Reversible inhibition of cellular respiration by nitric oxide in vascular inflammation.
Incubation of rat aortas with endotoxin and interferon-gamma for 24 h resulted in an aortic oxygen consumption that was substantially inhibited and strongly oxygen dependent (37% inhibition at 160 microM O(2) and 62% inhibition at 80 microM O(2) relative to untreated aortas). This respiratory inhibition was reversed by a nitric oxide (NO) scavenger (oxyhemoglobin) or by an inhibitor of inducible NO synthase [N-(3-(aminomethyl)benzyl)acetamide x 2HCl, 1400W], but not by an inhibitor of soluble guanylate cyclase (1H-[1,2,4]oxadiazolo[4,3-a]-quinoxalin-1-one). Addition of 1 microM NO to untreated aortas caused rapid and reversible inhibition of oxygen consumption that was greater at lower oxygen concentrations. Incubation of endothelial cells isolated from rat aortas with endotoxin and interferon-gamma for 24 h resulted in a steady-state NO concentration of approximately 0.5 microM and 90% inhibition of cellular oxygen consumption that was immediately reversed by an NO scavenger (oxyhemoglobin). These results suggest that during inflammation and sepsis, tissue respiration may be substantially reduced due to inhibition by NO of cytochrome oxidase.
Borutaite
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Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United Kingdom. vb207@mole.bio.cam.ac.uk
Matthias
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Harris
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Moncada
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Brown
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GC
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000166:cytology / Q000378:metabolism*; D001596:Benzylamines / Q000494:pharmacology; D019069:Cell Respiration / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010069:Oxadiazoles / Q000494:pharmacology; D010108:Oxyhemoglobins / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014657:Vasculitis / Q000378:metabolism*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000578:Amidines; D000970:Antineoplastic Agents; D001596:Benzylamines; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D010069:Oxadiazoles; D010108:Oxyhemoglobins; D011810:Quinoxalines; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat