Mechanisms of quinidine-induced depression of maximum upstroke velocity in ovine cardiac Purkinje fibers.
A major advance in understanding how quinidine depresses maximum upstroke velocity (Vmax) is the Hondeghem-Katzung mathematical model which incorporates voltage-independent rate constants for binding to and unbinding from resting, open, and inactive Na channels, and a voltage shift of -40 mV for the Hodgkin-Huxley h-kinetics of quinidine-associated Na channels. Using a double microelectrode voltage clamp technique to control transmembrane voltage and apply conditioning pulses, we found that quinidine blockade increased as transmembrane voltage became more positive in the range -60 to +40 mV, and that the rate of quinidine dissociation increased as transmembrane voltage became more negative in the range -60 to -140 mV. The relationship of Vmax to transmembrane voltage obtained at drive cycles from 500 msec to 20 seconds conformed to the model modified to include voltage-dependent rate constants without the postulated -40-mV shift for quinidine-associated channels. Thus binding of quinidine to inactive Na channels and unbinding from resting channels are both voltage-dependent and can explain frequency and voltage dependent actions of quinidine on Vmax without any voltage shift for quinidine-associated channels.
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001665:Binding Sites; D004553:Electric Conductivity; D006329:Heart Conduction System / Q000378:metabolism*; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects; D011690:Purkinje Fibers / Q000378:metabolism* / Q000502:physiology; D011802:Quinidine / Q000378:metabolism / Q000494:pharmacology*; D012756:Sheep; D012964:Sodium / Q000378:metabolism
D007473:Ion Channels; D012964:Sodium; D011802:Quinidine