Ascorbate protects against impaired arteriolar constriction in sepsis by inhibiting inducible nitric oxide synthase expression

Wu, Feng; Wilson, John X.; Tyml, Karel

doi:10.1016/j.freeradbiomed.2004.06.025

Cited by 87 publications

(119 citation statements)

References 38 publications

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“…Further evidence of the importance of vitamin C is that its parenteral administration decreases mortality in wild-type mice that are ascorbate-replete before exposure to septic insults. For example, bolus injection of ascorbate (10-200 mg/kg) improves survival in mice made septic by either CLP or fecal stem solution injection into peritoneum (FIP) (18,59,64) (Fig. 2).…”

Section: Mortality and Morbiditymentioning

confidence: 99%

“…Further, a major experimental design issue that affects extrapolation to clinical settings is the omission of antibiotics and other supportive interventions that are typical of sepsis care bundles. For example, the effect of ascorbate on survival after CLP has been tested in mice receiving buprenorphine analgesia and fluid resuscitation but not antibiotic therapy (64) (Fig. 2).…”

Section: Mortality and Morbiditymentioning

confidence: 99%

“…Ascorbate protects microvascular function and improves survival in septic mice (18,59,64). It is not certain to what extent, if any, this protection is an indirect result of bacteriostasis.…”

Section: Bacterial Replicationmentioning

confidence: 99%

“…Although prophylactic injection i.v. of ascorbate (200 mg/kg) in mice does not alter the number of bacterial colony forming units in peritoneal lavage fluid at 6 h post-CLP (6.5 h after injection of ascorbate) (64), it is possible that the vitamin may cause bacteriostasis at other times or locations.…”

Section: Bacterial Replicationmentioning

confidence: 99%

“…This defect causes refractory vasodilation that contributes to hypotension and shock. The mechanism underlying the impairment of vasoconstriction in sepsis includes activation of soluble guanylate cyclase, activation of cyclic guanosine 3¢,5¢-monophosphate-dependent protein kinase, stimulation of large conductance potassium channels, and subsequent smooth muscle cell membrane hyperpolarization that counteracts the depolarizing effects of vasoconstrictors (64). A key mediator of impaired arteriolar reactivity is inducible nitric oxide synthase (iNOS), because this enzyme is the source of high levels of NO that activate soluble guanylate cyclase.…”

Section: Ascorbate Preserves Arteriolar Reactivitymentioning

confidence: 99%

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Evaluation of Vitamin C for Adjuvant Sepsis Therapy

Wilson

2013

Antioxidants & Redox Signaling

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Significance: Evidence is emerging that parenteral administration of high-dose vitamin C may warrant development as an adjuvant therapy for patients with sepsis. Recent Advances: Sepsis increases risk of death and disability, but its treatment consists only of supportive therapies because no specific therapy is available. The characteristics of severe sepsis include ascorbate (reduced vitamin C) depletion, excessive protein nitration in microvascular endothelial cells, and microvascular dysfunction composed of refractive vasodilation, endothelial barrier dysfunction, and disseminated intravascular coagulation. Parenteral administration of ascorbate prevents or even reverses these pathological changes and thereby decreases hypotension, edema, multiorgan failure, and death in animal models of sepsis. Critical Issues: Dehydroascorbic acid appears to be as effective as ascorbate for protection against microvascular dysfunction, organ failure, and death when injected in sepsis models, but information about pharmacodynamics and safety in human subjects is only available for ascorbate. Although the plasma ascorbate concentration in critically ill and septic patients is normalized by repletion protocols that use high doses of parenteral ascorbate, and such doses are tolerated well by most healthy subjects, whether such large amounts of the vitamin trigger adverse effects in patients is uncertain. Future Directions: Further study of sepsis models may determine if high concentrations of ascorbate in interstitial fluid have pro-oxidant and bacteriostatic actions that also modify disease progression. However, the ascorbate depletion observed in septic patients receiving standard care and the therapeutic mechanisms established in models are sufficient evidence to support clinical trials of parenteral ascorbate as an adjuvant therapy for sepsis.

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Section: Mortality and Morbiditymentioning

confidence: 99%

Section: Mortality and Morbiditymentioning

confidence: 99%

Section: Bacterial Replicationmentioning

confidence: 99%

Section: Bacterial Replicationmentioning

confidence: 99%

Section: Ascorbate Preserves Arteriolar Reactivitymentioning

confidence: 99%

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Evaluation of Vitamin C for Adjuvant Sepsis Therapy

Wilson

2013

Antioxidants & Redox Signaling

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Mechanism of action of vitamin C in sepsis: Ascorbate modulates redox signaling in endothelium

2009

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Circulating levels of vitamin C (ascorbate) are low in patients with sepsis. Parenteral administration of ascorbate raises plasma and tissue concentrations of the vitamin and may decrease morbidity. In animal models of sepsis, intravenous ascorbate injection increases survival and protects several microvascular functions, namely, capillary blood flow, microvascular permeability barrier, and arteriolar responsiveness to vasoconstrictors and vasodilators. The effects of parenteral ascorbate on microvascular function are both rapid and persistent. Ascorbate quickly accumulates in microvascular endothelial cells, scavenges reactive oxygen species, and acts through tetrahydrobiopterin to stimulate nitric oxide production by endothelial nitric oxide synthase. A major reason for the long duration of the improvement in microvascular function is that cells retain high levels of ascorbate, which alter redox-sensitive signaling pathways to diminish septic induction of NADPH oxidase and inducible nitric oxide synthase. These observations are consistent with the hypothesis that microvascular function in sepsis may be improved by parenteral administration of ascorbate as an adjuvant therapy.

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Effects of vitamin K1 supplementation on vascular responsiveness and oxidative stress in a rat femoral osteotomy model

Taşatargil

Cadir

Dalaklıoğlu

et al. 2006

Cell Biochemistry & Function

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The main function of vitamin K1 is to act a co-factor for gamma-glutamyl carboxylase. However, it has also been shown to lessen oxidative stress. This study was aimed to evaluate the effect of vitamin K1 supplementation on vascular responsiveness and oxidative status in rats that underwent femoral osteotomy. Twenty-four male rats were divided into three groups to serve as sham, osteotomy and vitamin K1 groups. Indices of oxidative stress (catalase), and oxidative damage (malondialdehyde) were analysed in erythrocytes. In order to evaluate vascular reactivity, concentration-response curves to phenylephrine, angiotensin II, 5-hydroxytryptamine, bradykinin and histamine were constructed. The findings of this study clearly show that oxidative stress clearly increases after femoral osteotomy in rats. Also, this operation causes a significant depression in vascular responsiveness to contracting agents and endothelium-dependent vasodilators. However, vitamin K1 supplementation prevents vascular hyporeactivity by reducing oxidative stress and may represent a novel approach during osteotomy healing.

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Ascorbate protects against impaired arteriolar constriction in sepsis by inhibiting inducible nitric oxide synthase expression

Cited by 87 publications

References 38 publications

Evaluation of Vitamin C for Adjuvant Sepsis Therapy

Evaluation of Vitamin C for Adjuvant Sepsis Therapy

Mechanism of action of vitamin C in sepsis: Ascorbate modulates redox signaling in endothelium

Effects of vitamin K1 supplementation on vascular responsiveness and oxidative stress in a rat femoral osteotomy model

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