METABOLIC ACTION OF THE CARDIAC GLYCOSIDES

I. INFLUENCE ON RESPIRATION OF HEART MUSCLE AND BRAIN CORTEX

¹ From the Department of Pharmacology, Harvard Medical School, Boston

1. The cardiac glycoside ouabain, in concentrations ranging from 2 to 3 x 10^–7, increases the oxygen uptake of slices of guinea pig heart muscle in the presence of glucose or lactate; at higher concentrations this increase (maximally 50 per cent) is followed by a depression (maximally 80 per cent). Among a variety of other guinea pig tissues studied, brain cortex alone responds in a similar manner, but is only about as sensitive as heart muscle.

2. The oxidation of Succinate in cardiac slices is not inhibited at all by ouabain; in brain cortex slices it is inhibited only to a moderate extent. In the presence of pyruvate, the oxygen uptake of cardiac slices, which is high initially, is depressed by ouabain without preceding stimulation. The effect of the drug on the oxygen uptake of brain cortex slices is the same in pyruvate as in glucose or lactate medium.

3. The increase in the respiration of cardiac slices produced by ouabain is dependent upon the presence and concentration of appropriate substrate in the surrounding.

4. The inhibition of the respiration of brain cortex slices produced by ouabain cannot be reversed by washing. On the contrary, placing ouabain-treated, but still actively respiring slices into fresh, ouabain-free medium causes an immediate precipitous fall in activity.

5. Ouabain has no significant effect on the respiratory activity of homogenized heart and brain and of isolated oxidative systems.

6. It is concluded: (a) that ouabain does not directly interfere with the catalytic function of respiratory enzymes; (b) that its influence on the respiration of heart muscle and brain cortex is dependent upon the integrity of cellular structure; (c) that the cell surface is the probable site of action of ouabain on sliced heart muscle and brain cortex, the increase in respiration being due, at least in part, to facilitation of the entry of exogenous substrate in the cell, and the subsequent inhibition to the loss of one or more diffusible respiratory catalysts.

7. These findings and conclusions are discussed in relation to the action of the cardiac glycosides in vivo.

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