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

Selective type II (inducible) nitric oxide synthase (NOS) inhibitors have several potential therapeutic applications, including treatment of sepsis, diabetes, and autoimmune diseases. The ability of two novel, selective inhibitors of type II NOS, S-ethylisothiourea (EIT) and 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), to inhibit type II NOS function in vivo was studied in lipopolysaccharide (LPS) treated rats. Type II NOS activity was assessed by measuring changes in plasma nitrite and nitrate concentrations ([NOx]). Both EIT and AMT elicited a dose-dependent and > 95% inhibition of the LPS-induced increase in plasma [NOx]. The ED50 values for EIT and AMT were 0.4 and 0.2 mg/kg, respectively. In addition, the administration of LPS and either NOS inhibitor resulted in a dose-dependent increase in animal mortality; neither compound was lethal when administered alone. Pretreatment with L-arginine (but not D-arginine) prevented the mortality, while not affecting the type II NOS-dependent NO production, suggesting the toxicity may be due to inhibition of one of the other NOS isoforms (endothelial or neuronal). Thus, although EIT and AMT are potent inhibitors of type II NOS function in vivo, type II NOS inhibitors of even greater selectivity may need to be developed for therapeutic applications.
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PMID:In vivo pharmacological evaluation of two novel type II (inducible) nitric oxide synthase inhibitors. 758 35

The normal or hyperdynamic circulatory response during the early phases of the systemic septic response is associated with renal microvascular constriction and can result in renal dysfunction. Intrarenal redistribution of blood flow from the outer cortex to the medulla appears to account for decreased glomerular filtration in spite of normal or elevated renal blood flow, but the mechanisms of this response are not well described. Nitric oxide is recognized as an important regulator of regional blood flow during both normal and pathologic conditions including sepsis, and we hypothesized that alterations in nitric oxide contribute to redistribution of renal blood flow during sepsis. The current study used laser Doppler fluximetry and clearance of p-aminohippuric acid (effective renal plasma flow, ERPF) to study intrarenal distribution of blood flow during basal conditions and during normodynamic Escherichia coli bacteremia, with and without inhibition of nitric oxide. Inhibition of nitric oxide in normal animals resulted in a decrease in ERPF (-19%) with a decrease in cortical flux (-39%) without alteration of medullary flux. Bacteremia resulted in a decrease in cortical flow (-17%), an increase in medullary flow (36%), and a modest reduction (-9%) in ERPF. Inhibition of nitric oxide synthase during bacteremia worsened cortical flow (-43%), reversed the increase in medullary flux (-42%), and further impaired ERPF (-28%). These data suggest that nitric oxide regulates renovascular tone during normal conditions and bacteremia, and indicate that it is a prime mediator of intrarenal redistribution of blood flow during sepsis.
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PMID:Nitric oxide mediates redistribution of intrarenal blood flow during bacteremia. 763 15

We have previously proposed that cytokine-stimulated nitric oxide (NO) production is responsible for reversible myocardial depression in sepsis, trauma and ischemia. NO previously has been found to inhibit mitochondrial activity in other cell types. Accordingly, we sought to determine if cytokine-stimulated NO production inhibited cardiac myocyte mitochondrial activity. Treatment of neonatal rat cardiac myocytes with interleukin-beta (IL-1) resulted in the expression of mRNA for inducible NO synthase (iNOS) and stained positively for iNOS protein by immunohistochemistry. No iNOS staining was detected in untreated cells. IL-1 treatment resulted in significant nitrite levels vs control over 48 hrs (4.2 +/- 0.7 vs 0.3 +/- 0.2 nmol/1.25 x 10(5) cells, respectively) (n = 12) that was inhibited by 1mM NMA (0.3 +/- 0.2 nmoles; p < .01; n = 12). Mitochondrial activity was assessed by the MTT colorimetric assay using (3-4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and OD 570-630. Mitochondrial activity was significantly inhibited by IL-1 vs control cells (0.436 +/- 0.01 vs 0.608 +/- 0.03) and reversed by 1mM NMA (0.549 +/- 0.03) or removal of IL-1 (0.662 +/- 0.02) (p < .01; n = 12 for each). These data strongly suggest that cytokine-stimulated NO production by cardiac myocytes results in reversible inhibition of mitochondrial activity.
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PMID:Cytokine-stimulated nitric oxide production inhibits mitochondrial activity in cardiac myocytes. 765 17

