UMLS:C0036690 - FACTA Search

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Query: UMLS:C0036690 (sepsis)
59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Systemic sepsis is associated with acute deterioration in renal function despite normal or increased cardiac output. The kidney is often structurally normal, but severe renal vasoconstriction underlies a marked decrease in the glomerular filtration rate (GFR). The mechanisms underlying renal vasoconstriction in sepsis include locally and systemically released vasoconstrictors. Novel peptide and lipid-derived mediators that have been implicated in experimental models of sepsis include endothelin (ET)-1, thromboxane A2 (TXA2), leukotrienes (LTs), and, most recently, noncyclooxygenase-derived prostaglandin F2 (PGF2) analogues. Plasma ET-1 levels are elevated in septic patients and following endotoxin administration in experimental animals; antagonism of the endogenous actions of ET-1 is associated with improvement in renal perfusion and function during experimental endotoxemia. Antagonists of the TXA2 receptor and/or TXA2 synthesis in vivo have been associated with selective improvement in renal vascular tone and preservation of GFR during experimental endotoxemia in several mammalian species. Furthermore, antagonism of the TXA2 receptor inhibits the actions of endogenously released free radical-generated PGF compounds. The latter are the most potent renal vasoconstrictors among the family of arachidonic acid derivatives. Sulfidopeptide LTs, in particular LTC4 and LTD4, are also implicated in the renal vasoconstriction that attends sepsis in rats and other experimental animals. LT hepatobiliary elimination is suppressed during sepsis and endogenous LT production is enhanced. Antagonism of LTD4 receptors is associated with amelioration of renal vasoconstriction. Taken together, these novel potential mediators of renal vasoconstriction during sepsis constitute specific molecular targets for future therapeutic interventions.
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PMID:Sepsis-associated renal vasoconstriction: potential targets for future therapy. 151 7

1. Male Sprague-Dawley or Wistar rats were injected with bacterial lipopolysaccharide (LPS; 5 mg kg-1, i.p.) and killed after 1, 3, 6, 15, and 24 h. The brains, mesenteries, spleens, lungs, livers, kidneys, hearts, aortae and diaphragms were removed and frozen immediately. Control rats were injected with sterile saline and killed after 6 h. 2. The organs were homogenized in a semi-frozen state and NO synthase (NOS) activity measured in tissues from both LPS-treated and saline-treated groups by the ability of homogenates to convert [3H]-L-arginine to [3H]-L-citrulline in a NADPH-dependent manner. 3. The NOS activity in all organs taken from control animals was found to be calcium-dependent, with the highest activity being in the brain. After LPS-treatment an induced calcium-independent NOS was detected in all tissues tested, with the exception of the brain. The spleen, lung, mesentery and liver had the highest amounts of LPS-induced NOS activity. No induction of calcium-dependent NOS was detected. 4. Induction of NOS was maximum 6 h after administration of LPS and had returned to control levels in 24 h. 5. The constitutive NOS in brain and mesentery and the LPS-induced activities in the spleen, lung, liver and mesentery were inhibited by NG-monomethyl-L-arginine (L-NMMA) or NG-nitro-L-arginine methyl ester (L-NAME) according to concentration. The IC50 for L-NAME was 2.5 microM against the constitutive NOS from brain, and 20-25 microM against the inducible NOS. For L-NMMA the IC50 was 20-25 microM against either NOS isoform. 7. The vascular responses to endothelin-I (ET-1), the thromboxane A2-mimetic 11 alpha,9 alpha-epoxymethanoprostaglandin F2alpha (U46619), phenylephrine (PE) or 5-hydroxytryptamine (5-HT) were measured in the simultaneously perfused arterial and venous mesenteric vascular beds from both control and LPS-treated(6 h) rats. Vasoconstrictor responses to all agonists tested were unaffected by LPS treatment. In the presence of L-NAME (100 microM) vasoconstrictor responses were potentiated in both the arterial and venous portion of the mesenteric beds from both control and LPS-treated rats. The potentiation of responses to U46619 was significantly greater in beds from LPS-treated rats.8. Injection of LPS i.p. is associated with induction of NOS in all organs tested, except for the brain. In the mesentery this is not accompanied by a hyporesponsiveness to constrictor agents suggesting an increased sensitivity, particularly to U46619. This may explain the poor perfusion and tissue damage in the splanchnic circulation associated with sepsis.
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PMID:Induction by endotoxin of nitric oxide synthase in the rat mesentery: lack of effect on action of vasoconstrictors. 768 6

