Upregulation of the rat cardiac sodium channel by in vivo treatment with a class 1 antiarrhythmic drug

Class I antiarrhythmic drugs inhibit the sodium channel by binding to a drug receptor associated with the channel. In this report we show that in vivo administration of the class I antiar-rhythmic drug mexiletine to rats induces sodium channel up-regulation in isolated cardiac myocytes. The number of sodium channels was assessed with a radioligand assay using the so-dium channel-specific toxin j3HIbatrachotoxinin benzoate (PHIBTXB). The administration of mexiletine to rats induced a dose-dependent increase in PI-HBTXB total specific binding (B.) on isolated cardiac myocytes. Sodium channel numbers were 15±5, 29±9, and 54±4 fmol/105 cells after 3 d treatment with 0, 50 mg/kg per d, and 150 mg/kg per d mexiletine (P < 0.001, analysis of variance). Sodium channel number in-creased monoexponentially to a steady-state value within 3 d with a half-time of increase of 1.0 d. After cessation of treat-ment with mexiletine the number of sodium channels returned to normal within 12 d. Finally, treatment with mexiletine al-tered only sodium channel number, the Kd for I3HjBTXB and the IC5o for mexiletine were not different for myocytes prepared from control and mexiletine-treated rats. (J. Clin. Invest. 1991