Rate-Dependent Effects of Lidocaine on His-Purkinje Conduction in the Intact Neonatal Heart - Characterization and Amplification by N- Acetylprocainamide
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According to mathematical models of antiarrhythmic drug-receptor interactions, lidocaine binds preferentially to the sodium channel when the membrane is depolarized (i.e., the 'inactivated' channel state). Therefore, the effect of lidocaine on conduction should be greater when the action potential duration is prolonged. To test this prediction in vivo we evaluated the rate-dependent effects of lidocaine on His-Purkinje conduction in the intact newborn canine heart. Lidocaine's effect was assessed alone and then when given in combination with N-acetylprocainamide, a Class III antiarrhythmic agent. Utilizing intracardiac electrical stimulation and electrogram recording techniques, changes in the steady-state His-Purkinje conduction time during atrial pacing at increasingly rapid cycle lengths, changes in the conduction time of pacing trains delivered directly to the His bundle and changes in conduction time during His bundle extrastimulation were measured. After bilateral sectioning of the vagi and the administration of propranolol (1.0 mg/kg i.v.), His-Purkinje conduction was assessed in newborn canines (ages 5-15 days) under the following conditions: 1) control (n = 18); 2) after an i.v. infusion of lidocaine HCl (serum concentration 3.7 ± 0.8 μg/ml) (n = 12); and 3) after the combined administration of lidocaine and N-acetylprocainamide (serum concentration, 26.4 ± 6.3 μg/ml) (n = 12). Rate-dependent changes in His-Purkinje conduction time were observed in the newborn in response to lidocaine at rapid paced cycle lengths. These changes were significantly amplified by the coadministration of N-acetylprocainamide. Furthermore, the time constant of recovery from rate-dependent conduction delay, determined during His bundle extrastimulation, was 45 msec, which is notably shorter than values reported for lidocaine in the adult. These findings support in vivo a major prediction of antiarrhythmic drug-receptor models.
& Pickoff, A.
(1991). Rate-Dependent Effects of Lidocaine on His-Purkinje Conduction in the Intact Neonatal Heart - Characterization and Amplification by N- Acetylprocainamide. Journal of Pharmacology and Experimental Therapeutics, 259 (2), 535-542.