BACKGROUND: Nitric oxide (NO), a small effector molecule produced enzymatically from L-arginine by nitric oxide synthase (NOS), is a mediator not only of important homeostatic mechanisms (e.g., blood vessel tone and tissue perfusion), but also of key aspects of local and systemic inflammatory responses. Previous efforts to develop inhibitors of NOS to protect against NO-mediated tissue damage in endotoxin shock have been unsuccessful, largely because such competitive NOS antagonists interfere with critical vasoregulatory NO production in blood vessels and decrease survival in endotoxemic animals. Accordingly, we sought to develop a pharmaceutical approach to selectively inhibit NO production in macrophages while sparing NO responses in blood vessels. MATERIALS AND METHODS: The process of cytokine-inducible L-arginine transport and NO production were studied in the murine macrophage-like cell line (RAW 264.7). A series of multivalent guanylhydrazones were synthesized to inhibit cytokine-inducible L-arginine transport. One such compound (CNI-1493) was studied further in animal models of endothelial-derived relaxing factor (EDRF) activity, carrageenan inflammation, and lethal lipopolysaccharide (LPS) challenge. RESULTS: Upon activation with cytokines, macrophages increase transport of L-arginine to support the production of NO by NOS. Since endothelial cells do not require this additional arginine transport to produce NO, we reasoned that a competitive inhibitor of cytokine-inducible L-arginine transport would not inhibit EDRF activity in blood vessels, and thus might be effectively employed against endotoxic shock. CNI-1493, a tetravalent guanylhydrazone, proved to be a selective inhibitor of cytokine-inducible arginine transport and NO production, but did not inhibit EDRF activity. In mice, CNI-1493 prevented the development of carrageenan-induced footpad inflammation, and conferred protection against lethal LPS challenge. CONCLUSIONS: A selective inhibitor of cytokine-inducible L-arginine transport that does not inhibit vascular EDRF responses is effective against endotoxin lethality and significantly reduces inflammatory responses.
BACKGROUND:Nitric oxide (NO), a small effector molecule produced enzymatically from L-arginine by nitric oxide synthase (NOS), is a mediator not only of important homeostatic mechanisms (e.g., blood vessel tone and tissue perfusion), but also of key aspects of local and systemic inflammatory responses. Previous efforts to develop inhibitors of NOS to protect against NO-mediated tissue damage in endotoxin shock have been unsuccessful, largely because such competitive NOS antagonists interfere with critical vasoregulatory NO production in blood vessels and decrease survival in endotoxemic animals. Accordingly, we sought to develop a pharmaceutical approach to selectively inhibit NO production in macrophages while sparing NO responses in blood vessels. MATERIALS AND METHODS: The process of cytokine-inducible L-arginine transport and NO production were studied in the murine macrophage-like cell line (RAW 264.7). A series of multivalent guanylhydrazones were synthesized to inhibit cytokine-inducible L-arginine transport. One such compound (CNI-1493) was studied further in animal models of endothelial-derived relaxing factor (EDRF) activity, carrageenaninflammation, and lethal lipopolysaccharide (LPS) challenge. RESULTS: Upon activation with cytokines, macrophages increase transport of L-arginine to support the production of NO by NOS. Since endothelial cells do not require this additional arginine transport to produce NO, we reasoned that a competitive inhibitor of cytokine-inducible L-arginine transport would not inhibit EDRF activity in blood vessels, and thus might be effectively employed against endotoxic shock. CNI-1493, a tetravalent guanylhydrazone, proved to be a selective inhibitor of cytokine-inducible arginine transport and NO production, but did not inhibit EDRF activity. In mice, CNI-1493 prevented the development of carrageenan-induced footpad inflammation, and conferred protection against lethal LPS challenge. CONCLUSIONS: A selective inhibitor of cytokine-inducible L-arginine transport that does not inhibit vascular EDRF responses is effective against endotoxin lethality and significantly reduces inflammatory responses.
Authors: K J Tracey; B Beutler; S F Lowry; J Merryweather; S Wolpe; I W Milsark; R J Hariri; T J Fahey; A Zentella; J D Albert Journal: Science Date: 1986-10-24 Impact factor: 47.728
Authors: D A Geller; A K Nussler; M Di Silvio; C J Lowenstein; R A Shapiro; S C Wang; R L Simmons; T R Billiar Journal: Proc Natl Acad Sci U S A Date: 1993-01-15 Impact factor: 11.205
Authors: J P Cobb; C Natanson; W D Hoffman; R F Lodato; S Banks; C A Koev; M A Solomon; R J Elin; J M Hosseini; R L Danner Journal: J Exp Med Date: 1992-10-01 Impact factor: 14.307
Authors: P S Cohen; H Schmidtmayerova; J Dennis; L Dubrovsky; B Sherry; H Wang; M Bukrinsky; K J Tracey Journal: Mol Med Date: 1997-05 Impact factor: 6.354
Authors: K kerlund; H Erlandsson Harris; K J Tracey; H Wang; T Fehniger; L Klareskog; J Andersson; U Andersson Journal: Clin Exp Immunol Date: 1999-01 Impact factor: 4.330
Authors: Erin D Milligan; Carin Twining; Marucia Chacur; Joseph Biedenkapp; Kevin O'Connor; Stephen Poole; Kevin Tracey; David Martin; Steven F Maier; Linda R Watkins Journal: J Neurosci Date: 2003-02-01 Impact factor: 6.167