INHIBITION OF RESPIRATORY AND BIOENERGETIC MECHANISMS BY HYDROGEN-SULFIDE IN MAMMALIAN BRAIN

The biochemical effects of hydrogen sulfide were investigated by treat ing enzyme homogenates and synaptosomes prepared from mammalian brain with sodium sulfide. Brain cytochrome c oxidase activity was highly se nsitive to inhibition by sodium sulfide, as demonstrated by an IC50 of 0.13 mu M. Sodium sulfide was also found to inhibit carbonic anhydras e activity in cerebellum, frontal cortex, and hippocampus. Synaptosoma l oxy gen consumption was significantly reduced as the concentration o f sodium sulfide was increased from 20 to 100 mu M; this was accompani ed by a concentration-dependent depolarization of the synaptosomal mit ochondrial membrane in situ and a reduction in synaptosomal ATP concen tration. In other experiments using synaptosomes, sodium sulfide cause d a significant calcium-independent increase in the extracellular accu mulation of L-glutamate, inhibited Na+-dependent uptake of [H-3]glutam ate, but was unable to influence intrasynaptosomal free ionic Ca2+. Pa rallel studies conducted in vivo showed that rats exposed over a 5-d p eriod 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 extensiv e disruption to respiratory and related mitochondrial functions in mam malian brain in vitro. The reduced capacity of nerve endings to take u p L-glutamate may contribute to the raised L-glutamate levels observed in vivo.