UMLS:C0406810 - FACTA Search

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Query: UMLS:C0406810 (NAME)
13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelin 1 (ET-1) is a potent vasoactive and mitogenic peptide that is thought to participate in the hemodynamic effects elicited by drugs that block the biosynthesis and release of endothelium-derived nitric oxide (NO), such as NO synthase inhibitors. Using the nonpeptide endothelin receptor antagonists bosentan and LU-135252, we tested the hypothesis that endothelins contribute to the pressor activity of diaspirin-crosslinked hemoglobin (DCLHb), a hemoglobin-based oxygen carrier, whose pressor activity in mammals is attributed primarily to a scavenging action towards NO. The NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME), ET-1, and noradrenaline (NA) were used as reference drugs. Bosentan markedly reduced the pressor effects elicited by DCLHb, L-NAME, and ET-1, but not those evoked by NA. LU-135252 attenuated the pressor effect elicited by DCLHb and ET-1, but not that produced by L-NAME or NA. The decreases in heart rate associated with the pressor effect of DCLHb and L-NAME were reduced by LU-135252, whereas only those elicited by DCLHb were attenuated by bosentan. In contrast with bosentan, LU-135252 caused a decrease in the baseline blood pressure and heart rate. These results suggest that endothelins may participate in the pressor activity of DCLHb. They suggest also that nonpeptide endothelin receptor antagonists such as bosentan or LU-135252 may be useful to counteract endothelin-mediated undesirable hemodynamic effects of drugs that inhibit the activity of the NO system.
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PMID:Nonpeptide endothelin receptor antagonists attenuate the pressor effect of diaspirin-crosslinked hemoglobin in rat. 1053 92

We have investigated the mediators and mechanisms underlying the vasodilator effects of the potent vasoactive peptide, endothelin-1 (ET-1) and its isomers ET-2 and ET-3 in human skin, in vivo, using cutaneous microdialysis to quantify the release of mediators within the dermal response and scanning laser Doppler imaging to measure changes in blood flux. The effects of local anaesthesia, inhibition of nitric oxide synthase (NOS) by L-NAME and ET receptor blockade on the ET-induced vascular response were also investigated. ET-1, -2 and -3 all caused a dose-dependent area of pallor surrounded by a long-lasting flare which was accompanied by a short-lived burning pruritus. The concentration of nitric oxide (NO) in dialysate collected within the pallor response to 5 microM ET-1 (1.43 +/- 0.64 microM, n = 5) was not significantly different from baseline levels collected prior to injection (0.86 +/- 0.38 microM) whilst that in the flare increased to reach a peak value of 2.28 +/- 0.61 microM at between 4 and 10 min after intradermal injection (P < 0.004). Pretreatment with local anaesthetic slowed the development of the flare and significantly reduced its size by up to 52% at 20 min after injection (P < 0.05) but had no significant effect on the central pallor. L-NAME, delivered by dialysis also caused a significant reduction in the ET-1-induced flare (P < 0.005). Bosentan, the non-selective ET(A)/ET(B) antagonist, when given by dialysis at the site of injection, reduced the area of both the ET-1-induced pallor and surrounding flare by 41 and 26%, respectively. No significant increase in tissue histamine was measured within either the pallor or flare response to ET-1, -2 or -3. Together these data confirm that the vasodilator response to endothelin-1 in human skin is neurogenic in origin and that it is in part mediated by the local release of nitric oxide. There appears to be little evidence for the involvement of mast cell-derived histamine in the initiation or modulation of ET-induced vasodilatation, in vivo.
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PMID:The neurogenic vasodilator response to endothelin-1: a study in human skin in vivo. 1118 78

