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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate the role of nitric oxide (NO) in the attenuated vascular reactivity observed in sepsis, we utilized the specific NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME). Male Sprague-Dawley rats (n = 16) were randomized to either sepsis induced by cecal ligation and perforation (CLP; n = 8) or sham procedure (Sham; n = 8). Vascular reactivity was assessed by measuring the pulmonary pressor response to hypoxia (HPV) (fractional inspired O2 concentration = 0.08) and the pulmonary and systemic pressor response to an intravenous infusion of phenylephrine (1.5-6.0 micrograms.kg-1.min-1). Twenty-four hours after surgery, CLP animals had significantly attenuated HPV compared with Sham animals. In response to hypoxia the change in total pulmonary vascular resistance during hypoxia was 0.008 +/- 0.004 and 0.021 +/- 0.006 mmHg.min-ml-1 in CLP and Sham animals, respectively (P < 0.05). The pulmonary and systemic blood pressure response to phenylephrine was also attenuated in CLP compared with Sham animals. After L-NAME infusion (15 mg/kg), there was a significant augmentation of the HPV response in Sham animals. In contrast, the HPV response in CLP animals was unchanged after L-NAME. The attenuated pressor response to phenylephrine in neither the pulmonary nor the systemic circulation was changed after the administration of L-NAME. These data suggest that in rats, excess NO is not an important mediator of the attenuated vascular reactivity observed in sepsis.
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PMID:Effect of inhibition of NO synthase on vascular reactivity in a rat model of hyperdynamic sepsis. 752 65

Hyperdynamic sepsis is associated with a redistribution of organ blood flow. We hypothesized that increased nitric oxide (NO) production could mediate this process. The objective of this study was to determine the effect of a NO synthesis inhibitor on systemic and organ blood flows in vivo in septic and in normal rats. Rats were instrumented for hemodynamic monitoring and randomized to undergo cecal ligation and perforation (CLP) or control laparotomy. Cardiac output and organ blood flow were measured by thermodilution and radioactive microspheres, respectively. Baseline values were obtained at 24 h after CLP or control laparotomy and after the administration of L-nitro-arginine methyl ester (L-NAME) at 2, 4, 8, and 16 mg/kg intravenously. All studies were performed in awake, unrestrained animals. Septic animals were normotensive and hyperdynamic. L-NAME decreased cardiac index and increased systemic vascular resistance and mean arterial blood pressure to an equivalent degree in control and in CLP animals. CLP was associated with significantly increased relative blood flow to the small bowel and portal circulation. Although cardiac output decreased with L-NAME, blood flow to the diaphragm, liver, and brain was relatively well preserved. Absolute blood flow to other organs, including small bowel, decreased in parallel to the cardiac output. The effect of L-NAME on organ blood flow was comparable in control and in CLP animals. We conclude that the influence of NO on organ blood flows appears to vary between organs, but that NO does not explain the redistribution of blood flow observed in hyperdynamic sepsis.
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PMID:Modulation of hemodynamics and organ blood flow by nitric oxide synthase inhibition is not altered in normotensive, septic rats. 752 82

Nitric oxide (NO) has been reported to have a protective function in attenuating hepatic injury during endotoxemia or sepsis. As a result, the role of NO in attenuating the hepatic microcirculatory alterations associated with endotoxemia was investigated in mice by in vivo microscopy. The livers were examined 2 h after intravenous injection of Escherichia coli 0111:B4 lipopolysaccharide (LPS) alone or in combination with inhibitors of the synthesis of NO, NG-nitro-L-arginine methyl ester or NG-monomethyl-L-arginine. In the animals treated with the combination of NO synthase inhibitors and LPS, leukocyte adherence was increased threefold above that in animals treated with LPS alone. This was accompanied by a 33% reduction in sinusoidal blood flow. Simultaneous administration of L-arginine, but not D-arginine, eliminated these microcirculatory disturbances. The results demonstrate that inhibition of LPS-stimulated NO production results in an early hepatic microvascular inflammatory response to a dose of endotoxin which by itself is scarcely inflammatory. This suggests that NO plays a significant role in stabilizing the hepatic microcirculation during endotoxemia, thereby helping to protect the liver from ischemia and leukocyte-induced oxidative injury.
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PMID:Protective role of NO in hepatic microcirculatory dysfunction during endotoxemia. 752 79

Inhibitors of nitric oxide (NO) synthesis have been used in the treatment of septic and endotoxic shock. However, several studies question the beneficial effect of inhibiting NO production in sepsis and endotoxemia. We have investigated the effect of inhibition of NO synthesis after endotoxemia in the isolated perfused rat heart. In hearts from endotoxin-treated animals, coronary flow was elevated 64% and oxygen consumption was elevated 20% compared with control hearts. NADH fluorescence imaging was used as an indicator of regional hypoperfusion. A homogeneous low-surface NADH fluorescence, indicative of adequate tissue perfusion, was observed in both control and endotoxin-treated hearts. The increase in coronary flow and oxygen consumption could only partially be prevented by pretreatment of the animals with dexamethasone. Addition of N omega-nitro-L-arginine (NNLA), an inhibitor of NO synthesis, to the perfusion medium eliminated differences in coronary flow and oxygen consumption between normal and endotoxin-treated hearts. However, NADH surface fluorescence images of endotoxin-treated hearts after NNLA revealed areas of high fluorescence, indicating local ischemia, whereas the control hearts remained without signs of ischemia. The ischemic areas were present at various perfusion pressures and disappeared after the infusion of L-arginine, the natural precursor of NO, or the exogenous NO donor sodium nitroprusside. Methylene blue (MB), an inhibitor of soluble guanylate cyclase, the effector enzyme of NO, also eliminated differences in coronary flow and produced similar areas of local myocardial ischemia in endotoxin-treated hearts but not in control hearts.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of nitric oxide synthesis causes myocardial ischemia in endotoxemic rats. 753 18

We examined vascular reactivity to vasoconstrictors [phenylephrine (PE), serotonin (5-HT), and high K+] and vasodilators [acetylcholine (ACh), A23187, L-arginine, and nitroglycerin (NTG)] in isolated mesenteric arterial rings from control and septic rats. Sepsis was induced by cecal ligation and puncture (CLP). A possible mechanism underlying CLP-induced alteration in vascular reactivity was also investigated with N omega-nitro-L-arginine (L-NNA 50 microM), methylene blue (MB 10 microM), and indomethacin (5 microM). In vivo, septic rats manifested two distinct hemodynamic phases, a hyperdynamic state during early (9 h after CLP) phase, followed by a hypodynamic state during late (18 h after CLP) phase. Therefore, we examined ex vivo vascular reactivity in these two phases. Results demonstrated that CLP operation caused hyporesponsiveness to contractile agents and hyperresponsiveness to vasodilator agents. After endothelium removal, most of the contractile responses were enhanced in both CLP-operated (9 and 18 h after operation) and sham-operated rats, whereas enhancement of high-K(+)-induced contraction was observed only in denuded rings from CLP 18-h rats. In addition, augmentation of relaxation induced by ACh at 9 or 18 h after CLP was abolished by N omega-nitro-L-arginine or MB but not by indomethacin. A possible mechanism responsible for alterations of vascular reactivity may be overproduction of nitric oxide (NO) which is blocked by L-NNA or MB.
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PMID:Alterations of ex vivo vascular reactivity in intraperitoneal sepsis. 753 57

The benefits of nitric oxide synthase (NOS) inhibitors in the treatment of endotoxemia or sepsis presumably arise from inhibition of the type II (inducible) NOS. However, inasmuch as the effect of these inhibitors on NOS function in vivo is rarely assessed, NOS activity was evaluated in rats and mice by measuring changes in plasma nitrite and nitrate concentrations ([NOx]) after administration of lipopolysaccharide (LPS). In both species, [NOx] peaked at 20 hr, returning to base line by 48 to 72 hr. The ED50 values (dose that elicited a 50% inhibition of the LPS-dependent increase in [NOx] 6 hr after LPS administration) for L-NG-monomethylarginine acetate, L-NG-nitroarginine methyl ester and aminoguanidine (administered 3 hr after LPS) were 34, 21 and 19 mg/kg in the rat and 32, 5 and 4 mg/kg in the mouse. These compounds also decreased the survival of LPS-challenged animals, which in the case of L-NG-nitroarginine methyl ester was reversed by L-arginine. Dexamethasone (which prevents the induction of type II NOS) also inhibited the LPS-dependent increase in [NOx] with ED50 values of 0.05 mg/kg (rat) and 1 mg/kg (mouse), but did not lead to decreased survival. Thus, inhibition of the type I (neuronal) or type III (endothelial) NOS, rather than the type II isoform, may be a possible mechanism for the animal mortality. These models provide a simple and reproducible means for assessing the in vivo inhibition of type II NOS by various compounds.
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PMID:Lipopolysaccharide-induced changes in plasma nitrite and nitrate concentrations in rats and mice: pharmacological evaluation of nitric oxide synthase inhibitors. 753 50

Nitric oxide (NO), an important vasodilatory modulator of systemic and pulmonary vascular tone, is synthesized from L-arginine by the enzyme NO synthase in vascular endothelial and smooth muscle cells. L-Arginine analogs, such as N omega-nitro-L-arginine methyl ester (L-NAME), are competitive antagonists of NO synthase and inhibit NO synthesis. Group B streptococcus (GBS) causes pulmonary hypertension, hypoxemia, lung vascular injury, and reduced cardiac output in both human newborns and neonatal piglets. Lung vascular injury associated with prolonged GBS infusion in piglets may attenuate NO production and thus promote severe pulmonary hypertension. We studied the effect of the NOS inhibitor, L-NAME and the precursor of NO, L-arginine, on pulmonary and systemic hemodynamics during late-phase GBS sepsis in the piglet model. Neonatal piglets were anesthetized, ventilated with room air, and randomized to receive a continuous infusion of saline (n = 5) or GBS (n = 5) for 4 h. After 3 h of infusion, both groups received a bolus of L-NAME (3 mg/kg). Hemodynamic and gas exchange indices were measured at baseline, 30 min, and 3 h of infusion, and 30 min and 1 h after L-NAME treatment. L-NAME treatment caused 1) significant increases in mean pulmonary arterial pressure, pulmonary vascular resistance, mean systemic arterial pressure, and systemic vascular resistance for both groups; 2) a similar percentage of increase in pulmonary vascular resistance for the two groups; 3) greater reduction in cardiac output and SV in the GBS compared with the control group; and 4) no significant alterations in arterial partial pressure of oxygen or the difference between alveolar and arterial partial pressure of oxygen for either group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of nitric oxide synthase inhibition during group B streptococcal sepsis in neonatal piglets. 753 3

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

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


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