Basis for tetrodotoxin and lidocaine effects on action potentials in dog ventricular myocytes.
We studied the effects of tetrodotoxin (TTX) and lidocaine on transmembrane action potentials and ionic currents in dog isolated ventricular myocytes. TTX (0.1-1 x 10(-5) M) and lidocaine (0.5-2 x 10(-5) M) decreased action potential duration, but only TTX decreased the maximum rate of depolarization (Vmax). Both TTX (1-2 x 10(-5) M) and lidocaine (2-5 x 10(-5) M) blocked a slowly inactivating toward current in the plateau voltage range. The voltage- and time-dependent characteristics of this current are virtually identical to those described in Purkinje fibers for the slowly inactivating inward Na+ current. In addition, TTX abolished the outward shift in net current at plateau potentials caused by lidocaine alone. Lidocaine had no detectable effect on the slow inward Ca2+ current and the inward K+ current rectifier, Ia. Our results indicate that 1) there is a slowly inactivating inward Na+ current in ventricular cells similar in time, voltage, and TTX sensitivity to that described in Purkinje fibers; 2) both TTX and lidocaine shorten ventricular action potentials by reducing this slowly inactivating Na+ current; 3) lidocaine has no additional actions on other ionic currents that contribute to its ability to abbreviate ventricular action potentials; and 4) although both agents shorten the action potential by the same mechanism, only TTX reduces Vmax. This last point suggests that TTX produces tonic block of Na+ current, whereas lidocaine may produce state-dependent Na+ channel block, namely, blockade of Na+ current only after Na+ channels have already been opened (inactivated-state block).
Wasserstrom
J A
JA
Department of Medicine, University of Chicago Pritzker School of Medicine, Illinois 60637.
Salata
J J
JJ
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004285:Dogs; D004347:Drug Interactions; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D008012:Lidocaine / Q000494:pharmacology*; D008839:Microelectrodes; D012964:Sodium / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology*; D016276:Ventricular Function
D007473:Ion Channels; D013779:Tetrodotoxin; D008012:Lidocaine; D012964:Sodium