endothelin-1 and Cerebrovascular-Disorders

Valid experimental models and behavioral tests are indispensable for the development of therapies for stroke. The translational failure with neuroprotective drugs has forced us to look for alternative approaches. Restorative therapies aiming to facilitate the recovery process by pharmacotherapy or cell-based therapy have emerged as promising options. Here we describe the most common stroke models used in cell-based therapy studies with particular emphasis on their inherent complications, which may affect behavioral outcome. Loss of body weight, stress, hyperthermia, immunodepression, and infections particularly after severe transient middle cerebral artery occlusion (filament model) are recognized as possible confounders to impair performance in certain behavioral tasks and bias the treatment effects. Inherent limitations of stroke models should be carefully considered when planning experiments to ensure translation of behavioral data to the clinic.

Topics: Animals; Brain Ischemia; Cell- and Tissue-Based Therapy; Cerebrovascular Disorders; Disease Models, Animal; Endothelin-1; Psychomotor Disorders; Rats

The purpose of this study was to investigate the significance of circulating micro RNAs (miRNAs) in the pathogenesis of reversible cerebral vasoconstriction syndrome (RCVS).. We prospectively recruited 3 independent cohorts of patients with RCVS and age-matched and sex-matched controls in a single medical center. Next-generation small RNA sequencing followed by quantitative polymerase chain reaction (PCR) was used to identify and validate differentially expressed miRNAs, which was cross-validated in migraine patients in ictal stage or interictal stage. Computational analysis was used to predict the target genes of miRNAs, followed by in vitro functional analysis.. We identified a panel of miRNAs including miR-130a-3p, miR-130b-3p, let-7a-5p, let-7b-5p, and let-7f-5p that well differentiated patients with RCVS from controls (area under the receiver operating characteristics curve [AUC] was 0.906, 0.890, and 0.867 in the 3 cohorts, respectively). The abundance of let-7a-5p, let-7b-5p, and let-7f-5p, but not miR-130a-3p nor miR-130b-3p, was significantly higher in patients with ictal migraine compared with that of controls and patients with interictal migraine. Target prediction and pathway enrichment analysis suggested that the transforming growth factor-β signaling pathway and endothelin-1 responsible for vasomotor control might link these miRNAs to RCVS pathogenesis, which was confirmed in vitro by transfecting miRNAs mimics or incubating the patients' cerebrospinal fluid (CSF) in 3 different vascular endothelial cells. Moreover, miR-130a-3p was associated with imaging-proven disruption of the blood-brain barrier (BBB) in patients with RCVS and its overexpression led to reduced transendothelial electrical resistance (ie, increased permeability) in in vitro human BBB model.. We identified the circulating miRNA signatures associated with RCVS, which may be functionally linked to its headache, BBB integrity, and vasomotor function. ANN NEUROL 2021;89:459-473.

Topics: Adult; Blood-Brain Barrier; Capillary Permeability; Case-Control Studies; Cerebrovascular Disorders; Circulating MicroRNA; Computer Simulation; Electric Impedance; Endothelial Cells; Endothelin-1; Female; High-Throughput Nucleotide Sequencing; Human Umbilical Vein Endothelial Cells; Humans; In Vitro Techniques; Male; MicroRNAs; Middle Aged; Migraine Disorders; Reproducibility of Results; Sequence Analysis, RNA; Transforming Growth Factor beta; Vasoconstriction; Vasomotor System

