Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although circulating plasma levels of endothelin (ET)-1 are elevated in endotoxemia, little is known about the myocardial expression of the ET system in endotoxic shock. We assessed the temporal mRNA expression pattern of key components of the ET system (pre-pro ET (ppET) -1, -2, ET-converting enzyme-1, ET(A) and ET(B) receptors) by reverse transcription polymerase chain reaction in a rat model of early endotoxic shock. Lipopolysaccharide (5 mg/kg, i.p.) caused a transient increase (p < 0.05) in inducible nitric oxide synthase mRNA expression. ppET-1 mRNA expression was increased at 2 h (approximately 12-fold increase; p < 0.05) in the lipopolysaccharide compared with the saline group and ppET-2 mRNA expression was unaltered. ET-converting enzyme-1, ET(A), and ET(B) receptor mRNA expression was unaltered in the lipopolysaccharide compared with the saline group. While ppET-1 mRNA expression is selectively upregulated in ventricular myocardium of lipopolysaccharide-treated rats, an absence of alteration in ET-converting enzyme-1 mRNA expression suggests an excess capacity of ET-converting enzyme-1 to cope with the increased expression of ET-1. At the level of the receptor, endotoxic shock did not affect the expression of either ET(A) or ET(B) receptor mRNA. These data are consistent with the increased expression of myocardial ET-1 as an acute-phase response due to hemodynamic instability associated with the early stages of endotoxic shock.
J Cardiovasc Pharmacol 2001 Aug
PMID:Myocardial expression of the endothelin system in endotoxin-treated rats. 1148 76

Hypertension-associated alterations of the nitric oxide (NO) pathway were analyzed in middle cerebral arteries (MCA) from normotensive (WKY) and hypertensive (SHR) rats. The vasoconstrictor response to prostaglandin F2alpha (PGF(2 alpha), 30 and 100 microM) was smaller in MCA from SHR than from WKY. Endothelium-dependent relaxations to bradykinin (1 nM-10 microM) or acetylcholine (10 microM) were similar in MCA from both strains, whereas the endothelium-independent response to sodium nitroprusside (1 nM-0.1 mM) was smaller in MCA from SHR. L-arginine (L-Arg, 10 microM) similarly inhibited the vasoconstrictor responses in both strains; however, the inhibitory effect of 100 microM of L-Arg was greater in MCA from SHR. N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 microM), but not aminoguanidine (100 microM) or 7-nitroindazole (10 microM), increased basal tone, potentiated the PGF(2 alpha)-induced vasoconstrictor responses and reduced the bradykinin-elicited relaxation in a similar way in MCA from WKY and SHR. N(omega)-nitro-L-arginine methyl ester also antagonized the inhibitory effect of 10 microM of L-Arg. Incubation for 5 h with lipopolysaccharide (10 microg/ml) similarly reduced the response to PGF(2 alpha) in MCA from WKY and SHR; this reduction was antagonized by dexamethasone (1 microM). Cerebral arteries expressed endothelial (eNOS) and neuronal (nNOS) NO synthase similarly in both strains, but inducible NOS (iNOS) expression was more evident in SHR. Lipopolysaccharide increased iNOS expression in both strains to a similar level. The basal constitutive NOS (cNOS) and iNOS activities were similar in arteries from WKY and SHR. Lipopolysaccharide increased iNOS activity only in arteries from SHR. These results indicate that hypertension did not impair endothelial NO production by NOS activation but induced an up-regulation of basal iNOS expression.
J Cardiovasc Pharmacol 2002 Mar
PMID:Alterations of the nitric oxide pathway in cerebral arteries from spontaneously hypertensive rats. 1186 17

The aim of this study was to assess the effects of dexamethasone (DEX) on the inducible bioconversion of glyceryl trinitrate (GTN) into nitric oxide in cultured smooth muscle cells, endothelial cells, and the J774 macrophage cell line as well as in vivo and ex vivo in rats either untreated or pretreated with Escherichia coli lipopolysaccharide. In vitro, an increased bioconversion of GTN to nitrite and an elevation of cyclosine guanosine 3,5;-monophosphate (cGMP) levels occurred after treatment with lipopolysaccharide (LPS) (0.5 microg/ml, 18 h). This effect was ablated by co-incubation with DEX (10 microM, 18 h). Rats treated with an intraperitoneal (IP) injection of LPS (4 mg/kg) 18 h beforehand showed enhanced hypotensive responses to GTN (1 mg/kg, intravenously [IV]) and this was prevented when DEX (4 mg/kg, IP) was given together with LPS. Progesterone (50 mg/kg, IP) had no effect on GTN-induced hypotensive response. Conversely, exposure of rat aortic strips obtained from animals pretreated with LPS produced an enhanced vasorelaxant response in LPS-treated rats. Also, this effect was inhibited by pretreatment with DEX. Thus, the induction of the pathway leading to the formation of nitric oxide from GTN is blocked by DEX both in vitro and in vivo, and this may represent a useful tool in the assessment of the enhanced bioconversion of organic nitrates into nitric oxide occurring via inflammatory mechanisms.
J Cardiovasc Pharmacol 2002 Apr
PMID:Dexamethasone inhibits the inducible bioconversion of glyceryl trinitrate to nitric oxide. 1190 28

