Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial cells can produce contracting factors; endothelin, a 21-amino acid peptide, is one of the most potent of these factors, which can control local vascular tone. The peptide is formed from its precursor, big endothelin, via the activity of the endothelin converting enzyme. The basal production of the peptide is stimulated by epinephrine, angiotensin II, arginine vasopressin, transforming growth factor beta, thrombin, interleukin-1 and the calcium ionophore A23187. In vascular smooth muscle cells, endothelin binds to its specific receptor (ETA-receptor and possibly ETB-receptor) which activate phospholipase C and lead to the formation of inositol trisphosphate, diacylglycerol and increased intracellular calcium levels. In certain blood vessels, the endothelin receptor is linked to voltage-operated calcium channels via a Gi-protein. This linkage may explain why calcium antagonists inhibit endothelin-induced contractions in certain, but not other blood vessels. In large conduit arteries, such as the human internal mammary artery, endothelin-induced contractions are primarily mediated by release of intracellular calcium and hence, calcium antagonists do not markedly affect the response. In contrast, in the human forearm circulation, calcium antagonists of different classes do prevent endothelin-induced contractions. Similarly, in mesenteric resistance arteries of the rat, calcium antagonists can reverse endothelin-induced contraction suggesting that calcium antagonists are particularly potent in inhibiting endothelin-induced contraction in resistance arteries, where peripheral vascular resistance and hence, blood pressure is regulated.
 ...
PMID:Endothelin-induced vasoconstriction and calcium antagonists. 128 11

Steroid hormones have been shown to modulate a number of physiological processes in addition to their potent antiinflammatory effects. Endothelin (ET) is a newly discovered vasoconstrictor that is synthesized and released by endothelial cells and acts on adjacent vascular smooth muscle cells by interacting with specific cell surface receptors. Proinflammatory agents such as thrombin and transforming growth factor beta have been shown to up-regulate ET gene expression in vascular endothelial cells. We wondered whether the anti-inflammatory steroids might have any regulatory effect on the ET receptors present in the vascular smooth muscle cells. Rat vascular smooth muscle cells (A-10 cell line, ATCC.CRL 1476) were used as a model system to study the effects of glucocorticoids on ET receptor expression and function. These cells display high density and high affinity ET receptors that belong to the ETA subtype. Pretreatment of these cells with dexamethasone reduced the number of ET receptors by 50-60% without changing the affinity. Of the steroids tested, dexamethasone was most effective followed by prednisolone and hydrocortisone. Aldosterone, a mineralocorticoid, was 5000-fold less potent than dexamethasone. This effect of dexamethasone was dependent on the time of pretreatment and concentration of the steroid used. This down-regulation of ET receptors was also accompanied by an attenuated response to ET-1 in dexamethasone-pretreated cells. The inhibitory effect of dexamethasone was selective for ET receptors because the vasopressin-mediated response was unaffected. In addition, dexamethasone pretreatment of these cells resulted in 50-60% reduction in the steady-state level of ETA receptor mRNA as revealed by Northern analysis. These results suggest that glucocorticoid pretreatment of smooth muscle cells resulted in the down-regulation of the ETA receptor at the mRNA level.
 ...
PMID:Dexamethasone down-regulates the expression of endothelin receptors in vascular smooth muscle cells. 132 58

Endothelial cells produce the 21-amino acid peptide endothelin, which is formed from its precursor, big endothelin, via the activity of converting enzyme. The basal production of the peptide is stimulated by epinephrine, angiotensin II, arginine vasopressin, transforming growth factor beta, thrombin, interleukin-1, and hypoxia. In vascular smooth muscle, endothelin binds to a specific receptor (ETA-subtype), which activates phospholipase C, leads to the formation of inositol trisphosphate, diacylglycerol (which activates protein kinase C), and increased intracellular Ca2+. In certain blood vessels, the endothelin receptor on vascular smooth muscle is linked to a voltage-operated Ca2+ channel via a G-protein. This explains why Ca2+ antagonists inhibit endothelin-induced contractions in certain, but not all, blood vessels. In the human forearm circulation, Ca2+ antagonists do prevent endothelin-induced contractions and unmask endothelin-induced vasodilation mediated by endothelial prostacyclin production (via the ETB-receptor). The pulmonary circulation plays an important role in the metabolism of endothelin, as the lungs take up large quantities of the peptide during passage. Endothelin has profound vasoconstrictor effects in the pulmonary circulation (and also in bronchial tissue), and its production is augmented in pulmonary hypertension. In systemic hypertension, the circulating endothelin levels appear to be normal. In atherosclerosis and other forms of vascular disease, circulating endothelin levels are increased. Thus, endothelin is a potent mediator in the systemic and pulmonary circulation and, in particular, in diseases of the vasculature.
 ...
PMID:Endothelin: systemic arterial and pulmonary effects of a new peptide with potent biologic properties. 133 60

