KINETIC EFFECTS OF QUARTERNARY LIDOCAINE BLOCK OF CARDIAC SODIUM-CHANNELS - A GATING CURRENT STUDY

The interaction of antiarrhythmic drugs with ion channels is often des cribed within the context of the modulated receptor hypothesis, which explains the action of drugs by proposing that the binding site has a variable affinity for drugs, depending upon whether the channel is clo sed, open, or inactivated. Lack of direct evidence for altered gating of cardiac Na channels allowed for the suggestion of an alternative mo del for drug interaction with cardiac channels, which postulated a fix ed affinity receptor with access limited by the conformation of the ch annel (guarded receptor hypothesis). We report measurement of the gati ng currents of Na channels in canine cardiac Purkinje cells in the abs ence and presence of QX-222, a quarternary derivative of lidocaine, ap plied intracellularly, and benzocaine, a neutral local anesthetic. The se data demonstrate that the cardiac Na channel behaves as a modulated rather than a guarded receptor in that drug-bound channels gate with altered kinetics. In addition, the results suggest a new interpretatio n of the modulated receptor hypothesis whereby drug occupancy reduces the overall voltage-dependence of gating, preventing full movement of the voltage sensor.