We describe characteristics of a selective endothelin (ET) ET(B) receptor antagonist, BQ-788 [N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D-1-methoxycarbonyltryptophanyl-D-norleucine], which is widely used to demonstrate the role of endogenous or exogenous ETs in vitro and in vivo. In vitro, BQ-788 potently and competitively inhibited (125)I-labeled ET-1 binding to ET(B) receptors in human Girrardi heart cells (hGH) with an IC(50) of 1.2 nM, but only poorly inhibited the binding to ET A receptors in human neuroblastoma cell line SK-N-MC cells (IC(50), 1300 nM). In isolated rabbit pulmonary arteries, BQ-788 showed no agonistic activity up to 10 microM and competitively inhibited the vasoconstriction induced by an ET(B)-selective agonist (pA(2), 8.4). BQ-788 also inhibited several bioactivities of ET-1, such as bronchoconstriction, cell proliferation, and clearance of perfused ET-1. Thus, it is confirmed that BQ-788 is a potent, selective ET(B) receptor antagonist. In vivo, in conscious rats, BQ-788, 3 mg/kg/h, i.v., completely inhibited a pharmacological dose of ET-1- or sarafotoxin6c (S6c) (0.5 nmol/kg, i.v.)-induced ET(B) receptor-mediated depressor, but not pressor responses. Furthermore, BQ-788 markedly increased the plasma concentration of ET-1, which is considered an index of potential ET(B) receptor blockade in vivo. In Dahl salt-sensitive hypertensive (DS) rats, BQ-788, 3 mg/kg/h, i.v., increased blood pressure by about 20 mm Hg. It is reported that BQ-788 also inhibited ET-1-induced bronchoconstriction, tumor growth and lipopolysaccharide-induced organ failure. These data suggest that BQ-788 is a good tool for demonstrating the role of ET-1 and ET(B) receptor subtypes in physiological and/or pathophysiological conditions.
Cardiovasc Drug Rev 2002
PMID:BQ-788, a selective endothelin ET(B) receptor antagonist. 1207 May 34

The inhibition of nitric oxide (NO) synthesis by chronic administration of NG-nitro-l-arginine methyl ester (l-NAME) in rats is responsible for systemic hypertension. However, the mechanisms involved in this hypertension remain unclear. The effects of chronic l-NAME on kidney and blood NO production were studied in rats in a state of endotoxic shock due to lipopolysaccharide (LPS). A nitric oxide spin trapping technique using electron spin resonance (ESR) spectroscopy has been used to identify and measure the production of NO in the kidney. This method is based on the trapping of nitric oxide by a metal-chelator complex consisting of N-methyl-d-glucamine dithiocarbamate (MGD) and reduced iron (Fe2+) forming a water-soluble NO-FeMGD complex detected by ESR. After LPS injection (14 mg/kg, IV, 6 h before the sacrifice) to rats pretreated with l-NAME (10 mg/kg/d over 14 days), the NO-FeMGD complex was evaluated in the kidney (arbitrary units [AU]/g of kidney) and the density of polynuclear neutrophils was counted by light microscopy. Chronic inhibition of NO synthase by l-NAME, a nonspecific inhibitor, was responsible for a decrease of the NO-FeMGD complex levels in the kidney (24.9 +/- 1.6 AU versus 13.8 +/- 1.3 AU). LPS administration was responsible for a large increase in both NO-FeMGD complex and neutrophil levels in the kidney of normotensive rats (332.6 +/- 12.8 AU versus 24.9 +/- 1.6 AU for NO-FeMGD complex and 1.36 +/- 0.41 versus 0.11 +/- 0.03 for neutrophils). Conversely, LPS administration in hypertensive, l-NAME-pretreated rats was linked to a smaller increase in the NO-FeMGD complex (85.1 +/- 7.9 AU versus 332.6 +/- 12.8 AU) and a larger increase in glomerular neutrophils (2.48 +/- 0.36 versus 1.36 +/- 0.41) compared with normotensive rats. These results are in agreement with a direct implication of NO during LPS-and l-NAME-induced kidney injuries.
J Cardiovasc Pharmacol 2002 Jul
PMID:Intrarenal detection of nitric oxide using electron spin resonance spectroscopy in hypertensive lipopolysaccharide-treated rats. 1207 72

