Cardiac NaK ATPase activity during positive inotropic and toxic actions of ouabain

In order to define pharmacological actions of ouabain in the dog heart, ouabain uptake and subcellular distribution and its effect on NaK ATPase (MG2+ dependent, Na+-K+-activated adenosinetriphosphate phosphohydrolase, E.C. 3.6.1.3), have been investigated in 21 open-chest dogs. A continuous infusion of ouabain (0.036 mug/kg/min) after a loading dose (20 mug/kg) produced a relatively constant plasma concentration of approximately 10(-8) M (6 ng/ml) ouabain, which induced a sustained positive inotropic response for the 300 min experimental period. In these hearts much greater binding of ouabain was noted in the NaK ATPase and microsomal fractions than in other myocardial fractions. No statistically significant inhibition of NaK ATPase activity was noted. Doubling the loading and infusion doses of ouabain raised the plasma level of ouabain to approximately 3 X 10(-8) M and produced various types of arrhythmia within an hour, which persisted for the rest of the 5 h experimental period. Under this experimental protocol there was a significant inhibition of NaK ATPase activity and increased binding of ouabain to this enzyme. This study does not support the hypothesis that there is a causal relationship between inotropic response to ouabain and NaK ATPase inhibition. It was concluded that NaK ATPase inhibition might be causally related to the development of ouabain toxicity.