Papillary muscle-false tendon tissue preparations isolated from dog hearts were perfused with Tyrode's solution containing propranolol in concentrations ranging from 0.1 to 20.0 mg/liter. Transmembrane action potentials of both ventricular muscle fibers and Purkinje fibers were recorded. With sufficient concentration of drug, the velocity of the upstroke and the overshoot of both fiber types decreased. The curve relating upstroke velocity to level of membrane potential for Purkinje fibers was displaced to the right and down. The ability of both ventricular muscle fibers and Purkinje fibers to respond to rapid frequencies of stimulation was decreased. Repolarization of Purkinje fibers was accelerated by propranolol, but repolarization of ventricular muscle fibers was unaffected. Duration of the effective refractory period of Purkinje fibers decreased; that of ventricular muscle fibers was unchanged. Graded responses and decremental impulse conduction in Purkinje fibers were abolished in the presence of propranolol. Low doses of propranolol which caused no change in the transmembrane potential completely blocked the increase in Purkinje diastolic depolarization normally induced by epinephrine. The possible mechanisms by which propranolol might exert its antiarrhythmic actions on ventricular arrhythmias were discussed. ADDITIONAL KEY WORDS cardiac arrhythmias effective refractory period epinephrine diastolic depolarization rapid electrical stimulation• A number of currently available drugs can block catecholamine beta-receptors (1-5). Many of these compounds exert actions against certain experimentally-induced cardiac arrhythmias. Dichloroisoproterenol, pronethalol, and propranolol prevent the ventricular arrhythmias induced by catecholamines (6-11) and prevent or terminate the ventricular arrhythmias induced by cardiac glycosides (8-16). Other drugs that are unrelated chemically to the above group but also block beta-receptors (4, 5) prevent the arrhythmias induced by catecholamines but not those elicited by cardiac glycosides (8, 9,

Right atria from excised beating dog hearts were immersed in Tyrode solution with the endocardial surface of the anterior wall exposed. Glass microelectrodes were used to impale fibers in different anatomical areas of this preparation. Fibers with action potentials similar in contour to those of ventricular Purkinje fibers were found along the caval border of the crista terminalis in the area of the posterior internodal tract. The action potential of these fibers (plateau fibers) had a resting potential of -85 to -95 mv, a sharp spiked overshoot, a long plateau phase, and inherent diastolic depolarization. The maximum velocity of the action potential upstroke of plateau fibers was consistently greater than that of simultaneously recorded fibers which lacked a plateau phase (regular fibers). Epinephrine or isoproterenol produced an increase in both rate and magnitude of diastolic depolarization of plateau fibers and on occasion converted them to true pacemakers. Acetylcholine accelerated repolarization of plateau fibers with disappearance of the plateau. Increases in extracellular concentration of potassium ions from 2.7 to 10.8 mM rendered regular atrial fibers inexcitable, but plateau fibers continued to show action potentials. Plateau atrial fibers possess several characteristics exhibited by specialized conducting and impulse generating fibers. The possibility that these fibers constitute the posterior internodal tract and function in preferential conduction of excitation to the A-V node was discussed. ADDITIONAL KEY WORDShigh extracellular potassium concentration posterior internodal tract epinephrine diastolic depolarization acetylcholine latent pacemaker activity isoproterenol• While it is generally accepted that fibers of the sJnoatrial (S-A) node serve as the pacemakers in the normal mammalian heart, the manner in which excitation spreads from this node through the atria and to the atrioventricular (A-V) node is not completely settled. Lewis et al. (1) concluded from studies using surface electrodes that excitation spreads radially from the S-A node through a syncytium composed of homogeneous tissue. The concept of radial spread of the impulse was challenged by Eyster and Meek (2-5) who presented evidence for spread of excitation from the S-A node to the From the Department of Physiology, University of Wisconsin Medical School, Madison, Wisconsin 53706.This investigation was supported in part by grants from the Wisconsin Heart Association and U. S. Public Health Service Grants 5-T1-HE53705-08 and 2-T1-HE5540-06.Accepted for publication June 27, 1968.CiratlM 'on esearch, Vol. XXIII, September 1968 A-V node along a preferential pathway. Also evidence for rapid spread of the impulse from the right to the left atrium was given by Bachmann (6) who described a special bundle of tissue linking the atria ventrally. Both anatomical and electrophysiological evidence has accumulated to support the contentions of Eyster and Meek for a preferential internodal pathway. In a recent review, Robb and Petri (7...