Endothelins (ET-1, ET-2 and ET-3) are a family of 21 amino acid peptides produced by endothelial cells. They are thought to regulate the local vasomotor tone with endothelium-derived relaxing factors. ETs are the most potent vasoconstrictor substances yet identified and veins and renal vasculature are the most sensitive targets. They reduce cardiac output and have positive inotropic and chronotropic effects. ETs increase the secretion of atrial natriuretic peptide (ANP), aldosterone and catecholamines but reduce renal blood flow and glomerular filtration and they also have mitogenic properties. ETs bind to receptors (ETA and ETB), activate phospholipase C, modulate intracellular Ca2+ concentration and open Ca2+ channels. Vasoactive agents (adrenaline, angiotensin, vasopressin, thrombin, endotoxins) and hypoxia stimulate the release of ET and also ET gene expression. Raised concentrations of plasma ET have been found to occur in several clinical conditions such as hypertension, myocardial infarction, cardiogenic shock, pregnancy induced hypertension, arteriosclerosis, Raynaud's disease, subarachnoid haemorrhage, uraemia, ulcerative colitis, Crohn's disease and surgical operations suggesting that ETs have a role in several patophysiological processes.
 ...
PMID:Endothelin peptides: biological activities, cellular signalling and clinical significance. 138 14

In studies of the regulation of parathyroid hormone (PTH) signal transduction, we observed that the peptide endothelin-1 (ET) added prior to PTH greatly increased the calcium transients elicited by PTH in UMR-106 osteosarcoma cells and mouse primary osteoblastic cells. Enhancement by ET also occurred in the presence of EGTA. The ETB receptor-specific agonist sarafotoxin 6c (S6c) likewise enhanced PTH-induced Ca2+ transients. Blocking the ETA receptor-mediated component of the ET signal with BQ123 failed to abolish enhancement of PTH responses by ET. The nonselective ETA/ETB receptor antagonist PD 142893 blocked both ET and S6c-induced enhancement of the PTH responses. Prostaglandin F1 alpha (PGF1 alpha) pretreatment also maximally potentiated PTH responses, whereas alpha-thrombin, epidermal growth factor (EGF), or prostaglandin E1 (PGE1) did not affect the PTH responses. Neither active phorbol ester nor forskolin mimicked the ET effect. The ET effect was not prevented by indomethacin, NG-mono-methylarginine, genistein, pertussis toxin, 4-aminopyridine, tetraethylammonium chloride, okadaic acid, or long-term treatment with phorbol-12,13-dibutyrate. ET pretreatment did not abolish the inhibition of PTH signals by PTH(3-34), although in ET-pretreated cells the suppression of the PTH signal by PTH(3-34) was not as great. ET pretreatment did not enhance the cAMP response to PTH; rather, there was a significant inhibition of the cAMP response. Thus, the calcium signal elicited by PTH is selectively modulated by activation of the ETB receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:EndothelinB receptor activation enhances parathyroid hormone-induced calcium signals in UMR-106 cells. 750 6

Endothelin (ET) isopeptides are synthetized in the kidney and act as local hormones with an impressive number of diverse autocrine and paracrine functions. A variety of proinflammatory and vasoactive agents including thrombin, transforming growth factor beta, angiotensin II as well as mechanical forces enhance the renal synthesis of ET. Two receptor subtypes, ETA and ETB, are widely expressed in the kidney, coupled to multiple intracellular signal transduction pathways that mediate distinct activities. Renal vessels are peculiarly sensitive to the vasoconstrictive effect of ET, which, infused in the kidney, decreases renal blood flow and glomerular filtration rate. This effect, together with the capability of ET to induce contraction and proliferation of mesangial cells, as well as accumulation of mesangial matrix proteins, have suggested that ET may participate in the renal events that lead to renal disease progression. Evidence is now available that renal ET does play a role in the process of progressive renal injury in chronic models of renal disease to the extent that the selective pharmacological manipulation of ET pathway has a major positive impact on the progression of the disease. By contrast, more work is necessary to define the role of ET in the pathophysiology of human glomerulopathy. The recent availability of orally active compounds with potential human use, may hopefully speed progress in the area.
 ...
PMID:Endothelin in the progressive renal disease of glomerulopathies. 756 77

