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)

The effects of L-arginine on the adrenergic responses to either electrical transmural stimulation or phenylephrine were studied in isolated endothelium-denuded strips of rat tail arteries treated with lipopolysaccharide for 6 h in vitro. L-arginine did not relax the strips precontracted by phenylephrine. However, the adrenergic contractions induced by electrical transmural stimulation were significantly inhibited by the addition of L-arginine. This inhibitory effect was reversed by NG-nitro-L-arginine (a nitric oxide synthase inhibitor) or methylene blue (a soluble guanylate cyclase inhibitor) but was not affected by hemoglobin (a scavenger of nitric oxide). These results indicate that the adrenergic neurogenic contractions may be directly modulated by nitric oxide derived from the sympathetic nerves and/or neighboring cells in the lipopolysaccharide-treated rat tail arteries, and the nitric oxide production may be associated with the reduction of sympathetic tone in sepsis.
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PMID:Selective inhibition of sympathetic nerve-mediated contraction by L-arginine in lipopolysaccharide-treated tail artery of rats. 753 6

1. We measured nitric oxide synthase activity in peripheral blood polymorphonuclear leucocytes from 10 patients with sepsis syndrome and 10 healthy subjects. 2. Synthase activity was significantly higher in patients with sepsis than in control subjects (1202 +/- 579 compared with 595 +/- 544 pmol of nitric oxide min-1 mg-1 of cell protein, P < 0.05). 3. Activity was greatest in those patients with the larger number of organ failures, although this failed to reach significance (1489 +/- 560 in patients with three or more organ failures and 843 +/- 404 pmol of nitric oxide min-1 mg-1 of cell protein in those with less than three, P = 0.11). 4. This study provides evidence for the role of overproduction of the vasodilator nitric oxide in sepsis syndrome.
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PMID:Nitric oxide synthase activity is increased in patients with sepsis syndrome. 753 46

Nitric oxide and vasoactive intestinal peptide (VIP) are potent vasodilators and postulated as inducers of hypotension. These mediators activate guanylate cyclase and adenylate cyclase, respectively, with subsequent biosynthesis of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) producing vascular smooth muscle relaxation and vasodilatation. Cyclic nucleotides and VIP were evaluated during Escherichia coli septicemia in two groups of rabbits; 1) sepsis alone and 2) sepsis and a competitive inhibitor of nitric oxide synthase, NG-monomethyl-L-arginine. Arterial blood was obtained for determination of bacteremia, lactic acidemia, nucleotides, nitrites, and VIP levels. Significant bacteremia, endotoxemia, tachycardia, lactic acidosis, and hypotension occurred in all animals (P < 0.005). Circulating blood levels of cGMP, nitrites, cAMP, and VIP (P < 0.005) increased with development of shock. The NG-monomethyl-L-arginine treated animals had less cGMP, nitrites, cAMP, and VIP produced (P < 0.01). Plasma cGMP levels remained stable, suggesting that stimulated phagocytes in whole blood were responsible for increased cGMP levels. Infusion of VIP produced profound hypotension and lactic acidemia. Results of these experiments provide definitive evidence that nitric oxide and VIP are mediators during septic shock and their messengers are cGMP and cAMP, respectively. In addition, phagocytic stimulation with increased production of cGMP may initiate shock, with these mediators acting synergistically to prolong hypotension.
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PMID:Cyclic nucleotides and vasoactive intestinal peptide production in a rabbit model of Escherichia coli septicemia. 753 47

