ABSTRACT
The discovery of numerous biochemical effects of cyanide not directly related to the inhibition of the respiratory chain, including the involvement of apoptosis, has challenged the basis of traditional antidote treatment, which primarily depends on nitrite-induced conversion of hemoglobin into methemoglobin, releasing the blockade of cytochrome c oxidase by high-affinity binding of cyanide as cyanmethemoglobin. The fact that amyl nitrite has antidotal effects not related to methemoglobin formation has unfolded new mechanism of actions of nitrites including release of nitric oxide (NO). In this study, we characterized the effect of various NO donor compounds on cyanide-induced cell death in cultured chick embryonic neurons. Apoptosis was induced by treating the neuronal cultures with 1 mM NaCN for 1 h, followed by a cyanide-free incubation period of 23 h. Using this treatment protocol, we showed that cyanide-induced apoptosis was blocked in the presence of the different NO donors sodium nitroprusside, S-nitrosoglutathione, S-nitroso-N-acetylpenicillamin, nitroglycerin, 3-morpholinosydnonimine, and diethylamine nitric oxide, indicating independence of the redox-related species of NO released. The effect was confirmed to be mediated by NO, since exhausted NO donors did not afford protection, and the mechanism likely involved chemical modification of thiol groups, since the effect was completely reversed by dithiothreitol. Furthermore, NMDA antagonists protected against cyanide-induced cell death, whereas inhibitors of nitric oxide synthase increased cyanide-induced apoptotic damage, indicating a protective effect of endogenously generated NO, at least in cell cultures.
Subject(s)
Apoptosis/drug effects , Enzyme Inhibitors/toxicity , Glutathione/analogs & derivatives , Neurons/drug effects , Neuroprotective Agents/pharmacology , Nitric Oxide Donors/pharmacology , Penicillamine/analogs & derivatives , Sodium Cyanide/toxicity , Animals , Apoptosis/physiology , Cell Death/drug effects , Cells, Cultured , Chick Embryo , Dithiothreitol/pharmacology , Dose-Response Relationship, Drug , Drug Interactions , Excitatory Amino Acid Antagonists/pharmacology , Glutamic Acid/toxicity , Glutathione/pharmacology , Hydrazines/pharmacology , Kynurenic Acid/pharmacology , Molsidomine/analogs & derivatives , Molsidomine/pharmacology , NG-Nitroarginine Methyl Ester/pharmacology , Neurons/cytology , Nitrogen Oxides , Nitroglycerin/pharmacology , Nitroprusside/pharmacology , Nitroso Compounds/pharmacology , Penicillamine/pharmacology , S-Nitroso-N-Acetylpenicillamine , S-NitrosoglutathioneABSTRACT
Receptor compartments can be hydrophilic or hydrophobic. The hydrophobic character can be revealed from the logarithmic relationship between the octanol-water partition coefficient (Po/w) and the equipotent equilibrium concentration (Cw) measured in the water compartment (Franke: Theoretical Drug Design Methods. Elsevier, Amsterdam 1984). For activation of the sensory irritant receptor during exposure to airborne chemicals the Cw values at equilibrium can be obtained from the gas or vapour concentrations [( A]a) and the water-gas partition coefficients (Pw/g). However, if the octanol-gas partition coefficients (Po/g) are used, the analysis can be carried out directly from the gas or vapour concentrations. The thermodynamic activity can also be used to reveal whether the environment of the receptor is hydrophobic or not. We have adapted Franke's theory to a series of homologous airborne sensory irritants. Our results suggest that the environment of the sensory irritant receptor is likely to be a hydrophobic site within the polar part of the nerve membrane. The extended theory is general and it is therefore suggested that it applies to other airborne exposure concentrations which are in equilibrium with a hydrophobic receptor.
