Reversal of lidocaine effects on sodium currents by isoproterenol in rabbit hearts and heart cells.
We demonstrated recently that isoproterenol enhanced the cardiac voltage-dependent sodium currents (INa) in rabbit ventricular myocytes through dual G-protein regulatory pathways. In this study, we tested the hypothesis that isoproterenol reverses the sodium channel blocking effects of class I antiarrhythmic drugs through modulation of INa. The experiments were performed in rabbit ventricular myocytes using whole-cell patch-clamp techniques. Reversal of lidocaine suppression of INa by isoproterenol (1 microM) was significant at various concentrations of lidocaine (20, 65, and 100 microM, P < 0.05). The effects of isoproterenol were voltage dependent, showing reversal of INa suppression by lidocaine at normal and hyperpolarized potentials (negative to -80 mV) but not at depolarized potentials. Isoproterenol enhanced sodium channel availability but did not alter the steady state activation or inactivation of INa nor did it improve sodium channel recovery in the presence of lidocaine. The physiological significance of the single cell INa findings were corroborated by measurements of conduction velocities using an epicardial mapping system in isolated rabbit hearts. Lidocaine (10 microM) significantly suppressed epicardial impulse conduction in both longitudinal (theta L, 0.430 +/- 0.024 vs. 0.585 +/- 0.001 m/s at baseline, n = 7, P < 0.001) and transverse (theta T, 0.206 +/- 0.012 vs. 0.257 +/- 0.014 m/s at baseline, n = 8, P < 0.001) directions. Isoproterenol (0.05 microM) significantly reversed the lidocaine effects with theta L of 0.503 +/- 0.027 m/s and theta T of 0.234 +/- 0.015 m/s (P = 0.014 and 0.004 compared with the respective lidocaine measurements). These results suggest that enhancement of INa is an important mechanism by which isoproterenol reverses the effects of class I antiarrhythmic drugs.
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City 52242.
H C
HC
Lee
J J
JJ
Matsuda
S I
SI
Reynertson
J B
JB
Martins
E F
EF
Shibata
D000818:Animals; D002478:Cells, Cultured; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006329:Heart Conduction System / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology*; D008012:Lidocaine / Q000037:antagonists & inhibitors*; D008564:Membrane Potentials / Q000187:drug effects; D011817:Rabbits; D015222:Sodium Channels / Q000187:drug effects*
D015222:Sodium Channels; D008012:Lidocaine; D007545:Isoproterenol