Serum biomarkers are associated with hemorrhagic transformation and brain edema after cerebral infarction. However, whether serum biomarkers predict hemorrhagic transformation in large vessel occlusion stroke even after mechanical thrombectomy, which has become widely used, remains uncertain. In this prospective study, we enrolled patients with large vessel occlusion stroke in the anterior circulation. We analyzed 91 patients with serum samples obtained on admission. The levels of matrix metalloproteinase-9 (MMP-9), amyloid precursor protein (APP) 770, endothelin-1, S100B, and claudin-5 were measured. We examined the association between serum biomarkers and hemorrhagic transformation within one week. Fifty-four patients underwent mechanical thrombectomy, and 17 patients developed relevant hemorrhagic transformation (rHT, defined as hemorrhagic changes ≥ hemorrhagic infarction type 2). Neither MMP-9 (no rHT: 46 ± 48 vs. rHT: 15 ± 4 ng/mL, P = 0.30), APP770 (80 ± 31 vs. 85 ± 8 ng/mL, P = 0.53), endothelin-1 (7.0 ± 25.7 vs. 2.0 ± 2.1 pg/mL, P = 0.42), S100B (13 ± 42 vs. 12 ± 15 pg/mL, P = 0.97), nor claudin-5 (1.7 ± 2.3 vs. 1.9 ± 1.5 ng/mL, P = 0.68) levels on admission were associated with subsequent rHT. When limited to patients who underwent mechanical thrombectomy, the level of claudin-5 was higher in patients with rHT than in those without (1.2 ± 1.0 vs. 2.1 ± 1.7 ng/mL, P = 0.0181). APP770 levels were marginally higher in patients with a midline shift ≥ 5 mm than in those without (79 ± 29 vs. 97 ± 41 ng/mL, P = 0.084). The predictive role of serum biomarkers has to be reexamined in the mechanical thrombectomy era because some previously reported serum biomarkers may not predict hemorrhagic transformation, whereas the level of APP770 may be useful for predicting brain edema.

Topics: Aged; Aged, 80 and over; Amyloid beta-Protein Precursor; Biomarkers; Brain Edema; Cerebral Infarction; Cerebrovascular Disorders; Claudin-5; Endothelin-1; Female; Gene Expression; Humans; Male; Matrix Metalloproteinase 9; Predictive Value of Tests; Prospective Studies; S100 Calcium Binding Protein beta Subunit; Stroke; Thrombectomy

The effects of cold air on cardiovascular and cerebrovascular diseases were investigated in an experimental study examining blood pressure and biochemical indicators. Zhangye, a city in Gansu Province, China, was selected as the experimental site. Health screening and blood tests were conducted, and finally, 30 cardiovascular disease patients and 40 healthy subjects were recruited. The experiment was performed during a cold event during 27-28 April 2013. Blood pressure, catecholamine, angiotensin II (ANG-II), cardiac troponin I (cTnI), muscle myoglobin (Mb) and endothefin-1 (ET-1) levels of the subjects were evaluated 1 day before, during the 2nd day of the cold exposure and 1 day after the cold air exposure. Our results suggest that cold air exposure increases blood pressure in cardiovascular disease patients and healthy subjects via the sympathetic nervous system (SNS) that is activated first and which augments ANG-II levels accelerating the release of the norepinephrine and stimulates the renin-angiotensin system (RAS). The combined effect of these factors leads to a rise in blood pressure. In addition, cold air exposure can cause significant metabolism and secretion of Mb, cTnI and ET-1 in subjects; taking the patient group as an example, ET-1 was 202.7 ng/L during the cold air exposure, increased 58 ng/L compared with before the cold air exposure, Mb and cTnI levels remained relatively high (2,219.5 ng/L and 613.2 ng/L, increased 642.1 ng/L and 306.5 ng/L compared with before the cold air exposure, respectively) 1-day after the cold exposure. This showed that cold air can cause damage to patients' heart cells, and the damage cannot be rapidly repaired. Some of the responses related to the biochemical markers indicated that cold exposure increased cardiovascular strain and possible myocardial injury.

