Deleterious effects of buthionine sulfoximine on cardiac function during continuous endotoxemia.
Sepsis has been associated with reversible cardiac injury. To determine whether this injury is mediated by generation of reactive oxidants, tissue glutathione (GSH)--the major intracellular antioxidant--was depleted before endotoxemia. Basal values of cardiac contractile function, perfusion, and cardiac output were measured 5-7 days postsurgery. Salmonella enteritidis endotoxin was continuously infused at 3 micrograms/kg/hr iv via an osmotic pump (Alzet Corp). Endotoxemia significantly reduced myocardial glutathione content (394 +/- 46) to 206 +/- 9 micrograms/g), indicating oxidant stress during endotoxemia. Buthionine sulfoximine (BSO) pretreatment significantly reduced cardiac glutathione in sham pigs from 394 +/- 46 to 199 +/- 26 micrograms/g; and in endotoxemic pigs, BSO pretreatment significantly reduced cardiac glutathione to 106 +/- 18 micrograms/g. Vehicle- and BSO-treated endotoxemic groups demonstrated similar cardiovascular responses to endotoxin challenge. Heart rate increases (122 +/- 15 to 140 +/- 17 bpm) and cardiac outputs decreases (1.50 +/- 0.24 to 1.11 +/- 0.35 l/min) were similar, indicating similar cardiovascular insults induced by endotoxemia. Percent short axis shortening and end-systolic pressure-diameter relation (ESPDR) were significantly reduced in BSO pretreated compared with vehicle-treated endotoxemic pigs. Results support a conclusion that endotoxemia-induced cardiac injury is mediated, in part, by free radical injury. This conclusion is based upon the finding that endogenous myocardial glutathione was depleted by continuous endotoxin infusion and that prior depletion of myocardial glutathione by buthionine sulfoximine exacerbated cardiac injury.
Lee
K J
KJ
Department of Physiology, Albany Medical College, New York 12208, USA.
Andrejuk
T
T
Dziuban
S W
SW
Goldfarb
R D
RD
D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity; D019328:Buthionine Sulfoximine; D002302:Cardiac Output / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004731:Endotoxins / Q000097:blood / Q000633:toxicity*; D005260:Female; D005609:Free Radicals; D005978:Glutathione / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D012477:Salmonella enteritidis; D013552:Swine
D001427:Bacterial Toxins; D004731:Endotoxins; D005609:Free Radicals; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005978:Glutathione