Thrombin-mediated down-regulation of endothelin (ET) receptors was studied in rat glomerular mesangial cells. Overnight incubation of mesangial cells with thrombin (10 nM) resulted in a significant decrease (67%) in the number of ET receptors, with no change in affinity. Northern analysis of the mRNA from these cells showed a corresponding decrease in the ETA receptor message. Such a decrease in ET receptors could result from an increase in ET levels caused by an increase in synthesis and/or a decrease in degradation. It has been previously reported that thrombin stimulates ET production in endothelial and mesangial cells. Because ET is known to be degraded by neutral endopeptidase (NEP), which is present at high levels in the kidney, the potential effects of thrombin on NEP activity were evaluated. There was a decrease of NEP activity in mesangial cells at 16 and 24 hr after treatment with 10 nM thrombin. This effect was specific for thrombin, because NEP activity was not altered after treatment with thrombin in the presence of hirudin, an inhibitor of thrombin activity. The thrombin-mediated decrease in NEP activity correlated with a decrease in NEP protein and mRNA levels, as determined by Western and Northern analyses, respectively. To determine whether the thrombin-mediated decrease in ET receptors had a functional corollary, ET-1-stimulated intracellular calcium mobilization was measured. Overnight incubation with 10 nM thrombin resulted in a significant inhibition of ET-stimulated intracellular calcium mobilization. This effect was specific for ET, because thrombin pretreatment did not affect vasopressin-stimulated intracellular calcium mobilization in mesangial cells. These results indicate that the thrombin-mediated down-regulation of ET receptors is due, in part, to a thrombin-stimulated increase in ET resulting from the down-regulation of NEP and the reported increase in ET synthesis. In addition, pretreatment of mesangial cells with ET-1 caused a significant decrease (85%) in ET receptor number and ET-1-mediated intracellular calcium release (84%), without affecting vasopressin- or thrombin-mediated responses.
 ...
PMID:Thrombin-mediated down-regulation of endothelin receptors in mesangial cells coincides with the down-regulation of neutral endopeptidase activity. 760 55

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.
 ...
PMID:Endothelin and endothelin antagonists: pharmacology and clinical implications. 771 86

Endothelin is a peptide with potent biologic effects in vascular and nonvascular cells. Its effects are mediated by two receptors, ETA and ETB, and possibly also by a third receptor, ETC. In vascular smooth muscle cells, endothelin causes profound contraction and also has proliferative effects, mainly through activation of ETA but also through ETB receptors. Activation of endothelin receptors on vascular smooth muscle explains the profound vasoconstriction observed in isolated blood vessels as well as with infusion of the peptide in vivo. Endothelial cells can express ETB receptors linked to the formation of nitric oxide or prostacyclin. Activation of these receptors leads to the transient vasodilation observed with intravascular infusion of the peptide. In vascular smooth muscle, activation of endothelin receptors stimulates phospholipase C, with concomitant formation of inositol triphosphate and diacylglycerol. These events lead to the release of intracellular calcium and initiation of contraction. In addition, endothelin can activate voltage-operated calcium channels via Gi proteins, thereby increasing influx of extracellular calcium. The later phenomenon may explain the ability of calcium antagonists to inhibit endothelin-induced contractions. Normally, circulating endothelin levels, as well as production of the peptide in isolated blood vessels, are rather low due to the absence of stimuli and the presence of potent inhibitory mechanisms. Important stimulators of endothelin production are thrombin, angiotensin II, arginine vasopressin, and transforming growth factor-beta, as well as certain cytokines and physicochemical factors such as hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Endothelin, endothelin receptors, and endothelin antagonists. 785 Apr 17

To evaluate the role of protein kinase C (PKC) in regulation of cellular responsiveness to mitogens, we used rat 6 (R6) fibroblasts that stably overexpress the beta 1 isoenzyme of protein kinase C (PKC-beta 1). The potent vasoconstrictor and mitogen endothelin-1 (ET-1; 100 nM) was substantially more effective in stimulating InsP3 accumulation in PKC-beta 1-overexpressing fibroblasts (PKC3 cells) than in control fibroblasts lacking the PKC-beta 1 cDNA insert. PKC3 cells were found to express a 7-fold greater number of endothelin receptors than did control cells, whereas both cell lines showed equivalent Kd values. These receptors were of the ETA subtype, as defined by a 1000-fold greater affinity for ET-1 than for ET-3. Changes in intracellular free Ca2+ levels ([Ca2+]i) in response to ET-1 measured with the fluorescent Ca2+ indicator fura-2 showed that ET-1 was more potent and efficacious in stimulating [Ca2+]i in PKC3 cells than in control fibroblasts. The ET-1-induced Ca2+ rise was completely blocked by the selective ETA antagonist BQ123, but only slightly diminished by extracellular application of 2 mM EGTA. In contrast with the effects of PKC-beta 1 overexpression on responsiveness to ET-1, alpha-thrombin, which was previously found to have a weaker effect on InsP3 accumulation in PKC-beta 1-overexpressing cells, was also a less effective stimulator of [Ca2+]i in PKC3 cells than in control cells. These results demonstrate that, although the Ca2+ response to alpha-thrombin is diminished by PKC-beta 1 overexpression, ETA receptor number and cellular responsiveness to ET-1 are increased in PKC-beta 1-overexpressing cells.
 ...
PMID:Endothelin (ETA) receptor number and calcium signalling are up-regulated by protein kinase C-beta 1 overexpression. 836 66


1 2 Next >>