Topics: Adult; Aged; Air; Angiotensin II; Biomarkers; Blood Pressure; Cardiovascular Diseases; Case-Control Studies; Catecholamines; Cerebrovascular Disorders; Cold Temperature; Endothelin-1; Female; Humans; Male; Middle Aged; Myoglobin; Troponin I

Clinical and experimental evidence suggests that endothelin-1 (ET-1) plays a role in cardiac and vascular disease. In the present study, we investigated the prognostic significance of ET-1 for cerebrovascular and cardiovascular outcome, in a 20-year follow-up.. We studied 82 originally healthy individuals, referred to our Unit of Cardiovascular Prevention, to evaluate the presence of asymptomatic carotid lesions. We subdivided these individuals into two groups, according to the plasma values of ET-1 (respectively ≤ or >2.7 pg/ml). Traditional cardiovascular risk factors were investigated, and by carotid ultrasound examination, we distinguished between normal individuals and those with intima-media thickening or asymptomatic carotid plaque.. Major cardiac and cerebral events (all-cause death, myocardial infarction, revascularization procedures, fatal and nonfatal stroke) were registered in 41 individuals and significantly more in those with high vs. low ET-1 levels (95 vs. 5%; P < 0.0001). Furthermore, by logistic multivariate regression analysis, we found that among all evaluated baseline clinical and laboratory variables, hypertension [odds ratio (OR): 20.4 (3.3-127), P = 0.001], high ET-1 concentrations [OR: 1.4 (1.0-1.8), P = 0.02] and the presence of intima-media thickness or asymptomatic carotid plaque [OR: 3.7 (1.14-12.1), P = 0.02] were independent predictors of future events. Finally, integrating technical and laboratory data, high levels of ET-1 have defined a high risk of major cardiac and cerebral event and stroke at follow-up, which increased in relation to the progression of carotid atherosclerosis (P < 0.05).. ET-1 plasmatic levels significantly influence the cardiovascular and cerebrovascular risk profile, beyond traditional cardiovascular risk factors and preclinical carotid atherosclerosis.

Topics: Adult; Aged; Asymptomatic Diseases; Biomarkers; Cardiovascular Diseases; Carotid Artery Diseases; Carotid Intima-Media Thickness; Cerebrovascular Disorders; Endothelin-1; Female; Follow-Up Studies; Humans; Male; Middle Aged; Plaque, Atherosclerotic; Predictive Value of Tests; Prognosis; Prospective Studies; Risk Factors

To investigate the relationship between interleukin-6 (IL-6), endothelin-1 (ET-1), E-selectin and the risk of cardio-cerebrovascular events.. Based on a cohort study in which 2 589 Mongolians had been followed up for 10 years, a nested case-control study was carried out to analyze the relationship between IL-6, ET-1, E-selectin and the risk of cardio-cerebrovascular events. Logistic regression analysis was used to calculate the odds ratio (OR) and 95% confidence intervals (95%CI).. The average level of IL-6 (7.66 vs. 8.77 pg/ml), ET-1 (0.74 vs. 0.75 pg/ml) and E-selectin (17.96 vs. 18.32 ng/ml)were not significantly different between the case and the control groups (P > 0.05). Data from the logistic regression analysis showed that IL-6, ET-1 and E-selectin were not significantly associated with the risk of cardio-cerebrovascular events. The multivariable adjusted ORs (95%CI) on the risk of cardio-cerebrovascular events were 0.69 (0.41-1.16), 1.10 (0.66-1.85) and 1.19 (0.71-2.00) for the participants with IL-6>23.91 pg/ml, ET-1>1.33 pg/ml and E-selectin>24.43 ng/ml, respectively, compared with those having IL-6≤23.91 pg/ml, ET-1≤1.33 pg/ml or E-selectin≤24.43 ng/ml.. Data from our study indicated that the levels of IL-6, ET-1 and E-selectin at baseline were not significantly associated with the risk of cardio-cerebrovascular events in people from Inner Mongolia.

