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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The presence of the endothelin isopeptides and endothelin receptors on neurons, glial cells and brain capillary endothelium suggests that endothelins may play a significant role in neuromodulation, astrocytic function and in regulation of cerebral blood flow. Furthermore, endothelins may play a significant role in the central regulation of neuroendocrine and autonomic nervous system functions (i.e., plasma volume, cardiovascular and respiratory control). Endothelin has potent cerebrovascular and proliferative effects suggesting a pathogenic role in cerebrovascular diseases. Endothelin receptors may represent important therapeutic targets for the treatment of both hemorrhagic and ischemic stroke. A review of the available data on endothelin levels and the effects of endothelin antagonists in cerebrovascular diseases is provided in the present report. Most notably is evidence in support of increased brain endothelin levels in hemorrhagic and ischemic stroke both in animal models and in humans. Also, endothelin receptor antagonists exert significant efficacy in animal models of cerebrovascular disease. For example, SB 209670, a rationally designed, potent, nonpeptide endothelin receptor antagonist, exerts therapeutic efficacy in reducing vasospasm following subarachnoid hemorrhage and neuroprotection following ischemic stroke. Certainly the available data warrants further evaluation of novel, selective endothelin receptor antagonists or endothelin converting enzyme inhibitors in cerebrovascular diseases.
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PMID:Therapeutic effects of endothelin receptor antagonists in stroke. 747 39

Diaspirin cross-linked hemoglobin (DCLHb) is a promising hemoglobin-based, oxygen-carrying resuscitative solution. DCLHb (400 mg/kg, iv) produces significant cardiovascular effects, along with an increase in plasma endothelin-1 (ET-1) level, when administered to conscious or anesthetized rats. Present studies were performed to determine whether the cardiovascular effects of DCLHb are due to an increase in the conversion of proendothelin-1 (1-38) (proET-1) to ET-1 by endothelin-converting enzyme (ECE). The regional circulatory and systemic hemodynamic effects of proET-1 (20 micrograms/kg, iv) and DCLHb (400 mg/kg, iv) were determined by using a radioactive microsphere technique in control rats and rats pretreated with phosphoramidon (ECE inhibitor). Administration of proET-1 produced an immediate increase in mean arterial pressure (MAP)(52%) and total peripheral resistance (TPR) (55%); stroke volume (SV) and cardiac output were not affected in the initial phase but were decreased subsequently. Heart rate (HR) was not affected after administration of proET-1. A significant increase in blood flow to the heart (39%), brain (46%), kidneys (74%), portal system (40%), and gastrointestinal tract (GIT) (42%) was also observed after administration of proET-1. Vascular resistance was found to be significantly increased in the mesentery and pancreas (168%) and in the musculoskeletal system (147%) and decreased in the kidneys (-11%) after administration of proET-1. Phosphoramidon (4 mg/kg, iv) pretreatment attenuated the increase in MAP and TPR induced by proET-1. Phosphoramidon pretreatment significantly attenuated the proET-1-induced increase in blood flow to the heart, brain, kidneys, portal system, and GIT. The increase in vascular resistance induced by proET-1 in the mesentery and pancreas and in the musculoskeletal system was also attenuated by phosphoramidon. DCLHb increased MAP (63%) and TPR (54%) without affecting HR. DCLHb increased blood flow to the heart (95%), GIT (45%), portal system (43%), and skin (79%) and increased vascular resistance in the musculoskeletal system (58%). In phosphoramidon-treated rats, DCLHb increased MAP (99%), HR (25%), cardiac output (37%), and TPR (60%). DCLHb increased blood flow to the heart (104%), brain (66%), kidneys (49%), GIT (59%), portal system (63%), and skin (100%) when administered to phosphoramidon-treated rats. Phosphoramidon did not attenuate any of the DCLHb-induced cardiovascular effects. It is concluded that proET-1 increases blood flow to various organs and that phosphoramidon, an ECE inhibitor, could block the proET-1-induced increases in regional blood flow.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Role of endothelin-converting enzyme in the systemic hemodynamics and regional circulatory effects of proendothelin-1 (1-38) and diaspirin cross-linked hemoglobin in rats. 749 May 15

We investigated the upright bicycle exercise cardiopulmonary response in 20 patients with left ventricular dysfunction (LVD, secondary to previous myocardial infarction, left ventricular ejection fraction range 18-44%). Ten patients (48 +/- 7 years) asymptomatic (I NYHA class) without drug treatment (LVD group). The others (n = 10) (50 +/- 1 years) complained of dyspnea and/or fatigue despite therapy (NYHA II-III). They represented the heart failure (HF) group. Eight sedentary men (40 +/- 10 years) served as controls. Controls and patients performed stress testings under drug treatment, when administered. Anaerobic ventilatory threshold (ATge) was considered as an index of submaximal exercise while peak exercise VO2 (Peak VO2) was considered the maximal volitional exercise capacity. The ratio between minute ventilation (VE) to carbon dioxide release (VCO2) (VE/VCO2) was assessed to evaluate the ventilatory response during exercise. We coupled gas exchange assessment (2001, MGC) with noninvasive monitoring of stroke volume (SV) by impedance cardiography (NCCOM3, BOMED) and total systemic vascular resistances (TSVR; by auscultatory blood pressure measurement). In controls VO2 increase during exercise was related to higher heart rate (HR) and SV both from resting to ATge and from this point to the peak. TSVR declined during both steps. In patients with HF VO2 rose from resting to ATge (by faster HR and unchanged SV). VO2 increased slightly from this point to Peak VO2. This result was related to flat HR increase and unchanged SV as well as TSVR. In patients with LVD VO2 increased similarly to controls from resting to ATge and less above the threshold. In these patients both HR and SV increased during submaximal exercise. From ATge to Peak VO2 only HR increased. TSVR declined significantly similarly to controls. The VE/VCO2 ratio was higher at peak exercise in patients with HF compared to controls. Different determinants were demonstrated in patients with left ventricular dysfunction with mild or symptomatic chronic heart failure (CHF). These findings and the increased ventilatory response in patients with CHF can explain different changes of VO2 in these patients during submaximal and maximal voluntary exercise and contribute to explain exercise-induced exertion in these subjects.
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PMID:Cardiopulmonary exercise response in patients with left ventricular dysfunction or heart failure: a noninvasive study by gas exchange and impedance cardiography monitoring. 865 32

Endothelins are ubiquitously produced 21-amino-acid peptides that were discovered as an endothelial product and may play important roles in cardiovescular physiology and pathophysiology. The main endothelin produced by the endothelium is endothelin-1. The vasoconstrictor role of endothelins may participate in blood pressure elevation and vascular hypertrophy in salt-dependent models of hypertension (deoxycorticosterone acetate-salt hypertensive rats, spontaneously hypertensive rats treated with deoxycorticosterone, acetate and salt, and Dehl salt-sensitive rats), and in stroke-prone spontaneously hypertensive rats. In humans, endothelins may play important roles in moderate to severe essential hypertension, and in the hypertension of African-Americans. Endothelins may be involved in cardiac hypertrophy, and there is increasing evidence of their participation in heart failure, in which acute endothelin antagonism in humans exerts beneficial effects. Endothelin expression is enhanced in smooth muscle cells migrating into the intima of arteries in atherosclerosis, suggesting a role in atherogenesis. Endothelin may participate as a vasoconstrictor in coronary artery disease, and as a contributor to intimal proliferation in restenosis after coronary angioplasty. In patients with myocardial infarction, cardiac production of endothelin is increased, particularly in those with cardiogenic shock. There is a potential for participation of endothelins in vasospasm accompanying stroke or subarachnoid hemorrhage: in the latter, endothelin antagonism has shown beneficial effects in experimental models. In neonatal and in primary pulmonary hypertension, endothelin expression is enhanced, and in experimental models endothelin antagonism resulted in favorable responses. Systemic sclerosis is another, peripheral, form of vascular disease in which endothelin may play a role and in which endothelin antagonism may be an interesting therapeutic alternative. The pathophysiologic role of endothelins is becoming increasingly apparent in cardiovascular disease, generating interesting potential therapeutic targets for the use of endothelin antagonists or endothelin-converting enzyme inhibitors.
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PMID:Clinical significance of endothelin in cardiovascular disease. 926 47

