinesia assessment task represents a significant advancement in evaluating bradykinesia in rat models because it directly measures forelimb speed. The task is fully automated, so a single experimenter can test multiple animals simultaneously with typically in excess of 300 trials each per day, resulting in high statistical power. Several parameters of the task can be modified to adjust difficulty, which permits application to a broad spectrum of motor dysfunction models. Here we show that two distinct models of brain damage, ischemic lesions of primary motor cortex and hemorrhagic lesions of the dorsolateral striatum, cause impairment in all facets of performance measured by the task. The bradykinesia assessment task provides insight into bradykinesia and motor dysfunction in multiple disease models and may be useful in assessing therapies that aim to improve forelimb function following brain damage.

Topics: Animals; Brain Ischemia; Cerebral Hemorrhage; Conditioning, Operant; Corpus Striatum; Disease Models, Animal; Endothelin-1; Equipment Design; Female; Forelimb; Hypokinesia; Microbial Collagenase; Motor Cortex; Movement Disorders; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Time Factors

To investigate the association between vasculopathy and survival during experimental cerebral malaria (ECM), and to determine whether targeting the endothelin-1 (ET-1) pathway alone or in combination with the anti-malaria drug artemether (a semi-synthetic derivative of artemisinin) will improve microvascular hemorrhage and survival.. C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) were randomly assigned to four groups: no treatment, artemether treated, ET(A) receptor antagonist (HJP-272) treated, or HJP-272 and artemether treated. The uninfected control mice were treated with HJP-272 and artemether. We analyzed survival, cerebral hemorrhage, weight change, blood glucose levels and parasitemia.. Our studies demonstrated decreased brain hemorrhage in PbA-infected (ECM) mice treated when HJP-272, a 1,3,6-trisubstituted-2-carboxy-quinol-4-one novel ET(A) receptor antagonist synthesized by our group, is used in conjunction with artemether, an anti-malarial agent. In addition, despite adversely affecting parasitemia and weight in non-artemether treated infected mice, HJP-272, seemed to confer some survival benefit when used as adjunctive therapy, though this did not reach significance.. Previous studies demonstrate that the endothelin pathway is associated with vasculopathy, neuronal injury and inflammation in ECM. As demonstrated here, components of the ET-1 pathway may be important targets for adjunctive therapy in ECM, and may help in preventing hemorrhage and in improving survival when used as adjunctive therapy during malaria infection. The data presented suggest that our novel agent, HJP-272, may ameliorate alterations in the vasculature which can potentially lead to inflammation, neurological dysfunction, and subsequent death in mice with ECM.

Topics: Animals; Antimalarials; Artemether; Artemisinins; Cerebral Hemorrhage; Drug Synergism; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Endothelin-1; Female; Hydroxyquinolines; Malaria, Cerebral; Mice; Mice, Inbred C57BL; Microvessels; Parasitemia; Plasmodium berghei; Random Allocation; Survival

The markers of regulation vascular tone, such as rennin, endothelin-1, and C-type natriuretic peptide, are of great value for prognosis of hemorrhagic transformation and fatal outcome of ischemic stroke. A change in the vascular tone in case of hemorrhagic transformation at the affected site precedes activation of the coagulation component of hemostasis as a mechanism preventing blood loss and increasing fibrinogen level. This work was aimed to study the balance of the above markers and fibrinogen in the prognosis of hemorrhagic transformation and fatal outcome in the acute period of ischemic stroke. It included 62 patients receiving no thrombolytic therapy. It was shown that symptomatic hemorrhagic transformation was associated with elevated rennin levels without a marked fall in the level of C-type natriuretic peptide and asymptomatic hemorrhagic transformation with elevated endothelin-1 levels and decreased concentration of natriuretic peptide. Fibrinogen level on day 4 of the observation proved to be a reliable predictor of negative prognosis. Asymptomatic hemorrhagic transformation without fatal outcome was associated with systemic and local vasoconstriction and inhibition of local vasodilation. Symptomatic hemorrhagic transformation with the fatal outcome was accompanied by dysregulation of vascular tone in the form of activation of systemic and local vasoconstriction, insufficient inhibition of local vasodilation and compensatory reaction in the form of activation of hemostatic mechanisms manifest as elevated fibrinogen levels on day 4. The lethal outcome without hemorrhagic transformation was associated with systemic vasoconstriction, activation of local vasodilation and vasoconstriction leading to local "biochemical paralysis" of vascular tone regulation.

