Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01185 (vasopressin)
 23,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The diverse biological actions of endothelins (ET) appear to be mediated by specific cell-surface receptors. Autoradiography and membrane binding studies have shown abundant ET binding sites in the kidney. However, their expression in specific types of renal cells is unclear. We studied the binding of 125I-labelled endothelin-1 in freshly isolated cell suspensions from canine inner medullary collecting duct. Competition binding experiments revealed the presence of specific high-affinity binding sites: unlabelled ET-1 and ET-2 compared with the radioligand with an IC50 of 135 and 83 pM, respectively, while the IC50 of ET-3 and big ET-1 were 2 and 4 orders of magnitude higher, indicating the presence of ETA-type receptor. Angiotensin II, vasopressin, and atrial natriuretic peptide (ANP) did not compete for ET binding even at a concentration of 10(-6) M. Saturation binding experiments showed a single class of binding sites of high density (Bmax = 56.7 +/- 10.3 fmol/10(6) cells) and high affinity (Kd = 69.8 +/- 10 pM). In contrast, ANP receptors in the same cell preparations appeared as two classes of binding sites with widely different affinity and density. The high-affinity ANP site (Kd = 311 +/- 48 pM) was compatible with ANP-B (guanylate cyclase-coupled) receptor. ET-1 did not compete for this receptor. ET-1 (10(-7) M) did not alter ANP-induced cGMP generation in these cells (3.8-fold increase at 10(-7) M ANP), nor basal levels of cGMP.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Specific endothelin binding sites in renal medullary collecting duct cells: lack of interaction with ANP binding and cGMP signalling. 128 83

We have investigated the role of endothelin (ET) in the stimulus-secretion coupling mechanism in the posterior pituitary. We report that isolated nerve endings contain immunoreactive endothelin, the level of which is regulated by homeostatic mechanisms involved in control of water balance. ET-1 and ET-3 potentiate vasopressin release induced by depolarization through interaction with specific receptors of the ETA subtype and this response is antagonized by sarafotoxin S6b. The second messenger for this effect, however, remains unknown since the potentiation of depolarization-induced vasopressin release occurs in the absence of an increase in cellular calcium.
 ...
PMID:Endothelin regulation of neuropeptide release from nerve endings of the posterior pituitary. 132 55

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

Vascular tissues such as rat aorta and mesenteric arteries are extensively used experimentally for the study of cardiovascular diseases. To further our understanding of the signal transduction mechanisms involved in responses to several potent vasoconstrictors, such as [Arg8]vasopressin (AVP), endothelin 1 (ET-1), and prostaglandin F2 alpha (PGF2 alpha), we have investigated the time course for production of inositol monophosphate (InsP1), bisphosphate (InsP2), and trisphosphate (InsP3) in response to these agonists as well as their relative potency for phosphatidylinositol hydrolysis. Time-course studies of production of the different inositol phosphates in response to AVP and PGF2 alpha showed an early increase after 15-30 s of stimulation. Thereafter InsP3 declined towards baseline, with a secondary increase towards steady state after 5-10 min. Rapid turnover of InsP3 was reflected by accumulation of InsP1 and InsP2 in the presence of LiCl (20 mM) to inhibit monophosphatases. After 15-30 min of stimulation, there was accumulation of the Ins(1,3,4)P3 isomer. All three agonists induced greater accumulation of InsP2 in mesenteric arteries than in thoracic aorta, suggesting that turnover of Ins(1,4,5)P3 may be faster in the former than in the latter. The accumulation of total inositol phosphates induced by maximum concentrations of ET-1 was greater than in response to AVP or PGF2 alpha. Dose-response curves showed that the rank order of potency for stimulation of production of inositol phosphates was AVP > ET-1 > PGF2 alpha, similar to the sensitivity of blood vessels to these agents. Comparison of responses to ET-1 and ET-3 showed that the receptors stimulated by endothelins were of the isopeptide selective ETA subtype.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Inositol phosphate production in response to [Arg8]vasopressin, endothelin 1, and prostaglandin F2 alpha in rat aorta and mesenteric arteries. 133 16

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 this study, the short-term regulation of endothelin-1-(ET-1) induced phosphoinositide (PI) hydrolysis and arachidonic acid release were investigated in cultured rat aortic smooth-muscle cells. ET-1, but not the ETB-selective peptide sarafotoxin (SFX) S6c, induced a dose-dependent increase in [3H]inositol phosphate release (EC50 = 0.4 +/- 0.1 nM). ET-3 stimulated this response only at concentrations > 0.1 microM. The ETA receptor antagonist BQ-123 inhibited ET-1-induced PI turnover, with an IC50 value of 97 +/- 15 nM. Pre-exposure of intact cells to ET-1 resulted in a 72% and 73% reduction in the ability of ET-1 or SFX S6b, respectively, to stimulate [3H]inositol phosphate release, without affecting the response to vasopressin. In contrast, PI turnover induced by ET-1 or SFX S6b was only slightly lowered, by 28% and 22%, after a 30-min preincubation period with SFX S6b. ET-1, but not SFX S6c, also stimulated [3H]arachidonic acid release by two-fold (EC50 = 3 +/- 0.8 nM). Pretreatment of intact cells with neomycin or phorbol-12-myristate-13-acetate resulted in a 49% and 44% inhibition of ET-1-induced [3H]inositol phosphate accumulation but did not decrease ET-1-stimulated [3H]arachidonic acid release, suggesting that these responses are separately regulated events in these cells.
 ...
PMID:Short-term regulation of endothelin receptor-mediated phosphoinositide hydrolysis and arachidonic acid release in A7r5 smooth-muscle cells. 750 34