Endothelins (ET) are 21-aminoacid peptides produced ubiquitously, which were discovered originally as endothelial products. These peptides may play important roles in cardiovascular physiology and pathophysiology. As the pathophysiologic roles of endothelins in cardiovascular disease become increasingly apparent, the potential therapeutic use of endothelin antagonists or endothelin converting enzyme inhibitors is recognized. The main endothelin produced by the endothelium is ET-1. Endothelin-1 is overexpressed in the vascular wall of salt-dependent models of hypertension, such as DOCA-salt hypertensive rats, DOCA-salt-treated spontaneously hypertensive rats (SHR) and Dahl salt-sensitive rats, and in stroke-prone SHR, angiotensin II-infused rats and 1-kidney 1 clip Goldblatt hypertensive rats, but not in SHR, 2-K 1C hypertensive rats or L-NAME-treated rats. The vasoconstrictor effect of ET-1 may contribute to blood pressure elevation and its growth-promoting action to vascular hypertrophy in the hypertensive models which overexpress ET-1 in blood vessels. In rats without generalized activation of the endothelin system, expression of ET-1 is often enhanced in coronary arteries, which suggests a role for ET-1 in myocardial ischemia in hypertension. In rats overexpressing ET-1, ETA/B and ETA-selective antagonists lowered blood pressure slightly, and significantly reduced vascular growth, particularly of small arteries, suggesting that ET-1 has a direct effect on growth. Protection from renal injury and from stroke has also been demonstrated in hypertensive rats treated with endothelin antagonists. In normotensive human subjects endothelin-dependent tone can be shown in the forearm. In a study of mild hypertensive patients, the ETA/B antagonist bosentan reduced blood pressure similarly to an ACE inhibitor. Moderate to severe hypertensive patients presented enhanced expression of ET-1 mRNA in the endothelium of subcutaneous resistance arteries. In blacks with familial hypertension increased plasma levels of endothelin have been found. Thus, ET-1 may play a role in some experimental hypertensive models and in human hypertension. In summary, endothelial ET-1 may be overexpressed in the more severe forms of hypertension, and in certain special populations which may respond particularly well to endothelin antagonism. Endothelin antagonists may prove to be effective disease-modifying agents if in future clinical trials they are shown clinically to blunt vascular growth and endothelial dysfunction, reduce stroke and exert the cardioprotective and renal protective effects already reported in experimental hypertension. These agents could contribute to reduce the long-term complications of hypertension, which remains to be demonstrated in humans.
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PMID:Endothelin: role in hypertension. 983 May 7

Melatonin has previously been shown to be neuroprotective in rodent models of ischemic stroke. Herein, we tested whether this antioxidant may also be suitable for prophylactic use against stroke. To clarify this issue, melatonin was administrated orally for 9 wk (4 mg/kg/day) in mice and its effects on subsequent injury development after 90 min of intraluminal middle cerebral artery (MCA) occlusion were tested. To evaluate its neuroprotective properties, the protective actions of prophylactic melatonin were compared with both acute melatonin (4 mg/kg, i.p.) administration and with a diluent (sham)-treated control condition. MCA occlusion resulted in reproducible ischemia, as revealed by laser Doppler flowmetry; this was followed by a rapid restoration of blood flow immediately after reperfusion onset. Laser Doppler flow values after reperfusion onset were moderately elevated by melatonin, both when the indole was given prophylactically and when acutely administrated after stroke. In control animals, reproducible brain infarcts were observed 24 hr after reperfusion onset. Treatment with melatonin significantly reduced the infarct size by approximately 30-35%, independent of whether the indole was given prophylactically before or acutely after ischemia. To test whether brain protection involved vascular mechanisms, as suggested earlier, the effects of melatonin on endothelin converting enzyme-1 (ECE-1) levels were studied using Western blots. Interestingly, delivery of melatonin was accompanied by a marked inhibition of ECE-1 levels, which was similarly seen after both acute and chronic melatonin treatment. Our data suggest that melatonin, given at pharmacological doses, may be suitable as a prophylaxis against stroke. Tissue protection may involve an inhibition of ECE-1, which improves vasodilation, after ischemia.
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PMID:Prophylactic use of melatonin protects against focal cerebral ischemia in mice: role of endothelin converting enzyme-1. 1548 50

Alzheimer's disease (AD) is linked to certain common brain pathologies (e.g., ischemia, stroke, and trauma) believed to facilitate its development and progression. One of the logical approaches to this problem is to study the effects of ischemia and hypoxia on the metabolism of amyloid precursor protein, which plays one of the key roles in the pathogenesis of AD. This involves an analysis of (1) proteases, which participate in proteolysis of amyloid precursor protein either by the nonamyloidogenic route (alpha-secretase) or the amyloidogenic pathway and lead to formation of toxic beta-amyloid peptides (beta- and gamma-secretases) and (2) several metallopeptidases that might play a role in degradation of beta-amyloid peptide (Abeta). The study of the effects of prenatal hypoxia and acute hypoxia in adult animals allowed us to conclude that oxygen deprivation results not only in an increase of amyloid precursor protein expression in the brain but also in a decrease in the activity of alpha-secretase. In some brain structures involved in AD pathology (the cortex and striatum), we also observed a decrease in the expression of two of the Abeta degrading enzymes, neprilysin and endothelin-converting enzyme, after hypoxia. A decrease in expression of these metalloproteases was also observed in the model of four-vessel occlusion ischemia in rats with their restoration to the control levels after reperfusion. Preconditioning to mild hypoxia both in the prenatal period and in adults appeared to have a neuroprotective effect restoring, in particular, the levels of amyloid precursor protein, activity of alpha-secretase, and expression of neprilysin and endothelin-converting enzyme to their control values.
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PMID:Effect of hypoxia/ischemia and hypoxic preconditioning/reperfusion on expression of some amyloid-degrading enzymes. 1568 98