In previous studies, we have observed that endothelin participates in the progression of renal vascular and glomerular fibrosis during hypertension by activating collagen I gene synthesis. The present study investigated whether administration of endothelin receptor antagonists leads to the regression of renal sclerotic lesions. Experiments were performed in transgenic mice harboring the luciferase gene under the control of the collagen I-alpha2 chain promoter. Hypertension was induced by long-term inhibition of nitric oxide synthesis by N(G)-nitro-L-arginine methyl ester (L-NAME); systolic pressure gradually increased, reaching a plateau of 165 mm Hg after 10 weeks of hypertensive treatment. At the same time, collagen I gene expression was increased 2- and 5-fold compared with control animals in afferent arterioles and glomeruli, respectively (P<0.01). This increase was accompanied by the appearance of sclerotic lesions within the renal vasculature. When renal vascular lesions had been established (20 weeks of L-NAME), animals were divided into 2 subgroups: the one continued to receive L-NAME, whereas in the other, bosentan, a dual endothelin antagonist, was coadministered with L-NAME for an additional period of 10 weeks. Bosentan coadministration did not alter the increased systolic pressure at 30 weeks; in contrast, collagen I gene activity returned almost to control levels in renal vessels and glomeruli. In this subgroup of animals, renal vascular lesions (collagen and/or extracellular matrix deposition) and mortality rates were substantially reduced compared with untreated mice. These data indicate that endothelin participates in the mechanism(s) of renal vascular fibrosis by activating collagen I gene. Treatment with an endothelin antagonist normalizes expression of collagen I gene and leads to the regression of renal vascular fibrosis and to the improvement of survival, thus providing a complementary curative approach against renal fibrotic complications associated with hypertension.
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PMID:Regression of renal vascular fibrosis by endothelin receptor antagonism. 1123 Mar 24

We evaluated the role of endothelin-1 (ET-1) and the involvement of nitric oxide in cardiovascular and respiratory dysfunction, during endotoxic shock, in 18 anaesthetised, mechanically ventilated pigs, divided into three groups. Group 1 was i.v. infused with LPS (20 microg/Kg/h for 240 min). Group 2 was pre-treated with bosentan, a dual inhibitor of ET-1 receptors, and at 180 min of endotoxic shock, L-NAME (N(G)-nitro-L-arginine methyl ester, 10 mg/Kg), a non-selective inhibitor of NO synthases, was i.v. administered. Group 3 was infused with LPS and L-NAME was administered similarly to group 2. Results show that LPS caused systemic hypotension, pulmonary biphasic hypertension, decrease in compliance (C(rs)) and increase in resistance (R(max,rs)) of respiratory system. Bosentan completely abolished the pulmonary hypertension and the changes in C(rs)and R(max,rs). L-NAME does not affect the LPS-dependent changes in respiratory mechanics, but it worsens the cardiovascular effects, causing death of pigs. Pre-treatment with bosentan prevents this deleterious effect. Our study demonstrates that the LPS-dependent respiratory effects are mediated by ET-1, which, probably causing pulmonary oedema, is responsible for the decrease in C(rs)and the increase of R(max,rs).
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PMID:Improvement of respiratory function by bosentan during endotoxic shock in the pig. 1154 27

The fetal ductus can be constricted by drugs, including cyclooxygenase inhibitors (indomethacin), nitric oxide synthesis antagonists [N-nitro-L-arginine monomethyl ester (L-NAME)], and glucocorticoid hormones (dexamethasone). Constriction of the fetal ductus by endothelin (ET) 1 was reported in an in vitro study. We studied the preventive effect of a dual ET receptor antagonist (bosentan) and a selective ET-A blocker (CI-1020) on pharmacologic fetal ductal constriction in rats. Near-term pregnant Wistar rats at d 21 and preterm rats at d 19 were used. The fetal ductus was constricted by four medications: orogastric administration of indomethacin (10 mg/kg) on fetal d 21, orogastric indomethacin 1 mg/kg combined with muscular injection of L-NAME (10 mg/kg) on fetal d 21, and muscular injection of L-NAME or dexamethasone (1 mg/kg) on fetal d 19. Bosentan (0.1, 1, 10, or 100 mg/kg) was injected intraperitoneally either simultaneously with indomethacin, L-NAME, or dexamethasone, or 4 h after administration of 10 mg/kg indomethacin. CI-1020 (0.01, 0.1, 1, or 10 mg/kg) was injected intraperitoneally simultaneously with indomethacin. After maternal atlas dislocation, cesarean section, fetal whole-body freezing, and cutting on the freezing microtome, measurements were made of the inner diameters of the ductus, main pulmonary artery, and ascending aorta. Bosentan blocked fetal ductal constriction by indomethacin, indomethacin plus L-NAME in the near-term rats, and constriction by L-NAME and dexamethasone in the preterm rats dose dependently. Fetal ductal constriction was nearly completely blocked by simultaneously administered 100 mg/kg of bosentan or 10 mg/kg of CI-1020. Dual ET receptor antagonist (bosentan) and selective ET-A blocker (CI-1020) prevent constriction of the fetal ductus arteriosus induced by ductus-constricting agents in rats, indicating that ET and ET-A receptors are essential in fetal ductal constriction.
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PMID:Inhibition of in vivo constriction of fetal ductus arteriosus by endothelin receptor blockade in rats. 1259 98