Infection is a major complication of patients with diabetes, and endotoxemic shock is a serious complication during sepsis. The purpose of this study was to determine whether the action of bacterial lipopolysaccharide (LPS) on vasocontractility is altered in diabetic vessels. Diabetes was induced in 10-week-old Wistar rats by an intraperitoneal injection of streptozotocin. LPS-induced increase in cGMP (cyclic guanosine 3',5'-monophosphate) level was lower in aortae from streptozotocin-induced hyperglycemic (diabetic) rats than in those from vehicle-injected control rats, while LPS-induced nitric oxide production was not different in the diabetic and control aortae. Phenylephrine-induced contraction of diabetic aortae was lower than that of the control aortae. LPS treatment resulted in depression of contractile response to phenylephrine in both diabetic and control aortae, and the degree of depression was much lower in diabetic aortae. Treatment with N monomethyl l-arginine (l-NMMA) prevented diminution of phenylephrine-induced contraction of the aortae after LPS stimulation, and the degree of the preventive effect by l-NMMA was significantly lower in diabetic aortae than in the control aortae. Protein expression of inducible nitric oxide synthase detected by Western blot analysis was not different in the diabetic and control aortae. The decrease in cGMP production after LPS stimulation in diabetic aortae was not prevented by treatment of the aortae with superoxide dismutase but was partially prevented by that with Tiron (4,5-dihydroxy-1,3-benzene disulfonic acid), a cell-permeable scavenger of reactive oxygen species. These results suggest that LPS-induced depression of vasocontractility is attenuated in diabetic aortae due to a decrease in nitric oxide-stimulated cGMP production, probably resulting from increased inactivation of inducible nitric oxide by excessive intracellular oxidative stress. It is concluded that contractility of aortae from streptozotocin-induced hyperglycemic rats may be less affected by LPS during endotoxemia.
J Cardiovasc Pharmacol 2003 Feb
PMID:Decreased modulation by lipopolysaccharide of aortic smooth muscle contractility in streptozotocin-induced hyperglycemic rats. 1254 75

The aim of this study was to investigate the effects of in vivo administration of genistein on rat cardiovascular abnormalities induced by lipopolysaccharide (LPS). Four hours after injection, LPS (10 mg/kg) caused a stable fall in mean arterial pressure (13%) accompanied by ex vivo vascular hyporeactivity to noradrenaline (NA) and relaxation to l-arginine (L-arg), which were inhibited by previous incubation with l-NAME. Endotoxin also caused impairment of aortic relaxant response to acetylcholine, increase nitrite and malonaldehyde plasma levels by 8.6-fold and 2-fold, respectively, and induced aortic expression of inducible nitric-oxide synthase (iNOS) and nitrotyrosine protein. Genistein (1 mg/kg) and daidzein (1 mg/kg) reduced contractile response to NA in vascular tissue, but only genistein was able to inhibit hyporesponsiveness to NA, relaxation to l-arg, increase in nitrite plasma levels, and iNOS expression produced by endotoxin. Moreover, genistein restored impaired aortic relaxation to acetylcholine, lipid peroxidation, and suppressed long-term hypotension. In conclusion, genistein administrated in vivo prevents hypotension and vascular alterations induced by LPS. These protective effects are mediated by both its antioxidant properties and the inhibition of nitric oxide overproduction from de novo synthesis of iNOS due to its tyrosine kinase inhibitor effect.
J Cardiovasc Pharmacol 2003 Sep
PMID:In vivo vascular effects of genistein on a rat model of septic shock induced by lipopolysaccharide. 1296 Jun 77

