PH-DEPENDENCE OF KINETICS AND STEADY-STATE BLOCK OF CARDIAC SODIUM-CHANNELS BY LIDOCAINE

The local anesthetic-class antiarrhythmic drugs produce greater depres sion of conduction in ischemic compared with normal myocardium. The ba sis for this relatively selective action is uncertain. A model of the pH-dependent interaction of tertiary amine drugs with the sodium chann el suggests that the low pH occurring during ischemia slows drug disso ciation from the channel by changing the drug's protonation. The impor tance of the proton exchange reaction and the effect of overall slowin g of drug dissociation on steady-state sodium channel blockade is unce rtain. We have measured whole cell sodium channel current in rabbit at rial myocytes during control and exposure to lidocaine while external pH was varied between 6.8 and 7.8 at membrane potentials of -140, -120 , and -100 mV. Tonic blockade was little influenced by external pH. De creasing the external pH from 7.8 to 6.8 showed both the rate of devel opment of phasic block and recovery from the block. Decreasing the mem brane potential from -140 to -100 mV increased the degree of phasic bl ock attained in the steady state. Block was further enhanced when low pH was combined with membrane depolarization. Experiments in which deu terium ions were substituted for protons suggest that the kinetics of proton exchange is not rate limiting in the dissociation of drugs from the sodium channel. We conclude that it is the combined effect of low pH and membrane depolarization that may be critical in the enhanced b locking action of local anesthetic-class drugs during ischemia.