Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endothelins (ET) are potent 21-amino-acid vasoconstrictor peptides produced in many different tissues, particularly in the endothelium of blood vessels. ET-1 is the main endothelin secreted by the endothelium, and acts in a paracrine or autocrine fashion on blood vessels by interacting with ETA or ETB receptors on smooth muscle to stimulate contraction or on ETB receptors on endothelial cells to induce the release of vasorelaxants (nitric oxide and prostacyclin). Production of ET-1 is enhanced in several experimental models of hypertension in the rat, such as sodium-sensitive forms, e.g. deoxycorticosterone acetate (DOCA)-salt hypertensive, DOCA-salt-treated spontaneously hypertensive rats (SHR) and Dahl salt-sensitive rats, as well as other models such as stroke-prone SHR, angiotensin II-infused rats and fructose-fed rats, and possibly 1-K 1C Goldblatt hypertensive rats. In contrast, SHR, 2-K 1C Goldblatt hypertensive rats and nitric oxide-deficient (L-NAME-treated) hypertensive rats do not exhibit an ET-1 component. Endothelin dependency is manifested by excessive vascular growth, particularly in small arteries, and blood pressure lowering and regression of vascular growth after treatment with endothelin antagonists. The latter may be combined ETA/ETB or selective ETA antagonists, of which several are orally active and already in clinical development. In humans, endothelin-dependent vascular tone has been shown in studies of forearm blood flow. Enhanced expression of ET-1 mRNA has been demonstrated in the endothelium of small arteries of patients with moderate to severe hypertension. In a 4-week trial the combined ETA/ETB antagonist bosentan reduced the blood pressure of essential hypertensive patients equally to enalapril. Bosentan improved hemodynamics in patients with heart failure in acute and 2-week-long studies. Endothelin antagonists also offer promise in a rapidly fatal condition, primary pulmonary hypertension. Thus, the endothelin system appears to be involved in different forms of cardiovascular disease in experimental animals and humans, and its interruption offers great promise as a new therapeutic intervention in hypertension, heart failure and other diseases.
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PMID:Endothelin and endothelin antagonists in hypertension. 988 74

Endothelin-1 (ET-1) is overexpressed in the vascular wall in certain models of experimental hypertension: deoxycorticosterone acetate salt-treated rats, deoxycorticosterone acetate salt-treated spontaneously hypertensive rats (SHR), stroke-prone SHR, Dahl salt-sensitive rats, angiotensin II-infused rats, and 1-kidney 1 clip Goldblatt rats; it is not overexpressed in SHR, 2-kidney 1-clip hypertensive rats, or L-NAME-treated rats. In hypertensive rats without generalized vascular overexpression, however, expression of ET-1 was often enhanced in intramyocardial coronary arteries, suggesting a role of endothelin in myocardial ischemia in hypertension. In rats overexpressing ET-1, ET(A/B) and ET(A)-selective receptor antagonists lowered blood pressure and reduced vascular growth, particularly in small arteries, beyond what could be attributed to blood pressure lowering, suggesting a direct effect of ET-1 on growth. Hypertensive rats treated with endothelin antagonists are protected from stroke and renal injury. The ET(A/B) antagonist bosentan induced blood-pressure reductions in mildly hypertensive patients similar to those achieved with an angiotensin-converting enzyme inhibitor. Moderately to severely hypertensive patients presented with enhanced expression of prepro-ET-1 mRNA in the endothelium of subcutaneous resistance arteries, suggesting that these stages of hypertension may respond particularly well to endothelin antagonism. Hypertensive patients with coronary artery disease have increased arterial expression of ET-1, and increased plasma levels of immunoreactive endothelin have been described in black patients. ET-1 plays an important role in atherosclerosis, for which hypertension is an important risk factor. Thus, ET-1 may be involved in experimental and human hypertension. Endothelin antagonists may prove effective as disease-modifying agents if they are shown clinically, as they are experimentally, to offer target organ protection and reduce long-term complications of hypertension. This remains to be demonstrated in humans.
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PMID:State-of-the-Art lecture. Role of endothelin-1 in hypertension. 1052 77

