Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously suggested that the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway protects both hepatocytes and endothelial cells against liver ischemia-reperfusion injury in rat. We study here the ability of NO to protect isolated hepatocytes against an in vitro oxidative stress induced with hypochlorite solution (ClO(-)). The severity of ClO(-)-induced stress was quantified by the measurement of total glutathione and membrane lipid peroxidation. Cell damage was assessed by morphologic (cell viability and bleb formation) and biologic (transaminase release) criteria. A 30-minute incubation of hepatocytes with 100 micromol/L ClO(-) maximally decreased cell viability (-40%) and increased bleb formation (+300%) and release of transaminases activities (aspartate transaminase [AST] = +60% and alanine transaminase [ALT] = +300%). A good correlation was observed between morphologic and biologic criteria. A preincubation of cells with 50 micromol/L 8-Br-cGMP, did not affect the adverse ClO(-) effects on the morphologic criteria. In the presence of 20 micromol/L spermineNONOate, an NO donor, ClO(-) did not decrease cell viability, whereas its deleterious effects on bleb formation was unchanged. A preincubation with a specific inhibitor of the soluble guanylate cyclase, the 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 micromol/L), did not affect the beneficial effect of NO on the cell viability. Our results suggest that NO protects hepatocytes against oxidative stress by a mechanism, which is cGMP-independent. However, taking into account the cytoprotective effects of cGMP in the liver, it is likely that the rapid effect of NO observed in vitro is relayed in vivo by a more long-lasting mechanism, which would be inhibited by ODQ and mimicked by 8-Br-cGMP.
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PMID:Protective effect of nitric oxide on isolated rat hepatocytes submitted to an oxidative stress. 1183 44

The physiological roles of CO in neurotransmission, vasorelaxation, and cytoprotective activities have raised interest in the design and syntheses of CO-releasing materials (CORMs) that could be employed to modulate such biological pathways. Three iron-based CORMs, namely, [(PaPy(3))Fe(CO)](ClO(4)) (1), [(SBPy(3))Fe(CO)](BF(4))(2) (2), and [(Tpmen)Fe(CO)](ClO(4))(2) (3), derived from designed polypyridyl ligands have been synthesized and characterized by spectroscopy and X-ray crystallography. In these three Fe(II) carbonyls, the CO is trans to a carboxamido-N (in 1), an imine-N (in 2), and a tertiary amine-N (in 3), respectively. This structural feature has been correlated to the strength of the Fe-CO bond. The CO-releasing properties of all three carbonyls have been studied in various solvents under different experimental conditions. Rapid release of CO is observed with 2 and 3 upon dissolution in both aqueous and nonaqueous media in the presence and absence of dioxygen. With 1, CO release is observed only under aerobic conditions, and the final product is an oxo-bridged diiron species while with 2 and 3, the solvent bound [(L)Fe(CO)](2+) (where L = SBPy(3) or Tpmen) results upon loss of CO under both aerobic and anaerobic conditions. The apparent rates of CO loss by these CORMs are comparable to other CORMs such as [Ru(glycine)(CO)(3)Cl] reported recently. Facile delivery of CO to reduced myoglobin has been observed with both 2 and 3. In tissue bath experiments, 2 and 3 exhibit rapid vasorelaxation of mouse aorta muscle rings. Although the relaxation effect is not inhibited by the soluble guanylate cyclase inhibitor ODQ, significant inhibition is observed with the BK(Ca) channel blocker iberiotoxin.
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PMID:Designed iron carbonyls as carbon monoxide (CO) releasing molecules: rapid CO release and delivery to myoglobin in aqueous buffer, and vasorelaxation of mouse aorta. 2138 44