SUMMARY. 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 MM) prolonged action potential at 90% repolarization, while leaving phase zero upstroke slope (Vm«) unchanged at a cycle length 300-8000 msec; at 10 MM, V,,,,,, 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 V^ depression) and were partially reversed by tetrodotoxin (1 M M )-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 JIM 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 MM and 14/18 (78%) at 10 MM. Early afterdepolarizations were eliminated by increasing stimulation rates, raising 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 afterdepolarizations. 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. (Circ Res 56: 857-867, 1985)

Repolarization during phase 1 of cardiac action potential is important in that it may influence both impulse conduction in partially depolarized tissue and action potential duration. Thus, it is important to know the properties and regulation of the underlying currents. In about 50% of canine ventricular myocytes, the actin potential displays a phase 1 of fast repolarization and a prominent notch between phase 1 and the plateau. A transient outward current is responsible for both. This current is composed of two components: one (Ito1) blocked by 4-aminopyridine and the other (Ito2) blocked by manganese. In the present study, we characterized each of the components in isolation from the other. Both had an activation threshold between -30 and -20 mV. At the same voltage, Ito1 was larger than Ito2 and had a shorter time to peak. The peak current-voltage relationship for Ito1 was almost linear, but that for Ito2 was bell-shaped. Ito1 decayed during sustained depolarization with a single exponential time course: tau less than 30 msec at all voltages. It recovered from inactivation with a voltage-dependent time course: tau = 70 msec at -90 mV and 720 msec at -40 mV. Ito2 was augmented by elevating [Ca2+]o or by isoproterenol. It was inhibited by caffeine, ryanodine, or a preceding transient inward current, suggesting that it was activated by intracellular calcium released from sarcoplasmic reticulum. We conclude that Ito1 and Ito2 in canine ventricle are similar to those described for many other cardiac tissues, but the kinetics of Ito1 are significantly faster than in other tissues.

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 mM 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+.

We have characterized, in dogs, a model of inducible regular atrial tachycardia that resembles atrial flutter. The model involves creating a Y-shaped lesion comprised of an intercaval incision and a connected incision across the right atrium. It is suitable for serial studies of the effects of pacing or antiarrhythmic drugs in chronically instrumented animals studied in the awake state for at least several months. The postoperative cycle length of the induced tachycardia varies from 143 to 188 msec, depending on the size of the dog. The tachycardia cycle length was consistent for each dog, and the rhythm--once induced--was very stable until terminated by pacing. The mechanism of the tachycardia was reentry due to circus movement based on the ability to induce and terminate it by premature impulses or overdrive, the ability to reset the tachycardia by single premature stimuli, the pattern of entrainment during overdrive stimulation, and the ability to terminate the tachycardia by interrupting the conduction pathway. The window of reset determined by the range of coupling intervals of premature stimuli that were able to enter and reset the tachycardia ranged from 56 to 82 msec. There appears to be incomplete recovery of excitability by the end of the excitable gap as evidenced by the fact that even late premature impulses that enter the reentrant circuit conduct more slowly than the tachycardia impulse, and because stimulation of muscarinic receptors that shortens the duration of the action potential and refractoriness also reduces the cycle length of the tachycardia. Epicardial and endocardial activation mapping during tachycardia showed the reentrant pathway does not merely encircle the lesion, particularly over the left atrial epicardium near the intercaval lesion. Rather, the impulse appears to travel around the atrial tissue just above the tricuspid ring, including a portion that travels through the right side of the lower intraatrial septum. Thus, the model involves circus movement around an anatomic barrier through normal tissue that contains no depressed segments. During the circus movement, there is a relatively long excitable gap during which there is incomplete recovery of excitability. This model should be useful for studies of the mechanism of antiarrhythmic drug action and the responses to premature stimulation in this particular subclass of reentrant rhythms, and for comparison with the behavior and responses of other forms of reentry.