Tested was the hypothesis that enhanced nitric oxide (NO) production that is stimulated by increased renal endothelin activity mediates decreased distal nephron HCO(3) secretion that is induced by dietary protein. Munich-Wistar rats that ate minimum electrolyte diets with 50% casein-provided protein (HiPro) compared with controls that ate 20% protein for 3 wk had higher urine excretion of endothelin-1 (80 +/- 15.7 versus 29 +/- 3.9 fmol/kg body wt per d; P < 0.02) and of the NO metabolites NO(2)/NO(3) (21.2 +/- 1.9 versus 14.9 +/- 0.8 mumol/kg body wt per d; P < 0.03). Bosentan, an endothelin A/B receptor antagonist, reduced HiPro rats' urine excretion of net acid (5859 +/- 654 versus 8017 +/- 1103 micromol/d; P < 0.03, paired t test) and NO(2)/NO(3) (18.1 +/- 1.1 versus 22.9 +/- 2.0 micromol/kg body wt per d; P < 0.05, paired t test). N-nitro-l-arginine methyl ester (L-NAME), an NO synthase inhibitor, also decreased urine net acid excretion (6621 +/- 717 versus 8449 +/- 1086 micromol/d; P < 0.05, paired t test) but was not additive to bosentan. L-NAME increased in situ late distal nephron HCO(3) delivery in HiPro rats (18.8 +/- 1.7 versus 9.6 +/- 1.4 pmol/mm per min; P < 0.001) that was mediated by increased distal nephron HCO(3) secretion (-7.2 +/- 0.7 versus -3.5 +/- 0.4 pmol/mm per min; P < 0.001) without changes in distal nephron transtubule HCO(3) permeability or H(+) secretion. Bosentan decreased H(+) secretion and increased HCO(3) secretion in the distal nephron of HiPro rats, but L-NAME had no additive effect on either component. The data support that dietary protein augments distal nephron acidification through decreased HCO(3) secretion that is mediated through endothelin-stimulated NO.
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PMID:Endothelin-induced increased nitric oxide mediates augmented distal nephron acidification as a result of dietary protein. 1639 62

