Ethanol-sedative hypnotic interactions: in vitro studies on Na-K-activated adenosine triphosphatase

The combined in vitro effects of ethanol wih methaqualone, phenobarbital, pyrazole or disulfiram were studied using rat brain microsomal NA-K-ATPase. Methaqualone and phenobarbital, either alone or in combination with ethanol, showed a dose-dependent inhibition of Na-K-ATPase activity. Kinetic studies showed that the inhibitory effects were competitive with the respect to K+ and uncompetitive with respect to MgATP for phenobarbital either alone or in combination with ethanol. Methaqualone showed a noncompetitive type of inhibition with respect to K+, whereas a mixed type of inhibition was seen in combinations with ethanol. Furthermore, methaqualone either alone or in combination with ethanol also showed an uncompetitive type of inhibition with respect to MgATP. The dose-dependent inhibition of brain Na-K-ATPase activity by disulfiram was independent of K+ and additive in combination with ethanol. Pyrazole showed no effect on brain Na-K-ATPase activity. The inhibitions by phenobarbital and methaqualone, either alone or in combination with ethanol, were significantly greater at low K+ (1 mM) and high Na+ (100-200 mM). A greater inhibition by these drugs was also obtained when Na+ is low (5 mM) and K+ is high (15 mM). The inhibition by these drugs appears to depend on K+ and Na/K ratio in the reaction medium. The combined effects of ethanol and the other CNS depressants on brains Na-K-ATPase may be important to their interaction toxicities.