An electronic mechanism in the actions of drugs and other cardinal adsorbents. I. Effects of ouabain on the relative affinities of the cell surface beta- and gamma-carboxyl groups for K+, Na+, glycine and other ions.

The effects of ouabain on the effectiveness of glycine, Li+, Na+, K+, Rb+, and Cs+ in the external medium in reducing the rate of entry of labeled Cs+ into frog sartorius muscles were studied. The results showed that in the absence of ouabain the effectiveness of glycine and alkali-metal ions in inhibiting labeled Cs+ entry follows the rank order: K+ greater than Cs+, Rb+ greater than Na+, Li+ greater than glycine. Exposure to ouabain in essence reverses this order which then becomes: glycine greater than Li+, Na+ greater than K+, Rb+, greater than Cs+. These results confirm the prediction of the basic electronic interpretation of drug action according to the association-induction hypothesis. In addition, it shows that the action of ouabain on the surface beta- and gamma-carboxyl groups of frog muscle mediating Cs+ entry is quite similar to its action on the cytoplasmic beta- and gamma-carboxyl groups that are the seats of K+ accumulation in the bulk phase cytoplasm as well as to its action on the cell surface beta- and gamma-carboxyl groups responsible for the generation of the resting potential. In all these cases, ouabain acts as an electron-donating cardinal adsorbent (EDC). Finally the marked increase of the binding strength of glycine on the surface beta- and gamma-carboxyl groups was used to explain the primary pharmacodynamic effect of cardiac glycosides in combating heart failure.