Enhanced NO and superoxide generation in dysfunctional hearts from endotoxemic rats.
Free radicals have been implicated in the etiology of cardiac dysfunction during sepsis, but the actual species responsible remains unclear. We studied the alterations in myocardial nitric oxide (NO), superoxide, and peroxynitrite generation along with cardiac mechanical function and efficiency in hearts from lipopolysaccharide (LPS)-treated rats. Six hours after LPS (4 mg/kg ip) or saline (control) treatment, hearts were isolated and perfused for 1 h with recirculating Krebs-Henseleit buffer and paced at 300 beats/min. Cardiac work, O(2) consumption, and cardiac efficiency were markedly depressed in LPS hearts compared with controls. Plasma nitrate/nitrite level was elevated in LPS rats, and ventricular NO production was enhanced as measured by electron spin resonance spectroscopy, Ca(2+)-independent NO synthase (NOS) activity, and inducible NOS immunohistochemistry. Ventricular superoxide production was also enhanced in LPS-treated hearts as seen by lucigenin chemiluminescence and xanthine oxidase activity. Increased nitrotyrosine staining (immunohistochemistry) and higher lipid hydroperoxides levels were also detected in LPS-treated hearts, indicating oxygen radical-induced stress. Enhanced generation of both NO and superoxide, and thus peroxynitrite, occur in dysfunctional hearts from endotoxemic rats.
Departments of Pharmacology and Pediatrics, Cardiovascular Research Group, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
Fadi H
FH
Khadour
Donna
D
Panas
Péter
P
Ferdinandy
Costas
C
Schulze
Tamás
T
Csont
Manoj M
MM
Lalu
Stephen M
SM
Wildhirt
Richard
R
Schulz
D000818:Animals; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism*; D006331:Heart Diseases / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000201:enzymology*; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D010101:Oxygen Consumption / Q000502:physiology; D030421:Peroxynitrous Acid / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000139:chemically induced / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D014969:Xanthine Oxidase