The role of endothelins (ET) in blood pressure elevation remains controversial. Data supporting involvement of the ET system in different forms of genetic and experimental hypertension in the rat has appeared in the literature in recent years. Production of endothelin (ET)-1 may be enhanced in several experimental rat models of hypertension. Examples of these exhibiting increased preproendothelin-1 mRNA or peptide in the vasculature include salt-sensitive forms like deoxycorticosterone (DOCA)-salt hypertension, DOCA-salt treated spontaneously hypertensive rat (SHR) and Dahl salt-sensitive rats, and other models like stroke-prone SHR, angiotensin II-infused rats and fructose-fed rats, and possibly 1-kidney 1 clip (1-K 1C) Goldblatt hypertensive rats. SHR, 2-kidney 1 clip (2-K 1C) Goldblatt hypertensive rats and chronic N(omega)-nitro-L-arginine methyl ester (L-NAME)-treated hypertensive rats do not appear to exhibit an ET-1 component. Significant vascular growth, and a hypotensive response and regression of vascular growth after treatment with an ET antagonist demonstrate the endothelin-dependency present in some hypertensive models. Severity of high blood pressure elevation, salt-sensitivity and insulin resistance may be common denominators of involvement of the ET system in hypertension. ET antagonism in hypertension may result in regression of vascular damage, prevention of stroke and renal failure and improvement of heart failure. Whether the same is true in human hypertension remains to be established.
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PMID:Endothelin: role in experimental hypertension. 1097 78

Endothelin-1 (ET-1) is a powerful vasoconstrictor peptide and regulator of blood flow that plays an important role in blood pressure (BP) elevation in some models of experimental hypertension such as DOCA-salt rat, DOCA-salt-treated spontaneously hypertensive rats (SHR), stroke-prone SHR, Dahl salt-sensitive rats, angiotensin II-infused rats, and one-kidney, one-clip Goldblatt rats, but not in SHR, two-kidney, one-clip hypertensive rats, transgenic (mREN2)27 rats, or Nomega-nitro-L-arginine methyl ester chronically treated rats. In those models of hypertension in which ET-1 plays a vasoconstrictor role, ET-1 was shown to be overexpressed in the vessel walls, or BP has been lowered by administration of ET(A/B)- and ET(A)-selective receptor antagonists. In these experimental models, endothelin receptor antagonists also regressed vascular growth and inflammation, and improved endothelial dysfunction. Hypertensive rats treated with endothelin antagonists were protected from stroke and renal injury. In hypertensive rats without generalized vascular overproduction of ET-1, expression of ET-1 was often enhanced in intramyocardial coronary arteries, suggesting a role of ET in myocardial ischemia in hypertension. Moderate-to-severe hypertensive patients presented enhanced expression of pre-proET-1 mRNA in the endothelium of subcutaneous resistance arteries, suggesting that this stage of hypertension may respond particularly well to endothelin antagonism. In some hypertensive patients, exaggerated vascular responses to ET-1 were found. Hypertensive patients with coronary artery disease have increased arterial expression of ET-1. Increased plasma levels of immunoreactive ET have been described in African Americans. ET-1 plays an important role in atherosclerosis, for which hypertension is an important risk factor, and in ischemic heart disease and stroke. Endothelin-1 may also be involved in other forms of vascular disease, including pulmonary hypertension, after angioplasty restenosis, after allograft vasculopathy, and vasculitis. Thus, ET-1 may participate in vascular damage in cardiovascular disease and in BP elevation in experimental models and in human hypertension. Endothelin antagonists could become effective disease-modifying agents in different forms of cardiovascular disease.
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PMID:Role of endothelin-1 in hypertension and vascular disease. 1141 70

The blood pressure lowering effect of a fruit and vegetable-rich diet is a necessary dietary lifestyle measure now included the guidelines for the management of arterial hypertension. Furthermore, flavonoids represent a major class of plant polyphenolics. The present review addresses the antihypertensive effect of quercetin, one of the most abundant flavonoids present in fruits and vegetables, and probably the best studied flavonoid because of its high biological activity. Quercetin has been shown to induce a progressive, dose-dependent and sustained reduction in blood pressure when given chronically in several rat models of hypertension, including spontaneously hypertensive rats, L-NAME-treated rats, DOCA-salt hypertensive rats, two-kidney one-clip Goldblatt rats, rats with aortic constriction and Dahl salt-sensitive hypertensive rats. Quercetin was also effective in reducing blood pressure in rat models of metabolic syndrome, including the obese Zucker rats as well as rats treated with a high-sucrose, high-fat diet. Quercetin also prevented morphological and functional changes in the heart, vessels and kidney, while increasing production of reactive oxygen species associated with hypertension. A high dose of quercetin also reduced blood pressure in stage 1 hypertensive patients in a randomized, double-blind, placebo-controlled, crossover study. Since raised blood pressure is the major cause of stroke as well as an important risk factor for ischemic heart disease, we propose that the blood pressure-lowering effect of quercetin could be an important mechanism contributing to the reduced risk of myocardial infarction and stroke observed with fruit and vegetables-rich diets, and possibly with flavonoid-rich diets.
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PMID:Antihypertensive effects of the flavonoid quercetin. 1930 94


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