The effects of diphenylbydantoin (DPH) were studied on isolated, perfused Purkinje fibers over a range of concentrations from lCh 8 to 10 -4 M. The time course of repolarization of the transmembrane action potential shortened due to abbreviation of all phases of repolarization. The effective refractory period also shortened during exposure to DPH, but to a lesser extent than the action potential. As a result the earliest effective test stimulus elicited action potentials with greater amplitude and dv/dt of phase 0 than under control conditions. In driven fibers with normal action potentials, DPH had little effect on the amplitude or rate of rise (dv/dt) of phase 0 of the action potential. In driven fibers which were partially depolarized, or those with low dv/dt of phase 0 despite normal resting potentials, DPH caused an increase in the rate of rise of phase 0 of the action potential. DPH caused a decrease in the firing rate of normal automatic fibers by decreasing the slope of phase 4 depolarization. In automatic fibers which showed generalized diastolic depolarization and decreased maximum diastolic potential, DPH caused an increase in the latter as well as a decrease in the slope of phase 4 depolarization.

Action potential durations and local refractory periods were mapped along the course of canine conducting tissue from bundle branches to the termination of false tendons in ventricular muscle. Standard microelectrode techniques were used. Areas of maximum action potential duration, which coincided with areas of maximum local refractory periods, were consistently found 2 to 3 mm proximal to the termination of conducting fibers in muscle. The refractory periods at the areas of maximum action potential duration were quantitatively identical in the multiple false tendons of a segment of the conducting system, providing a uniform functional limit for the propagation of premature impulses across the distal end of the conducting system of the segments studied. It was demonstrated that appropriately timed premature impulses could be confined within conducting tissue either proximal or distal to the area of maximum action potential duration. This occurred when the area of maximum duration was sail refractory, after other areas of the conducting system had recovered excitability. In most preparations, maximum action potential durations and functional refractory periods across distal false tendons were longer in tissue from the right side than from the left side of the conducting system. ADDITIONAL KEY WORDSfunctional block aberrant conduction action potentials conduction functional refractory period local refractory period reentry premature impulses arrhythmias action potential duration • Aberrant ventricular conduction of premature supraventricular impulses most commonly results in complexes showing a right bundle branch block configuration in both the human (1, 2) and canine heart (3). A clear electrophysiological explanation for the tendency to an apparently longer functional refractory period on the right side of the From the 361 362 MYERBURG, STEWART, HOFFMANthe left and right sides. Moreover, the functional characteristics of this region, the area of maximum action potential duration, indicate that it may have physiological significance beyond its role in functional block. MethodsAll of the experiments were performed on tissue obtained from adult mongrel dogs. The animals were anesthetized with sodium pentobarbital, 30 mg/kg iv, and a right lateral thoracotomy was performed. The heart was removed rapidly and placed in cool, oxygenated Tyrode's solution containing the following, in mmolars: NaCl, 137; NaHCO-,, 12; dextrose, 5.5; NaH 2 -PO 4 , 1.8; MgCl 2 , 0.5; CaCl 2 , 2.7; and KC1, 3.0. The tissue preparations (see below) were mounted with small steel pins in a wax-bottomed, double-chambered tissue bath, through which Tyrode's solution equilibrated with a 95% O 2 -5% CO 2 gas mixture was flowing at a rate of about 6 ml/min to each chamber. The volume of each chamber was 12 ml. Both chambers of the tissue bath were maintained between 36 and 37°C; and each was kept within 0.25°C of the odier by altering the rate of flow through the heating system to one chamber or the other. For some experiments requiring a larger tis...

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The mechanism of atrioventricular delay has been studied in isolated rabbit hearts. Multiple intracellular microelectrodes have been employed to obtain simultaneous records from single fibers of atrium, A-V node and His bundle. An appreciable delay in the transmission of excitation has been found only in the atrial portion of the A-V node. Action potentials recorded from single fibers in this area show a low resting potential, slow diastolic depolarization, slow upstroke and low amplitude. These action potentials frequently show one or more notches or steps on the rising phase. Action potentials recorded from fibers of the His bundle are similar in shape and amplitude to those of peripheral Purkinje fibers. Records obtained at several sites between the atrial portion of the node and the His bundle show a gradual transition in action potential shape. The mechanism of slow transmission across the A-V node is discussed in relation to the electrical activity of fibers at the atrial end of this structure.