L-2-Oxothiazolidine-4-carboxylic acid prevents endotoxin-induced cardiac dysfunction.
We tested the hypothesis that treatment with the glutathione repleting agent, L-2-oxothiazolidine-4-carboxylic acid (OTZ), could prevent endotoxin-induced ventricular dysfunction. Rabbits were treated with OTZ 2.4 g/kg (10% solution subcutaneously), or an equal volume and osmolality of saline, 24 h prior to, and again (intravenously) just prior to, infusion of 1 mg/kg E. coli endotoxin (or vehicle control). Ventricular contractility was measured in isolated hearts perfused by support rabbits. Contractility did not change in control groups (Saline/Control [n = 7] or OTZ/Control [n = 7]) over 6 h. However, Emax decreased in the Saline/Endotoxin group (-16.1 +/- 4.5% from baseline, n = 7, p < 0.05) and this was prevented by pretreatment with OTZ in the OTZ/ Endotoxin group (+6.3 +/- 4.1%, n = 7, p < 0.05 by analysis of variance). To better understand the mechanism of this effect we measured myocardial glutathione concentration and found it to be greater in OTZ/Endotoxin animals (104 +/- 4 ng/g) than in the Saline/Endotoxin animals (80 +/- 3 ng/g, p < 0.05). OTZ did not appreciably alter the endotoxin-induced increase in serum concentration of tumor necrosis factor (TNF) or the endotoxin-induced increase in myocardial leukocyte content. We conclude that oxygen radicals contribute to the early decrease in left ventricular contractility after endotoxin infusion and this decrease may be prevented by OTZ.
Pulmonary Research Laboratory, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
B Y
BY
Poon
C M
CM
Goddard
C D
CD
Leaf
J A
JA
Russell
K R
KR
Walley
D000704:Analysis of Variance; D000818:Animals; D004731:Endotoxins / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D004926:Escherichia coli; D005609:Free Radicals / Q000037:antagonists & inhibitors / Q000378:metabolism; D005978:Glutathione / Q000032:analysis / Q000187:drug effects / Q000378:metabolism; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D007958:Leukocyte Count; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D011355:Prodrugs / Q000008:administration & dosage / Q000627:therapeutic use*; D011761:Pyrrolidonecarboxylic Acid; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D053778:Thiazolidines; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000517:prevention & control*
D004731:Endotoxins; D005609:Free Radicals; D011355:Prodrugs; D017382:Reactive Oxygen Species; D013844:Thiazoles; D053778:Thiazolidines; D014409:Tumor Necrosis Factor-alpha; D005978:Glutathione; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid