title: Class I antiarrhythmic drug effects on ouabain binding to guinea pig cardiac Na+ -K+ ATPase.
abstract: The notion that the inhibition of the Mg2+ -dependent ATP-hydrolytic function of the myocardial Na+ -K+ ATPase by class I antiarrhythmic agents occurs as a result of their binding to the same receptor sites as the digitalis glycosides was tested by performing competitive binding assays of [3H]ouabain (OUA) with eight drugs: disopyramide, encainide, lidocaine, lorcainide, phenytoin, procainamide, quinidine, and tocainide in guinea pig heart microsomal preparations. In the first set of experiments, 10-200 microM concentrations of the drugs were preincubated with the enzyme and displacement assays performed with 250 nM OUA. The drugs showed receptor occupancy of 19-32% at 50 microM, 25-44% at 100 microM, and 37-56% at 200 microM. Then, 10-500 nM concentrations of OUA were preincubated with the enzyme, and competitive assays were performed using 200 microM concentrations of the drugs. OUA occupied 39-51% of the receptor sites at 100 nM, 44-67% at 250 nM, and 62-82% at 500 nM, displacing the drugs in a concentration-dependent fashion. The results show that antiarrhythmic drugs interact with the same or similar receptor sites as ouabain on the Na+ -K+ ATPase, pointing to a possible contribution of these interactions to the mechanism for their inhibitory actions on the enzyme, and perhaps their arrhythmogenic effects.
authors.affiliation: Department of Pharmacology, King Saud University, Riyadh, Saudi Arabia. dzimiri@kfshrc.edu.sa
authors.forename: A A
authors.initials: AA
authors.lastname: Almotrefi
authors.forename: C
authors.initials: C
authors.lastname: Basco
authors.forename: A
authors.initials: A
authors.lastname: Moorji
authors.forename: N
authors.initials: N
authors.lastname: Dzimiri
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008861:Microsomes / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D010042:Ouabain / Q000378:metabolism*; D011869:Radioligand Assay; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000889:Anti-Arrhythmia Agents; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase