Use-dependent block of cardiac sodium channels by quaternary derivatives of lidocaine

Modulation of the reduction of fast inward sodium current by local anesthetics due to changes in electrical activity has been termed use-dependent block (Courtney 1975). To determine the mechanisms responsible for use-dependent block of cardiac sodium channels and to compare use-dependent block in cardiac and nerve preparations, we investigated use-dependent block of cardiac sodium channels by the quaternary lidocaine analogues QX-314 and QX-222 (two agents previously studied in nerve). We used canine cardiac Purkinje fibers, and assessed changes in the fast inward sodium current using changes in the maximum rate of rise of the action potential upstroke (\(\dot V_{\max }\)). Two microelectrode voltage clamp and current clamp techniques were used to control membrane potential prior to stimulated upstrokes. Use-dependent block was not affected by shortening the action potential duration during rapid stimulation. Partial recovery from use-dependent block was observed during rapid stimulation with brief depolarizing prepulses terminating immediately prior to the upstroke. Similar prepulses also prevented the development of use-dependent block following an abrupt increase in the stimulation rate. Hyperpolarizing prepulses during rapid stimulation caused recovery from use-dependent block; recovery was greater and more rapid with increasingly negative prepulses. Hyperpolarization during periods of electrical quiescence also caused greater recovery. These results, interpreted using the modulated receptor hypothesis (Hille 1977; Hondeghem and Katzung 1977), suggest that use-dependent block of cardiac sodium channels by quaternary local anesthetics is due to drug association with the inactivated sodium channel receptor which occurs only after these drugs gain access to the receptor site through open sodium channels.