Use-dependent effects of lidocaine on conduction in canine myocardium: application of the modulated receptor hypothesis in vivo.
Lidocaine is a commonly used antiarrhythmic drug that causes use-dependent blockade of sodium channels in vitro and reduces conduction velocity in vitro and in vivo. According to the modulated receptor hypothesis of antiarrhythmic drug action, lidocaine has a low affinity for rested sodium channels but a high affinity for open and inactivated channels. In the present experiments, we characterized use-dependent conduction slowing and recovery from slowing by lidocaine in anesthetized dogs. The His-to-ventricular conduction interval was used as the indicator of conduction velocity. We found that prolongation of conduction time was greater as the stimulation frequency was increased. Moreover, on abruptly changing the stimulation frequency, a new steady-state conduction time was approached in two to three depolarizations. On discontinuation of stimulation, the conduction time of progressively less premature extrastimuli shortened exponentially with a terminal phase time constant of 152 +/- 115 msec. These effects by lidocaine were enhanced during acidosis and enhancement was reversed by correction of the acidosis. It is concluded that the effects in vivo of lidocaine on conduction under several conditions of rate, rhythm, and pH are similar to its effects on the maximum upstroke velocity of the action potential in vitro. Although these experiments were not designed to validate the modulated receptor hypothesis, it appears that the modulated receptor hypothesis can predict the effects of lidocaine on conduction in vivo.
Davis
J
J
Matsubara
T
T
Scheinman
M M
MM
Katzung
B
B
Hondeghem
L H
LH
D000818:Animals; D002036:Bundle of His / Q000187:drug effects; D005117:Cardiac Complexes, Premature / Q000503:physiopathology; D004285:Dogs; D004562:Electrocardiography; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D007473:Ion Channels; D008012:Lidocaine / Q000494:pharmacology*; D008297:Male; D008991:Monitoring, Physiologic; D009200:Myocardial Contraction / Q000187:drug effects; D011955:Receptors, Drug / Q000502:physiology; D012964:Sodium / Q000378:metabolism
D007473:Ion Channels; D011955:Receptors, Drug; D008012:Lidocaine; D012964:Sodium