A rapidly increasing body of evidence is implicating endothelin and TNF in the pathogenesis of septic acute renal failure. TNF causes renal damage by recruiting leukocytes, accelerating fibrin accumulation, promoting cell lysis, stimulating the release of vasoconstrictor substances, and other mechanisms. ET-1 causes renal dysfunction in sepsis and endotoxaemia primarily by evoking severe reductions in RBF and GFR. While these are only two of the many agents that mediate renal dysfunction during sepsis, they stand out by virtue of their combined ability to modulate numerous inflammatory pathways and to elicit marked alterations in renal function. Clearly the development of specific TNF and endothelin antagonists holds out promise for the treatment and prevention of septic acute renal failure.
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PMID:Role of endothelin and tumour necrosis factor in the renal response to sepsis. 780 Feb 73

We determined the plasma levels of type-II phospholipase A2 (type II PLA2), platelet-activating factor acetylhydrolase (PAFAH) leukotriene B4 (LTB4) and of several complements (C3a, C4a, and C5a), which are considered to be among the cytokines and eicosanoids involved in vascular endothelial disorders and that vary in concentration during sepsis. We investigated the relationship between those levels and those of ET-1 and TM levels in plasma. Plasma levels of type II PLA2, PAFAH, LTB4, C3a, C4a, ET-1, and TM at the time that sepsis was diagnosed in 30 patients were 218.3 +/- 179.9 ng/ml, 23.92 +/- 9.66 nmol/min/ml, 90.35 +/- 31.49 pg/ml, 838.73 +/- 2.30 pg/ml, 1951.46 +/- 1697.78 pg/ml, 6.98 +/- 4.08 pg/ml and 7.80 +/- 3.34 ng/ml, respectively. The C5a plasma level was below the limit of detection in all cases. There were significant correlations between type II PLA2 and ET-1 plasma levels (r = 0.39, p = 0.032) and C3a and ET-1 plasma levels (r = 0.60, p = 0.03). There were also significant correlations between type II PLA2 and TM levels in plasma (r = 0.76, p = 0.0017), PAFAH and TM plasma levels (r = 0.53, p = 0.037), LTB4 and TM plasma levels (r = 0.46, p = 0.016) and C4a and TM plasma levels (r = 0.58, p = 0.037). Results suggest that the elevation of type II PLA2, PAFAH, LTB4 and complement in plasma is involved in vascular endothelial disorders in patients with sepsis.
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PMID:Relationships between plasma levels of type-II phospholipase A2, PAF-acetylhydrolase, leukotriene B4, complements, endothelin-1, and thrombomodulin in patients with sepsis. 793 1

1. In patients with sepsis syndrome, plasma levels of ET-LI and NA were elevated. In the porcine endotoxin shock model, plasma ET-1-L1 levels were also elevated and increased plasma levels of NA, A and NPY-LI indicated enhanced sympatho-adrenal activation. 2. ET-1 infusion in healthy human subjects to arterial plasma levels of ET-1-LI below or similar to those seen in patients with sepsis syndrome, induced a fall in splanchnic and renal blood flow, indicating that circulating ET-1-LI at levels seen in sepsis syndrome, have vasoactive effects. 3. In man, ET-1-LI was extracted in the pulmonary, splanchnic, renal and skeletal muscle vascular beds, but not in the cerebral circulation. The pulmonary circulation eliminated almost half of the administered ET-1. Apart from an initial short half-life of plasma ET-1-LI (1-2 min) after infusion, a prolonged presence of slightly elevated plasma ET-1-LI may have contributed to the long-lasting vasoconstrictor effect of the peptide in lung, splanchnic and renal circulations. In contrast, signs of vasodilation were present in the cerebral and skeletal muscle circulations, indicating net ETB receptor activation in these vascular beds. In the pig, upon infusion of similar doses of ET-1, the vascular response was slightly smaller than that in man while the pulmonary fractional extraction of ET-1-LI was similar in both species. At high levels of ET-1-LI the extraction capacity in the pig lung was saturated. Pretreatment with diclofenac did not significantly change the cardiovascular response to ET-1 nor plasma levels of ET-1-LI or the disappearance rate of ET-1-LI after infusion. 4. In the pig, pretreatment with diclofenac led to a more stable haemodynamic course during endotoxin infusion. Further, it abolished the first peak in the biphasic increase in PAP and PVR seen in endotoxin controls, indicating participation of products from the cyclooxygenase pathway in both the pulmonary hypertension and systemic hypotension seen in endotoxin shock. The increase in arterial plasma levels of ET-1-LI was delayed but not reduced by diclofenac whereas the activation of the sympathetic nervous system was attenuated. 5. A low dose of inhaled NO (10 ppm) markedly reduced the second, more prolonged phase of pulmonary hypertension during endotoxaemia. No signs of tachyphylaxis was seen during 2.5 h of NO inhalation, and upon cessation a rapid (within 15 min) elevation of PAP and PVR was seen. The effect was selective to the lung circulation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Circulatory responses to endothelin-1 and nitric oxide with special reference to endotoxin shock and nitric oxide inhalation. 837 40

