Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelins (ET) are a family of peptides with potent biological properties. Endothelial cells produce exclusively ET-1 while other tissues produce ET-2 and ET-3. The production of ET requires an increase in intracellular Ca2+. This increase can be induced by physical chemicals (i.e. hypoxia) or receptor-operated stimuli (i.e. thrombin, angiotensin II, arginine vasopressin, transforming growth factor beta 1, interleukin-1). Most of ET is released abluminally towards vascular smooth muscle and less luminally. The main vascular effect of ET are vasodilation (transient), profound and sustained vasoconstriction as well as proliferation of vascular smooth muscle. These biological effects are mediated by distinct receptors. Three ET receptors have been cloned, i.e. ETA-, ETB- and ETC-receptors. In vascular tissue ETA-receptors are expressed on vascular smooth muscle and responsible for vasoconstriction. ETB-receptors are expressed on endothelium and linked to nitric oxide and/or prostacyclin release. Activation of these receptors explains the transient vasodilation with intraluminal application of ET. Vascular smooth muscle cells can express ETB-receptors which contribute to ET-induced vasoconstriction particularly at lower concentrations. The role of the recently cloned ETC-receptor in the vasculature is still uncertain. ET production is increased (as judged from circulating plasma levels) in vascular disease and atherosclerosis in particular, in myocardial infarction and heart failure, pulmonary hypertension and renal disease. ET production is increased in arterial hypertension remains controversial. Non-peptidic ET antagonists have been developed which either block ETA- receptors or ETA- and ETB-receptors simultaneously. The advantage of ETA-receptors is that they leave the endothelium-dependent vasodilation to ET (via ETB-receptor) intact. However, ETB-mediated contraction remains unaffected by these antagonists. In contrast ETA-/ETB-antagonists fully prevent ET-induced vasoconstriction, however, they also inhibit the endothelial effects of the peptide. ET antagonists interfere with the effects of ET in isolated vascular tissue (including that obtained from humans) as well as in vivo. In humans, ETA as well as ETA-/ETB-antagonists inhibit endothelin-induced vasoconstriction. Hence in summary ET are a family of potent peptides with profound effects in the vasculature. Several studies suggest a role of ET in cardiovascular disease. The newly developed ET-antagonists are potent and selective tools to delineate the (patho-)physiological roles of ET and may become a new class of cardiovascular drugs.
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PMID:Endothelin and endothelin antagonists: pharmacology and clinical implications. 771 86

Prolonged incubation with 1 nmol/L interleukin-1 induced high levels of nitric oxide release and cytotoxicity in vascular smooth muscle cells. NG-Monomethyl-L-arginine, an inhibitor of nitric oxide synthesis, inhibited interleukin-1-induced cytotoxicity at a concentration of 3 mmol/L. Furthermore, prolonged incubation with 0.1 mmol/L sodium nitroprusside, a nitric oxide donor, also induced cytotoxicity. On the other hand, endothelin-1 at concentrations from 10(-10) to 10(-7) mol/L induced a concentration-dependent enhancement of cytotoxicity induced by interleukin-1. However, endothelin-1 did not affect interleukin-1-induced nitric oxide production. Coculture study of vascular smooth muscle cells and endothelial cells without direct cell contact revealed that incubation for 72 hours with interleukin-1 induced high levels of nitric oxide release from cocultured vascular smooth muscle cells to the same degree as release from vascular smooth muscle cells alone. However, interleukin-1-induced cytotoxicity was more enhanced in cocultured vascular smooth muscle cells than in vascular smooth muscle cells alone. Furthermore, coincubation with 20 nmol/L BQ-485, an antagonist of one type of endothelin receptor (ETA), prevented the enhancement of interleukin-1-induced cytotoxicity in cocultured vascular smooth muscle cells. These findings suggest that endothelin-1 secreted from endothelial cells may enhance nitric oxide-induced cytotoxicity by means of the ETA receptor in vascular smooth muscle cells.
Hypertension 1995 Apr
PMID:Endothelin-1 enhances nitric oxide-induced cytotoxicity in vascular smooth muscle. 772 26