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

Induction of nitric oxide synthase by cytokines has been hypothesized as a mechanism of the hyporesponsiveness to catecholamines that occurs in clinical septic shock. We measured responses of resistance arterioles in rat cremaster muscle to topically suffused norepinephrine in vivo with the use of image-shearing videomicroscopy. Rats made septic by cecal ligation and puncture were compared with controls that underwent sham ligation. The norepinephrine concentration-response curve was shifted to the right in septic rats [50% effective concentration (EC50) 9.1 +/- 5.4 vs. 0.10 +/- 0.02 microM, P < 0.05]. Contractions at doses of 10(-9), 10(-8), and 10(-7) M norepinephrine were 26, 41, and 38%, respectively, of sham controls. Superfusion of the muscle with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine at 100 microM restored the arteriolar responsiveness of the septic rats (EC50 0.14 +/- 0.07 vs. 6.8 +/- 3.1 microM, P < 0.05). This effect was reversed with superfusion of excess (1 mM) L-arginine. These experiments demonstrate impaired vasoconstriction in response to norepinephrine in resistance arterioles of septic rats in vivo. NG-monomethyl-L-arginine reversed this hyporesponsiveness, implying that nitric oxide synthase may mediate the decreased catecholamine responsiveness associated with sepsis.
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PMID:Nitric oxide synthase inhibition reverses arteriolar hyporesponsiveness to catecholamines in septic rats. 768 May 41

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

Previous reports have suggested that the endotoxin-resistant C3H/HeJ strain of mouse is more susceptible to infection than is the endotoxin-sensitive parent strain, C3H/HeN, although they have never been compared in an i.v. model of sepsis. We therefore have used these mouse strains in an i.v. model of Gram-negative sepsis to compare their sensitivities to infection, their cytokine responses, and the levels of induction of the enzyme nitric oxide synthase assayed in their livers. By using i.v. infection with Escherichia coli we have found that both strains are approximately equally sensitive to this organism, despite the C3H/HeJ mice having a markedly attenuated TNF-alpha response. IFN-gamma levels after infection were identical in the two strains; the levels of nitric oxide synthase induced in their livers were about fourfold greater in the C3H/HeJ mice. This difference could not be explained by differences in bacterial load. These experiments suggest that factors other than TNF-alpha are important in determining outcome from Gram-negative sepsis and that TNF-alpha is not a major factor in the induction of hepatic nitric oxide synthase after infection in vivo.
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PMID:Differences in cytokine response and induction of nitric oxide synthase in endotoxin-resistant and endotoxin-sensitive mice after intravenous gram-negative infection. 768 16

Gram-negative sepsis and administration of tumor necrosis factor alpha (TNF alpha) are associated with hypotension and peripheral neuropathies suggestive of impaired sympathetic neurotransmission. We examined the effect of TNF alpha on the responses of the bovine pulmonary artery (BPA) to transmural sympathetic nerve stimulation (SNS). BPA contracted to SNS (0.5-32 Hz, 5-10 V, 2-msec duration, 2-msec delay) in a frequency-dependent manner. The contractions of the BPA to SNS were mediated by norepinephrine and activation of postsynaptic alpha 1-adrenoceptors, since they were attenuated by prazosin. Maximum contraction of the BPA to SNS was significantly enhanced (148 +/- 37% increase, n = 6) after inhibition of nitric oxide synthase with L-NG-monomethylarginine (LNMMA, 500 microM), an effect abrogated by L-arginine (1 mM). TNF alpha (0.0042, 0.042, and 0.42 micrograms/ml) selectively inhibited contractions of the BPA to SNS without affecting the contraction of the BPA to exogenous norepinephrine. In BPA incubated with LNMMA (5-500 microM), TNF alpha facilitated rather than inhibited SNS. TNF alpha increased the formation of amperiometrically measured free nitric oxide in bovine adrenal chromaffin cells in primary culture. The data show that in the absence of LNMMA, TNF alpha releases free nitric oxide from a sympathetic neuron and selectively inhibits the contractions of the BPA to SNS. In BPA in which nitric oxide synthase I is inhibited by LNMMA, TNF alpha amplifies the contractions to SNS, even in the absence of endothelium. Thus, TNF alpha can modify vascular smooth muscle tone by affecting SNS. TNF alpha inhibits SNS at the level of the neuron by a mechanism involving the L-arginine-nitric oxide pathway. TNF alpha-induced suppression of SNS and neurotransmission may contribute to the hypotension and peripheral neuropathy of sepsis.
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PMID:Tumor necrosis factor alpha inhibits contractions to sympathetic nerve stimulation by a nitric oxide-dependent mechanism. 768 1

