Ascorbate Inhibits Reduced Arteriolar Conducted Vasoconstriction in Septic Mouse Cremaster Muscle

McKinnon, Rebecca L.; Lidington, Darcy; Tyml, Karel

doi:10.1080/10739680701410389

Cited by 27 publications

(23 citation statements)

References 31 publications

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“…Indeed, in iNOS knockout and NADPH oxidase-deficient mice, LPS induced much less production of NO and superoxide, respectively (7,26). Moreover, CLP remarkably increases nNOS activity without affecting nNOS protein expression in mouse skeletal muscle (34). The results from the present study indicate that both NADPH oxidase and eNOS uncoupling are responsible for stimulation by CLP of superoxide production and that both iNOS and nNOS activity generate the excessive NO in septic skeletal muscles.…”

Section: Discussionmentioning

confidence: 62%

Ascorbate protects against vascular leakage in cecal ligation and puncture-induced septic peritonitis

Zhou

Kamenos

Pendem

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Vascular leakage in multiple organs is a characteristic pathological change in sepsis. Our recent study revealed that ascorbate protects endothelial barrier function in microvascular endothelial cell monolayers through inhibiting serine/threonine protein phosphatase 2A (PP2A) activation (Han M, Pendem S, Teh SL, Sukumaran DK, Wu F, Wilson JX. Free Radic Biol Med 48: 128-135, 2010). The present study addressed the mechanism of protection by ascorbate against vascular leakage in cecal ligation and puncture (CLP)-induced septic peritonitis in mice. CLP caused NADPH oxidase activation and endothelial nitric oxide synthase (eNOS) uncoupling to produce superoxide, increased NO production by inducible NOS (iNOS) and neuronal NOS (nNOS) activity, and elevated 3-nitrotyrosine (a product of peroxynitrite) formation and PP2A activity in the hindlimb skeletal muscles at 12 h after CLP. The increase in PP2A activity was associated with decreased levels of phosphorylated serine and threonine in occludin, which was immunoprecipitated from freshly harvested endothelial cells of the septic skeletal muscles. Moreover, CLP increased the vascular permeability to fluorescent dextran and Evans blue dye in skeletal muscles. An intravenous bolus injection of ascorbate (200 mg/kg body wt), given 30 min prior to CLP, prevented eNOS uncoupling, attenuated the increases in iNOS and nNOS activity, decreased 3-nitrotyrosine formation and PP2A activity, preserved the phosphorylation state of occludin, and completely inhibited the vascular leakage of dextran and Evans blue. A delayed ascorbate injection, given 3 h after CLP, also prevented the vascular permeability increase. We conclude that ascorbate injection protects against vascular leakage in sepsis by sequentially inhibiting excessive production of NO and superoxide, formation of peroxynitrite, PP2A activation, and occludin dephosphorylation. Our study provides a scientific basis for injection of ascorbate as an adjunct treatment for vascular leakage in sepsis.

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Section: Discussionmentioning

confidence: 62%

Ascorbate protects against vascular leakage in cecal ligation and puncture-induced septic peritonitis

Zhou

Kamenos

Pendem

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Importantly, this is a dynamic process, as capillaries in which there is no flow at a given time may be perfused a few minutes later. These alterations have been reported after administration of endotoxin or live bacteria and during bacterial peritonitis, 8 , 9 , 11 and have been observed in rodents 12 , 13 as well as in large animals 9 , 11 . In addition, all studied organs have been affected, including the skin, 14 muscle, 12 , 13 eye, 15 tongue, 9 gut, 9 , 10 liver, 7 heart, 16 and even the brain 11 .…”

Section: Microcirculatory Alterations In Sepsis: Where Is the Evidence?mentioning

confidence: 77%

Pathophysiology of microcirculatory dysfunction and the pathogenesis of septic shock

Backer¹,

et al. 2013

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Multiple experimental and human trials have shown that microcirculatory alterations are frequent in sepsis. In this review, we discuss the various mechanisms that are potentially involved in their development and the implications of these alterations. Endothelial dysfunction, impaired inter-cell communication, altered glycocalyx, adhesion and rolling of white blood cells and platelets, and altered red blood cell deformability are the main mechanisms involved in the development of these alterations. Microcirculatory alterations increase the diffusion distance for oxygen and, due to the heterogeneity of microcirculatory perfusion in sepsis, may promote development of areas of tissue hypoxia in close vicinity to well-oxygenated zones. The severity of microvascular alterations is associated with organ dysfunction and mortality. At this stage, therapies to specifically target the microcirculation are still being investigated.

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“…Most of the reports assigned the effects observed in vivo to MnTBAP 3À SOD-like activity. Only two ''shy'' reports claimed no effects with MnTBAP 3À (172,214). We have clearly shown that MnTBAP 3À is not an SOD mimic, as it has negligible SODlike activity (log k cat ¼ 3.16) (31,264).…”

Section: Electrostaticsmentioning

confidence: 80%

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

Batinić‐Haberle

Rebouças

Spasojević

2010

Antioxidants & Redox Signaling

471

689

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Oxidative stress has become widely viewed as an underlying condition in a number of diseases, such as ischemia-reperfusion disorders, central nervous system disorders, cardiovascular conditions, cancer, and diabetes. Thus, natural and synthetic antioxidants have been actively sought. Superoxide dismutase is a first line of defense against oxidative stress under physiological and pathological conditions. Therefore, the development of therapeutics aimed at mimicking superoxide dismutase was a natural maneuver. Metalloporphyrins, as well as Mn cyclic polyamines, Mn salen derivatives and nitroxides were all originally developed as SOD mimics. The same thermodynamic and electrostatic properties that make them potent SOD mimics may allow them to reduce other reactive species such as peroxynitrite, peroxynitrite-derived CO 3 _ À , peroxyl radical, and less efficiently H 2 O 2 . By doing so SOD mimics can decrease both primary and secondary oxidative events, the latter arising from the inhibition of cellular transcriptional activity. To better judge the therapeutic potential and the advantage of one over the other type of compound, comparative studies of different classes of drugs in the same cellular and=or animal models are needed. We here provide a comprehensive overview of the chemical properties and some in vivo effects observed with various classes of compounds with a special emphasis on porphyrin-based compounds. Antioxid. Redox Signal. 13, 877-918.

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Ascorbate Inhibits Reduced Arteriolar Conducted Vasoconstriction in Septic Mouse Cremaster Muscle

Abstract: These data indicate that early and delayed intravenous boluses of ascorbate prevent/reverse sepsis-induced deficit in arteriolar conducted vasoconstriction in the cremaster muscle by inhibiting nNOS-derived NO production.

Cited by 27 publications

References 31 publications

Ascorbate protects against vascular leakage in cecal ligation and puncture-induced septic peritonitis

Ascorbate protects against vascular leakage in cecal ligation and puncture-induced septic peritonitis

Pathophysiology of microcirculatory dysfunction and the pathogenesis of septic shock

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

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