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)

A number of studies using endothelin (ET) receptor antagonists support the participation of ETs in a variety of cardiovascular, renal, and other disorders. It has also been established that a number of cytokines, which are released in such diseases, modulate the expression and production of ETs and thus activate the ET system. This effect may represent one pathway by which these inflammatory mediators operate. By regulating endothelin-converting enzyme (ECE) activities, and thus ET synthesis, one can potentiate or attenuate the production of ETs and the receptor affinity/density in such pathologic conditions. Here, the stimulated (lipopolysaccharide or interleukin-1 beta) production of ET-1 from guinea pig tracheal epithelial cells was abolished by CGS 26303 or CGS 26393, two ECE/neutral endopeptidase (NEP) inhibitors, but was unaffected by CGS 24592, a specific NEP inhibitor. Therefore, such dual, and eventually selective ECE inhibitors are effective agents to prevent the stimulated production of ETs.
J Cardiovasc Pharmacol 1998
PMID:Effects of dual endothelin-converting enzyme/neutral endopeptidase inhibitors, CGS 26303 and CGS 26393, on lipopolysaccharide or interleukin-1 beta-stimulated release of endothelin from guinea pig tracheal epithelial cells. 959 86

To elucidate the pathologic role of endothelin-1 (ET-1) in septic shock, we measured plasma ET-1 concentrations after bacterial lipopolysaccharide (LPS) administration in dogs and determined systemic, pulmonary, and renal hemodynamics and blood gas parameters with or without the nonselective ET receptor antagonist TAK-044. Plasma ET-1 concentrations increased significantly after LPS administration, which correlated positively with mean arterial pressure, mean pulmonary arterial pressure, pulmonary capillary wedge pressure, and central venous pressure. LPS infusion induced hypotension, metabolic acidosis, hypoxemia, and renal dysfunction. TAK-044 prevented LPS-induced metabolic acidosis, hypoxemia, and renal dysfunction, but not hypotension. These findings suggest that increased circulating ET-1 plays a compensatory role in the reversal of systemic vasodilatation in septic shock, but exerts deleterious effects on renal and pulmonary circulation.
J Cardiovasc Pharmacol 1998
PMID:Pathologic role of endothelin-1 in septic shock. 959 46

Many pathologic conditions are associated with elevations in the production of endothelin-1 (ET-1) in the blood vessel wall. Because many of these conditions are cytokine-driven we examined the effects of a mixture of cytokines and lipopolysaccharide on ET-1 production in human vascular smooth-muscle (VSMC) cells derived from the internal mammary artery (IMA) and saphenous vein (SV). Incubation of VSMCs from IMA and SV with a combination of tumor necrosis factor-alpha (10 ng/ml), interferon-gamma (1,000 U/ml), interleukin-1 beta (500 U/ml) and lipopolysaccharide (10 micrograms/ml) for up to 48 h markedly elevated the expression of mRNA for ET-1 and the release of ET-1 into the culture medium. We conclude that low levels of ET-1 mRNA and peptide production in human VSMCs are markedly increased by exposure to cytokines and LPS. This suggests that during inflammatory states the VSMC, as well as the endothelium, may be a site of significant ET-1 production in the blood vessel wall.
J Cardiovasc Pharmacol 1998
PMID:Cytokine and lipopolysaccharide stimulation of endothelin-1 release from human internal mammary artery and saphenous vein smooth-muscle cells. 959 78

Septic shock is a life-threatening disorder caused by lipopolysaccharide (LPS) and other bacterial products. Accumulating evidence indicates a role for vasoactive substances and cytokines in this disease process. In this study we examined the effect of LPS on the gene expression of endothelin-1 (ET-1) and adrenomedullin (AM), two major vasoactive peptides predominantly produced by vascular endothelial cells, to investigate their role in the pathophysiology of septic shock. LPS induced ET-1 and AM gene expression in the heart, lung, kidney, liver, and aorta within 6 h. In the liver, whereas basal ET-1 and AM mRNA were hardly detectable, ET-1 and AM gene expression and peptide production were markedly increased by LPS. This LPS-induced upregulation of ET-1 and AM expression is greatly potentiated by D-galactosamine (D-GalN), although D-GalN alone could not induce ET-1 and AM gene expression. These results, together with the previous findings that liver injury induced by LPS and D-GalN is mainly mediated by tumor necrosis factor-alpha (TNF-alpha), suggest that the LPS-cytokine pathway may cause upregulation of ET-1 and AM production, leading to dysregulation of systemic and regional vascular tone.
J Cardiovasc Pharmacol 1998
PMID:Upregulation of endothelin-1 and adrenomedullin gene expression in the mouse endotoxin shock model. 959 37

