INTERACTION OF BRETYLIUM TOSYLATE WITH GUINEA-PIG MYOCARDIAL NA+ K+-ATPASE

1. The effects of bretylium on myocardial Mg2+-dependent, Na+-K+-ATPase (EC 3.6.1.3) activity were compared with those of ouabain in guinea-pig heart preparations. 2. Both ouabain and bretylium inhibited microsomal Na+-K+-ATPase activity in a concentration-dependent fashion in the range of 0.01-100 and 1.0-4000-mu-M, respectively. The IC50 values were 1.93 +/- 0.27-mu-M for ouabain and 2.45 +/- 0.17 mM for bretylium. 3. In another set of experiments, the effects of bretylium on the enzyme activity were tested in combination with 2.5 or 5.0-mu-M ouabain. 4. The combined effects of the two drugs resulted in a net reduction in the total inhibitory activities of the individual drugs, which became more marked the higher the bretylium concentration. This trend seems to suggest a competitive mode of interaction of the two drugs in their inhibitory actions on Na+-K+-ATPase activity. 5. The results demonstrate therefore that bretylium is a potent inhibitor of ouabain-inhibited ATP hydrolysis by myocardial Na+-K+-ATPase. These actions may be pertinent with regard to some of its cardiac actions.