Effects of nitric oxide synthesis inhibition in hyperdynamic endotoxemia

Meyer, J.; Lentz, Christopher W.; Stothert, Joseph C.; Traber, Lillian D.; Herndon, David N.; Traber, Daniel L.

doi:10.1097/00003246-199402000-00023

Cited by 105 publications

(38 citation statements)

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“…However, in various pathologic entities, proinflammatory cytokines, endotoxins, and bacterial infections have also been associated with enhanced production of NO, hyporesponsiveness to vasoconstrictors, and development of a hyperdynamic state (18)(19)(20). These physiological similarities, and the fact that endotoxemia is a common finding in cirrhosis (21)(22)(23)(24), led to the hypothesis proposed by Vallance and Moncada that bacterial endotoxin, directly or involving cytokines, may account for hemodynamic changes in advanced cirrhosis (25) by stimulating the expression of inducible NO synthase (iNOS) and, thus, NO production.…”

Section: Introductionmentioning

confidence: 99%

Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility

Wiest

Das²,

Cadelina³

et al. 1999

J. Clin. Invest.

281

184

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Nitric oxide (NO) has been implicated in the arterial vasodilation and associated vascular hyporesponsiveness to vasoconstrictors observed in liver cirrhosis. Bacteria, potent activators of NO and TNF-α synthesis, are found in the mesenteric lymph nodes (MLNs) of ascitic cirrhotic rats. Here, we investigated the impact of bacterial translocation (BT) to MLNs on TNF-α production, vascular NO release, and contractility in the mesenteric vasculature of ascitic cirrhotic rats. Vascular response to the α-adrenoagonist methoxamine, which is diminished in the superior mesenteric arterial beds of cirrhotic rats, is further blunted in the presence of BT. BT promoted vascular NO release in cirrhotic rats, an effect that depended on pressure-induced shear stress and was blocked by the NO inhibitor N ω -nitro-L-arginine. Removing the endothelium had the same effect. Endothelial NO synthase (eNOS), but not the inducible isoform (iNOS), was present in mesenteric vasculature of cirrhotic rats with and without BT, and its expression was enhanced compared with controls. TNF-α was induced in MLNs by BT and accumulated in parallel in the serum. This TNF-α production was associated with elevated levels of tetrahydrobiopterin (BH 4 ), a TNF-α-stimulated cofactor and enhancer of eNOSderived NO biosynthesis and NOS activity in mesenteric vasculature. These findings establish a link between BT to MLNs and increased TNF-α production and elevated BH 4 levels enhancing eNOSderived NO overproduction, further impairing contractility in the cirrhotic mesenteric vasculature.J. Clin. Invest. 104:1223-1233. mals subjected to experimental portal hypertension (41)(42)(43)(44). TNF-α is also known to be involved in the pathogenesis of the hyperdynamic circulatory syndrome in portal hypertension (42,45). Finally, the gut and its associated lymphoid tissue, the largest immunologic organ of the body, has recently been shown to produce and release TNF-α in response to BT, even in the absence of portal or systemic spread of bacteria (46,47).We designed this study to determine (a) whether there is any relationship between BT to MLNs and vascular contractility in the superior mesenteric arterial bed in cirrhosis; (b) if so, whether this additional vascular impairment is also due to vascular NO release; and (c) if that is the case, what NOS isoform is responsible for this additional NO overproduction and by what mechanism this NOS isoform is upregulated; and (d) whether TNF-α is playing any role in this process. MethodsAll experimental procedures in this study were conducted according to the American Physiological Society principles for the care and use of laboratory animals.Induction of liver cirrhosis in rats by CCl 4. Male SpragueDawley rats (Harlan Sprague Dawley Inc., Indianapolis, Indiana, USA), weighing 100-125 g, underwent inhalation exposure to CCl 4 and had phenobarbital (0.35g/L) added to their drinking water, as described previously by ourselves and others (4,5). This protocol produces a high yield of micronodular cirrhosis in about 12-16 we...