Topics: Cardiovascular Diseases; Case-Control Studies; Cerebrovascular Disorders; China; Cohort Studies; E-Selectin; Endothelin-1; Humans; Interleukin-6; Odds Ratio; Risk

This study characterized the association between endothelin-1, cerebral hemodynamics, and histopathology after fluid percussion brain injury in the newborn pig.. Lateral fluid percussion injury was induced in newborn pigs equipped with a closed cranial window. Cerebral blood flow was determined with radiolabeled microspheres and cerebrospinal fluid endothelin-1 was measured by radioimmunoassay.. Cerebrospinal fluid endothelin-1 was increased from 26±4 to 296±37 pg/ml (∼10(-10) M) at 8 hours following fluid percussion injury. Post-injury treatment (30 minutes) with the endothelin-1 antagonist BQ-123 (1 mg/kg, intravenous) blocked pial artery vasoconstriction to topical endothelin-1 (∼10(-10) M) and blunted fluid percussion injury-induced reductions in cerebral blood flow at 8 hours post-insult (56±6 and 26±4 ml/minute versus 57±6 and 40± ml/minute; 100 g for cerebral blood flow before injury and 8 hours post-fluid percussion injury in vehicle and BQ-123 post-treated animals, respectively). Fluid percussion injury resulted in neuronal cell loss and decreased microtubule associated protein 2 immunoreactivity in the parietal cortex, which were blunted by BQ-123.. These data indicate that fluid percussion injury-induced changes in cerebral hemodynamics are associated with neuronal damage and that endothelin-1 contributes to fluid percussion injury-induced histopathologic changes.

Topics: Animals; Animals, Newborn; Brain Injuries; Cerebrovascular Disorders; Child; Disease Models, Animal; Endothelin-1; Female; Hemodynamics; Humans; Male; Nerve Degeneration; Sus scrofa

Endothelin-1 is a 21-amino acid peptide that together with specific receptors, A (ETrA) and B (ETrB) is induced following traumatic brain injury (TBI) and has been closely linked to regulation of cerebral vasospasm, oxidative stress, and hypoperfusion. Specific endothelin receptor antagonists have been shown to ameliorate early evidence of neuronal cell injury, activation of microglial cells, and hypoperfusion following TBI. The exact mechanism involved in TBI-induced hypoperfusion is still unclear; however, it is thought that endothelin-1 engagement of ETrA is primarily responsible for changes in blood flow. In this study we question the role of the microvascular pericyte in endothelin-1-mediated pathophysiology in TBI.. Pericyte expression of endothelin-1, ETrA, and ETrB was examined in primary culture and in sham and impacted rat brain. Adult male rats were also given intracerebroventricular injections of ETrA (BQ-123) before being subjected to TBI using a closed head acceleration impact model.. Primary pericytes express both endothelin-1 and its receptors ETrA and ETrB. Following TBI, the number of alpha-smooth muscle actin (SMA) positive pericytes located in microvessels is significantly increased by 4 hours post-traumatic impact. Increases in pericyte expression of alpha-SMA correlated with evidence of a reduction in both arteriolar and capillary diameter. Capillary endothelin-1, ETrA, and ETrB transcript and protein was also increased. Increased endothelin-1 expression was seen by 2-4 hours post-impact. Upregulation of receptors was observed by 4-8 hours and maximum by 24 hours. ETrA antagonists decreased the number of alpha-SMA(+) pericytes as well as changes in microvascular diameter.. These results suggest that decreased vasoconstriction following TBI may be due to an endothelin-1-induced pericyte-mediated regulation of microvessel blood flow following TBI. Furthermore, results suggest that ETrA antagonists ameliorate trauma induced hypoperfusion, in part, by inhibiting endothelin-1-mediated upregulation of alpha-SMA in pericytes.

Topics: Animals; Brain Injuries; Cells, Cultured; Cerebral Arteries; Cerebrovascular Circulation; Cerebrovascular Disorders; Disease Models, Animal; Endothelin-1; Male; Microcirculation; Pericytes; Rats; Rats, Sprague-Dawley; Vasoconstriction