Nitric oxide (NO) is an important mediator of the hemodynamic effects of sepsis; however, its microcirculatory effects are unknown. To determine the role of NO in the small intestinal (SI) microcirculation, an intact SI loop was exteriorized from decerebrate rats into a controlled Krebs' bath. Bacteremic rats received 10(9) Escherichia coli intravenously. Videomicroscopy was used to measure arteriolar diameters (A1, A3) and optical Doppler velocimetry to quantitate flow. In controls, topical NO synthase (NO-S) substrate L-arginine (L-ARG; 10(-4) M) did not affect diameters or flow. Inhibition of NO-S by N omega-nitro-L-arginine methyl ester (L-NAME; 10(-4) M) caused constriction (A1 = -18%; A3 = -24% from baseline diameter) and reduced A1 flow by 62%. These alterations were similar to bacteremic controls (A1 = -20%; A3 = -18%; A1 flow = -42%), despite the increased cardiac output (+21%). L-NAME treatment of bacteremic rats resulted in further constriction (A1 = -31%; A3 = -32%) and decreased A1 flow (-75%). Topical L-ARG (10(-4) M) ameliorated constriction (A1 = -6%; A3 = +7%) and improved blood flow (-5%) during bacteremia. We conclude that: 1) NO is important for basal SI microvascular tone; 2) bacteremia causes SI arteriolar constriction and hypoperfusion; 3) NO-S inhibition during sepsis may exacerbate SI vasoconstriction and hypoperfusion.
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PMID:Role of nitric oxide in the small intestinal microcirculation during bacteremia. 753 19

To test the hypothesis that release of endothelium-derived relaxing factor/nitric oxide is inhibited by Gram-negative lipopolysaccharide (LPS; endotoxin), we examined endothelium-independent and endothelium-dependent vasodilator agents in aortic vascular smooth muscle isolated from guinea pigs 4 h after injection of saline (controls) or induction of Escherichia coli endotoxemia. LPS significantly inhibited vasodilator responses to the endothelium-dependent agonists acetylcholine (ACh; 10(-10)-10(-5) M) and ADP (10(-8)-10(-5) M). However, LPS did not affect vasodilator responses to the endothelium-independent agonist nitroprusside (10(-10)-10(-4) M). The nitric oxide synthase (NOS) inhibitor N gamma-nitro-L-arginine methyl ester (L-NAME) inhibited the vasodilator response to ACh; whereas, the cyclooxygenase inhibitor indomethacin (INDO) did not reduce vasodilator effects of ACh. Neither L-NAME nor INDO affected the vasodilator effects of nitroprusside in LPS or control vessels. In contrast, L-NAME converted the vasodilator action of ADP to a vasoconstrictor response that was blocked individually by INDO and the thromboxane synthase inhibitor dazoxiben, suggesting that ADP releases NO and also the vasoconstrictor and platelet aggregating eicosanoid thromboxane A2. These findings suggest that acute (4 h) endotoxemia inhibits function of the constitutive isoform of NOS in vascular endothelial cells. Since L-NAME unmasked a vasoconstrictor action of the endogenous purinoceptor agonist ADP, pharmacologic agents that inhibit NOS may exacerbate LPS-induced inhibition of endothelial NOS; this series of events could lead to diminution of vasodilator reserves and perhaps to augmentation of platelet aggregation during Gram-negative sepsis.
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PMID:Inhibition of endothelium-dependent vasodilation by Escherichia coli endotoxemia. 753 38

A major determinant of survival in patients with advanced viral or bacterial infection, or following severe trauma or burns complicated by multiple organ failure, is the combination of clinical signs termed the systemic inflammatory response syndrome (SIRS). SIRS is characterized by hypotension, tachypnea, hypo- or hyperthermia and leukocytosis as well as other clinical signs and symptoms, including a depression in myocardial contractile function. Heart failure complicating systemic sepsis or other causes of SIRS is usually not accompanied by coronary artery ischemia due to hypotension, myocardial necrosis, or marked cardiac interstitial inflammatory infiltrates, and thus the cause of cardiac contractile dysfunction in this syndrome has remained unclear. However, recent evidence has implicated an endogenous nitric oxide (NO) signalling pathway within cardiac myocytes and other cellular constituents of cardiac muscle, including the microvascular endothelium, as a possible contributor to the pathogenesis of heart failure in this syndrome. Cardiac myocytes are now known to express both constitutive NO synthase (cNOS) and inducible NO synthase (iNOS) activities. Activation of cNOS appears to modulate cardiac myocyte responsiveness to muscarinic cholinergic and beta-adrenergic receptor stimulation. Induction of iNOS by soluble inflammatory mediators, including cytokines, causes a marked depression in myocyte contractile responsiveness to beta-adrenergic agonists. Thus, inappropriate activation of cNOS or excessive or prolonged induction of iNOS in the myocardium may contribute to cardiac dysfunction complicating SIRS.
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PMID:Myocardial contractile dysfunction in the systemic inflammatory response syndrome: role of a cytokine-inducible nitric oxide synthase in cardiac myocytes. 753 82

