Ascorbate prevents microvascular dysfunction in the skeletal muscle of the septic rat

Armour, J. Andrew; Tyml, Karel; Lidington, Darcy; Wilson, John X.

doi:10.1152/jappl.2001.90.3.795

Cited by 121 publications

(154 citation statements)

References 42 publications

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“…In contrast, nonseptic control rats and ascorbate-injected (76 mg/kg i.v.) CLP rats have a normal peritoneal cavity (2). These autopsy results suggest that ascorbate may exert wound-healing and bacteriostatic actions in septic animals.…”

Section: Bacterial Replicationmentioning

confidence: 64%

“…Ascorbate (5 mM) completely inhibits the growth of Staphylococcus aureus in vitro, even when any effect of the vitamin on extracellular acidity is prevented by neutralization (31). A lower concentration of ascorbate (100 lM), which protects endothelial cells from injury by exogenous hydrogen peroxide, is sufficient to inhibit replication in vitro of bacteria obtained from the cecum (2). It is possible that the bacteriostatic mechanism may involve production of hydrogen peroxide during oxidation of ascorbate in culture medium.…”

Section: Bacterial Replicationmentioning

confidence: 99%

“…Incubation of ascorbate with dilute fecal samples obtained from rat cecum shows that the vitamin inhibits bacterial replication in vitro, with the maximal inhibitory concentration being 100 lM ascorbate (2). In contrast, incubation with 100-1000 lM ascorbate does not kill microvascular endothelial cells but, on the contrary, confers protection against the injurious actions of exogenous hydrogen peroxide (2).…”

Section: Bacterial Replicationmentioning

confidence: 99%

“…of ascorbate (76-200 mg/ kg) attenuates the loss of arteriolar and blood pressure responsiveness to the vasoconstrictors norepinephrine and angiotensin II in CLP rats and mice (2,40,63,64). An important mechanism for the protection of arteriolar reactivity by ascorbate is inhibition of iNOS expression in endothelial cells.…”

Section: Ascorbate Preserves Arteriolar Reactivitymentioning

confidence: 99%

“…Bolus injection i.v. of ascorbate blocks hypotension from developing in endotoxemic rats (53) Ascorbate also prevents hypotension for 24 h in CLP rats (2,58), attenuates the fall in baseline blood pressure for 6 h in CLP mice (63), and fails to protect baseline blood pressure in FIP mice (59). The reasons for this variation between the different septic peritonitis models may be that, compared to salinevehicle injected CLP rats (75% survival at 24 h), sepsis Ascorbate also blocked the increases in iNOS and nNOS activities, and the decrease in eNOS activity (B).…”

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: Bacterial Replicationmentioning

confidence: 64%

Section: Bacterial Replicationmentioning

confidence: 99%

Section: Bacterial Replicationmentioning

confidence: 99%

Section: Ascorbate Preserves Arteriolar Reactivitymentioning

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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Association of Vitamin C, Thiamine, and Hydrocortisone Infusion With Long-term Cognitive, Psychological, and Functional Outcomes in Sepsis Survivors

et al. 2023

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ImportanceSepsis is associated with long-term cognitive impairment and worse psychological and functional outcomes. Potential mechanisms include intracerebral oxidative stress and inflammation, yet little is known about the effects of early antioxidant and anti-inflammatory therapy on cognitive, psychological, and functional outcomes in sepsis survivors.ObjectiveTo describe observed differences in long-term cognitive, psychological, and functional outcomes of vitamin C, thiamine, and hydrocortisone between the intervention and control groups in the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) randomized clinical trial.Design, Setting, and ParticipantsThis prespecified secondary analysis reports the 6-month outcomes of the multicenter, double-blind, placebo-controlled VICTAS randomized clinical trial, which was conducted between August 2018 and July 2019. Adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction who survived to discharge or day 30 were recruited from 43 intensive care units in the US. Participants were randomized 1:1 to either the intervention or control group. Cognitive, psychological, and functional outcomes at 6 months after randomization were assessed via telephone through January 2020. Data analyses were conducted between February 2021 and December 2022.InterventionsThe intervention group received intravenous vitamin C (1.5 g), thiamine hydrochloride (100 mg), and hydrocortisone sodium succinate (50 mg) every 6 hours for 96 hours or until death or intensive care unit discharge. The control group received matching placebo.Main Outcomes and MeasuresCognitive performance, risk of posttraumatic stress disorder and depression, and functional status were assessed using a battery of standardized instruments that were administered during a 1-hour telephone call 6 months after randomization.ResultsAfter exclusions, withdrawals, and deaths, the final sample included 213 participants (median [IQR] age, 57 [47-67] years; 112 males [52.6%]) who underwent long-term outcomes assessment and had been randomized to either the intervention group (n = 108) or control group (n = 105). The intervention group had lower immediate memory scores (adjusted OR [aOR], 0.49; 95% CI, 0.26-0.89), higher odds of posttraumatic stress disorder (aOR, 3.51; 95% CI, 1.18-10.40), and lower odds of receiving mental health care (aOR, 0.38; 95% CI, 0.16-0.89). No other statistically significant differences in cognitive, psychological, and functional outcomes were found between the 2 groups.Conclusions and RelevanceIn survivors of sepsis, treatment with vitamin C, thiamine, and hydrocortisone did not improve or had worse cognitive, psychological, and functional outcomes at 6 months compared with patients who received placebo. These findings challenge the hypothesis that antioxidant and anti-inflammatory therapy during critical illness mitigates the development of long-term cognitive, psychological, and functional impairment in sepsis survivors.Trial RegistrationClinicalTrials.gov Identifier: NCT03509350

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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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Ascorbate prevents microvascular dysfunction in the skeletal muscle of the septic rat

Cited by 121 publications

References 42 publications

Evaluation of Vitamin C for Adjuvant Sepsis Therapy

Evaluation of Vitamin C for Adjuvant Sepsis Therapy

Association of Vitamin C, Thiamine, and Hydrocortisone Infusion With Long-term Cognitive, Psychological, and Functional Outcomes in Sepsis Survivors

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

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