Cytokines and bacterial lipopolysaccharide (LPS) induce the expression of inducible nitric oxide synthase (iNOS), resulting in the release of nitric oxide (NO) from vascular smooth muscle cells. We here demonstrated that disruption of F-actin formation by sequestration of G-actin with the toxin latrunculin B (Lat B) dramatically potentiated LPS-induced iNOS mRNA and protein expression. We also showed that Lat B enhanced interleukin-1beta- andbgr;- and TNFalpha-induced NO production. Lat B by itself had little or no effect on iNOS expression. Cytochalasin D also enhanced LPS-induced NO production. Lat B dose-dependently enhanced LPS-induced iNOS promoter activity but had no effect on the stability of iNOS mRNA. Staining of F-actin with nitrobenzoxadiazole (NBD)-phallacidin demonstrated that Lat B significantly impaired F-actin stress fiber formation. These data indicate that disruption of the actin cytoskeleton up-regulates cytokine-induced iNOS expression via transcriptional regulation. Further analysis of the signaling pathway from the actin cytoskeleton to iNOS expression may yield new insight into the mechanism of iNOS regulation.
J Cardiovasc Pharmacol 2004 Feb
PMID:Disruption of the actin cytoskeleton up-regulates iNOS expression in vascular smooth muscle cells. 2189 54

Diabetic patients have a higher rate of mortality from sepsis than do their nondiabetic septic counterparts. The hypothesis in this study is that chronic diabetes may make cardiovascular systems more sensitive to septicemia. To test this hypothesis, the authors investigated the effect of diabetes on endotoxin- induced cardiac toxicity. Diabetes was induced in FVB mice by injecting a single dose (150 mg/kg) of streptozotocin. Two months after streptozotocin treatment, the diabetic mice were treated with lipopolysaccharide by intraperitoneal injection at 2 mg/kg. Cardiac toxicity was evaluated by measuring levels of serum cardiac enzymes and cardiac morphology at 1 h, 4.5 h, and 24 h after lipopolysaccharide treatment. Serum and cardiac tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were detected by enzyme-linked immunosorbent assay methods at 1 h and 4.5 h after lipopolysaccharide treatment. Lipopolysaccharide treatment did not significantly affect the diabetic manifestations, including decreased body weight gain and increased glycated hemoglobin and serum triglyceride levels. However, diabetes significantly enhanced lipopolysaccharide-induced cardiac toxicity, which was demonstrated by significant increases in the levels of cardiac enzymes such as creatine phosphokinase and troponin T, abnormal morphological changes examined under light microscope with hematoxylin and eosin staining, and oxidative damage to proteins detected by 3-nitrotyrosine staining. Lipopolysaccharide treatment significantly increased serum and cardiac TNF-alpha and IL-6 concentrations. Diabetes did not alter the effect of lipopolysaccharide on serum and cardiac TNF-alpha elevation, but it significantly enhanced lipopolysaccharideinduced cardiac IL-6 production. These results suggest that diabetes significantly enhances endotoxin-induced cardiac toxicity, possibly through mechanisms that involve inflammatory/acute-phase cytokines.
Cardiovasc Toxicol 2003
PMID:Diabetes enhances lipopolysaccharide-induced cardiac toxicity in the mouse model. 1473 33

Recently, we showed that platelet phagocytosis occurs in human atherosclerotic plaques and leads to foam cell formation. Platelet phagocytosis, resulting in macrophage activation and iNOS induction, was associated with the formation of amyloid-beta peptide (Abeta) via proteolytic cleavage of platelet-derived amyloid precursor protein (APP), possibly by secretases. To test the involvement of gamma-secretase in this process, we used indomethacin, ibuprofen, and sulindac sulfide, non-steroidal anti-inflammatory drugs (NSAIDs) known to alter the gamma-secretase cleaving site of APP, on their ability to inhibit macrophage activation evoked by platelet phagocytosis. J774 macrophages were incubated with human platelets or lipopolysaccharide (LPS) with or without NSAIDs. Nitrite was quantified as a measure for inducible nitric oxide synthase (iNOS) activity. Indomethacin, ibuprofen, sulindac sulfide, and meloxicam concentration-dependently reduced nitrite production by macrophages incubated with platelets, but did not alter LPS-induced iNOS activity or platelet uptake. However, acetylsalicylic acid and naproxen, two NSAIDs without effect on the gamma-secretase cleaving site of APP, did not affect nitrite production in either platelet- or LPS-stimulated macrophages. Surface-enhanced laser desorption/ionization time-of-flight mass-spectrometry demonstrated time-dependent formation of Abeta-containing peptides after platelet phagocytosis, which could be inhibited by indomethacin. In conclusion, these results point to the involvement of gamma-secretase in macrophage activation following platelet phagocytosis.
J Cardiovasc Pharmacol 2004 Mar
PMID:Effect of non-steroidal anti-inflammatory drugs on amyloid-beta formation and macrophage activation after platelet phagocytosis. 1507 32


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