HSP INDUCTION INHIBITS INOS MESSENGER-RNA EXPRESSION AND ATTENUATES HYPOTENSION IN ENDOTOXIN-CHALLENGED RATS

Endotoxin (lipopolysaccharide, LPS)-induced hypotension is, in part, m ediated via induction of nitric oxide synthase (iNOS), release of nitr ic oxide, and suppression of vascular reactivity (vasoplegia). Inducti on of heat shock proteins (HSP) or inhibition of iNOS expression impro ves survival in LPS-challenged rodents. We studied the effect of induc tion of HSP on LPS-mediated iNOS expression and on LPS-induced vasople gia and hypotension. Rats were treated with the HSP inducer sodium ars enite (6 mg/kg iv) or saline control. Seventeen hours later, rats were challenged intravenously with 10 mg/kg of Escherichia coli LPS O127:B 8 or saline control. Arsenite pretreatment resulted in expression of H SP 70 mRNA and of HSP 70 and heme oxygenase-l proteins, inhibition of LPS-mediated iNOS mRNA induction, reversal of the LPS-induced hyporesp onsiveness to norepinephrine ex vivo in isolated mesenteric arteries, and attenuation of LPS-induced hypotension in vivo. Our data suggest t hat 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-i nduced hypotension.