Nitric oxide (.NO) is synthesized by the enzyme nitric oxide synthase (NOS). There are 2 constitutive forms of NOS (cNOS) and 1 inducible form (iNOS). Cells containing cNOS rapidly and transiently produce small amounts of NO in response to agonists that raise cytosolic levels of free Ca2+, whereas cells expressing inducible iNOS produce large amounts of .NO for extended periods after a lag of several hours during which time the enzyme is induced. Until recently, the 2 constitutive isoforms of NOS were thought to be confined to endothelial cells (eNOS) and brain (bNOS or nNOS). However, eNOS and bNOS have been identified in an increasing variety of additional cells. Many, if not most, types of cells are capable of expressing iNOS in response to cytokines, endotoxin, and phagocytosis. Regulation of iNOS occurs at transcriptional, translational, and posttranslational levels. Because .NO is rapidly diffusible and soluble in hydrophobic and aqueous environments, it is well suited to its role as an intercellular messenger with the unique ability to penetrate solid tissue. However, it is rapidly inactivated by hemoglobin. The biochemistry of .NO is dominated by its rapid reaction with oxygen and transitional metals, notably iron. The former reaction may be protective, as when neutralizing superoxide (.O2-), or harmful in forming additional highly damaging radicals such as peroxynitrite. Interaction of .NO with iron-containing proteins has a number of sequelae, including the activation of guanylate cyclase, inhibition of mitochondrial respiration, and inhibition of cell division. Nitric oxide has been implicated in a number of conditions of orthopaedic interest, including inflammation, arthritis, osteoporosis, sepsis, ligament healing, and aseptic loosening of joint prostheses.
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PMID:Nitric oxide and its role in orthopaedic disease. 754 92

1. The effects of endotoxin (E. coli lipopolysaccharide, LPS) and heat inactivated group B Streptococcus (GBS) were studied on the contractile responses to noradrenaline (NA) in isolated pulmonary arteries and on the activity of the constitutive and inducible nitric oxide synthase (NOS) in lung fragments of neonatal piglets. 2. Short-term (< or = 5 h) incubation with LPS (1 micrograms ml-1) or GBS (3 x 10(7) colonies forming units ml-1) did not modify the vascular responsiveness to NA (10(-8) M-10(-4) M) in isolated intrapulmonary arteries. However, long-term incubation (20 h) with LPS or GBS produced a significant reduction in the maximal contractile responses and shifted the concentration-response curve for NA downwards. 3. Endothelium removal or the cyclo-oxygenase inhibitor meclofenamate (10(-5) M) did not affect the GBS- and LPS-induced hyporesponsiveness to NA. 4. The presence of the nitric oxide (NO) precursor, L-arginine (10(-5) M), 30 min prior to the contractility challenge increased the LPS- and GBS-induced pulmonary vascular hyporesponsiveness to NA. In contrast, the addition, prior to the challenge with NA, of the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) or coincubation with dexamethasone (3 x 10(-6) M), a potent inhibitor of the induction of NOS, or with the protein synthesis inhibitor cycloheximide (10(-5) M) completely restored the reactivity to NA in LPS- and GBS-treated pulmonary arteries. 5. The incubation for 20 h of lung fragments with LPS and GBS produced a significant increase in the Ca2+-independent (inducible) NOS activity determined by the conversion of radiolabelled L-arginine to citrulline, but did not modify the constitutive NOS activity. This NOS induction was abolished by coincubation with dexamethasone (3 X 10-6 M).6. These results demonstrated that prolonged incubation with GBS and LPS causes an induction of NOS activity which results in a reduced vascular responsiveness to NA in pulmonary arteries of neonatal piglets. Thus, induction of NOS seems to be responsible for the delayed pulmonary vascular hyporesponsiveness induced by GBS (a Gram-positive) and E. coli (a Gram-negative), the most common causal agents of neonatal sepsis.
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PMID:Group B Streptococcus and E. coli LPS-induced NO-dependent hyporesponsiveness to noradrenaline in isolated intrapulmonary arteries of neonatal piglets. 754 18