Sepsis causes changes in vascular resistance and hypovolemia. Previous studies have demonstrated that the spleen regulates blood volume via atrial natiuretic peptide (ANP). We hypothesized that LPS alters extrasplenic responses to ANP via endothelial-dependent mechanisms and studied the role of NO and endothelin 1 (ET-1). Isolated extrasplenic arteries and veins (vessels in mesentery adjoining spleen) were obtained from male Wistar rats weighing 200 to 280 g (n = 102) and mounted on a pressure myograph to determine intraluminal diameter for 4 h. Isolated vessels constricted in response to the half-maximum response of ANP (veins, 30% +/- 1.7%; arteries, 34.5 +/- 1.7%; P < 0.05), and this was abolished by the NO donor S-nitroso-N-acetylpenicillamine (SNAP 75 microM). Arteries and veins incubated with LPS (50 microg mL(-1) for 4 h) were unresponsive to ANP, and constriction was not restored by the NOS inhibitor N omega-nitro-L-arginine methyl ester (L-NAME 100 microM). However, venular constriction returned in the presence of the ET-1 antagonist Bosentan, increasing from -1.5 +/- 1.2 (10 min) to -10 +/- 2.5% (4 h) with LPS + Bosentan (3 x 10(-6) M) compared with -2.3 +/- 1.2 and 0% with LPS alone. In conclusion, LPS abolished endothelial-dependent extrasplenic venular constriction to ANP partially due to increased ET-1, whereas NO seemed to modulate vascular responses to ANP.
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PMID:LPS abolishes extrasplenic vasoconstriction to atrial natriuretic peptide: the role of NO and endothelin 1. 1788 45

(+)-Dapoxetine hydrochloride, [(123)I]-BZA, 9-Aminocamptothecin; Abacavir sulfate/lamivudine, Adalimumab, Adefovir dipivoxil, Alemtuzumab, Alvocidib hydrochloride, Ambrisentan, Amsilarotene, Anacetrapib, Anakinra, Apricitabine, Aripiprazole, Arsenic trioxide, Atazanavir sulfate, Atazanavir/ritonavir, Atrasentan, Azacitidine; Banoxantrone, Bazedoxifene acetate, Bevacizumab, Bexarotene, Biphasic insulin aspart, Bortezomib, Bosentan, Bromfenac; Cachectin, Calcipotriol/betamethasone dipropionate, Canakinumab, Carfilzomib, CAT-354, CCX-282, Certolizumab pegol, Cetuximab, Choline fenofibrate, Clevudine, Clofarabine, CNTO-328, Corifollitropin alfa, Crofelemer; Daptomycin, Darbepoetin alfa, Darunavir, Dasatinib, Decitabine, Deferasirox, Denosumab, Duloxetine hydrochloride, Dutasteride; Emtricitabine, Enfuvirtide, Entecavir, Epoetin zeta, Erlotinib hydrochloride, Escitalopram oxalate, Eslicarbazepine acetate, Eszopiclone, Etravirine, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; Farglitazar, Febuxostat, Fosamprenavir calcium, FX-06; Gabapentin enacarbil, Gefitinib; HIVIS DNA; Imatinib mesylate, INCB- 18424, Indacaterol, Inotuzumab ozogamicin, Insulin detemir; JNJ-26854165; Lacosamide, Landiolol, Laromustine, Lenalidomide, Liposomal doxorubicin, L-NAME, Lopinavir, Lopinavir/ritonavir, Lumiracoxib; Maraviroc, Mepolizumab, Methoxy polyethylene glycol- epoetin-beta, Miglustat, MK-0493, MVA-CMDR, Mycophenolic acid sodium salt; Natalizumab, Nepafenac, Neratinib, Neridronic acid, Nesiritide, Nilotinib hydrochloride monohydrate; Olmesartan medoxomil, Omacetaxine mepesuccinate, Omalizumab; Paclitaxel poliglumex, Palifermin, Patupilone, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ ribavirin, Pemetrexed disodium, PHA-848125, Pitavastatin calcium, Posaconazole, Povidone-iodine liposome complex, Prasugrel, Pregabalin, Prucalopride; Raltegravir potassium, Retigabine, Revaprazan hydrochloride, rhFSH, Rilpivirine, Rivaroxaban, Romidepsin, Rosuvastatin calcium, RWJ-676070; SAR-109659, Sitagliptin phosphate monohydrate, Sorafenib, Stavudine/Lamivudine/Nevirapine, Sunitinib malate; Tadalafil, Telaprevir, Telbivudine, Tenofovir disoproxil fumarate, Tenofovir disoproxil fumarate/emtricitabine, Tenofovir disoproxil fumarate/emtricitabine/efavirenz, Teriparatide, Tigecycline, Tiotropium bromide, Tipifarnib, Tipranavir, Tocilizumab, Trifluridine/TPI; UP-780; Vandetanib, Vardenafil hydrochloride hydrate, Vatalanib succinate, Vitespen, Vorinostat; Yttrium 90 (90Y) ibritumomab tiuxetan; Zoledronic acid monohydrate.
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PMID:Gateways to clinical trials. 1953 62

