Selective inhibition of K+ ‐stimulation of Na,K‐ATPase by bretylium

1 The effects of bretylium were investigated on purified Na,K‐ATPase from guinea‐pig heart and on the Na/K pump in trout erythrocytes, with a view to further identifying the mechanism(s) associated with its antiarrhythmic effects. 2 Na,K‐ATPase activity of the thiocyanate‐dispersed enzyme was determined by the measurement of inorganic phosphate produced by ATP hydrolysis. 3 When the concentrations of each of the Na,K‐ATPase activating components were varied in turn, bretylium (1–5 mmol l−1) exhibited competitive‐type effects against K+ with a Ki of 1.4 mmol l−1 and noncompetitive‐type effects against Na+, Mg2+ and ATP. 4 In K+ influx studies in trout erythrocytes with 86Rb+ used as the marker, the inhibition of total influx observed with bretylium (5 and 10 mmol l−1) was attributable to the bretylium cation selectively inhibiting the Na/K pump‐mediated influx with the associated tosylate anion inhibiting Na/K cotransport. 5 The observed inhibition kinetics indicated that the bretylium cation (2–15 mmol l−1) competitively inhibited K+ stimulation of the Na/K pump at 6 and 1.25 mmol l−1 external K+ with a mean K1 of 2.3 mmol l−1. 6 The effects demonstrated on the functioning Na/K pump in erythrocytes confirmed the Na,K‐ATPase findings, with bretylium selectively inhibiting K+ stimulation of the pump mechanism in both cases. 7 It is suggested that Na,K‐ATPase inhibition may contribute to the antiarrhythmic and positive inotropic effects of bretylium with the cardiac accumulation of bretylium also possibly being a further important factor.