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Table 1 Pathophysiological effects and mechanisms of vitamin C in sepsis and ischemia reperfusion: animal studies

From: Vitamin C revisited

Model; dose and timing of ascorbate [study] Pathophysiological effect Mechanisms
Ischemia reperfusion   
Cardiac arrest (VF-ES) in rats; 50 and 100 mg/kg i.v. at start of CPR [33] Increases successful resuscitation after cardiac arrest rates and 72-hour survival (100 mg/kg better than 50 mg/kg) Preservation of histology
   Reduced mitochondrial swelling
   Preserves mitochondrial respiration (complex I and IV)
   Inhibits MDA ↑
LAD coronary artery ischemia ± ischemic preconditioning in pigs; 2 g i.v. + 25 mg/minute before IPC or before ischemia [42] Does not affect infarct size  
  Attenuates the beneficial effect of ischemic preconditioning indicating free oxygen radicals are involved in ischemic preconditioning  
Middle cerebral artery clamping in mice; DHA 40, 250 and 500 mg/kg, AA 250 and 500 mg/kg, before, 15 minutes and 3 hours after [81] DHA gives dose-dependent: DHA passes blood–brain barrier, ascorbate does not
  Reperfusion blood flow ↑ No beneficial effect of ascorbate
  Infarct size ↓  
  Neurological deficit ↓  
  Mortality ↓ (if given before ischemia)  
Abdominal aortic clamping in rats; 100 mg/kg i.v. before [37] Attenuates lung injury MDA in blood and lung ↓
Renal ischemia in rabbits; 15 mg/kg 24 hours and 1 hour before and 0.83 mg/minute during [34] Ameliorates renal structure and function PAF and PAF-like lipids ↓
   Myeloperoxidase activity ↓
Hepatic ischemia (clamping HA–PV) rats; 30, 100, 300, and 1,000 mg/kg 5 minutes before [38] Bile flow and cholate secretion ↑ 30 and 100 mg/kg:
  Extremely high dose is prooxidant AST and lipid peroxidation ↓
   Prevents ↓ of cytochrome P450 1,000 mg/kg
   Injury and loss of function ↑
IPC + hepatic ischemia (clamping left HA and PV) in rats; 100 mg/kg i.v. after IPC before clamping [41] Ascorbate or IPC plus ascorbate after IPC reduce mitochondrial damage and dysfunction Prevents mitochondrial:
   Swelling
   Peroxide ↑, MDA ↑
   GSH and GSH/GSSG ↓
   Glutamate dehydrogenase ↓
   ATP ↓ (ascorbate plus IPC)
Liver ischemia in rats; 100 mg/kg i.v. 1 hour before [40] Attenuates reperfusion liver injury Attenuation of O2 and NO release
Liver ischemia (clamping HA and PV) in rats; oral vitamin C for 5 days [39] Attenuates myocardial injury and protects cardiac function after liver ischemia Systemic hydroxyl radical ↓
   Myocardial MDA
Skeletal muscle ischemia in rats; oral vitamin C for 5 days [35] Preserves muscle function Muscle myeloperoxidase ↓
  Reduces edema Neutrophil infiltration ↓
   Respiratory burst ↓
Skeletal muscle tourniquet in rats; 50 mg/kg i.v. before ischemia, before reperfusion, or both [36] Preserves muscle function Blood malondialdehyde↓
  Reduces edema Muscle malondialdehyde =
   Neutrophil influx
Sepsis   
Systemic and microcirculation   
CLP in rats; 76 mg/kg i.v. directly after [32] Restores blood pressure and density of perfused capillaries  
CLP in mice; 200 mg/kg 30 minutes before [6] Improves microvascular constriction and arterial pressure responses to norepinephrine iNOS expression ↓
   iNOS mRNA ↓
   ROS production ↓
CLP in mice; baseline and 23 hours after 200 mg/kg [48] Restores arteriolar conducted vasoconstriction Reduces increased:
   nNOS activity
   Nitrite/nitrate
CLP in rats; 76 mg/kg after 1 hour, 6 hours and 2 hours [44] Prevents maldistributed blood flow and low arterial blood pressure Blood flow impairment:
   Requires NADPH oxidase
   Reversal by ascorbate or BH4
   eNOS dependent
FIP in mice; 10 or 200 mg/kg i.v. 6 hours after [47] Prevents/reverses septic impairment of capillary blood flow for 18 hours and improves survival Blood flow impairment depends on the NADPH oxidase subunit gp91phox
   Ascorbate effects are eNOS dependent
   Ascorbate suppresses iNOS ↑ activity
FIP in mice; 10 mg/kg i.v. prophylactic or delayed [46] Prevention or reversal of septic platelet adhesion and/or flow stoppage Capillary flow stoppage
   eNOS dependent
   Platelet adhesion predicts 90 %
CLP in mice; 200 mg/kg i.v. at baseline and 3 hours after [50] Prevents vascular leakage Inhibits production of:
   O2 and NO by NADPH oxidase, iNOS and nNOS
   Peroxynitrite
   3-Nitrotyrosine-positive proteins ↓
   Inhibits PP2A activation
   Preserves endothelial occludin phosphorylation
Organ injury and function   
Intraperitoneal LPS in guinea pigs; low vs. high vitamin C diet [51] Dietary vitamin C Hepatic lipid peroxidation ↓
  Increases hepatic vitamin C and vitamin E content Hepatic protein carbonyls ↓
  Reduces oxidative damage to lipids and proteins Hepatic GSH and GSH/GSSG ↑ (vitamin C + vitamin E)
CLP in rats; 100 mg/kg directly after [53] Decreases hepatic injury Suppresses AST and ALT ↑
  Improves drug-metabolizing function Prevents GSH and GSH/GSSG ↓
   Prevents CYP1A1 and CYP2E1 mRNA, and CYP1A2 activity
FIP or LPS in mice; 200 mg/kg i.p. after LPS [54] Attenuates sepsis-induced acute lung injury and improves 72-h survival Preserves lung architecture and barrier
   Proinflammatory chemokine expression ↓ microvascular thrombosis ↓
   Nuclear factor-kappaB activation ↓
   Normalizes coagulation
Immune defense against infection   
Klebsiella pneumonia in mice; ascorbate deficient vs. ascorbate supplemented for 25 days [56] Ascorbate deficiency increases death from infection No effect on:
   Cellular response
   Amino acid and lipid peroxidation
   Higher concentration of bacteria in ascorbate deficiency
  1. AA, ascorbic acid; ALT, alanine aminotransferase; AST, aminotransferase; BH4, tetrahydrobiopterin; CLP, cecal ligation and perforation; CPR, cardiopulmonary resuscitation; CYP, cytochrome P450; DHA, dehydroascorbic acid; eNOS, endothelial nitric oxide synthase; ES, electrical shock; FIP, feces injection into the peritoneum; GSH, reduced glutathion; GSSG, glutathione disulphide; HA, hepatic artery; IPC, ischemic preconditioning; LAD, left anterior descending; LPS, lipopolysaccharide; MDA, malondialdehyde (marker for lipid peroxidation); iNOS, inducible nitric oxide synthase; i.p., intraperitoneal; i.v., intravenous; NADPH, nicotinamide adenine dinucleotide phosphate; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; O2 , superoxide; PAF, platelet-activating factor; PPA2, protein phosphatase 2A; PV, portal vein; ROS, reactive oxygen species; VF, ventricular fibrillation. ↑, increase; ↓, decrease; =, constant.