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

We characterized the β-adrenoceptor-blocking property of mexiletine, a class Ib antiarrhythmic drug, on Chinese hamster ovary (CHO) cells stably expressing cloned human β₁-, β₂-, and β₃-adrenoceptors. In radioligand binding experiments, mexiletine (10μM-1mM) concentration-dependently displaced the specific binding of [¹²⁵I]cyanopindolol to human β₁- and β₂-adrenoceptors in the membrane fraction of the cells. High concentration (100μM-1mM) of mexiletine partially displaced the specific binding of [¹²⁵I]cyanopindolol to human β₃- adrenoceptor. On the other hand, high concentration (300μM and 1mM) of lidocaine, another class Ib antiarrhythmic drug, partially displaced the specific binding of [¹²⁵I]cyanopindolol to human β ₁-adrenoceptor, whereas it did not affect the specific binding of [¹²⁵I]cyanopindolol to human β₂- and β ₃-adrenoceptors. Mexiletine (5, 50, and 500μM) reduces basal adenosine 3′,5′-cyclic monophosphate (cAMP) level and isoprenaline-induced cAMP accumulation on CHO cells stably expressing cloned human β₁- and β₂-adrenoceptors. Lidocaine (10 and 100μM and 1mM) tend to reduce basal cAMP level on CHO cells stably expressing cloned human β₁-adrenoceptors, whereas the drug did not reduce the isoprenaline-induced cAMP accumulation on CHO cells stably expressing cloned human β₁-, β₂-, and β₃-adrenoceptors. Mexiletine and lidocaine have no effect on forskolin (0.1, 1, and 3μM)-induced cAMP accumulation. These results demonstrate that mexiletine blocks the binding of agonists to β ₁- and β₂-adrenoceptors, and thereby attenuates the agonist-induced cAMP accumulation, and that the action of mexiletine as an antagonist of β₁- and β₂-adrenoceptors is independent of its antiarrhythmic property.