Andrew L. Wit

Effect of Verapamil on the Sinoatrial and Atrioventricular Nodes of the Rabbit and the Mechanism by Which it Arrests Reentrant Atrioventricular Nodal Tachycardia

The effects of verapamil, an antiarrhythmic drug that apparently blocks slow inward currents, were studied on the isolated, superfused sinoatrial (SA) and atrioventricular (AV) nodes of the rabbit heart with intracellular microelectrodes. Verapamil decreased the rate of spontaneous impulse initiation by the SA node. This effect could be overcome with epinephrine. Concomitantly, verapamil decreased the amplitude of SA node action potentials without reducing maximum diastolic potential. The peak of the action potential fell well short of reversal after exposure to the drug. Verapamil had similar effects on the action potentials of the upper and middle AV nodal regions, reducing action potential amplitude so that the overshoot vanished without significantly reducing maximum diastolic potential. Action potentials of fibers in the lower region of the AV node were not affected as greatly. Verapamil slowed conduction of atrial impulses through the AV node; such slowing increased when the atrial rate increased. Verapamil also prolonged the effective refractory period of the AV node, thus slowing or blocking conduction of premature impulses. Verapamil prevented AV nodal reentry and initiation of atrial tachycardia by causing premature impulses to block rather than to conduct with the delay needed to initiate reentry. Verapamil had no effect on the rate of depolarization, action potential amplitude, or maximum diastolic potential of atrial or His bundle fibers. The results are consistent with the hypotheses that fibers in the SA and AV nodes show slow response activity, that the slow response plays a crucial role in causing certain cardiac arrhythmias, and that drugs that block the slow response are therefore antiarrhythmic.

Effect of Verapamil on the Normal Action Potential and on a Calcium Dependent Slow Response of Canine Cardiac Purkinje Fibers

The effect of verapamil on normal sodium (Na)-dependent and slow calcium (Ca)-dependent action potentials recorded from canine cardiac Purkinje fibers was studied. The Ca-dependent slow response was obtained in fibers exposed to solutions in which all NaCl was replaced by tetraethylammonium chloride and in which Ca ranged from 4 mM to 16.2 mM. Verapamil (0.25–2 mg/liter) had little or no effect on the upstroke of the normal action potential, but such concentrations of verapamil suppressed rhythmic activity and depressed excitability in fibers that showed Ca-dependent slow responses. Spontaneous activity and rhythmic activity evoked by long depolarizing pulses were depressed. Verapamil decreased the amplitude and the upstroke velocity and shifted the threshold potential toward zero in fibers that showed Ca-dependent slow responses. The effectiveness of verapamil varied with the level of Ca; 0.25 mg/liter of verapamil was as effective in suppressing activity in fibers exposed to 4 mM Ca as was 2 mg/liter of verapamil in fibers exposed to 16.2 mM Ca. Although verapamil did not alter the upstroke of the normal Na-dependent action potential, it did depress the plateau and prolong the action potential of fibers exposed to normal Tyrodes solution.

Genesis of Cardiac Arrhythmias

Activity of Automatic Cells The normal rhythm of the mammalian heart results from spontaneous excitation of cells in the sinoatrial node. These cells possess the property of automaticity. The transmembrane potential of working muscle fibers in the atria or ventricles demonstrates a rapid depolarization on excitation (phase 0), a period of variable duration during which the cell repolarizes (phases 1, 2, and 3), and then a stable resting potential (phase 4), which persists until the next propagated impulse arrives and causes excitation. In contrast, in cells of the sinoatrial node, repolarization is not followed by a period during which the transmembrane potential is stable. Instead, immediately after the end of repolarization the membrane potential begins to decrease slowly. This slow depolarization during phase 4 lowers the transmembrane potential toward the threshold potential, the value of transmembrane potential at which excitation occurs. If the slow depolarization attains the threshold potential, excitation occurs and the cell develops an action potential which then propagates to excite adjacent cells and, normally, the rest of the heart.2 All cells which demonstrate this slow diastolic depolarization are said to be automatic. This mechanism for spontaneous firing has been called the normal automatic mechanism to differentiate it from other

Slow conduction and reentry in the ventricular conducting system. II. Single and sustained circus movement in networks of canine and bovine Purkinje fibers.

Closed loops of fibers of the ventricular conducting system of canine or bovine hearts were used to study circus movement of excitation. Action potentials were recorded at three sites with intracellular microelectrodes. Discrete segments were depressed by application of K+-rich agar or the entire loop was depressed by modified Tyrodes solution containing 15−17 mM K+ and 1 to 5 × 10−6M epinephrine. The loops were 12−35 mm long and the effective conduction velocity was 0.02−0.08 m/sec. Impulses entering some loops traveled in one direction only, circling around the loop and returning to produce a second response at one or more sites (single circus movement). In other loops the impulse traveled around the circuit repeatedly (sustained circus movement). Circus movement around short loops requires a low conduction velocity and must be initiated by an impulse that travels around the loop in only one direction. Single circus movement can cause extrasystoles. Sustained circus movement can cause idioventricular rhythms and ventricular tachycardia.

Slow Conduction and Reentry in the Ventricular Conducting System I. RETURN EXTASYSTOLE IN CANINE PURKINJE FIBERS

Depression of excitability and responsiveness provoked by the action of high K+ and epinephrine on short bundles of excised canine Purkinje fibers yields reentrant excitation. An impulse entering a depressed area undergoes marked slowing of conduction; the impulse then may continue forward while also returning through the pathway by which the initiating impulse entered the depressed area. The impulse may be delayed or blocked in either the forward or the retrograde direction. The reentrant excitation can occur in the absence of premature excitation. Various methods of depression of excitability produce return extrasystoles in Purkinje fibers. The common factor is very slow conduction which depends upon the abolition of the fast upstroke and the appearance of a low-voltage, slowly propagated action potential that is readily blocked.

Some Effects of Electrical Stimulation on Impulse Initiation in Cardiac Fibers; its Relevance for the Determination of the Mechanisms of Clinical Cardiac Arrhythmias

Circus movement of excitation, spontaneous diastolic depolarization and other causes of rhythmic activity have been the subject of intensive investigation for many years, and studies utilizing microelectrode techniques have defined many important mechanisms (163, 168). These studies have suggested physiological and pharmacological interventions which can terminate such ectopic impulse initiation. Some interventions are specific for arrhythmias that depend on automaticity and others for arrhythmias that result from reentry (374). An ideal goal for therapy of any human cardiac arrhythmia would require determining the mechanism underlying its origin and the use of a therapeutic intervention specific for that mechanism to terminate the arrhythmia. Although attaining this goal is still in the future many basic electrophysiological discoveries have been applied to determine the mechanisms for human arrhythmias.