The aim was to test the hypothesis that occlusion of the middle cerebral artery (MCA) results in the development of epilepsy in rats. Further, we investigated whether lesion volume, hippocampal pathology, early seizures, or severity of behavioral impairment is associated with the development and severity of epilepsy or interictal spiking. MCA occlusion was induced by intracerebral injection of endothelin-1 (ET; 120 pmol). One group of ET-injected rats were followed-up for 6 months (n = 15) and another for 12 months (n = 20). Sham-operated animals were injected with saline (n = 12). Occurrence of early and late seizures was monitored by intermittent video-electroencephalography. Sensorimotor function was tested with the running wheel and tapered beam-walking tests. Emotional learning and memory were assessed with the fear conditioning test and spatial learning and memory with the Morris water maze. Finally, brains were processed for histology. Only one rat developed late spontaneous seizures (i.e., epilepsy). Epileptiform interictal spiking was detected in 9 of 26 animals. Early seizures did not predict the development of epilepsy, spiking activity, or severity of behavioral impairment. Production of MCA stroke by intracerebral injection of ET was not a strong trigger of epileptogenesis in adult rats. Further studies are needed to investigate the effect of age, genetic background, and location of ET-injection on the development of hyperexcitability and the risk of post-stroke epileptogenesis.

Topics: Animals; Behavior, Animal; Cerebrovascular Disorders; Conditioning, Psychological; Electrodes, Implanted; Electroencephalography; Endothelin-1; Epilepsy; Follow-Up Studies; Hippocampus; Male; Maze Learning; Middle Cerebral Artery; Rats; Rats, Sprague-Dawley; Seizures; Stroke; Video Recording

A beta peptides are the major protein constituents of Alzheimer's disease (AD) senile plaques and also form some deposits in the cerebrovasculature leading to cerebral amyloid angiopathy and hemorrhagic stroke. Functional vascular abnormalities are one of the earlier clinical manifestations in both sporadic and familial forms of AD. Most of the cardiovascular risk factors (for instance, diabetes, hypertension, high cholesterol levels, atherosclerosis and smoking) constitute risk factors for AD as well, suggesting that functional vascular abnormalities may contribute to AD pathology. We studied the effect of A beta on endothelin-1 induced vasoconstriction in isolated human cerebral arteries collected following rapid autopsies. We report that freshly solubilized A beta enhances endothelin-1 induced vasoconstriction in isolated human middle cerebral and basilar arteries. The vasoactive effect of A beta in these large human cerebral arteries is inhibited by NS-398, a selective cyclooxygenase-2 inhibitor and by SB202190, a specific p38 Mitogen Activated Protein Kinase inhibitor suggesting the involvement of a pro-inflammatory pathway. Using a scanner laser Doppler imager, we observed that cerebral blood flow is decreased in the double transgenic APPsw Alzheimer mouse (PS1/APPsw) compared to PS1 littermates and can be improved by chronic treatment with either NS-398 or SB202190. Altogether, our data suggest a link between inflammation and the compromised cerebral hemodynamics in AD.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cerebral Arteries; Cerebrovascular Circulation; Cerebrovascular Disorders; Cyclooxygenase 2; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Female; Humans; Isoenzymes; Male; Membrane Proteins; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Prostaglandin-Endoperoxide Synthases; Vasoconstriction

We studied the association of endothelin (ET)-1 with carotid atherosclerosis and asymptomatic cerebrovascular lesions in patients with essential hypertension. Neurologically normal patients with essential hypertension (n=293; 138 male, 155 female; mean age, 65 years) and age-matched control subjects (n=242) were studied with B-mode ultrasonography of the common and internal carotid arteries and magnetic resonance imaging of the brain. Plasma ET-1 was measured by enzyme immunoassay. Hypertensive patients were divided into groups with carotid plaques and low ET-1 concentrations (< 0.75 pg/ml; PL group); carotid plaques and mid-range ET-1 (0.75 to 1.55 pg/ml; PM group); carotid plaques and high ET-1 (> or = 1.55 pg/ml; PH group); no plaques and low ET-1 (NPL); no plaques and mid-range ET-1 (NPM); and no plaques and high ET-1 (NPH). Overall, ET-1 concentrations were significantly higher in patients than in control subjects. Carotid plaque prevalence was significantly related to ET-1 in hypertensive patients. ET-1 showed a significant positive relationship with the number of asymptomatic lacunar infarcts of the brain in hypertensive patients with carotid plaques (rho=0.48, p<0.001). No significant relationship was seen between ET-1 and periventricular hyperintensity scores in patients with plaques. ET-1 did not show a relationship to either brain lesion type in patients without carotid plaques. Thus, ET-1 may foster asymptomatic lacunar cerebral infarcts by promoting carotid atherosclerosis in patients with essential hypertension.

