title: Selective inhibition of K(+)-stimulation of Na,K-ATPase by bretylium.
abstract: 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.
authors.affiliation: Department of Pharmacology and Therapeutics, The University, Liverpool.
authors.forename: P E
authors.initials: PE
authors.lastname: Tiku
authors.forename: P T
authors.initials: PT
authors.lastname: Nowell
mesh_terms: D000818:Animals; D001949:Bretylium Compounds / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000201:enzymology; D010710:Phosphates / Q000378:metabolism; D011188:Potassium / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D012414:Rubidium Radioisotopes; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects / Q000378:metabolism*; D013861:Thiocyanates / Q000494:pharmacology; D014337:Trout
chemical_list: D001949:Bretylium Compounds; D010710:Phosphates; D012414:Rubidium Radioisotopes; D013861:Thiocyanates; D000254:Sodium-Potassium-Exchanging ATPase; D008274:Magnesium; D011188:Potassium