Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased release of endothelium-derived relaxing factor/nitric oxide has been proposed as the final common pathway for vasodilator responses to gram-negative lipopolysaccharide (endotoxin). To test this hypothesis, we examined endothelium-dependent and endothelium-independent vasodilator agents in vascular smooth muscle isolated from guinea pigs 16 hours after injection of saline (control group) or induction of Escherichia coli endotoxemia; aortic rings (approximately 1 mm in diameter) were studied with standard isometric tension techniques. Endotoxemia resulted in a significant loss of vasodilator responses to the endothelium-dependent receptor agonists acetylcholine (10(-10)-10(-5) M) and ADP (10(-8)-10(-5) M). In contrast, endotoxemia did not affect vasodilator responses to either the endothelium-dependent receptor agonist substance P (10(-11)-10(-7) M), the endothelium-dependent and receptor-independent agonist A23187 (10(-9)-10(-6) M), or the endothelium-independent agonist nitroprusside (10(-10)-10(-4) M). The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) inhibited the vasodilator response to acetylcholine more in vessels from lipopolysaccharide-injected than control guinea pigs. Unexpectedly, L-NAME converted the endothelium-dependent vasodilator action of ADP to an endothelium-dependent vasoconstrictor response that was blocked individually by the cyclooxygenase inhibitor indomethacin, the thromboxane synthase inhibitor dazoxiben, and the thromboxane A2 receptor antagonist SQ29548. We conclude that in vivo endotoxemia inhibits the constitutive isoform of nitric oxide synthase in endothelial cells by selectively disrupting receptor-coupled activation mechanisms shared by acetylcholine and ADP. Furthermore, since L-NAME unmasks a thromboxane A2-mediated vasoconstrictor action of the endogenous purinoceptor agonist ADP, drugs that inhibit nitric oxide synthase could exacerbate sepsis-induced vasoconstriction and ischemia by synergizing with lipopolysaccharide-induced inhibition of endothelial nitric oxide synthase.
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PMID:Selective inhibition of endothelium-dependent vasodilator capacity by Escherichia coli endotoxemia. 767 34

Endothelial nitric oxide exerts local vasodilatory actions in the gastrointestinal (GI) microvasculature and is proposed to play a role in enteric vasomotor regulation. The aims of this study were to characterize the tissue distribution of mRNA for endothelial nitric oxide synthase (NOS-III) and to examine its response to endotoxin challenge in vivo. We demonstrate the expression of NOS-III mRNA and protein in mucosa throughout the gastrointestinal tract and show for the first time that NOS-III mRNA expression in the GI mucosa was down-regulated in the rats treated with endotoxin. The ubiquitous expression of NOS-III mRNA in digestive tissues is consistent with the proposed role of NOS-III in the physiology of the gastrointestinal tract. The decreased NOS-III mRNA, in parallel to induction of inducible NOS (NOS-II) mRNA, may contribute to the impaired endothelium-dependent relaxation and damaged mucosal integrity during sepsis.
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PMID:Expression of endothelial constitutive nitric oxide synthase mRNA in gastrointestinal mucosa and its downregulation by endotoxin. 932 74

Vascular endothelium releases nitric oxide (NO), an important vasodilator that is continuously synthesised by the constitutive enzyme, endothelial nitric oxide synthase (NOS). This maintains a constant vasodilator tone which is diminished in adult hypertension, due to reduced endothelium-dependent vascular relaxation, which is NO dependent. In childhood, however, hypertension is often secondary, and normalisation of blood pressure by removal of cause (e.g. renal artery stenosis, catecholamine-producing tumour) suggests reversibility of endothelial dysfunction, if it is present. Raised plasma levels of endogenous inhibitors have been found, especially in children with secondary hypertension due to renal parenchymal and renovascular disease, and may contribute to hypertension by more than just inhibition of vascular NO release; e.g. by reduction of glomerular filtration rate and promotion of salt and water retention. These inhibitors also modulate renin release, which may be of relevance in cardiovascular physiology, and may also interfere with the anti-platelet properties of NO, increasing the likelihood of vascular thrombotic events. NO inhibitors also promote endothelial activation, with increased expression of adhesion molecules that may form seedlings of atherosclerosis. In chronic renal impairment, accumulation of NO inhibitors may contribute to hypertension. Efficient long-session dialysis helps better interdialysis control of blood pressure in these subjects, independent of salt and water removal, suggesting that removal of such vasoactive agents may be important for efficient blood pressure control. There are a few studies assessing NO generation in hypertensive children via plasma nitrite and nitrate, the NO end products, which suggest normal or increased production as opposed to a reduction, perhaps as a compensatory phenomenon. In the treatment of hypertension, nitroprusside and nitrates exert their actions via NO donation. Excessive production of NO (usually via inducible NOS) or excessive administration (nitrovasodilators) can be cytotoxic and may cause hypotension and shock, as in severe sepsis. NOS inhibitors and NO therefore appear to play a crucial role in aetiology, complications and therapy of childhood hypertension.
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PMID:Vascular endothelium and nitric oxide in childhood hypertension. 981 94