1. To search for a possible role for endothelin-1 (ET-1) in deoxycorticosterone acetate (DOCA)-salt-induced hypertension, we examined changes in concentration of ET-1 in vascular and renal tissue in DOCA-salt hypertensive rats and evaluated the antihypertensive effect of the ETA receptor antagonist, FR139317. 2. There was an increase in aortic immunoreactive-ET (IR-ET) concentrations in association with hypertension-induced treatment. There were no significant changes in ET-1 levels in the kidney with DOCA-salt treatment. 3. In DOCA-salt hypertensive rats, a significant correlation (r = 0.83, P < 0.01) was found between aortic IR-ET concentrations and systolic blood pressure. 4. High-performance liquid chromatography analysis of the aortic extract from DOCA-salt rats revealed one major component corresponding to the elution position of synthetic ET-1. 5. The intravenous bolus injection of FR139317 (10 mg kg-1) produced a slight decrease in blood pressure in the control rats and in the DOCA-salt hypertensive rat, FR139317 had a more pronounced hypotensive effect. 6. We propose that ET-1 production in vascular tissues is increased in DOCA-salt hypertensive rats. In addition, our study indicates the pathophysiological importance of increased endogenous ET-1 in the maintenance of DOCA-salt-induced hypertension, through interaction of the peptide with ETA receptors.
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PMID:Role of endothelin-1 and the ETA receptor in the maintenance of deoxycorticosterone acetate-salt-induced hypertension. 778 Jun 46

1. The aims of the present study were to characterize the pharmacological profile of a new endothelin (ET) receptor antagonist, TAK-044 and to consider whether it limits the extension of myocardial infarct size in rats. 2. Binding of [125I]-ET-1 to ET receptors on rabbit ventricular and cerebellar membrane fractions was inhibited by TAK-044 with IC50 values of 3.8 nM and 130 nM, respectively. 3. It inhibited ET-1, ET-2 and ET-3-induced vasoconstriction of porcine isolated coronary arteries in a competitive (ET-1, ET-2) and a non-competitive (ET-3) manner. 4. In the rat in vivo, the ET-1-induced blood pressure changes including transient hypotension followed by sustained hypertension, were inhibited by TAK-044 (0.1-10 mg kg-1, i.v.) in a dose-dependent manner. 5. Acute myocardial infarction induced by 1 h coronary occlusion followed by 24 h reperfusion in rats caused an infarct size of 60 +/- 2% (n = 12) of the area-at-risk by weight. 6. Intravenous injection of TAK-044 10 min before coronary occlusion reduced the infarct size in a dose-dependent manner: 32% and 54% reductions at 1 and 3 mg kg-1, respectively. 7. TAK-044 administered 10 min before or 1 h after reperfusion (1 mg kg-1, i.v.) showed similar inhibitory effects: 34% and 23% reductions, respectively. 8. We conclude that TAK-044 is an ETA/ETB receptor antagonist which shows strong inhibitory effects on the extension of myocardial infarct size after coronary artery occlusion-reperfusion in rats.
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PMID:Pharmacology of a non-selective ETA and ETB receptor antagonist, TAK-044 and the inhibition of myocardial infarct size in rats. 778 Jun 49

A comprehensive series of time-related behavioral, physiological and cerebral metabolic studies was conducted using conscious Sprague-Dawley rats to discern the anti-endothelin (ET) properties of the specific ETA receptor antagonist, FR139317. Endothelin-1 (9 pmol given by injection into one lateral ventricle, i.c.v.) produced convulsions, acute arterial hypertension, arterial hyperglycemia, and hyperventilation. Brain structures close to the i.c.v. site of injection, such as the caudate nucleus, lateral septal nucleus, corpus callosum and hippocampal CA3 medial lamellae, as well as 14 other individual structures, displayed moderate-to-intense levels of metabolic activation after endothelin. Data were assessed quantitatively by means of the autoradiographic [14C]deoxyglucose technique combined with image analysis. Neural circuits in the efferent projection paths of the stimulated forebrain structures, such as the midbrain oculomotor complex, amygdaloid nuclei, substantia nigra pars reticulata and caudal subicular subregions of the hippocampal formation, were stimulated focally by endothelin. Specific medullary nuclei and cerebellar cortical subregions displayed high rates of glucose metabolism following endothelin injection at the time of maximum behavioral and physiological stimulation. I.c.v. treatment with > or = 14 nmol FR139317 before endothelin significantly inhibited the effects produced by the peptide. At the highest dose of FR139317 (28 nmol), there was only mild behavioral stimulation following endothelin injection, and hypermetabolic responses in the brain were abolished except in two specific areas of the cerebellar cortex (approx 40% increases in metabolic activity in the copula pyramis and paramedian lobule). The results indicate that the cerebral stimulatory effects of i.c.v. endothelin are mediated by the A type of endothelin receptor. By itself, i.c.v. FR139317 had no effects on the parameters assessed. Further evaluation of FR139317 is warranted as a possible therapeutic agent for neuropathologies suspected of deriving from central neural or vascular stimulation by endothelin, such as aneurysmal vasospasm, ischemia, excitotoxicity, and peptide-mediated epilepsies.
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PMID:FR139317, a specific ETA-receptor antagonist, inhibits cerebral activation by intraventricular endothelin-1 in conscious rats. 786 51

