Characterization of mexiletine as an antagonist of β-adrenoceptor in Chinese hamster ovary cells expressing cloned human β-adrenoceptors

Abstract

We characterized the β-adrenoceptor-blocking property of mexiletine, a class Ib antiarrhythmic drug, on Chinese hamster ovary (CHO) cells stably expressing cloned human β 1-, β 2-, and β 3-adrenoceptors. In radioligand binding experiments, mexiletine (10 μM–1 mM) concentration-dependently displaced the specific binding of [ 125 I ]cyanopindolol to human β 1- and β 2-adrenoceptors in the membrane fraction of the cells. High concentration (100 μM–1 mM) of mexiletine partially displaced the specific binding of [ 125 I ]cyanopindolol to human β 3-adrenoceptor. On the other hand, high concentration (300 μM and 1 mM) of lidocaine, another class Ib antiarrhythmic drug, partially displaced the specific binding of [ 125 I ]cyanopindolol to human β 1-adrenoceptor, whereas it did not affect the specific binding of [ 125 I ]cyanopindolol to human β 2- and β 3-adrenoceptors. Mexiletine (5, 50, and 500 μM) reduces basal adenosine 3′,5′-cyclic monophosphate (cAMP) level and isoprenaline-induced cAMP accumulation on CHO cells stably expressing cloned human β 1- and β 2-adrenoceptors. Lidocaine (10 and 100 μM and 1 mM) tend to reduce basal cAMP level on CHO cells stably expressing cloned human β 1-adrenoceptors, whereas the drug did not reduce the isoprenaline-induced cAMP accumulation on CHO cells stably expressing cloned human β 1-, β 2-, and β 3-adrenoceptors. Mexiletine and lidocaine have no effect on forskolin (0.1, 1, and 3 μM)-induced cAMP accumulation. These results demonstrate that mexiletine blocks the binding of agonists to β 1- and β 2-adrenoceptors, and thereby attenuates the agonist-induced cAMP accumulation, and that the action of mexiletine as an antagonist of β 1- and β 2-adrenoceptors is independent of its antiarrhythmic property.