Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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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.
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PMID:Endothelin-induced vasoconstriction and calcium antagonists. 128 11

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.
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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.
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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)
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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.
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PMID:Endothelin in the progressive renal disease of glomerulopathies. 756 77

Endothelin-1, a potent vasoconstrictor of cerebral vessels, is produced by rat primary astrocytes and is subject to autostimulatory regulation in these cells. In this study we examined the effect of thrombin on astrocytic endothelins and report that endothelin-1 is released into the culture fluid in response to thrombin treatment. However, increased production of endothelin-1 is not accompanied by a concomitant increase in steady-state levels of endothelin-1 mRNA as assessed by reverse transcriptase-polymerase chain reaction, even though thrombin stimulation leads to increased inositolphospholipid turnover and activation of the nuclear factor AP1. Thus, astrocytic production of endothelin-1 may be mainly post-transcriptionally regulated in response to thrombin stimulation. In addition, two endothelin receptor genes (ET(A) and ETB) were found to be transcribed simultaneously in primary astrocyte cultures, and both thrombin and endothelin-1 stimulation result in a distinct temporary decrease in ET(A) mRNA. These studies suggest a role for thrombin in the regulation of brain perfusion through astrocytic endothelin-1 expression.
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PMID:Thrombin is a regulator of astrocytic endothelin-1. 767 2

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

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)
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PMID:Endothelin, endothelin receptors, and endothelin antagonists. 785 Apr 17

The presence of endothelin (ET) receptors and the nature of the subtype and expression of ET were investigated in the human megakaryoblastic cell line MEG-01. By the RT-PCR procedure, we have shown that both ETA and ETB receptor subtype mRNAs are expressed in the cells. However, binding experiments have shown that the selective ETB receptor antagonist BQ788, but not the selective ETA receptor antagonist BQ123, competes with the specific binding of [125I]ET-1. Using immunocytochemistry, RIA, and RT-PCR Southern blot, we have shown that MEG-01 cells express ET-1. In addition, ET (1-21)-like immunoreactivity was released from the cells into the culture medium, and this release was modulated by thrombin. These data suggest that an ET-1-mediated autocrine loop could occur in the human megakaryoblastic MEG-01 cell line.
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PMID:Expression of endothelin and ETB receptors in the megakaryoblastic MEG-01 cell line. 858 50

The role of endothelin (ET) receptors in thrombin-induced modulation of vascular tone was evaluated by direct measurement of ET-1 and ET receptor-coupled nitric oxide (NO) release and developed isometric tension in thrombin-treated aortic rings. Here we report that rapid release of ET-1 and subsequent ETB receptor activation are required for production of the potent vasodilator NO by thrombin-stimulated aorta. Thrombin-induced NO release is ablated by pretreatment with ETB receptor antagonists or after ET receptor desensitization by repeated stimulation with ET-1. Thrombin-induced relaxation of precontracted vessels was abrogated in the presence of ETB receptor antagonists and, in contrast, marked contraction to thrombin was observed. These data indicate that the endothelium-dependent vasodilator activity previously attributed to thrombin is indirect and requires ETB receptor-coupled NO release and suggest that ET receptor modulation of thrombin-induced vascular tone may contribute to the increased vasomotor tone observed in diseased and mechanically injured vessels.
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PMID:Thrombin-induced vascular reactivity is modulated by ETB receptor-coupled nitric oxide release in rat aorta. 884 23


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