Inhibition of the production of nitric oxide and vasodilator prostaglandins attenuates the cardiovascular response to bacterial endotoxin in adrenalectomized rats.
Bacterial lipopolysaccharide (LPS) is the toxic moiety of the gram-negative bacterial outer membrane which is responsible for many of the pathophysiological events that occur during endotoxic shock. Here we investigate the hypothesis that endogenous glucocorticoids modulate the formation of nitric oxide (NO) and of vasodilator cyclooxygenase metabolites in response to LPS. Intravenous administration of a small dose of Escherichia coli LPS (0.1 mg kg-1) to normal Wistar rats caused a moderate fall in blood pressure, and 120 min of endotoxaemia was not associated with an attenuation of the rise in blood pressure elicited by intravenous injection of noradrenaline (NA; vascular hyporeactivity). When adrenalectomized (ADX) rats, which lack endogenous glucocorticoids, were subjected to the same dose of LPS, they developed a much more severe form of circulatory shock, which was characterized by a profound fall in blood pressure and a vascular hyporeactivity to NA. Both hypotension and vascular hyporeactivity were prevented by pre-treatment with dexamethasone. Inhibition of NO biosynthesis with NG-methyl-L-arginine significantly attenuated the hypotension and the vascular hyporeactivity to NA caused by LPS in ADX rats. Similarly, the cyclooxygenase inhibitor indomethacin significantly attenuated the circulatory failure elicited by LPS in the ADX rats. Interestingly, 120 min of endotoxaemia resulted in a de novo biosynthesis of an induced isoform of NO synthase in the lungs of ADX, but not normal Wistar, rats. This induction of NO synthase was prevented by dexamethasone pre-treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Szabó
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C
William Harvey Research Institute, St Bartholomew's Hospital Medical College, London, U.K.
Thiemermann
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C
Vane
J R
JR
D000315:Adrenalectomy; D000594:Amino Acid Oxidoreductases / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D002118:Calcium / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D004926:Escherichia coli; D005938:Glucocorticoids / Q000502:physiology*; D007213:Indomethacin / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase; D009638:Norepinephrine / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000503:physiopathology; D013997:Time Factors; D019323:omega-N-Methylarginine
D005938:Glucocorticoids; D008070:Lipopolysaccharides; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D003907:Dexamethasone; D001120:Arginine; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D000594:Amino Acid Oxidoreductases; D002118:Calcium; D009638:Norepinephrine; D007213:Indomethacin