Effect of dexamethasone on the onset and persistence of vascular hyporeactivity induced by E. coli lipopolysaccharide in rats.
The effects of dexamethasone (DEX) were studied on early and delayed hyporesponsiveness to noradrenaline (NA) induced by Escherichia coli lipopolysaccharide (LPS) in pentobarbitone-anesthetized rats, and in aortic rings, which were either removed from LPS-treated rats or exposed to LPS in vitro. In all three preparations, the LPS-impaired responses to NA were restored by N omega-nitro-L-arginine methyl ester. In addition, delayed depression of NA-induced aortic contractions was enhanced by L-arginine (1 mM). In control conditions, DEX had no effect on responses to NA. When administered before LPS, or before hyporeactivity was fully developed, DEX (5-10 mg/kg or 10 microM) entirely prevented both the early decline in responses to NA or its progression, and the delayed impaired aortic contraction induced by LPS. However, DEX did not prevent the transient drop in mean arterial blood pressure (which was maximal at 20 min after the onset of LPS infusion) observed before the full development of impaired reactivity to NA (reached after 55 min). Neither did DEX modify the responses to NA, in vivo or in vitro, once LPS-induced hyporesponsiveness was fully established. These results indicate that DEX inhibits both the onset of impaired responsiveness to NA, which probably involves the early stimulation of the constitutive nitric oxide (NO) synthase, and persistent vascular hyporeactivity resulting from the delayed induction of NO-synthase by LPS. In addition, they show that DEX has no effect on hyporeactivity to NA once fully established.
Paya
D
D
Université Louis Pasteur de Strasbourg, Laboratoire de Pharmacologie Cellulaire et Moléculaire, CNRS URA 600, Illkirch, France.
Gray
G A
GA
Fleming
I
I
Stoclet
J C
JC
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D004926:Escherichia coli; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D019001:Nitric Oxide Synthase; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000209:etiology / Q000503:physiopathology*; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects*
D008070:Lipopolysaccharides; D003907:Dexamethasone; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D009638:Norepinephrine