The decrease in glomerular filtration rate that is characteristic of sepsis has been shown to result from the local glomerular inhibition of endothelial nitric oxide synthase (NOS) by nitric oxide (NO) generated from the inducible isoform of NOS (iNOS). iNOS activation depends on de novo synthesis of both RNA and protein. Therefore it is assumed that several hours are required for its full activation. Yet the renal hemodynamic response in sepsis has been documented as early as 60 minutes after lipopolysaccharide (LPS) administration. Experiments were designed to determine the time course of LPS-induced glomerular iNOS mRNA expression and activity in rats. Rats were treated with LPS (2 mg/kg body weight IP). Kidneys were removed after 1,2, 4, 6, and 16 hours. Glomeruli were isolated and incubated. Nitric oxide generation was measured with a Griess assay, and iNOS mRNA was studied by reverse transcriptase-polymerase chain reaction. Similar time course experiments were repeated in glomeruli isolated from normal rats and exposed to LPS in vitro. A significant increase in iNOS mRNA expression was evident as early as 60 minutes after both in vivo and in vitro administration of LPS. The quantity of iNOS mRNA reached its peak between 2 to 4 hours after administration and declined to baseline levels after 16 hours. Immunohistochemical studies were remarkable for a significant increase in the staining for iNOS in glomeruli 2 hours after the in vivo administration of LPS. Plasma nitric oxide concentration after the in vivo administration of LPS increased from a baseline level of 11.25 +/- 0.8 micromol/L to a peak level of 62.9 +/- 3.8 micromol/L (P < .05 vs baseline) at 4 hours and then decreased to 17.5 +/-1.9 micromol/L at 16 hours. Similar results were obtained when the glomerular generation of nitric oxide after in vivo administration of LPS was measured (2.6 +/- 0.8 pmol/h/microg tissue, 17.2 +/- 2.1 pmol/h/microg tissue (P < .05 vs baseline), and 0.4 +/- 0.65 pmol/h/microg tissue, respectively). These results provide evidence of the rapid activation of glomerular iNOS after in vivo and ex vivo administration of LPS and thus support the role of nitric oxide in the early renal hemodynamic response to LPS.
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PMID:Time course of lipopolysaccharide-induced nitric oxide synthase mRNA expression in rat glomeruli. 1056 Sep 40

The decrease in glomerular filtration rate (GFR) that is characteristic of sepsis has been shown to result from inhibition of glomerular endothelial nitric oxide synthase (eNOS) by nitric oxide (NO) generated from the inducible isoform of NOS (iNOS). Although l-arginine is the sole precursor for NO biosynthesis, its intracellular availability in glomeruli from septic animals has never been investigated. Arginine uptake was measured in freshly harvested glomeruli from the following experimental groups: 1) untreated rats; 2) rats pretreated with LPS (4 mg/kg body wt, 4 h before experiments); 3) rats treated with LPS as above with either l-N(6)-(1-iminoethyl)lysine hydrochloride (l-NIL), a selective iNOS antagonist, or 7-nitroindazole, a selective neuronal NOS antagonist; and 4) rats treated with l-NIL only. Both glomeular and mesangial arginine transport characteristics were found compatible with a y(+) system. Arginine uptake was augmented in glomeruli from LPS-treated rats. Treatment with l-NIL completely abolished this effect whereas l-NIL alone had no effect. Similar results were obtained when primary cultures of rat mesangial cells were preincubated with LPS (10 microg/ml for 24 h) with or without l-NIL. Using RT-PCR, we found that in vivo administration of LPS resulted in a significant increase in glomerular cationic amino acid transporter-2 (CAT-2) mRNA expression whereas CAT-1 mRNA was undetected. Northern blotting further confirmed a significant increase in glomerular CAT-2 by LPS. In mesangial cells, the expression of both CAT-1 and CAT-2 mRNA was augmented after incubation with LPS. In conclusion, in vivo administration of LPS augments glomerular arginine transport through upregulation of steady-state CAT-2 mRNA while downregulating CAT-1 mRNA. These results may correspond to the changes in glomerular iNOS and eNOS activity in sepsis.
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PMID:Differential regulation of glomerular arginine transporters (CAT-1 and CAT-2) in lipopolysaccharide-treated rats. 1247 43