The endothelins consist of a family of vasoconstrictor peptides originally isolated from endothelial tissue which are now known to be involved in neuroendocrine regulation. However, while there are data indicating the involvement of endothelins in the modulation of the hypothalamo-pituitary-adrenal (HPA) axis, the precise mechanisms involved have been unclear. We have therefore used a previously validated rat hypothalamic explant system in order to investigate the possible modulation of the neurohypophyseal hormones vasopressin and oxytocin, and corticotropin-releasing hormone (CRH), by endothelin-1 (ET-1) and endothelin-3 (ET-3). Following a period of stabilisation, the release of vasopressin, oxytocin and CRH remained approximately constant in successive 20-min incubations. Addition of ET-1 stimulated the release of vasopressin at a dose of 0.1 nmol/l (p < 0.05), and both vasopressin and oxytocin at 10 nmol/l (p < 0.01 and 0.05, respectively). The release of vasopressin and oxytocin induced by 10 nmol/l ET-1 were both totally blocked by co-incubation with either 1 or 10 mumol/l of the specific ETA receptor subtype antagonist cyclo (D-Trp-D-Asp-Pro-D-Val-Leu) (BQ-123). ET-1 had no effect on CRH release in the dose range of 0.1-1,000 nmol/l. In case any possible stimulation of CRH might be masked by simultaneous generation of nitric oxide (NO), an inhibitor of CRH secretion, addition of ET-1 was also carried out in the presence of the NO synthase inhibitor, L-NO-Arg: ET-1 was again without effect in this dose range.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Endothelin-1 stimulates the in vitro release of neurohypophyseal hormones, but not corticotropin-releasing hormone, via ETA receptors. 753 87

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

We characterized the endothelin (ET) receptor subtypes responsible for signal transduction in cultured porcine kidney epithelial LLC-PK1 cells. Both ET-1 (IC50, 43 pM) and ET-3 (IC50, 46 pM) inhibited the binding of [125I]ET-1 to LLC-PK1 cells to a similar extent. The binding affinity of LLC-PK1 cells was about 10,000 times higher for the ETB antagonist BQ-788 [N-cis-2,6-dimethyl-piperidinocarbonyl-L-tau-metylleucyl-D-+ ++Nin- methoxycarbonyltryptophanyl-D-norleucine] (IC50, 1.3 nM) than for the ETA antagonist BQ-123 [cyclo-(D-Trp-D-Asp-Pro-D-Val-Leu)] (IC50, 14 microM). ET-1 enhanced cyclic GMP (cGMP) production, but reduced vasopressin- and forskolin-stimulated cyclic AMP (cAMP) production. Both effects of ET-1 were antagonized by BQ-788, but not by BQ-123. The cAMP decrease, but not the cGMP increase, in response to ET-1 was inhibited by pertussis toxin, suggesting that the former response is mediated by pertussis toxin-sensitive Gi, whereas the latter is mediated by a pertussis toxin-insensitive G-protein. Therefore, the ETB receptors in LLC-PK1 cells couple to the two types of signal transduction cascades to reduce cAMP production and stimulate cGMP production via distinct G-proteins. ET-1 and probably also ET-3 may play a role in the regulation of renal epithelial transport by decreasing cAMP and increasing cGMP.
 ...
PMID:Endothelin ETB receptors couple to two distinct signaling pathways in porcine kidney epithelial LLC-PK1 cells. 793 50

The effectiveness of intradermal (i.d.) BQ-123 (cyclo[D-Asp-Pro-D-Val-Leu-D-Trp]) and i.d. Ro 47-0203 (bosentan, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyr imidin-4 - yl]-benzene-sulfonamide) has been evaluated on local microvascular responses to endothelin-1 and endothelin-3, measured by a multiple site 133Xe clearance technique in rat skin in vivo. Intradermal injection of endothelin-1 (0.3 pmol/site) and endothelin-3 (10 pmol/site) induced a similar (approximately 50-60%) decrease in basal blood flow in rat skin. BQ-123 (3-1000 pmol/site), a selective endothelin ETA receptor antagonist, caused a significant dose-dependent decrease in the vasoconstriction induced by endothelin-1 (P < 0.05) but was less effective on vasoconstriction induced by endothelin-3. Bosentan (3-1000 pmol/site), a new non-peptide mixed antagonist of endothelin ETA and endothelin ETB receptors, significantly reduced the vasoconstriction induced by endothelin-1 but was less effective than BQ-123. BQ-123 and bosentan were similarly effective as antagonists of endothelin-3. BQ-123 and bosentan had no effect on basal blood flow and no inhibitory activity on vasoconstriction induced by vasopressin (0.03 pmol/site) or phenylephrine (300 pmol/site). These findings indicate that BQ-123 and bosentan are effective and selective inhibitors of the vasoconstriction induced by endothelins in the rat skin microvasculature.
 ...
PMID:Effect of BQ-123 and Ro 47-0203 (bosentan) on endothelin-induced vasoconstriction in the rat skin. 795 19


1 2 3 Next >>