S [43], muscle [6] and plasma [32,44] of septic rodents. Endotoxin also depleted myocardial ascorbate in guinea pig hearts after as early as 4 hours, even after dietary supplementation for 5 weeks [45].Systemic circulation, microcirculation and permeabilityVitamin C prevented the increase in endotoxin-induced myocardial uric acid accumulation, a marker of ischemiainduced MS023 biological activity oxidative stress [45], and protected against endotoxin-induced oxidative damage to proteins in the guinea pig liver [51]. Ascorbate (100 mg/kg i.v.) reduced hepatic microvascular dysfunction during polymicrobial sepsis when administered immediately after CLP in rats by reducing oxidative stress and lipid peroxidation, and regulating hepatic vasoregulatory gene expression [52,53]. In addition, ascorbate prevented the sepsis-induced decrease in several cytochrome P450 enzyme activities, thereby improving drug-metabolizing function [53]. Ascorbate (200 mg/kg i.v.) also attenuated sepsis-induced acute lung injury in a mouse model of FIP or LPS [54,55] and improved 72-hour survival [54]. Finally, oral prefeeding with ascorbate decreased bacterial concentrations and improved survival after intraperitoneal injection of Klebsiella pneumonia in mice [56].Ascorbate (76 mg/kg i.v.) restored blood pressure and prevented microvascular dysfunction in skeletal muscle of septic rats [32]. In a mouse model of FIP, ascorbate (10 mg/kg i.v.) inhibited impairment of microvascular perfusion when administered early (0 hours) and reversed septic platelet adhesion and flow impairment with late administration (after 6 hours) [46]. Similarly, PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/27597769 ascorbate improved capillary blood flow by an eNOS-dependentRole of vitamin C in ischemia/reperfusion and sepsis: human volunteers In human volunteers, both ischemia/reperfusion injury (20 minutes of forearm ischemia) [57] and low-dose LPS [58] reduced plasma vitamin C concentrations and diminished acetylcholine-induced, endothelial-dependent vasodilatation. High-dose (24 mg/minute) intra-arterial vitamin C increased BH4 concentrations [59], reduced neutrophil oxidative burst and completely restored the response to acetylcholine, but not to glyceryl-trinitrate (endotheliumindependent dilatation), supporting its endothelial protective effect. Vitamin C also corrected the LPS-inducedOudemans-van Straaten et al. Critical Care 2014, 18:460 http://ccforum.com/content/18/1/Page 5 ofTable 1 Pathophysiological effects and mechanisms of vitamin C in sepsis and ischemia reperfusion: animal studiesModel; dose and timing of ascorbate [study] 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 Pathophysiological effect MechanismsReduced 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 sizeAttenuates 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 rain barrier, ascorbate does not No beneficial effect of ascorbateReperfusion blood flow Infarct size Neuro.