Nitric oxide (NO) production regulates vasodilation in many blood vessels. Additionally, constitutive NO release is being associated with positive biomedical phenomena, whereas inducible NO synthase (iNOS)-associated NO release with detrimental consequences in regard to endothelial inflammatory activities. As yet, an important link demonstrating why one is activated over the other is not available. Previous studies have demonstrated that morphine and anandamide effector processes are coupled to NO release in human endothelial cells (ECs). This study now extends this observation in that these endogenous signaling molecules may use NO directly to inhibit adenylate cyclase activity. Activation of human ECs, obtained from the saphenous vein, with morphine- or anandamide-stimulated NO release (35 nM and 28 nM, respectively) that peaked within 5 min and returned to basal levels within 10 min of agonist stimulation, consistent with constitutive NO synthase (cNOS) activation. Significant release of NO from ECs stimulated with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) occurred after 2 h after exposure and remained significantly increased over basal levels for 24-48 h (28 nM), consistent with iNOS activation. Preincubation of ECs with morphine or anandamide before, but not after, the addition of LPS + IFN, blocked iNOS activity. Exposure of ECs to the NO donor, SNAP, before the addition of LPS + IFN, blocked iNOS induction, whereas preincubation of ECs with inhibitors of NOS, before morphine or anandamide exposure, restored LPS + IFN induction of iNOS, suggesting a direct impact of NO on the regulation of iNOS activity. Morphine and anandamide stimulation of ECs did not stimulate cyclic adenosine monophosphate (cAMP) accumulation, whereas a marked increase in cAMP was observed in ECs treated with LPS + IFN (8.2 to 33 pmol/mg protein). Treatment of ECs with LPS + IFN did not induce cAMP accumulation in ECs treated with morphine, anandamide, or SNAP before LPS + IFN exposure. These data suggest that cAMP is required for the induction of iNOS in ECs and that NO may directly impair adenylate cyclase activity, preventing iNOS activation.
J Cardiovasc Pharmacol 1998 Jun
PMID:Antagonism of LPS and IFN-gamma induction of iNOS in human saphenous vein endothelium by morphine and anandamide by nitric oxide inhibition of adenylate cyclase. 964 64

The increased production of nitric oxide (NO) has been implicated as the basis for myocardial dysfunction and the lack of response to vasoconstrictors during endotoxin shock induced by lipopolysaccharide (LPS). Our objective was to evaluate and compare NO production in major organs of rats treated with LPS, 1 or 14 mg/kg. A NO spin-trapping technique using electron spin resonance (ESR) spectroscopy has been used to study NO production in the liver, the kidney, the aorta, and the heart. The method was based on the trapping of NO by a metal-chelator complex consisting of N-methyl-D-glucamine dithiocarbamate (MGD) and reduced iron (Fe2+) to form a stable [(MGD)2-Fe2+-NO] complex, giving rise to a characteristic triplet ESR spectrum with g = 2.04 and aN = 12.65 G: Iron was quantified in the different organs to study the [(MGD)2-Fe2+] complex distribution. Six hours after intravenous injection of 1 or 14 mg/kg of LPS, we observed large increases in the [(MGD)2-Fe2+-NO] adduct signal in the liver, the kidney, and in the aorta, strongly suggesting an increased production of NO in these organs. The [(MGD)2-Fe2+-NO] adduct was also detected in the heart, 6 h after injection of LPS. Moreover, we observed dose-dependent increases in [(MGD)2-Fe2+-NO] adduct in the heart, whereas no changes were observed in the other organs. Concurrently, the [(MGD)2-Fe2+-NO] adduct was not detected in the blood from rats treated with LPS, although circulating nitrosylhemoglobin, nitrite, and nitrate levels increased. The spin-trapping technique allowed us to monitor organ-specific formation of NO after LPS administration and for the first time demonstrated direct NO production in aorta and heart of LPS-treated animals.
J Cardiovasc Pharmacol 1999 Jan
PMID:Electron spin resonance detection of nitric oxide generation in major organs from LPS-treated rats. 989 Apr

