Inhibition of respiratory and bioenergetic mechanisms by hydrogen sulfide in mammalian brain.
The biochemical effects of hydrogen sulfide were investigated by treating enzyme homogenates and synaptosomes prepared from mammalian brain with sodium sulfide. Brain cytochrome c oxidase activity was highly sensitive to inhibition by sodium sulfide, as demonstrated by an IC50 of 0.13 microM. Sodium sulfide was also found to inhibit carbonic anhydrase activity in cerebellum, frontal cortex, and hippocampus. Synaptosomal oxygen consumption was significantly reduced as the concentration of sodium sulfide was increased from 20 to 100 microM; this was accompanied by a concentration-dependent depolarization of the synaptosomal mitochondrial membrane in situ and a reduction in synaptosomal ATP concentration. In other experiments using synaptosomes, sodium sulfide caused a significant calcium-independent increase in the extracellular accumulation of L-glutamate, inhibited Na+-dependent uptake of [3H]glutamate, but was unable to influence intrasynaptosomal free ionic Ca2+. Parallel studies conducted in vivo showed that rats exposed over a 5-d period to hydrogen sulfide (100 ppm for 3 h/d) had significantly higher concentrations of L-glutamate in the hippocampus compared to control animals. In summary, our results indicate that sulfide causes extensive disruption to respiratory and related mitochondrial functions in mammalian brain in vitro. The reduced capacity of nerve endings to take up L-glutamate may contribute to the raised L-glutamate levels observed in vivo.
Nicholson
R A
RA
Department of Biological Sciences, Simon Fraser University, Burnaby, British Columbia, Canada. russell_nicholson@sfu.ca
Roth
S H
SH
Zhang
A
A
Zheng
J
J
Brookes
J
J
Skrajny
B
B
Bennington
R
R
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000378:metabolism; D002256:Carbonic Anhydrases / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D018698:Glutamic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013440:Sulfides / Q000633:toxicity*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D002257:Carbonic Anhydrase Inhibitors; D013440:Sulfides; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D002256:Carbonic Anhydrases; C033479:sodium sulfide