Circulating endothelin-1 concentrations are elevated in animal models of sepsis. The major actions of endothelin-1 appear to be as a local autocrine and paracrine factor, rather than as a circulating hormone, and plasma concentrations may not reflect local tissue concentrations. We therefore measured tissue expression of mRNA encoding pre-pro-endothelin-1 by RNase protection assays, as an indicator of local production of ET-1 in an in vivo rat model of endotoxaemia. The effects of dexamethasone pre-treatment were also examined. There was a tissue-specific increase in pre-pro-endothelin-1 mRNA in endotoxaemia, apparent at 6h after endotoxin challenge in heart and lung. No significant changes in expression were seen in kidney or skeletal muscle. Dexamethasone pre-treatment significantly attenuated the rise in pre-pro-endothelin-1 mRNA in heart at 6h. Therefore, we have demonstrated tissue-specific differences in the effect of endotoxin upon pre-pro-endothelin-1 mRNA expression and in sensitivity to dexamethasone. This could account for some of the inter-tissue differences seen in local vascular response to endotoxin.
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PMID:Tissue expression of endothelin-1 mRNA in endotoxaemia. 857 67

The release of endogenous vasoconstrictors together with changes in the vascular responses are central to the pathophysiology of sepsis. The effects of in vitro incubation for 20 h with heat-killed group B Streptococcus (GBS, 3 x 10(7) colony-forming units mL-1) on the vasoconstrictor responses to noradrenaline (NA, 10(-8) to 10(-4) M), the thromboxane A2 analog 9,11-dideoxy-11 alpha, 9 alpha-epoxymethanoprostaglandin F2 alpha (U46619; 10(-10) M to 10(-6) M) and endothelin-1 (ET-1, 10(-11) to 3 x 10(-9) M) were evaluated on isolated intrapulmonary and mesenteric arteries from 10-17-d-old piglets. The incubation with GBS reduced the maximal contractile response to NA and ET-1 (p < 0.01) in both arteries. The nitric oxide (NO) synthase (NOS) inhibitor N omega-nitro-L-arginine methyl ester (L-NAME; 10(-4) M) completely reversed this hyporesponsiveness. GBS-treated mesenteric arteries also showed a significant reduction of the maximal contractions induced by U46619 (p < 0.05) and this effect was inhibited by 10(-4) M L-NAME. In contrast, the maximal contractile responses to U46619 were similar in control and in GBS-treated pulmonary arteries. Addition of L-NAME did not modify the contractile responses to U46619 in GBS-treated pulmonary arteries. In conclusion, GBS-treated systemic arteries from neonatal piglets showed decreased responses to NA, U46619, and ET-1 due to enhanced NO release. GBS-treated pulmonary arteries also exhibited decreased responses to NA and ET-1 but not to U46619. Induction of NOS in vascular smooth muscle may play a key role in the hypotension and loss of systemic vascular responsiveness that occurs in GBS sepsis. The absence of pulmonary hyporesponsiveness to U46619 may partially explain the coexistence during sepsis of pulmonary hypertension and lung NOS induction.
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PMID:Effects of group B Streptococcus on the responses to U46619, endothelin-1, and noradrenaline in isolated pulmonary and mesenteric arteries of piglets. 894 58

Recently much attention has been paid to the circulatory disturbance and peripheral vascular damage in patients with sepsis and septic shock. We intended to elucidate the interaction between nitric oxide (NO) and endothelin (ET)-1 under various pathological conditions by measuring the concentrations of NO3-, the principal metabolite of NO and immunoreactive ET-1. In cases with good prognosis after the septic shock, ET-1 was significantly higher as compared with these in sepsis without shock. In lethal cases with septic shock, these parameters were abnormally high as compared with the survived case. These levels elevated as the degree of severity progressed. When patients recovered from the septic shock, plasma ET-1 levels rapidly decreased. These results may mean that the level of the concentration of ET-1 plays a key role for prevention of the multiple organ failure even after the recovery from septic shock. The elevated level of NO3- during the initial several days in septic shock will mean that NO is acting to prevent platelet aggregation and to keep blood flow by dilating the arteries during septic shock. On the contrary, it may also be suggested that the elevated level of NO3- and ET-1 leads to the dysfunction of vascular endothelial cells and the apoptosis.
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PMID:[Measurement of levels of plasma endothelin-1 and serum nitrate anion in patients with sepsis]. 956 66

