MECHANISMS UNDERLYING POTENTIATION OF BARBITURATE ACTION BY SODIUM NITRITE IN THE MOUSE: THE ROLE OF METHEMOGLOBIN-INDUCED HYPOXIA

¹ Department of Pharmacology and Toxicology, University of Rhode Island, Kingston, Rhode Island

Subcutancous injection of sodium nitrite in mice at 23°C produced methemoglobinemia and hypothermia, increased brain -aminobutyric acid content and potentiated narcosis induced by hexobarbital or barbital. Potentiation of hexobarbital action correlated temporally with the degree of methemoglobin and hypothermia. At 30°C ambient temperature prolongation of barbital but not hexobarbital narcosis was abolished and the rise in brain -aminobutyric acid was prevented. Sodium nitrite inhibited hepatic metabolism of hexobarbital in vivo but not in vitro. Nitrite pretreatment shortened the onset of barbital action but did not alter the penetration of barbital-¹⁴C into brain. In addition. mice receiving sodium nitrite regained the righting reflex at a lower body concentration of hexobarbital. Further, sodium nitrite injected intracerebrally did not affect hexobarbital narcosis or body temperature. However, exposure to oxygen under high pressure abolished the effect of nitrite on hexoharbital action. These results suggest that nitrite treatment can enhance barbiturate action both by decelerating hepatic detoxification and by altering central nervous system sensitivity. The primary mechanisms underlying the alterations in barbiturate action induced by the chemical appear to he the result of a tissue hypoxia produced as a result of methemoglobin formation.