Isolated canine papillary muscles with attached false tendons were perfused with Tyrode's solution containing lidocaine. Transmembrane action potentials of ventricular muscle fibers and Purkinje fibers were recorded with glass microelectrodes. Repolarization of Purkinje fibers was accelerated by lidocaine but that of ventricular muscle fibers was unaffected. The maximum rate of rise of the action potential of Purkinje fibers decreased only at 50.0 mg/ liter lidocaine; that of ventricular muscle fibers was unchanged by any concentration. The curve relating rate of rise of premature responses to level of membrane potential for Purkinje fibers was unchanged with 5.0 mg/liter but shifted down and to the right with 10.0 and 50.0 mg/liter. The effective refractory period of Purkinje fibers shortened at 5.0 and lengthened at 50.0 mg/liter. The level of membrane potential needed to elicit premature propagated responses in Purkinje fibers with a standardized test stimulus increased and the earliest responses obtained in the presence of lidocaine were relatively large. Duration of the effective refractory period of ventricular muscle fibers was unchanged with 5.0 mg/liter but lengthened progressively with 10.0 and 50.0 mg/liter. Lidocaine impaired the ability of both fibers to respond to rapid frequencies of stimulation, slowed the rate of inherent diastolic depolarization of driven Purkinje fibers, decreased the rate of discharge of spontaneously beating preparations, and minimized the increase in rate and magnitude of diastolic depolarization caused normally by epinephrine. The possible role of these effects of lidocaine in regard to its antiarrhythmic actions was discussed.

The effects of variation in calcium concentration on the action potential of Purkinje fibers isolated from the dog heart were studied. Action potentials recorded during perfusion with Tyrode solution containing 2.7 mM calcium chloride were compared with those recorded during subsequent perfusion with solutions containing 0.675 ( l / 4 x ) , 1.35 ( l / 2 x ) , 5.4 (2x), or 10.8 (4x) mM calcium chloride. In both 1/2X and 1/4X solutions, the time required to repolarize to minus 60 mv and the duration of the action potential were increased. There were significant decreases in the slopes of phases 2 and 3 and the terminal phase of repolarization, while the slope of phase 1 increased. In 2x or 4X solutions, repolarization was speeded mainly by an earlier onset of phase 3. As a result the time to repolarize to minus 60 mv and the duration of the action potential were decreased significantly. The slope of phase 1 decreased significantly in 4x solution. In both high calcium solutions the rate and magnitude of diastolic depolarization increased. It was shown that the rate of the calcium-enhanced diastolic depolarization was dependent on the stimulus rate. The possible role of these changes in transmembrane potential in causing the ventricular arrhythmias following CaCl 2 infusion in intact animals is discussed. ADDITIONAL KEY WORDS calcium ions ventricular action potentials diastolic depolarization• The effect of calcium on the transmembrane action potential has been described for several types of mammalian cardiac fibers. Weidmann (1) found no appreciable change in the contour of the action potential of spontaneously beating Purkinje fibers isolated from calf or sheep hearts when the calcium concentration was varied between 0.675 and 10.8 mM. The main effect was that high calcium lowered (moved toward zero) the level of the threshold potential while low calcium had the opposite effect. Hoffman Department of Physiology, University of Wisconsin Medical School, Madison, Wisconsin. This work was supported by a grant from the Wisconsin Heart Association and Grant 5-T1-HE-5375 from the National Institutes of Health, U.S. Public Health Service.Mr. Temte is a Trainee, National Institutes of Health.A preliminary report of this work was presented at the fall meeting of the American Physiological Society in Houston, Texas, in August 1966. (The Physiologist 19:166, 1966 Accepted for publication November 1, 1966. and Suckling (2) showed that similar calcium concentrations do produce changes in the contour of the action potential of atrial and ventricular fibers of the dog. Increased calcium concentration accelerated repolarization, and decreased concentration slowed repolarization in both types of muscle fibers. In addition, they showed that reducing calcium to one-tenth of normal (0.27 mM) caused the action potential of Purkinje fibers to assume a shape similar to that normally recorded from fibers of the sino-atrial node. Seifen and co-workers (3) studied the effects of calcium on fibers of the sino-atrial node of rabbit...

Isolated canine papillary muscle-false tendon tissue preparations stimulated at a cycle length of 630 msec were treated with ouabain (2.1 x 10 -7 M ) until an increase in the slope of diastolic depolarization of Purkinje fibers was produced. Then the effects of changes in cycle length on the slope were tested. Sustained shortening of the cycle length increased the slope, and sustained lengthening had the opposite effect. An abrupt decrease in cycle length caused by a stimulus during phase 3 of a driven beat induced an increase in the slope of diastolic depolarization for one or more subsequent cycles. This procedure occasionally led to the spontaneous generation of an action potential which propagated into surrounding tissue. Suspension of stimulation often was followed by spontaneous beats. Shortening of the cycle length decreased the time of onset and increased the number and frequency of spontaneous beats. These effects were correlated with increases in the slope of diastolic depolarization. The diastolic depolarization of Purkinje fibers in false tendons was increased earlier and to a greater degree by ouabain than was the depolarization of Purkinje fibers on the muscle surface. These findings suggest that enhancement of diastolic depolarization of Purkinje fibers to the point of spontaneous discharge of action potentials may be a common means by which digitalis produces a variety of ventricular arrhythmias observed in intact animals.