Topics: Aged; Aged, 80 and over; Biomarkers; Blood Coagulation; Brain Ischemia; Cerebral Hemorrhage; Chymosin; Endothelin-1; Female; Fibrinogen; Humans; Male; Middle Aged; Natriuretic Peptide, C-Type; Predictive Value of Tests; Prognosis; Stroke; Survival Analysis; Vasomotor System

Diabetes increases the risk of as well as poor outcome after stroke. Matrix metalloprotease (MMP) activation disrupts blood-brain barrier integrity after cerebral ischemia. We have previously shown that type 2 diabetes promotes remodeling of middle cerebral arteries (MCA) characterized by increased media/lumen (M/L) ratio and MMP activity in an endothelin (ET)-1-dependent manner in the Goto-Kakizaki (GK) rat model. In the present study, we examined the effects of ET-1-mediated vascular remodeling on neurovascular damage following cerebral ischemic injury in GK rats 5 and 12 weeks after the onset of diabetes. The MCA structure, cerebral perfusion as well as infarct size, and hemorrhage were measured in control and diabetic rats subjected to transient MCA occlusion. M/L ratio was increased after 12 but not 5 weeks of diabetes. The baseline cerebral perfusion was lower and the infarct volume smaller in diabetic rats in both age groups. The incidence of hemorrhagic transformation was higher after 5 weeks of diabetes as compared to that after 12 weeks or in the control groups. These findings provide evidence that ET-1-mediated cerebrovascular remodeling does not worsen the neurovascular damage of ischemic brain injury in diabetes. It is possible that this early remodeling response is compensatory in nature to regulate vascular tone and integrity, especially when ischemia is layered on diabetic vascular disease.

Topics: Animals; Blood Glucose; Cerebral Hemorrhage; Cerebral Infarction; Cerebrovascular Circulation; Collagen; Diabetes Mellitus, Type 2; Disease Models, Animal; Endothelin-1; Male; Middle Cerebral Artery; Rats; Rats, Inbred Strains; Rats, Wistar; Reperfusion Injury; Tunica Media

To observe the respective effects of intervention either with endothelin (ET) antibody or with ET receptor antagonist on acute stress ulcer (ASU) subsequent to cerebral hemorrhage in rats.. Forty Sprague-Dawley (SD) rats were randomly divided into control group (group A, n=10), model group (group B, n=10), ET antibody (group C, n=10), and ET receptor antagonist group (group D, n=10). Right intracerebral hemorrhage was reproduced by injection of 200 microl autologous venous blood. Normal saline, ET antibody, or ET receptor antagonist was respectively administered intravenously per day for designated group. The rats were sacrificed at 3 days of the experiment. The incidence of ASU and ulcer index were assessed, serum ET-1 level, malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in serum, Rsvmit (Rsv) and Vvmit (Vv) of cerebral and gastric mucosa were measured, and pathological examination of the cerebral tissue and gastric mucosa was performed with light microscopy and electron microscopy.. In group B, serum ET-1 level did not changed. MDA content were markedly increased in serum, cerebral and gastric mucosa, SOD activity were markedly decreased, cerebral water content were markedly increased; Rsv in neuron and gastric parietal cell, Vv in gastric parietal cell both were markedly decreased (P<0.05 or P<0.01). ASU was only observed in group B (the incidence was 30%, ulcer index was 15). It was not observed in other groups. Compared with group B, MDA content were significantly decreased, and SOD activity were significantly increased in serum, cerebral and gastric mucosa in groups C and D, cerebral water content in group C were dramatically decreased (all P<0.01), but these were not statistically different between groups C and D. Rsv and Vv in neuron and gastric parietal cell in groups B, C and D were not statistically different, and serum ET-1 level were not statistically different among the groups (all P>0.05).. Intervention of ET antibody and ET receptor antagonist can both reduce occurrence and development of ASU subsequent to cerebral hemorrhage in rats.