Sepsis and septic shock are important causes of morbidity and lethality in noncoronary intensive care units. Circulating levels of high-density lipoproteins (HDLs) are reduced in sepsis/septic shock, and the magnitude of this reduction is positively correlated with the severity of the illness. The mechanisms underlying this phenomenon are incompletely understood, although increased levels of several acute-phase proteins, including serum amyloid A (SAA) and secretory phospholipase A2 (sPLA2), may contribute to the decrease in plasma HDLs. It has been suggested that HDLs possess anti-inflammatory properties and, hence, may play a crucial role in innate immunity by regulating the inflammatory response as well as being capable of reducing the severity of organ injury in animals and patients with septic shock. These protective effects of HDLs are mediated mainly via (a) lipopolysaccharide (LPS) binding and neutralization, (b) the HDL-associated enzymes, plasma paraoxonase (PON1) and platelet-activating factor acetylhydrolase (PAF-AH), which protect low-density lipoproteins against peroxidative damage, (c) inhibition of the expression of endothelial cell adhesion molecules and release of proinflammatory cytokines, which prevents inflammatory cell infiltration and subsequent multiple organ dysfunction, and (d) stimulation of the expression of endothelial nitric oxide synthase (eNOS). Thus, HDL exerts potent anti-inflammatory effects, some of which are independent of endotoxin binding and might be useful in the treatment of patients with not only sepsis/septic shock but also other conditions associated with an uncontrolled inflammatory response, such as ischemia-reperfusion injury and hemorrhagic shock.
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PMID:High-density lipoproteins in sepsis and septic shock: metabolism, actions, and therapeutic applications. 1477 33

Ketamine is the only intravenous anesthetic that causes an increase in mean arterial pressure without compromising cardiac output. These beneficial effects are basically linked to stimulation of the sympathetic nervous system, inhibition of adenosine triphosphate-sensitive potassium channels and interactions with the nitric oxide pathway. Experimental and clinical studies have shown that ketamine exerts antiinflammatory properties by inhibiting the release of proinflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6. In addition, there is increasing evidence that early ketamine administration reduces mortality in experimental sepsis models. In view of the current literature ketamine appears to represent a beneficial therapeutic option for long-term sedation of patients with arterial hypotension resulting from sepsis and systemic inflammatory response syndrome (SIRS). However, it has to be taken into account that ketamine inhibits endothelial nitric oxide synthase, thereby potentially aggravating impaired (micro) regional blood flow in sepsis. Future studies are required to investigate the role of ketamine in the treatment of patients with sepsis and SIRS.
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PMID:[Role of ketamine in sepsis and systemic inflammatory response syndrome]. 1677 27

This review describes the laboratory evidence and microvascular mechanisms responsible for the beneficial effects of statins in sepsis. During sepsis, changes occur within the microcirculation including alterations in arteriolar tone influencing blood pressure, adaptations to endothelial cell integrity causing leakage of proteins and macromolecules, and adhesion and migration of leucocytes through the vascular endothelium. Statins are widely used as cholesterol-lowering agents, but appear to have anti-inflammatory actions during sepsis. We have discussed the effects of statins on specific pathological processed within the microcirculation and focused on the role of nitric oxide (NO). The main mechanism by which statins appear to be an effective treatment for sepsis is increased expression of endothelial nitric oxide synthase (eNOS), in conjunction with down-regulation of inducible nitric oxide synthase. Combined, this results in an increase in physiological concentrations of NO, thus restoring endothelial function. Laboratory studies have therefore suggested that enhancement of eNOS activity during sepsis may lead to restoration of microvascular tone, maintenance of microvascular integrity, and inhibition of cell adhesion molecules. However, other mechanisms independent of lipid-lowering effects, including antioxidant activity and alterations in the development of vascular atherosclerosis, may also contribute to the beneficial effects of statins. We have also addressed the influence on the effects of statins of lipid solubility and pre- and pro-phylactic administration.
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PMID:Beneficial effects of statins on the microcirculation during sepsis: the role of nitric oxide. 1725 Dec 10

