GYY4137, a novel hydrogen sulfide-releasing molecule, protects against endotoxic shock in the rat.
GYY4137 (morpholin-4-ium-4-methoxyphenyl(morpholino) phosphinodithioate) is a slow-releasing hydrogen sulfide (H(2)S) donor. Administration of GYY4137 (50 mg/kg, iv) to anesthetized rats 10 min after lipopolysaccharide (LPS; 4 mg/kg, iv) decreased the slowly developing hypotension. GYY4137 inhibited LPS-induced TNF-alpha production in rat blood and reduced the LPS-evoked rise in NF-kappaB activation, inducible nitric oxide synthase/cyclooxygenase-2 expression, and generation of PGE(2) and nitrate/nitrite in RAW 264.7 macrophages. GYY4137 (50 mg/kg, ip) administered to conscious rats 1 or 2 h after (but not 1 h before) LPS decreased the subsequent (4 h) rise in plasma proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6), nitrite/nitrate, C-reactive protein, and L-selectin. GYY4137 administration also decreased the LPS-evoked increase in lung myeloperoxidase activity, increased plasma concentration of the anti-inflammatory cytokine IL-10, and decreased tissue damage as determined histologically and by measurement of plasma creatinine and alanine aminotransferase activity. Time-expired GYY4137 (50 mg/kg, ip) did not affect the LPS-induced rise in plasma TNF-alpha or lung myeloperoxidase activity. GYY4137 also decreased the LPS-mediated upregulation of liver transcription factors (NF-kappaB and STAT-3). These results suggest an anti-inflammatory effect of GYY4137. The possibility that GYY4137 and other slow-releasing H(2)S donors exert anti-inflammatory activity in other models of inflammation and in humans warrants further study.
Pharmaceutical Science Research Division, King's College, University of London, London, UK.
Ling
L
Li
Manuel
M
Salto-Tellez
Choon-Hong
CH
Tan
Matthew
M
Whiteman
Philip K
PK
Moore
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D006862:Hydrogen Sulfide / Q000737:chemistry / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009025:Morpholines / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009946:Organothiophosphorus Compounds / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D012772:Shock, Septic / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*
D000893:Anti-Inflammatory Agents; D016207:Cytokines; C529376:GYY 4137; D008070:Lipopolysaccharides; D009025:Morpholines; D016328:NF-kappa B; D009946:Organothiophosphorus Compounds; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D051546:Cyclooxygenase 2; D006862:Hydrogen Sulfide