Evidence for the binding of β-adrenoceptor blockers to microsomal Na+/K+-ATPase in guinea pig heart preparations

Abstract

We reported in a previous study that β-adrenoceptor blockers inhibit the Mg2+-dependent ATP-hydrolytic function of Na+/K+-ATPase. To determine if this action is a result of binding of β-blockers to the receptor sites that bind the digitalis glycosides, we performed displacement binding assays of eight β-blockers with [3H]-ouabain (OUA) in guinea pig myocardial microsomal preparations. In the first series of experiments, 10-200 µM of the β-blockers were displaced with 250 nM OUA. In the second set of experiments, 10-500 nM of OUA was displaced using 200 µM of the β-blockers. The drugs showed concentration-dependent receptor occupancy at the different OUA levels. Propranolol (PPN), metoprolol (MTP), and sotalol (STL) showed the strongest binding; nadolol (NDL), indenolol (IDN), and atenolol (ATN) had intermediate binding; carazolol (CRZ) and celiprolol (CLP) had the weakest binding properties. The results suggest that β-blockers may compete for the same binding sites with ouabain in their inhibition of the Na+/K+-ATPase. These actions may contribute to the mechanism for some of their cardiac effects, especially their proarrhythmic and arrhythmogenic actions.Key words: β-adrenoceptor blockers, antiarrhythmic agents, arrhythmogenic effects, Na+/K+-ATPase, ouabain binding.