Role of endogenous glutathione in the metabolism of glyceryl trinitrate by isolated perfused rat liver

Abstract

Glyceryl trinitrate (GTN) metabolism in perfused rat livers: (1) proceeded extremely rapidly with a half-time of approximately 1 min(inrecirculating perfusions); (2) was drastically inhibited (98 per cent) by bromobenzene pretreatment in vivo of rats; (3) was enhanced (42 per cent) by phenobarbital in vivo; and (4) was not altered by GTN tolerance. In non-recirculating experiments, GTN metabolism did not proceed at a constant rate, and the livers were only capable of degrading a fixed amount of GTN (about 70 m-moles/kg wet weight of liver). High concentrations of GTN perfused through the isolated rat liver resulted in an 85 per cent depletion of endogenous liver glutathione and an 80 per cent decrease in ATP. These results are hypothesized to be consistent with the fact that GTN metabolism in perfused rat livers appears to be dependent on the endogenous glutathione (GSH) reserve. High concentrations of GTN decrease liver ATP by inhibiting mitochondrial phosphorylation. The low ATP interferes with GSH synthesis and results in a net depletion of liver GSH and therefore a decreased ability to continuously degrade GTN.