HSP induction inhibits iNOS mRNA expression and attenuates hypotension in endotoxin-challenged rats.
Endotoxin (lipopolysaccharide, LPS)-induced hypotension is, in part, mediated via induction of nitric oxide synthase (iNOS), release of nitric oxide, and suppression of vascular reactivity (vasoplegia). Induction of heat shock proteins (HSP) or inhibition of iNOS expression improves survival in LPS-challenged rodents. We studied the effect of induction of HSP on LPS-mediated iNOS expression and on LPS-induced vasoplegia and hypotension. Rats were treated with the HSP inducer sodium arsenite (6 mg/kg iv) or saline control. Seventeen hours later, rats were challenged intravenously with 10 mg/kg of Escherichia coli LPS O127:B8 or saline control. Arsenite pretreatment resulted in expression of HSP 70 mRNA and of HSP 70 and heme oxygenase-1 proteins, inhibition of LPS-mediated iNOS mRNA induction, reversal of the LPS-induced hyporesponsiveness to norepinephrine ex vivo in isolated mesenteric arteries, and attenuation of LPS-induced hypotension in vivo. Our data suggest that induction of HSP expression protects rats from LPS by blocking LPS-induced iNOS expression, leading to inhibition of the overproduction of nitric oxide and thereby reversing LPS-induced vasoplegia and LPS-induced hypotension.
Hauser
G J
GJ
Division of Pediatric Critical Care Medicine, Georgetown University Children's Medical Center, Washington, District of Columbia 20007, USA.
Dayao
E K
EK
Wasserloos
K
K
Pitt
B R
BR
Wong
H R
HR
D000818:Animals; D018053:Arsenites / Q000494:pharmacology; D004285:Dogs; D004731:Endotoxins / Q000494:pharmacology*; D004790:Enzyme Induction; D004926:Escherichia coli; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D007022:Hypotension / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics*; D009638:Norepinephrine / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017670:Sodium Compounds / Q000494:pharmacology; D013152:Splanchnic Circulation / Q000187:drug effects; D014661:Vasoconstriction
D018053:Arsenites; D004731:Endotoxins; D018840:HSP70 Heat-Shock Proteins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D017670:Sodium Compounds; C017947:sodium arsenite; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing); D009638:Norepinephrine