Topics: Adult; Aged; Carotid Artery Diseases; Cerebral Infarction; Cerebrovascular Disorders; Endothelin-1; Female; Humans; Hypertension; Intracranial Arteriosclerosis; Magnetic Resonance Imaging; Male; Middle Aged; Osmolar Concentration; Reference Values; Ultrasonography

Diabetes mellitus produces abnormalities of the endothelium and impairs endothelium-dependent dilatation of large and small cerebral blood vessels. However, the effect of diabetes mellitus on cerebral vasoconstriction and the modulatory influence of nitric oxide on cerebral vasoconstriction is unclear. Thus, the first goal of this study was to examine the effect of diabetes mellitus on constrictor responses of the basilar artery in vivo. Our second goal was to examine a potential role for nitric oxide in modulating constrictor responses of the basilar artery. A craniotomy was performed over the ventral medulla to expose the basilar artery. The diameter of the basilar artery was measured using intravital microscopy in nondiabetic and diabetic (3-4 months after injection of streptozotocin; 50-60 mg/kg i.p.) rats in response to angiotensin II, arginine vasopressin, endothelin-1, and the thromboxane analogue, U-46619. Topical application of angiotensin II (10 and 100 nM) produced only minimal changes in diameter of the basilar artery which were similar in nondiabetic and diabetic rats (p>0.05). Arginine vasopressin (0.1 and 1.0 nM), endothelin-1 (10 and 50 nM), and U-46619 (10 and 100 nM) produced marked dose-related constriction of the basilar artery which also was similar in nondiabetic and diabetic rats (p>0.05). Next, we examine whether the synthesis/release of nitric oxide played a role in constriction of the basilar artery in response to the agonists. We found that L-NMMA (1.0 microM) did not alter constrictor responses of the basilar artery in nondiabetic and diabetic rats. Thus, responses of the basilar artery to important vasoactive agonists are not altered by diabetes mellitus. In addition, it does not appear that the synthesis/release of nitric oxide modulates constrictor responses of the basilar artery to angiotensin II, arginine vasopressin, endothelin-1 and U-46619. We suggest that preservation of vasoconstrictor responses, coupled with impaired vasodilator responses, may contribute to the pathogenesis of cerebrovascular abnormalities associated with diabetes mellitus.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin II; Animals; Arginine Vasopressin; Basilar Artery; Blood Pressure; Cerebrovascular Disorders; Diabetes Mellitus, Experimental; Endothelin-1; Enzyme Inhibitors; Male; Muscle, Smooth, Vascular; Nitric Oxide Synthase; omega-N-Methylarginine; Rats; Thromboxanes; Vasoconstriction; Vasoconstrictor Agents

The present study was designed to assess whether the orally active and highly specific endothelin A (ET(A)) receptor antagonist LU 135252 affects progressive renal dysfunction in a hypertensive rat model of renal damage, ie, the uninephrectomized (UNX) stroke-prone spontaneously hypertensive rat (SHRsp). The animals were examined on a normal salt (0.25%) diet and, to sensitize the kidney to hypertensive injury, also on a high salt (3%) diet. Stereological methods were used to quantify indices of glomerulosclerosis, vascular damage, and tubulointerstitial damage. Treatment with LU 135252 (100 mg/kg body wt) did not affect systolic blood pressure (BP) in animals on a normal salt diet during the whole period of the experiment (18 weeks) or in salt-loaded animals until week 10; subsequently, BP was slightly but significantly lower in salt-loaded UNX-SHRsp given LU 135252. Between weeks 6 and 12, 40% of the untreated UNX-SHRsp on a high salt diet, but none on a standard salt diet, died; such mortality was completely prevented by LU 135252. Indices of renal damage were more abnormal in salt-loaded UNX-SHRsp compared with UNX-SHRsp on a normal salt diet. Development of glomerulosclerosis and tubulointerstitial and vascular damage in UNX-SHRsp on high salt was completely prevented by LU 135252. The respective indices were no longer significantly different from those of salt-loaded sham-operated SHRsp controls. In the less severely damaged kidneys of UNX-SHRsp on normal salt, treatment with LU 135252 tended to ameliorate the indices, but the difference was not statistically significant. The results document a role of the ET system, specifically of ET(A) receptors, in the development of progressive renal injury in salt-loaded UNX-SHRsp. LU 135252 completely prevented death and renal damage resulting from salt loading.

Topics: Animals; Blood Pressure; Body Weight; Cerebrovascular Disorders; Endothelin Receptor Antagonists; Endothelin-1; Kidney; Male; Nephrectomy; Phenylpropionates; Pyrimidines; Rats; Rats, Inbred SHR; Receptor, Endothelin A; Sodium, Dietary

In this study, we examined whether endothelin (ET) plays a role in the short-term increase in mean arterial pressure (MAP) after nitric oxide synthase (NOS) inhibition with N(omega)-nitro-L-arginine methyl ester (L-NAME) in stroke-prone spontaneously hypertensive rats (SHRSPs). Experiments were performed by using Inactin-anesthetized male SHRSPs that were pretreated with chlorisondamine to block reflex autonomic cardiovascular effects. Injection of L-NAME (10 mg/kg, i.v.), but not D-NAME, produced rapid and marked increases (74 +/- 3 mm Hg) in MAP that were sustained for >1 h. In SHRSPs that were treated with the ET(A/B) receptor antagonist, L-754,142 (15 mg/kg + 15 mg/kg/h), L-NAME increased MAP by 45 +/- 4 mm Hg (p < 0.0001 compared with L-NAME alone). L-754,142 blocked pressor responses to big ET-1 by >90% but was without effect on pressor responses to norepinephrine. Plasma levels of ET-1 averaged 5 +/- 1 pg/ml in animals given vehicle and were slightly increased in animals given either L-NAME alone (7 +/- 2 pg/ml) or L-754,142 alone (7 +/- 2 pg/ml) but increased markedly when L-NAME and L-754,142 were given together (114 +/- 18 pg/ml). This may relate to an effect of L-754,142 to block ET-receptor-mediated clearance of ET-1. We conclude that ET plays a role in the short-term pressor response after NOS inhibition in SHRSPs.

Topics: Acetamides; Animals; Blood Pressure; Cerebrovascular Disorders; Chlorisondamine; Drug Synergism; Endothelin Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Injections, Intravenous; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Inbred SHR

Topics: Acute Disease; Brain Ischemia; Cerebrovascular Disorders; Endothelin-1; Humans

Recently, we have shown that chronic administration of N-Nitro-L-Arginine Methyl Ester (L-NAME, an inhibitor of nitric oxide synthase) precipitates stroke in stroke-prone spontaneously hypertensive rats (SHRSP). Enalapril maleate, an angiotensin converting enzyme inhibitor was shown to delay the onset of such stroke. In the present study, five groups of 4-week-old SHRSP were used. Three groups of SHRSP were made diabetic using streptozotocin (100 mg/kg i.p.). One week later, the SHRSP from groups I (non-diabetic) and III (diabetic) chronically received L-NAME (0.5 g/L) in saline as drinking water. Two SHRSP groups, II (non-diabetic) and IV (diabetic) received L-NAME (0.5 g/L) and enalapril maleate (20 mg/L) in saline as drinking water. Control SHRSP (group C; diabetic) received only saline to drink. SHRSP groups I and III developed stroke in 10+/-2 and 11+/-2 days, respectively. The average stroke-free period in groups II and IV was 19+/-2 and 28+/-2 days, respectively. Protective effect of streptozotocin-induced diabetes disappeared when SHRSP drinking L-NAME and enalapril, concurrently received subcutaneous injections of insulin (2 units daily per 100 g rat). Present data suggest that experimental diabetes delays the onset of L-NAME-induced stroke in SHRSP only in the absence of angiotensin converting enzyme activity. In addition, diabetes-induced enhancement of stroke-protective effect of enalapril appears to be independent of reduction in mean and systolic blood pressures.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cerebrovascular Disorders; Diabetes Mellitus, Experimental; Enalapril; Endothelin-1; Hypertension; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Inbred SHR; Streptozocin; Weight Gain