Sepsis-related acute kidney injury (AKI) is the leading cause of AKI in intensive care units. Endotoxin is a primary initiator of inflammatory and hemodynamic consequences of sepsis and is associated with experimental AKI. The present study was undertaken to further examine the role of the endothelium, specifically prostacyclin (PGI(2)), in the pathogenesis of endotoxemia-related AKI. A low dose of endotoxin (LPS, 1 mg/kg) in wild-type (WT) mice was associated with stable glomerular filtration rate (GFR) (164.0 +/- 16.7 vs. 173.3 +/- 6.7 microl/min, P = not significant) as urinary excretion of 6-keto-PGF(1alpha), the major metabolite of PGI(2), increased. When cyclooxygenase inhibition with indomethacin abolished this rise in 6-keto-PGF(1alpha), the same low dose of LPS significantly decreased GFR (110.7 +/- 12.1 vs. 173.3 +/- 6.7 microl/min, P < 0.05). The same dose of indomethacin did not alter GFR in WT mice. To further study the role of PGI(2) in endotoxemia, renal-specific PGI synthase (PGIs) transgenic (Tg) mice were developed that had increased PGIs expression only in the kidney and increased urinary 6-keto-PGF(1alpha). These Tg mice, however, demonstrated endotoxemia-related AKI with low-dose LPS (1 mg/kg) (GFR: 12.6 +/- 3.9 vs. 196.5 +/- 21.0 microl/min P < 0.01), which did not alter GFR in WT mice (164.0 +/- 16.7 vs. 173.3 +/- 6.7 microl/min, P = not significant). An elevation in renal cAMP, however, suggested an activation of the PGI(2)-cAMP-renin system in these Tg mice. Moreover, angiotensin-converting enzyme inhibition afforded protection against endotoxin-related AKI in these Tg mice. Thus endothelial PGIs-mediated PGI(2), as previously shown with endothelial nitric oxide synthase-mediated nitric oxide, contributes to renal protection against endotoxemia-related AKI. This effect may be overridden by excessive activation of the renin-angiotensin system in renal-specific PGIs Tg mice.
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PMID:Prostacyclin in endotoxemia-induced acute kidney injury: cyclooxygenase inhibition and renal prostacyclin synthase transgenic mice. 1765 70

Understanding the biochemical mechanisms influencing bubble pathophysiology may foster novel pharmacologic non-recompressive strategies that may prevent, ameliorate, and treat decompression sickness (DCS), and the injury sustained from arterial gas emboli (AGE) encountered in hyperbaric and hypobaric exposures, as well as in surgery and trauma. This review explores the biochemical effects of nitric oxide (NO) release agents, their potential impact on bubble pathophysiology, and possible use as a pharmacological intervention to reduce DCS risk and AGE injury. The hypotheses discussed contend that exogenous NO administration or mediators of endogenous NO up-regulation may reduce DCS risk and severity by mediating; (1) decreased populations of gaseous nuclei, (2) decreased bubble nuclei adherence, (3) depression of the deleterious bubble-mediated inflammatory and coagulation cascades and (4) preservation of endothelial integrity, which may defend against bubble-mediated injury. Statin medications alter numerous biochemical, and biophysical processes, which may influence bubble formation. Statins preserve endothelial integrity, reduce ischemia/reperfusion injury, and depress the interdependent inflammatory and coagulation cascades via pleiotropic properties involving up-regulation of endothelial nitric oxide synthase (eNOS) and NO. Numerous studies are researching statins, for their potential efficacy in reducing primary and secondary morbidity and mortality from cardiocerebrovascular, inflammatory (autoimmune), and infectious (sepsis) disease. Additionally, statin-mediated lipid reduction may reduce bubble generation via alterations in plasma "rheology", and surface tension. The statins are attractive potential NO release with minimal adverse side effects, and proven long-term safety, that may potentially mitigate the risk and severity of DCS. We will elaborate on the insight gained into the mechanisms proven and hypothesized for NO-mediated reductions in bubble formation, and DCS incidence and severity, with a focus on the potential for statin medications, in addition to the direct NO-donor medications such as isosorbide mononitrate and nitroglycerine.
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PMID:Investigating the potential of statin medications as a nitric oxide (NO) release agent to decrease decompression sickness: a review article. 1785 2


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