RT Journal Article SR Electronic T1 3H-1,2-Dithiole-3-thione Targets Nuclear Factor κB to Block Expression of Inducible Nitric-Oxide Synthase, Prevents Hypotension, and Improves Survival in Endotoxemic Rats JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 61 OP 67 DO 10.1124/jpet.105.096396 VO 317 IS 1 A1 Asok R. Karuri A1 Yong Huang A1 Sridevi Bodreddigari A1 Carrie Hayes Sutter A1 Bill D. Roebuck A1 Thomas W. Kensler A1 Thomas R. Sutter YR 2006 UL http://jpet.aspetjournals.org/content/317/1/61.abstract AB Septicemia is a major cause of death associated with noncoronary intensive care. Systemic production of nitric oxide (NO) by inducible nitric-oxide synthase (iNOS) is a major cause of hypotension and poor organ perfusion seen in septic shock. Here, we show that pretreatment of F344 rats with the cancer chemoprotective agent 3H-1,2-dithiole-3-thione (D3T) blocks lipopolysaccharide (LPS)-mediated induction of hepatic iNOS and significantly reduces the associated serum levels of NO metabolites and enzyme markers of toxicity provoked by treatment with LPS. Immunohistochemical analysis shows that this protective effect is largely due to suppression of iNOS expression in hepatocytes. Importantly, pretreatment of animals with D3T blunts LPS-mediated hypotension and dramatically increases their survival. Inasmuch as iNOS expression can be regulated by nuclear factor (NF) κB, mechanistic studies show that D3T blocks NFκB nuclear translocation and DNA binding and that these effects are accompanied by changes in the levels of phospho-inhibitor of NFκB. In conclusion, this study identifies new drug classes and targets that may improve the prevention and treatment of septic shock, as well as chronic diseases associated with the NFκB and iNOS pathways. The American Society for Pharmacology and Experimental Therapeutics