Topics: Animals; Anti-Ulcer Agents; Antibodies; Brain; Cerebral Hemorrhage; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Gastric Mucosa; Male; Malondialdehyde; Peptic Ulcer; Rats; Rats, Sprague-Dawley; Stomach; Superoxide Dismutase

In our study, we examined middle cerebral artery (MCA) contractile responses in two animal models. After hemorrhagic disturbances in rats of Krushinsky-Molodkina strain (KMRs) a decrease in contractile responses to serotonin (5-HT) was observed. During incomplete global cerebral ischemia, MCAs had increased responsiveness to endothelin-1 (ET-1), but reduced responsiveness to serotonin. These findings suggest that cerebral circulation disorders alter cerebrovascular function possibly leading to secondary disturbances in brain circulation.

Topics: Animals; Brain Ischemia; Cerebral Hemorrhage; Cerebrovascular Circulation; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Female; Male; Middle Cerebral Artery; Muscle Contraction; Muscle, Smooth, Vascular; Rats; Rats, Wistar; Serotonin; Vasoconstriction

Recently, the authors showed that thrombin contributes to the formation of brain edema following intracerebral hemorrhage. The current study examines whether the action of thrombin is due to an effect on cerebral blood flow (CBF), vasoreactivity, blood-brain barrier (BBB) function, or cell viability. In vivo solutions of thrombin were infused stereotactically into the right basal ganglia of rats. The animals were sacrificed 24 hours later; CBF and BBB permeability were measured. The actions of thrombin on vasoreactivity were examined in vitro by superfusing thrombin on cortical brain slices while monitoring microvessel diameter with videomicroscopy. In separate experiments C6 glioma cells were exposed to various concentrations of thrombin, and lactate dehydrogenase release, a marker of cell death, was measured. The results indicate that thrombin induces BBB disruption as well as death of parenchymal cells, whereas CBF and vasoreactivity are not altered. The authors conclude that cell toxicity and BBB disruption by thrombin are triggering mechanisms for the edema formation that follows intracerebral hemorrhage.

Topics: Animals; Blood-Brain Barrier; Brain Edema; Cell Death; Cell Membrane Permeability; Cells, Cultured; Cerebral Hemorrhage; Cerebrovascular Circulation; Endothelin-1; In Vitro Techniques; L-Lactate Dehydrogenase; Male; Rats; Rats, Sprague-Dawley; Thrombin; Vasoconstriction

Cerebral hematoma increases cerebrospinal fluid (CSF) endothelin-1 (ET-1). Inhibitors of ET-1 synthesis prevent this increment and hematoma-induced modification of cerebral arteriolar reactivity. We hypothesized that intrathecal ET-1 injection could 1) modify pial arteriolar reactivity similarly to hematoma; 2) increase CSF lysophosphatidic acid (LPA), a potential contributor to altered cerebrovascular reactivity; and 3) reduce the level of adenosine 3',5'-cyclic monophosphate (cAMP) in the CSF. Either ET-1 (10(-7) M) or artificial CSF was injected over the left parietal cortex of newborn pigs. Four days later, cranial windows were implanted. CSF ET was increased from a basal level of 11 fmol/ml to 18 fmol/ml 4 days after ET-1 injection, whereas CSF cAMP was reduced from 2,700 to 950 fmol/ml. The mean diameter of pial arterioles was reduced 31%. In control animals, 10(-12) M ET caused dilation, and higher concentrations induced vasoconstriction. Four days after ET-1 injection topical ET-1 caused constriction instead of dilation at 10(-12) M, and constrictions at higher doses were enhanced. Norepinephrine-induced constrictions were potentiated in the ET-1-injected group. Dilations to cAMP-dependent (but not independent) vasodilators were attenuated after ET-1. The concentration of the vasoconstrictor lipid mediator LPA increased approximately fourfold. Thus intrathecal injection of ET-1 mimics hematoma-induced modification of cerebral vascular reactivity and increase in LPA production. The mechanism(s) of ET-1- and hematoma-induced modifications may involve LPA, which is known to contribute to the loss of dilator responses by inhibition of cAMP product on. The present study further suggests that ET-1 together with LPA could be causing changes in cerebrovascular reactivity following cerebral hemorrhage. ET-1 stimulates the release of LPA from brain parenchyma independent of serum so that LPA could serve as a secondary mediator.

