Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Anti-Inflammatory Agents / administration & dosage*
-
Anti-Inflammatory Agents / chemistry
-
Anti-Inflammatory Agents / immunology
-
Anti-Inflammatory Agents / pharmacology
-
Blood Pressure / drug effects
-
Cell Line
-
Cyclooxygenase 2 / genetics
-
Cyclooxygenase 2 / immunology
-
Cyclooxygenase 2 / metabolism
-
Cytokines / genetics
-
Cytokines / immunology
-
Cytokines / metabolism
-
Cytoprotection / drug effects
-
Hydrogen Sulfide / chemistry
-
Hydrogen Sulfide / metabolism*
-
Lipopolysaccharides / immunology
-
Lipopolysaccharides / metabolism
-
Liver / drug effects
-
Liver / metabolism
-
Liver / pathology
-
Lung / drug effects
-
Lung / enzymology
-
Lung / pathology
-
Macrophages / drug effects*
-
Macrophages / immunology
-
Macrophages / metabolism
-
Macrophages / pathology
-
Male
-
Mice
-
Morpholines / administration & dosage*
-
Morpholines / chemistry
-
Morpholines / immunology
-
Morpholines / pharmacology
-
NF-kappa B / genetics
-
NF-kappa B / metabolism
-
Organothiophosphorus Compounds / administration & dosage*
-
Organothiophosphorus Compounds / chemistry
-
Organothiophosphorus Compounds / immunology
-
Organothiophosphorus Compounds / pharmacology
-
Rats
-
Rats, Sprague-Dawley
-
STAT3 Transcription Factor / genetics
-
STAT3 Transcription Factor / metabolism
-
Shock, Septic / chemically induced
-
Shock, Septic / immunology
-
Shock, Septic / pathology
-
Shock, Septic / prevention & control*
Substances
-
Anti-Inflammatory Agents
-
Cytokines
-
GYY 4137
-
Lipopolysaccharides
-
Morpholines
-
NF-kappa B
-
Organothiophosphorus Compounds
-
STAT3 Transcription Factor
-
Stat3 protein, rat
-
Cyclooxygenase 2
-
Hydrogen Sulfide