title: Protection against TNF-induced lethal shock by soluble guanylate cyclase inhibition requires functional inducible nitric oxide synthase.
abstract: Hypotension and shock observed in sepsis, SIRS, and tumor necrosis factor (TNF) or cytokine-based cancer treatment are the consequence of excessive nitric oxide (NO) production and subsequent soluble guanylate cyclase (sGC)-mediated vascular smooth muscle relaxation. We demonstrate here that, while NO synthase (NOS) inhibitors exacerbated toxicity, inhibitors of sGC activation protected against TNF-induced lethality, bradycardia, and hypotension. Importantly, sGC inhibition did not interfere with the antitumor activity of TNF. Using NOS inhibitors or iNOS-deficient animals, we furthermore observed that no protection against TNF toxicity could be obtained in the absence of NO. These data imply that iNOS- (and not eNOS-) derived NO is an endogenous protective molecule indispensable to survive a TNF challenge and exerting this beneficial effect via sGC-independent mechanisms.
authors.affiliation: MPET, Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology, Ghent University, Belgium. anje@dmb.rug.ac.be
authors.forename: A
authors.initials: A
authors.lastname: Cauwels
authors.forename: W
authors.initials: W
authors.lastname: Van Molle
authors.forename: B
authors.initials: B
authors.lastname: Janssen
authors.forename: B
authors.initials: B
authors.lastname: Everaerdt
authors.forename: P
authors.initials: P
authors.lastname: Huang
authors.forename: W
authors.initials: W
authors.lastname: Fiers
authors.forename: P
authors.initials: P
authors.lastname: Brouckaert
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D012769:Shock / Q000378:metabolism* / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
chemical_list: D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D006162:Guanylate Cyclase