Endothelin (ET) receptors, ET-1-like immunoreactivity and nitric oxide synthase (NOS) were examined in the brain of stroke-prone spontaneously hypertensive rats (SHRSPs) with cerebral apoplexy. Our receptor autoradiographic method with 125I-ET-1 and unlabeled selective ligands for ET receptors revealed de novo expressions of ET(A) and ET(B) receptors in areas of neural lesions with cerebrovascular damage in SHRSPs. Immunohistochemical staining for ET-1 showed clear ET-1-like immunoreactivity in areas with highly expressed ET receptors. Histochemical studies on astrocytes and microglia suggested that these glial cells, aggregating in lesions, may carry ET receptors, ET-1-like immunoreactivity. Furthermore, NOS detected histochemically using an NADPH-diaphorase staining method was rich on glial cells in damaged areas of the brain in SHRSPs with cerebral apoplexy. Our data suggest the pathophysiological significance of glial ET(A) and ET(B) receptors, ET-1 and NOS in neural lesions of SHRSPs.

Topics: Animals; Autoradiography; Binding Sites; Brain; Cerebrovascular Disorders; Disease Susceptibility; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Hypertension; NADPH Dehydrogenase; Nitric Oxide Synthase; Peptide Fragments; Peptides, Cyclic; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Endothelin

Endothelin-1 is known to exist in the nervous system. A notable increase of plasma endothelin-1 is associated with acute stroke. This study was designed to measure plasma endothelin-1 levels in Binswanger's disease and explore the relationship between endothelin-1 and this disorder.. Plasma levels of endothelin-1 were-examined by radioimmunoassay in 31 patients with Binswanger's disease and in three groups of control subjects. The ratio of the plasma concentration of endothelin-1 in the internal jugular vein to that in the antecubital vein was calculated as an indicator of endothelin-1 level in cerebral circulation.. Endothelin-1 ratio devation was seen more often in patients with Binswanger's disease than in acute stroke patients. Endithelin-1 ratios were significantly negatively correlated with Hasegawa's Dementia Scale scores is subjects with Binswanger's disease.. Abnormalities is vasoactive factors may make an important contribution to the pathophysiology of Binswanger's disease. Endothelin-1 might be involved in the pathogenesis of this illness.

Topics: Aged; Cerebrovascular Disorders; Dementia, Vascular; Endothelin-1; Female; Humans; Male; Middle Aged

Endothelin-1 is a potent vasoactive peptide which may play a role in the regulation of vascular resistance through its autocrine/paracrine effects. We have investigated the influence of salt loading on the renal and cardiac production of endothelin-1 in stroke prone spontaneously hypertensive rats, a classical model of hypertension. The results show that the dietary salt intake did not change systolic blood pressure nor the renal expression of the preproendothelin-1 mRNA but increased cardiac expression of the endothelin-1 gene transcript and a concomitant ventricular hypertrophy.

Topics: Animals; Blotting, Northern; Cerebrovascular Disorders; Endothelin-1; Endothelins; Genetic Predisposition to Disease; Heart; Kidney; Myocardium; Protein Precursors; Rats; Rats, Inbred SHR; RNA, Messenger; Sodium Chloride