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Section: Introductionmentioning

confidence: 99%

Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility

Wiest

Das²,

Cadelina³

et al. 1999

J. Clin. Invest.

281

184

View full text Add to dashboard Cite

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“…The inhibition of nitric oxide synthase in septic animals or patients prevents or corrects hypotension (3,4,19,21,22). However, a blockade of such magnitude may be deleterious.…”

Section: Introductionmentioning

confidence: 99%

“…However, a blockade of such magnitude may be deleterious. The cardiac output decreased in several studies due to an excessive systemic vasoconstriction (17,22) and the worsening in hemodynamic status increased the mortality in animal studies (5,6). In addition, pulmonary vascular resistance is often increased during sepsis and a further increase in pulmonary arterial pressure by nitric oxide synthesis inhibitors could precipitate right heart failure.…”

Section: Introductionmentioning

confidence: 99%

Blockade of the action of nitric oxide in human septic shock increases systemic vascular resistance and has detrimental effects on pulmonary function after a short infusion of methylene blue

Weingartner

Oliveira

Sant'Anna

et al. 1999

Braz J Med Biol Res

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To investigate the role of nitric oxide in human sepsis, ten patients with severe septic shock requiring vasoactive drug therapy and mechanical ventilation were enrolled in a prospective, open, non-randomized clinical trial to study the acute effects of methylene blue, an inhibitor of guanylate cyclase. Hemodynamic and metabolic variables were measured before and 20, 40, 60, and 120 min after the start of a 1-h intravenous infusion of 4 mg/kg of methylene blue. Methylene blue administration caused a progressive increase in mean arterial pressure (60 [55-70] Arterial lactate concentration decreased from 5.1 ± 2.9 to 4.5 ± 2.1 mmol/ l, mean ± SD (P<0.05) after 60 min. Heart rate, cardiac filling pressures, cardiac output, oxygen delivery and consumption did not change. Methylene blue administration was safe and no adverse effect was observed. In severe human septic shock, a short infusion of methylene blue increases systemic vascular resistance and may improve myocardial function. Although there was a reduction in blood lactate concentration, this was not explained by an improvement in tissue oxygenation, since overall oxygen availability did not change. However, there was a significant increase in pulmonary vascular tone and a deterioration in gas exchange. Further studies are needed to demonstrate if nitric oxide blockade with methylene blue can be safe for patients with septic shock and, particularly, if it has an effect on pulmonary function.

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“…In adult anesthetized dogs, Klabunde et al [27] noted that NOS inhibition alone increased systemic blood pressure and induced cardiac depression in the form of reduced cardiac output. However, in sheep the response to endotoxin is marked by a hyperdynamic phase, during which the initial response to endotoxin is an increase in cardiac output, followed by a decline [6,7]. Meyer et al [6,7] showed that the hyperdynamic phase was subsequently blocked by the NO inhibitor L-Name.…”

Section: Cardiac Effects Mechanisms Of Nomentioning

confidence: 99%

“…Their death is usually characterized by cardiovascular collapse, presumably mediated by endotoxins. The cardiovascular responses to endotoxin which have been studied extensively in both adult humans and animal models [3][4][5][6][7] have been less well characterized in the newborn [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Role of Nitric Oxide in Cardiovascular Responses to Endotoxemia in Neonatal Lambs

et al. 1999

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To determine whether systemic cardiovascular responses to gram-negative endotoxemia are mediated by nitric oxide, we evaluated time-dependent changes in contractility and hemodynamics in a neonatal sheep model subjected to nitric oxide synthesis inhibition with L-Name (N^ω-nitro-L-arginine methyl ester). Four groups were studied: control (C), endotoxin (E), endotoxin L-Name where the nitric oxide synthase inhibitor was given prior to endotoxin (ELN), and a control L-Name group pretreated with L-Name (CLN). The contractility, measured as end-systolic elastance (Ees), increased transiently in the E group and then returned to baseline. In contrast, Ees declined over time in the ELN group. In terms of peripheral hemodynamics, both the E and ELN groups demonstrated significant progressive decreases in blood pressure and vascular resistance. The results of this study suggest that nitric oxide contributes to the newborn contractile response of the heart to endotoxin, but does not appear to mediate the systemic vascular relaxation response.

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Effects of nitric oxide synthesis inhibition in hyperdynamic endotoxemia

Cited by 105 publications

References 0 publications

Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility

Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility

Blockade of the action of nitric oxide in human septic shock increases systemic vascular resistance and has detrimental effects on pulmonary function after a short infusion of methylene blue

Role of Nitric Oxide in Cardiovascular Responses to Endotoxemia in Neonatal Lambs

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