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide originally purified from endothelial cell-conditioned medium. It has multiple biological activities and has been implicated in a number of human diseases, including hypertension and atherosclerosis. Contradictory reports have been published regarding whether ET-1 is a mitogen for vascular smooth muscle cells (SMC); thus, this issue is presently unresolved. In this study, we demonstrate that rat aortic SMC express functional endothelin cell surface receptors but do not proliferate when ET-1 is added to serum-free culture medium on every other day for a period of 1 week. To determine whether ET-1 could function in an autocrine manner to promote SMC growth, we transfected this same cell line with an ET-1 expression plasmid. Several independent lines expressing variable levels of ET-1 mRNA and biologically active ET-1 were obtained. Cell proliferation assays indicated that the transfected SMC line secreting the highest level of ET-1 had an enhanced growth rate when compared with untransfected or vector-alone transfected cells. The growth rate of this SMC line, but not of untransfected cells, was significantly reduced when the ETA receptor subtype-selective antagonist BQ-123 was included in the culture medium. These results indicate that constitutive ET-1 overexpression can promote SMC proliferation. Therefore, it is possible that under certain conditions ET-1 could be an important factor controlling SMC replication in vivo.
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PMID:Constitutive endothelin-1 overexpression promotes smooth muscle cell proliferation via an external autocrine loop. 814 11

Cyclosporin A (CsA) treatment is associated with hypertension and renal dysfunction. Increased circulating endothelin (ET) has been implicated in this renal dysfunction, which is secondary to renal vasoconstriction and decreases in RBF. The effects of the selective blockade of ETA receptors or the combined blockade of ETA and ETB receptors on the acute hemodynamic response to CsA in anesthetized rats were examined. Rats were pretreated with vehicle, BQ-123 (selective ETA receptor antagonist; 0.6 micron/kg per minute), or BQ-123 and PD 142893 (combined ETA/ETB receptor antagonist; 0.6 micron/kg per minute) to achieve both ETA and ETB receptor blockade. After a 10-min pretreatment, CsA (20 mg/kg over 10 min) was administered; mean arterial blood pressure, RBF, and iliac blood flow were monitored continuously. Hemodynamic responses to exogenous endothelin-1 (ET-1, 0.3 and 1 nmol/kg) with and without antagonist pretreatment were measured in separate groups to demonstrate effective receptor blockade. CsA elevated blood pressure 17 to 20% in all three groups; renal resistance maximally increased 23, 20, and 23% in vehicle, BQ-123, and BQ-123 and PD 142893 pretreated groups, respectively. In contrast, the combination of BQ-123 and PD 142893 blocked systemic pressor responses to 0.3 and 1 nmol of ET-1 approximately 50 and 37%, respectively; changes in renal resistance were blocked 81 and 89%, respectively. In conclusion, the elevation in systemic blood pressure and the renal vasoconstrictor activity of CsA do not appear to be mediated through ETA or ETB receptors.
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PMID:Effects of selective endothelin antagonists on the hemodynamic response to cyclosporin A. 816 26