Endothelin-1 has been shown to aggravate the ischemic-reperfusion injury in the neocortex of rats. The purpose of this study was to examine the effect of an endothelin-converting enzyme inhibitor, CGS 26303, on neurological deficit, infarct size, and extent of edema after transient occlusion of the middle cerebral artery and bilateral common carotid arteries (triple vessel occlusion) in rats. In the pretreatment study, male Sprague-Dawley rats underwent a 90-minute triple vessel occlusion, and CGS 26303 was administered intravenously 30 minutes before triple vessel occlusion. The compound was subsequently administered at 6, 12 and 18 hours post-triple vessel occlusion, and neurological status was evaluated 1, 12 and 24 hours after triple vessel occlusion. Animals were sacrificed at 24 hours post-triple vessel occlusion, brains were perfusion-fixed, and infarct areas and brain swelling were determined. Total infarct areas were reduced when compared with vehicle-treated animals by 48%, 50%, and 57% in rats receiving CGS 26303 at 1, 3, and 10 mg/kg, respectively, while the neurological score was significantly improved in the highest-dose CGS 26303-treated group. In another study, CGS 26303 treatment was initiated 1 hour after triple vessel occlusion. Total infarct areas were reduced by an average of 42-50% in the CGS 26303 treatment group. Neurological scores of animals treated with CGS 26303 at 10 mg/kg were decreased by 59% and 45% upon evaluation at 12 and 24 hours post-triple vessel occlusion, respectively. These results demonstrate that CGS 26303 may have potential for the treatment of focal ischemic stroke.
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PMID:Neuroprotective effect of CGS 26303, an endothelin-converting enzyme inhibitor, on transient middle cerebral artery occlusion in rats. 1583 55

In recent years endothelin-converting enzyme (ECE-1) has been suggested to play an important role in amyloid-beta peptide metabolism as one of the amyloid-degrading enzymes. In this connection, the analysis of the levels of expression and distribution of ECE-1 in the brain under normal and pathologic conditions could be important in neurodegeneration and pathogenesis of Alzheimer disease. In our previous studies, we have demonstrated that expression of ECE-1 was significantly reduced in the cortex of adult rats after 15 mins of global ischemia. It was also significantly reduced in the striatum of rats subjected to prenatal hypoxia. In the present study, we analyzed effects of hypoxia and oxidative stress on ECE-1 in human neuroblastoma NB7 cells and effects of the cholinergic agonist carbachol and the phorbol ester, phorbol 12-myristate 13-acetate (PMA). We have found that chronic (24 hrs) hypoxia and oxidative stress resulted in 30% and 20% decrease in expression of ECE-1 at the protein level, respectively, although at the level of ECE-1 mRNA there were no statistically significant changes. Serum withdrawal from the incubation medium as well as addition of carbachol or PMA for 24 hrs also led to a significant reduction of the levels of ECE-1 protein in NB7 cells. Further study of the downstream signaling cascades involved in downregulation of ECE expression in NB7 cells and primary neuronal cells might provide us with new insights into possible therapeutic strategies for prevention or treatment of Alzheimer disease in elderly patients and those who suffer from stroke or cerebrovascular disorders.
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PMID:Regulation of endothelin-converting enzyme-1 expression in human neuroblastoma cells. 1674 Oct 47

Homeostasis of the brain is dependent on the blood-brain barrier (BBB). This barrier tightly regulates the exchange of essential nutrients and limits the free flow of immune cells into the CNS. Perturbations of BBB function and the loss of its immune quiescence are hallmarks of a variety of brain diseases, including multiple sclerosis (MS), vascular dementia, and stroke. In particular, diapedesis of monocytes and subsequent trafficking of monocyte-derived macrophages into the brain are key mediators of demyelination and axonal damage in MS. Endothelin-1 (ET-1) is considered as a potent pro-inflammatory peptide and has been implicated in the development of cardiovascular diseases. Here, we studied the role of different components of the endothelin system, i.e., ET-1, its type B receptor (ET(B)) and endothelin-converting enzyme-1 (ECE-1) in monocyte diapedesis of a human brain endothelial cell barrier. Our pharmacological inhibitory and specific gene knockdown studies point to a regulatory function of these proteins in transendothelial passage of monocytes. Results from this study suggest that the endothelin system is a putative target within the brain for anti-inflammatory treatment in neurological diseases.
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PMID:Brain endothelial barrier passage by monocytes is controlled by the endothelin system. 2177 46


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