Nitric oxide (NO) induces vascular relaxation via cGMP in vascular smooth muscle (VSM) and is an important mediator of vascular tone during sepsis, as endothelial NO synthase (eNOS) may be upregulated during the early stages. Atrial natriuretic peptide (ANP) also stimulates cGMP via eNOS hence, this study aimed to investigate the role of NO in time-dependent altered vascular responses to ANP during the first 4h of exposure to bacterial lipopolysaccharide (LPS). We used male rat saphenous arteries [internal relaxed diameter 63-152 microm, n=48], mounted on a wire myograph and pre-constricted with phenylephrine. At 2h in the presence of LPS, there was increased relaxation to ANP in arteries exposed to LPS [16.3+/-2.4%, P<0.05]. However the response to ANP was not altered by the NOS inhibitor Nomega-nitro-l-arginine methyl ester (L-NAME, 10(-4)M) and following denudation (vessels without endothelium). At 4h there was no longer increased relaxation to ANP in the presence of LPS. Moreover the vasodilator response to ANP was significantly reduced following L-NAME or denudation [4.4+/-1.0% and 4.3+/-1.1% respectively, P<0.05]. However, the non-specific endothelin-1 (ET-1) receptor antagonist Bosentan [10(-5)M] increased dilatation in LPS exposed arteries at 1 and 2h, reaching significance at 4h [14.0+/-3.4%, P<0.05]. In summary, an endothelial and NO dependent mechanism is responsible for increased relaxation to ANP following 2h exposure to LPS. However after 4h an endothelial and NO independent process involving ET-1 is responsible for decreased relaxation to ANP. The enhanced response to ANP may exacerbate early systemic vasodilatation during early sepsis.
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PMID:Lipopolysaccharide alters vasodilation to atrial natriuretic peptide via nitric oxide and endothelin-1: time-dependent effects. 1973 54

Chronic use of human recombinant erythropoietin (r-HuEPO) is accompanied by serious vascular side effects related to the rise in blood viscosity and shear stress. We investigated the direct effects of r-HuEPO on endothelium and nitric oxide (NO)-dependent vasodilatation induced by shear stress of cannulated and pressurized rat mesenteric resistance arteries. Intravascular flow was increased in the presence or absence of the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME; 10(-4) mol/L). In the presence of r-HuEPO, the flow-dependent vasodilatation was attenuated, while L-NAME completely inhibited it. The association of r-HuEPO and L-NAME caused a vasoconstriction in response to the rise in intravascular flow. Bosentan (10(-5) mol/L), an inhibitor of endothelin-1 (ET-1) receptors, corrected the attenuated vasodilatation observed with r-HuEPO and inhibited the vasoconstriction induced by flow in the presence of r-HuEPO and L-NAME. r-HuEPO and L-NAME exacerbated ET-1 vasoconstriction. At shear stress values of 2 and 14 dyn/cm(2) (1 dyn = 10(-5) N), cultured EA.hy926 endothelial cells incubated with r-HuEPO, L-NAME, or both released greater ET-1 than untreated cells. In conclusion, r-HuEPO diminishes flow-induced vasodilatation. This inhibitory effect seems to implicate ET-1 release. NO withdrawal exacerbates the vascular effects of ET-1 in the presence of r-HuEPO. These findings support the importance of a balanced endothelial ET-1:NO ratio to avoid the vasopressor effects of r-HuEPO.
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PMID:Human recombinant erythropoietin alters the flow-dependent vasodilatation of in vitro perfused rat mesenteric arteries with unbalanced endothelial endothelin-1 / nitric oxide ratio. 2177 87

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