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

We characterized the beta-adrenoceptor-blocking property of mexiletine, a class Ib antiarrhythmic drug, on Chinese hamster ovary (CHO) cells stably expressing cloned human beta1-, beta2-, and beta3-adrenoceptors. In radioligand binding experiments, mexiletine (10 microM-1 mM) concentration-dependently displaced the specific binding of [125I]cyanopindolol to human beta1- and beta2-adrenoceptors in the membrane fraction of the cells. High concentration (100 microM-1 mM) of mexiletine partially displaced the specific binding of [125I]cyanopindolol to human beta3-adrenoceptor. On the other hand, high concentration (300 microM and 1 mM) of lidocaine, another class Ib antiarrhythmic drug, partially displaced the specific binding of [125I]cyanopindolol to human beta1-adrenoceptor, whereas it did not affect the specific binding of [125I]cyanopindolol to human beta2- and beta3-adrenoceptors. Mexiletine (5, 50, and 500 microM) reduces basal adenosine 3',5'-cyclic monophosphate (cAMP) level and isoprenaline-induced cAMP accumulation on CHO cells stably expressing cloned human beta1- and beta2-adrenoceptors. Lidocaine (10 and 100 microM and 1 mM) tend to reduce basal cAMP level on CHO cells stably expressing cloned human beta1-adrenoceptors, whereas the drug did not reduce the isoprenaline-induced cAMP accumulation on CHO cells stably expressing cloned human beta1-, beta2-, and beta3-adrenoceptors. Mexiletine and lidocaine have no effect on forskolin (0.1, 1, and 3 microM)-induced cAMP accumulation. These results demonstrate that mexiletine blocks the binding of agonists to beta1- and beta2-adrenoceptors, and thereby attenuates the agonist-induced cAMP accumulation, and that the action of mexiletine as an antagonist of beta1- and beta2-adrenoceptors is independent of its antiarrhythmic property.