Brian F. Hoffman

Marked QT prolongation with induction of polymorphous ventricular tachycardia ("Torsades de Pointes") is a well-described phenomenon during quinidine therapy, frequently occurring at low plasma quinidine concentrations, low serum potassium, and slow heart rates. We have therefore assessed the dose-electrophysiological effects of quinidine as a function of extracellular potassium and cycle length in canine Purkinje fibers, using standard microelectrode techniques. Quinidine (1 microM) prolonged action potential at 90% repolarization, while leaving phase zero upstroke slope (Vmax) unchanged at a cycle length 300-8000 msec; at 10 microM, Vmax depression became evident. Increases in the action potential at 90% repolarization were most marked at long cycle lengths and low extracellular potassium (in contrast to Vmax depression) and were partially reversed by tetrodotoxin (1 microM). The relationship between log of cycle length and action potential at 90% repolarization was linear (for cycle length 300-8000 msec) in the absence of quinidine. Quinidine increased the slope of this relationship in a concentration-related fashion, whereas increasing extracellular potassium shifted the curve rightward (without changing slope), regardless of the presence or absence of quinidine. Action potentials were also measured following pauses of 5-60 seconds. In the absence of quinidine, the action potential depolarization returned to its baseline value in a monoexponential fashion (time constant 36.0 +/- 4.9 sec, mean +/- SE, n = 10). In the presence of 1 microM quinidine, this return was better fit as a biexponential process (time constants 4.2 +/- 1.2 and 40.7 +/- 6.2 seconds, n = 14). At slow stimulation rates (cycle length greater than 4000 msec) in low extracellular potassium (2.7 mM), quinidine produced early afterdepolarizations in 7/14 (50%) of fibers at 1 microM and 14/18 (78%) at 10 microM. Early afterdepolarizations were eliminated by increasing stimulation rates, raising the extracellular the extracellular potassium concentration to 5 mM, or adding tetrodotoxin. These data suggest that prolongation by quinidine of action potentials at 90% repolarization is multifactorial, with both a "tonic" prolonging effect and a prominent frequency-dependent action potential shortening effect. At long cycle lengths and low extracellular potassium, low quinidine concentrations consistently produced early after-depolarizations. The parallels between this form of triggered activity and clinical arrhythmias induced by quinidine suggest that early afterdepolarizations may play a role in quinidine-induced Torsades de Pointes.

The action potentials recorded from heart muscle with a suction electrode have been compared to those recorded with an intracellular microelectrode. It has been found that if the suction electrode is properly used the monophasic potentials recorded with it may be taken as a reliable index of the time of arrival of excitation at the electrode and as a reliable index of the shape of the action potential during the entire phase of repolarization. The suction electrode potentials differ from the microelectrode potentials in showing a lower rise velocity, a smaller amplitude, a quantitatively different reversal or overshoot and, in the beating heart, ‘afterpotentials’ caused by mechanical effects. When the shape of the action potential, as observed with the microelectrode, is changed by ions such as K + or Ca ++ a similar change is observed in the potential recorded with the suction electrodes.

Depressed excitability and responsiveness were created in excised bundles of canine Purkinje fibers. A segment 8 mm long was depressed by being encased in agar containing 47 m M K + , the ends of the bundle outside the agar remaining normal. Either normal end could be excited through extracellular electrodes. Action potentials were recorded by intracellular microelectrodes at each end and within the depressed segment. Conduction velocity within the depressed segment fell as low as 0.05 m/sec. Abnormalities of impulse transmission through the depressed segment included delay, 2:1 block, higher degrees of block, rate-dependent block, and block showing the Wenckebach phenomenon. Asymmetries of conduction seen included one-way block. Action potentials in the depressed segment were of low amplitude and showed slow upstrokes. Variations in action potential duration occurred in the depressed segment when conduction failed or was very slow and when impulses were dropped. Delay in conduction too great to result simply from a slow upstroke is attributed to summation of excitatory events across regions of block in a syncytium of cells. The results prove that conduction delays great enough to permit re-entry can occur in short segments of Purkinje fibers subjected to high K + .