Ketoisocaproate infusion improves survival from experimental sepsis by an antioxidant mechanism.
Sepsis was induced in rats by cecal ligation and puncture. A nutrient mixture was infused that also contained either (A) sodium 2-ketoisocaproate (NaKIC) or (B) NaHCO3, at 18.75 mmol kg/day. In group A, 34 of 43 rats (79%) survived, while only 24 of 44 rats (55%) in group B survived (P < 0.02). In a second experiment, cecal ligation and puncture were performed 1 week after bilateral adrenalectomy or sham adrenalectomy. All adrenalectomized rats died within 2 days of CLP, whether corticosterone replacement level was low, normal, or high. Four of eight sham-adrenalectomized rats receiving NaHCO3 died, but none of seven receiving NaKIC died. Combining both experiments by ANOVA, the effect of KIC on survival in adrenal-intact animals is highly significant (P = 0.002). In NaKIC-infused rats, blood level of pyruvate was higher on day 5 (P < 0.01), and plasma as well as blood levels of oxidized glutathione and ratio of oxidized/reduced glutathione were significantly lower. We conclude that KIC infusion improves survival of septic rats by an antioxidant mechanism, probably involving reaction with hydrogen peroxide.
Yonekura
T
T
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Matsusue
S
S
Walser
M
M
D000315:Adrenalectomy; D000596:Amino Acids / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001424:Bacterial Infections / Q000188:drug therapy* / Q000401:mortality; D003345:Corticosterone / Q000097:blood; D005978:Glutathione / Q000097:blood; D007651:Keto Acids / Q000627:therapeutic use*; D008297:Male; D011773:Pyruvates / Q000097:blood; D019289:Pyruvic Acid; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate
D000596:Amino Acids; D000975:Antioxidants; D007651:Keto Acids; D011773:Pyruvates; C013082:alpha-ketoisocaproic acid; D019289:Pyruvic Acid; D005978:Glutathione; D003345:Corticosterone