Topics: Animals; Animals, Newborn; Arterioles; Cerebral Hemorrhage; Cerebrovascular Circulation; Cyclic AMP; Endothelin-1; Endothelins; Hematoma; Lysophospholipids; Microcirculation; Swine; Vasoconstriction; Vasodilator Agents

Endothelin-1 (ET-1) has been implicated in hematoma-induced cerebral vasoconstriction and modification of cerebral microvascular reactivity, particularly attenuation of vasodilation to cAMP-dependent dilators and enhanced vasoconstriction to ET-1. We examined effects of the ET-1 antagonist, BQ-123, on hematoma-induced modification of pial arteriolar responses to ET-1 and iloprost, a cAMP-dependent dilator, in vivo, plus the effects of such treatment on the cortical CSF cAMP. Closed cranial windows were implanted in alpha-chloralose anesthetized piglets 4 days following cortical subarachnoid injection of: (1) artificial cerebrospinal fluid (aCSF); (2) autologous blood; (3) BQ-123 alone; or (4) BQ-123 in combination with blood. ET-1 in CSF was significantly elevated from 3 in control to 45 fmol/ml 6 h following hematoma, dropping to 24 fmol/ml at 24 h but remaining above control 4 days later (14 fmol/ml). The mean diameters of pial arterioles were reduced 30% 4 days following blood injection. This reduction was prevented by pretreatment with BQ-123. In the control piglets, pial arterioles dose-dependently dilated to topical application of iloprost with increases in diameter of 10%, 16% and 21% at 10(-12) M, 10(-10) M and 10(-8) M, respectively. Iloprost-induced dilation was attenuated by hematoma to 4%, 9% and 14% at 10(-12) M, 10(-10) M and 10(-8) M, respectively. Treating piglets with BQ-123 along with hematoma on day 1 prevented the hematoma-induced attenuation of pial arteriolar dilation to iloprost on day 4 (14%, 21% and 29% at 10(-12) M, 10(-10) M and 10(-8) M, respectively). Conversely, dilation to sodium nitroprusside (SNP) was not different among the groups. Topical ET-1 dilated pial arterioles at 10(-12) M and produced dose-dependent constriction at higher doses in the control piglets. The dilation at 10(-12) M ET-1 was reversed to constriction 4 days following hematoma and constrictions to higher doses were enhanced. BQ-123 treatment along with hematoma prevented both the loss of low dose dilation and the enhanced vasoconstriction to ET-1. Treatment with BQ-123 alone on day 1 did not affect the dilation to iloprost or constriction to ET-1, 4 days later. The cortical CSF level of cAMP was significantly reduced from 1637 fmol/ml in controls to 294 fmol/ml in piglets with hematoma. Treatment with BQ-123 along with hematoma blocked the reduction in cAMP (3369 fmol/ml). Initial elevation of ET-1 and the subsequent activation of ETA, receptor may play

Topics: Animals; Animals, Newborn; Blood Vessels; Cerebral Arteries; Cerebral Hemorrhage; Cerebrovascular Circulation; Cyclic AMP; Endothelin-1; Hematoma; Iloprost; Nitroprusside; Peptides, Cyclic; Pia Mater; Swine; Time Factors; Vasoconstriction; Vasodilation; Vasodilator Agents

Plasma big endothelin (BE) levels were studied in 17 patients during the first 2 weeks following spontaneous intracerebral hemorrhage (ICH). Three patients had experienced an infratentorial hemorrhage of the pons and cerebellum. The group of 14 patients with supratentorial hemorrhage presented with 8 hematomas of the putamen, 4 of the capsula interna and 2 in the thalamus. Significant elevations of BE during the first 2 weeks after the initial ICH, significant differences between the different localisations and between patients with different prognoses were not apparent (mean BE level: 2.95 +/- 1.39, control group: 2.68 +/- 1.29 fmol/ml). These results support the theory that endothelins do not play a significant pathophysiological role in acute severe ICH.

Topics: Adult; Aged; Cerebral Hemorrhage; Cerebral Ventricles; Endothelin-1; Endothelins; Female; Glasgow Coma Scale; Humans; Hypertension; Male; Middle Aged; Protein Precursors; Radioimmunoassay; Subarachnoid Hemorrhage