Impaired vascular contractility is a hallmark of sepsis and endotoxemia. The purpose of the present investigation was to determine mechanisms responsible for the abnormal contractility in sepsis using the rat cecal ligation and perforation (CLP) model. 24 h after CLP or sham surgery, rats were anesthetized with halothane and a segment of the thoracic aorta removed. Aortic rings measuring 1.6-2.0 mm in length were mounted in a water bath and stretched to optimal diameter. Aortic rings from control rats demonstrated a 57% increase in maximum contraction to phenylephrine and a 68% increase to KCl compared to aortic rings from rats with sepsis (p < .01). There was no difference in the concentrations of phenylephrine or KCl which elicited a half-maximal contraction (EC50) in control versus septic aortic rings. Removal of the endothelium increased the sensitivity of aortas to both phenylephrine and KCl in septic and control aortic rings but did not reverse the defects in contraction in sepsis. Treatment of the aortic rings with N gamma-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, increased contraction in aortic rings from both septic and control rats but also failed to correct the contractile defect in sepsis. The frequency and amplitude of the oscillations in wall tension which occurred with phenylephrine were slower, i.e., .07 +/- .10 vs. .17 +/- .02 Hz, for septic and control rings, respectively (p < .05), and had a greater amplitude .65 +/- .01 vs. .41 +/- .09 mN/mm, for septic and control rings, respectively (p < .05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Sepsis decreases phenylephrine- and KCl-induced aortic ring contraction and decreases the frequency of oscillations in active wall tension. 772 82

The role of nitric oxide (NO) inhibition on liver circulation during sepsis is unknown. To answer this question, we studied the effects of L-arginine (the substrate for the NO synthase), linsidomine (a direct NO donor), and N omega-nitro-L-arginine (an NO inhibitor) on the liver circulation in anesthetized rabbits previously injected with endotoxin (Escherichia coli, Salmonella enteridis, and Salmonella minnesota, 400 micrograms each). After endotoxin administration, and without fluid resuscitation, rabbits showed a hypodynamic shock with decrease in mean arterial pressure (MAP) and aortic blood flow velocity. Portal vein blood flow velocity decreased, whereas hepatic artery blood flow velocity increased. Saline or treatments were injected, 75 min after endotoxin administration. In saline-treated rabbits, MAP, aortic and portal vein blood flow velocities remained steady but hepatic artery blood flow velocity decreased. Only N omega-nitro-L-arginine (7.5 mg/kg, intravenously) significantly increased MAP compared to saline treatment. However, aortic, portal vein, and hepatic artery blood flow velocities were lower in rabbits treated with N omega-nitro-L-arginine than in saline-treated rabbits. L-Arginine (600 mg/kg, intravenously) increased aortic blood flow and portal vein blood flow velocity with no change on hepatic artery blood flow velocity. In contrast, linsidomine (1 mg) increased both hepatic flows. These results show that NO inhibition after endotoxin injection reduces systemic and liver flows, while NO release from linsidomine improves them. These findings question the usefulness of NO inhibition during septic shock, particularly as hepatic failure frequently occurs in the evolution of the disease.
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PMID:Effect of modifying nitric oxide pathway on liver circulation in a rabbit endotoxin shock model. 774 50


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