The vasoactive peptides endothelin-1 (ET-1) and angiotensin-II (AII) have been implicated in chronic hypertension and may play important roles in related vascular diseases such as restenosis and atherosclerosis. Using a rat aortic smooth muscle (RASM) cell model, both ET-1 and AII induced concentration-dependent delayed increases in DNA synthesis relative to that in the serum-deprived controls. Stimulation of DNA synthesis was maximal at 100 nM for each peptide. All treatment of RASM cells resulted in a greater mitogenic effect (4- to 7-fold) than that observed for ET-1 (3-fold). When added in the presence of AII, ET-1 had a supplemental effect on DNA synthesis (5- to 10-fold above control). Although RASM cells expressed both ETA and AT1 receptors, radioligand binding experiments indicated that approximately 10-fold as many AT1 receptors as ETA receptors were present. In signal transduction studies, ET-1 and AII each elicited concentration-dependent increases in the intracellular Ca2+ concentration. ET-1 and AII also stimulated phosphoinositide metabolism and phosphorylation of a specific substrate for protein kinase-C. The release of total inositol phosphates in response to ET-1 and AII was concentration dependent and inhibited by the ETA receptor-selective antagonist BQ-123 and the AT1 receptor-selective antagonist losartan, respectively. In addition, tyrosine phosphorylation of 120- and 75-kilodalton proteins as well as the mitogen-activated protein kinases p44mapk and p42mapk was observed within 5 min of the addition of either ET-1 or AII. Taken together, these data indicate that ET-1 and AII may promote smooth muscle cell growth through common intracellular signaling mechanisms.
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PMID:Endothelin-1 and angiotensin-II stimulate delayed mitogenesis in cultured rat aortic smooth muscle cells: evidence for common signaling mechanisms. 817 Apr 71

The existence of vasoconstrictive factors originating from the endothelium was confirmed by the description of endothelin, a 21-amino-acid peptide derived from a series of precursors, preproendothelin and a 38-amino-acid big endothelin. Three isoforms of endothelin, endothelin-1, -2 and -3, and 3 receptors (ETA, ETB and ETC) have been described and cloned. The cellular mode of action of endothelin seems to involve the modulation of intracellular calcium (through inositol trisphosphate, diacylglycerol and phospholipase C) and activation of calcium channels. The effects of endothelin are predominantly on the cardiovascular system. Its major effect is vasoconstriction, both systemic and pulmonary, with additional positive chronotropic and inotropic effects on the heart. It has also been implicated in homeostatic regulation of kidney microcirculation, and has powerful mitogenic effects on fibroblasts and smooth muscle cells. Many additional effects have been described on the endocrine system and on other systems. However, the clinical relevance of such effects is uncertain. Increased plasma endothelin levels have been reported in many diseases, but as yet it is not certain whether they are a cause or a consequence of the pathology. Pathologies most probably related to endothelin dysfunction are the vasospastic diseases, especially vasospasm after subarachnoid haemorrhage. Endothelin could be implicated to a lesser measure in diseases typical of the elderly population, such as hypertension or atherosclerosis. Drugs are being developed which act on endothelin metabolism, the most promising of which appear to be the inhibitors of endothelin converting enzyme and endothelin receptor antagonists. Some already existing drugs, such as calcium channel blockers or angiotensin converting enzyme inhibitors, probably act at least in part by interfering with endothelin metabolism or effects.
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PMID:Endothelins. A potential target for pharmacological intervention in diseases of the elderly. 819 96

To determine whether endothelin (ET) has a role in maintaining circulatory support during hypotensive hemorrhage, we (1) examined cardiac and systemic hemodynamics after a 6-mL hemorrhage in the presence and absence of the ETA receptor blocker BQ-123, (2) examined cardiac and systemic hemodynamics during BQ-123 infusion in nonhemorrhaged rats, (3) measured changes in circulating immunoreactive endothelin (IR-ET) after a 6-mL hemorrhage, and (4) infused pathophysiological doses of ET-1 into rats anesthetized with thiobutabarbital. Twenty minutes after hemorrhage, cardiac output and mean arterial pressure had stabilized in part because of an increase in systemic vascular resistance from 0.86 +/- 0.04 (baseline) to 1.04 +/- 0.05 (20 minutes) mm Hg/mL per minute. The rise in systemic vascular resistance was temporally associated with a significant (24%) increase in circulating IR-ET from 29 +/- 2 to 36 +/- 3 pg/mL 20 minutes after hemorrhage. During BQ-123 infusion mean arterial pressure at 5, 10, and 20 minutes after hemorrhage was 9 +/- 2, 23 +/- 4, and 23 +/- 3 mm Hg lower than values obtained after hemorrhage alone (P < .05). Mean arterial pressure was unaffected by BQ-123 infusion at baseline and 30 minutes after hemorrhage. Systemic vascular resistance was not affected at baseline by BQ-123 infusion. However, systemic vascular resistance was significantly lower 5, 10, 20, and 30 minutes after hemorrhage during BQ-123 infusion compared with hemorrhage alone at each time point. Infusion of BQ-123 into nonhemorrhaged rats had no effect on mean arterial pressure, systemic vascular resistance, or cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1994 Feb
PMID:Endothelin blockade lowers total peripheral resistance in hemorrhagic shock recovery. 830 30


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