Nitric oxide (NO), produced by either constitutive or inducible isoforms of NO synthase (cNOS or iNOS), influences myocardial inotropic and chronotropic responses. This pathway has been studied using NO donors or NOS inhibitors or by immune-mediated stimulation of iNOS. Although inhibition of constitutive NO activity in the heart does not influence indices of myocardial contractility, NO donors, in some species and preparations, may exert a negative inotropic effect as well as an enhancement of diastolic relaxation. The best documented cardiac action of NO is inhibition of the positive inotropic and chronotropic responses to beta-adrenergic receptor stimulation. Basal NO production, presumable via cNOS, appears to exert a mild tonic inhibition of beta-adrenergic responses. On the other hand, excessive NO production mediated by iNOS may contribute to the myocardial depression and beta-adrenergic hyporesponsiveness associated with conditions such as sepsis, myocarditis, cardiac transplant rejection, and dilated cardiomyopathy. Muscarinic cholinergic stimulation of the heart appears to stimulate NO production that mediates, at least partially, parasympathetic slowing of heart rate and inhibition of beta-adrenergic contractility. NO-stimulated production of 3',5'-cyclic guanosine monophosphate via guanylyl cyclase accounts for many of the observed physiological actions of NO. 3',5'-Cyclic guanosine monophosphate inhibits the beta-adrenergic-stimulated increase in the slow-inward calcium current and reduces the calcium affinity of the contractile apparatus, actions that could contribute to a negative inotropic effect, an abbreviation of contraction, and an enhancement of diastolic relaxation. Biochemical, immunocytochemical, and molecular biological techniques have been used to show the presence of both cNOS and iNOS within the myocardium. cNOS is expressed in myocytes, endothelial cells, and neurons in the myocardium, and there is evidence for iNOS in myocytes, small vessel endothelium, vascular smooth muscle cells, and immune cells that infiltrate the heart. Taken together, these observations suggest that NO influences normal cardiac physiology and may play an important role in the pathophysiology of certain disease states associated with cardiac dysfunction.
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PMID:Role of nitric oxide in the regulation of myocardial function. 756 4

Septic shock is associated with high mortality. There is in vitro evidence that the induction of nitric oxide synthase (iNOS) in vascular smooth muscle cells may be an important mediator of the systemic vasodilation and hypotension associated with sepsis. In this study, an in vivo murine model of sepsis was used to further examine this important question. Lipopolysaccharide (LPS), the major wall component of gram-negative bacteria, was administered to rats. By the use of a selective cDNA probe for iNOS, mRNA for iNOS was demonstrated in the aortas of these rats. The functional significance of this iNOS was then examined with aminoguanidine, a preferential inhibitor of iNOS. Aminoguanidine reversed the blunted phenylephrine-evoked contraction of endothelium-denuded aortic rings from LPS-treated rats or rings exposed to LPS in vitro. Aminoguanidine did not impair the relaxation of aortic rings with endothelium to acetylcholine, a known stimulator of endothelial NOS. The reversal of LPS-induced vascular hyporesponsiveness by aminoguanidine therefore strongly supports the functional importance of iNOS mRNA expression in the aorta of endotoxemic rats. Future clinical trials in treating septic shock should therefore consider the preferential inhibition of iNOS while maintaining the integrity of endothelial NOS.
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PMID:Expression and preferential inhibition of inducible nitric oxide synthase in aortas of endotoxemic rats. 757 55


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