Conscious, male Long Evans rats (350-450 g) chronically instrumented for the measurement of regional haemodynamics, were infused with FR 167653, a dual inhibitor of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) synthesis (0.32 mg/kg/h) for 24 h, beginning 1 h before coinfusion of saline, or with saline for 24 h beginning 1 h before coinfusion of lipopolysaccharide (150 microg/kg/h), or with FR 167653 beginning 1 h before coinfusion of lipopolysaccharide. Animals infused with FR 167653 and saline showed progressive hindquarters vasoconstriction over the 24-h period, but this was not different from the change seen in animals (n = 3) infused with saline alone. However, plasma analysis at the end of the coinfusion of FR 167653 and saline showed substantial elevation in levels of creatine kinase, lactate dehydrogenase, and potassium, consistent with some tissue damage (heart, liver, or skeletal muscle, or a combination of these). Animals coinfused with saline and lipopolysaccharide showed biphasic decreases in mean arterial blood pressure accompanied by renal hyperaemic vasodilatation, and decreases followed by increases in mesenteric and hindquarters flows and vascular conductances. At the end of the infusion period, plasma analysis showed signs of renal dysfunction (elevated creatinine) and hepatic dysfunction (elevated alkaline phosphatase, gamma-glutamyl transferase, and alanine aminotransferase). In the presence of FR 167653, the hypotensive effects of lipopolysaccharide were abolished, but regional haemodynamics were unchanged, as were signs of organ dysfunction. One explanation of these observations is that FR 167653 causes a relative improvement in cardiac function during infusion of lipopolysaccharide, and this opposes the hypotensive effects of the latter, in spite of its persistent vasodilator effects.
J Cardiovasc Pharmacol 1999 Jul
PMID:Influence of FR 167653, an inhibitor of TNF-alpha and IL-1, on the cardiovascular responses to chronic infusion of lipopolysaccharide in conscious rats. 1041 69

Our previous study described a novel biologic function of compound 48/80 (48/80) in the downregulation of monocytic tissue factor (TF)-initiated hypercoagulation in response to bacterial endotoxin (lipopolysaccharide; LPS). The inhibition was not due to the blockade of LPS cell signaling, as evidenced by the unaffected LPS-induced TF synthesis. We herein determined the mechanism by which 48/80 inhibits the extrinsic coagulation in agonist-challenged THP-1 monocytes. LPS as well as A23187 substantially induced TF activity. TF synthesis was enhanced by LPS but not by A23187. However, the elevated FVII binding to monocytes accompanying the upregulation of factor VII (FVII) activation was uniformly observed in both cases. A 5-min preincubation of the cells with a sheep anti-humanTF antibody (anti-hTF Ab) showed the downregulation of FVII activation, indicating a regulatory role of FVII binding in the modulation of the extrinsic coagulation. The 48/80 blocked FVII binding to monocytes, leading to the preferential inhibition of FVII activation. As the result of the diminished FVIIa formation, monocytic TF-initiated extrinsic coagulation was downregulated in agonist-challenged THP-1 monocytes.
J Cardiovasc Pharmacol 2000 Nov
PMID:IV. Anticoagulant activity of compound 48/80: inhibition of factor VII activation in leukemia THP-1 monocytes. 1106 26

The relationship between soluble and membrane-bound endothelin-converting enzyme (ECE) activity with the level of endothelin-1 (ET-1) synthesis was investigated in cultured endothelial cells. Escherichia coli lipopolysaccharide (LPS) was used to stimulate ET-1 synthesis, and brefeldin A, monensin, colchicine or cytochalasin B, which disrupt peptide biosynthetic pathways in a variety of ways, were tested for their ability to modify changes in ET-1 synthesis and ECE levels. LPS increased ET-1 secretion by more than twofold. Levels of soluble ECE activity, but not those of membrane-bound ECE activity, correlated with ET-1 synthesis. These results suggest the soluble ECE activity is likely to play a role in ET-1 biosynthesis.
J Cardiovasc Pharmacol 2000 Nov
PMID:Relationship between soluble intracellular endothelin-converting enzyme and endothelin-1 synthesis: effect of inhibitors of the secretory pathway. 1107 24

The gene expression and levels of endothelins (ETs) are increased in various animal models of lipopolysaccharide-(LPS) induced septic shock as well as in patients with endotoxaemia (ENDO). A positive correlation was reported between the expression and production of ETs, and the severity of haemodynamic and haematological disturbances, organ injury and circulatory failure in ENDO. Previous studies using ET(A)- and/or ET(B)-receptor antagonists exacerbated the effects of LPS in anaesthetized and conscious rats. We investigated the effect of a selective neutral endopeptidase (NEP) (CGS 24592) or a mixed NEP/endothelin-converting enzyme (ECE) (CGS 26303) inhibitor in LPS-induced ENDO in anaesthetized Sprague-Dawley rats. Four hours post-LPS injection, blood pressure was 39% lower in the presence of CGS 26303, compared to control-saline or LPS-injected rats. In rats treated with CGS 26303, white blood cells and platelet counts decreased, whereas lymphocytes increased. In addition, progressive liver dysfunction, characterized by increases in plasma bilirubin and alanine transferase, became even more apparent (higher than in those injected with LPS). Plasma creatinine and blood urea were similar to those of the LPS-injected group. Similar results were observed with CGS 24592. Thus, these inhibitors enhanced some, but not all, of the LPS-induced deleterious effects.
J Cardiovasc Pharmacol 2000 Nov
PMID:Effects of a selective neutral endopeptidase and a nonselective neutral endopeptidase/endothelin-converting enzyme inhibitor on lipopolysaccharide-induced endotoxaemia in anaesthetized Sprague-Dawley rats. 1107 21


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