Polymicrobial sepsis is characterized by an early, hyperdynamic phase followed by a late, hypodynamic phase. Although studies have suggested that endothelins (ETs) contribute to the development of shock after a bolus injection of endotoxin, little is known about the role of ETs in the transition from the hyperdynamic phase to the hypodynamic phase of sepsis. To study this, male adult rats were subjected to sepsis by cecal ligation and puncture (CLP) followed by fluid resuscitation. Plasma levels of ET-1 and ET-2 were measured by radioimmunoassay at 2, 5, 10 h (i.e. the early stage of sepsis), and 20 h (late stage) following CLP or sham operation. Tissue levels of ET-1 and ET-2 were determined in the heart, lungs, small intestine, and spleen at 5 h after CLP or sham operation. In addition, preproendothelin-1 (precursor of ET-1) gene expression was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) at 5 h in the heart, lungs, small intestine, spleen, and liver. The results indicate that plasma levels of ET-1 and ET-2 were not different from values of sham groups at 2 and 20 h, but were significantly higher than the sham values at 5 and 10 h after CLP. While there were no significant increases in tissue levels of ET-1 and ET-2 at 5 h post-CLP, RT-PCR analysis indicates a significant upregulation of preproendothelin-1 gene expression in the heart, spleen, and liver (but not in the lungs or small intestine) at 5 h after the onset of sepsis. These results indicate that the heart, spleen, and liver appear to be important ET-producing organs during the early stage of sepsis. The lack of significant increases in tissue ET levels could be due to the possibility that the newly converted peptide is quickly transferred to the bloodstream. Since the hyperdynamic phase of sepsis occurs at 2-10 h and the hypodynamic phase occurs at 20 h after CLP, the increased plasma levels of ET at 5 and 10 h suggest that mediators other than ETs (such as adrenomedullin) are responsible for producing the biphasic hemodynamic responses during the progression of polymicrobial sepsis.
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PMID:The dissociation between upregulated endothelins and hemodynamic responses during polymicrobial sepsis. 1083 94

We conducted this study to elucidate the role of endothelins (ET-1) in mediating the hepatic microcirculatory dysfunction observed in response to sepsis. Following 24 h of cecal ligation and puncture (CLP), we performed intravital microscopy both in vivo and on isolated perfused livers. Portal resistance increased in response to ET-1 in both sham and septic rats, with no significant difference between the two in either in vivo or in isolated livers. Sinusoidal volumetric flow (Qs) was evaluated using red blood cell velocity (V(RBC)) and sinusoidal diameter (Ds) to determine microvascular hemodynamic integrity. Qs decreased in response to ET-1 in livers from CLP rats compared with sham (P < 0.05, CLP vs. sham) in both in vivo and isolated livers. In vivo infusion of ET-1 resulted in greater constriction of sinusoids in the CLP group compared with sham (P < 0.05), resulting in higher sinusoidal resistance. Microvascular hyper-responsiveness was accompanied by hepatocellular injury in CLP rats, but not in sham rats. RT-PCR was performed to measure mRNA levels of ET-1, its receptors ET(A) and ET(B), inducible and constitutive nitric oxide (NO) synthase (iNOS and eNOS, respectively), and heme oxygenase 1 (HO-1). After CLP, both ET-1 and ET(B) mRNA increased, whereas ET(A) mRNA tended to decrease, although the change was not statistically significant. Livers from CLP rats showed no significant change in levels of eNOS mRNA, but showed a significant increase in iNOS expression (13.5-fold over sham). There was no change in the level of HO-1 mRNA between sham and CLP groups. Taken together, these results suggest that sepsis sensitizes the hepatic microcirculation to ET-1. More importantly, an impaired microcirculatory flow due to ET-1 in sepsis contributes to hepatic injury. Further, localized imbalances between endothelins and NO may mediate the altered microvascular response during sepsis.
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PMID:Potentiated hepatic microcirculatory response to endothelin-1 during polymicrobial sepsis. 1241 19

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