J. ELECTROCARDIOLOGY, 9 (4) 1976 335-343

The Effect of Adrenergic Enhancement on Overdrive Excitation BY MARIO VASSALLE, M.D.,* RANDOLPH E. KNOB, M.D.,t GUSTAVA. LARA, M.D.** AND JACKSON H. STUCKEY, M.D.tt

SUMMARY

Studies conducted in this laboratory have shown t h a t driving the ventricles in dogs with recently-induced atrioventricular block m a y induce arrhythmias. 1 This phenomenon has been termed ~%verdrive excitation" and resembles a similar finding described in Purkinje fibers overdriven in vitro in the presence of norepinephrine. 2 The factors responsible for overdrive excitation in vivo have not been clarified. It has been shown t h a t operative and postoperative stress is associated with increased plasma level of catecholaminesP Such an increase, occurring with the operation n e c e s s a r y to i n d u c e t h e a t r i o v e n t r i c u l a r block, could have played a role in overdrive excitation in vivo. If this is the case, it should be possible to induce overdrive excitation (or enhance it when already present) by driving the ventricles d u r i n g adrenergic enhancemeAt (sympathetic stimulation or norepinephrine administration). A n u m b e r of other questions also needs to be answered. For example, in the absence of adrenergic enhancemeAt, a prolonged fast drive is followed by s u p p r e s s i o n ('~overdrive suppression"4-9); however, it is not known how overdrive suppression and overdrive excitation interact in the presence of enhanced adrenergic activity. It also remains to be established whether calcium potentiates the action of catecholamines on overdrive excitation. This is conceivable since catecholamines enhance calcium current during cardiac activation, 1~ and this, in turn, may play a role in the origin of the arrhythmias. The a i m s of t h e p r e s e n t s t u d y were to investigate: (1) the influence of adrenergic e n h a n c e m e n t on overdrive excitation; (2) the relationships between overdrive excitation and suppression during adrenergic enhancement; and (3) the role of calcium in overdrive excitation.

The effect o f adrenergic e n h a n c e m e n t ( s t i m u l a t i o n o f a s t e l l a t e g a n g l i o n or administration of norepinephrine) on arrhythmias induced by ventricular overdrive ("overdrive excitation") was studied in dogs with complete atrioventricular block. The following results were obtained. (1) Adrenergic enhancement may lead to abnormal ventricular rhythms. (2) A brief drive during a d r e n e r g i c e n h a n c e m e n t i n d u c e d or enhanced fast ventricular rhythms. (3) The induced rhythms were characterized by an abrupt onset, a fast rate of discharge, and a moderate degree of slowing before an abrupt cessation. (4) The induced rhythms were accelerated by further drive. (5) Increasing the duration of overdrive during adrenergic enhancement resulted in overdrive suppression and not in overdrive excitation. (6) Prolonged drive could induce a few beats (instead of suppression) but at a rate below control ("inhibited e x c i t a t i o n " ) . (7) The a r r h y t h m o g e n i c e f f e c t s of overdrive and adrenergic enhancement were potentiated by the simultaneous administration of calcium. It is concluded that interventions which increase the inward calcium current (overdrive, adrenergic enhancement and higher [Ca]o) favor the onset and the maintenance of overdrive excitation. From the Departments of Physiology and Surgery, State University of New York, Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, New York. Supported in part by grants from the United States Public Health Service. During this investigation, Dr. Vassalle was a Career Scientist of the New York Health Research Council. *Professor of Physiology, Dept. of Physiology, Downstate Medical Center; tAssistant Resident in Surgery, Dept. of Surgery, Downstate Medical Center; **Assistant Resident in Surgery, Dept. of Surgery, Downstate Medical Center; ttProfessor of Surgery, Dept of Surgery, Downstate Medical Center. Reprint requests to: Dr. Mario Vassalle, Department of Physiology -- Box 31, Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203.

MATERIALS AND METHODS Sixteen mongrel dogs of either sex were anesthetized with intravenous administration of thiopental sodium, and a complete atrioventricular block was induced by placing a suture ligature around the His bundle through the right atriotomy under venous inflow occlusion. One to three days after the operation, the animals were anesthetized with morphine sulfate (5 mg/kg intramuscularly, Lilly Laboratories) and alpha chloralose (75/mg/kg 335

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VASSALLE ET AL

intravenously, Fisher Scientific Corp.). Additional chloralose was given during the experiment as required to maintain adequate anesthesia. The animals were intubated, ventilated with an Engstrom respirator (Model 200, Mivab Co.) and the chest opened through a midsternal incision. A polyethylene catheter was introduced into the abdominal aorta and was connected to a Statham pressure transducer (Model P23Db). Local electrical activity of the myocardium was recorded by means of bipolar silver electrodes. An electrode was sutured on the epicardial surface in each of the following five locations: the right atrium; posterior wall of the left ventricle; and the proximal, middle, and distal portions of the anterior wall of the left ventricle. The ventricles were driven either through an electrode sutured over the midportion of the right ventricle or through one of the electrodes on the left ventricle. An American Electronics Laboratories stimulator (Model 104A) was used to drive the ventricles via a stimulus isolation unit. The parameters of the stimuli were 1 msec, 8 v, and 12-240 pulses/min. On occasion, single stimuli were delivered. The lefL stellate ganglion was isolated from all connections except the cardiac branches and was stimulated at different frequencies by means of a bipolar gold electrode connected to another American Electronics Laboratories stimulator via a stimulus isolation unit. The stimulus characteristics were 1 msec, 8 v, and 1-20 pulses/sec. The esophageal temperature was monitored by a Digitec Thermistor (Model 581B) and the temperature was maintained at about 37~ with a heating system (Thermorite Products Corporation). The recordings were made with an Electronics for Medicine DR8 Recorder on photographic paper moving at a speed of 10-25 mm/sec. Norepinephrine (Levophed, Winthrop Laboratories) and calcium chloride (Upjohn Laboratories) were infused by means of a motor-driven syringe (Harvard Infusion Pump, Model 600) connected to a femoral vein by means of a p o l y e t h y l e n e catheter. The experimental runs were usually repeated more than once and the results were averaged. The beats elicited by the electrical stimuli will be referred to as "driven beats." The beats of the rhythm induced by drive will be referred to as ~induced beats." The stimulation of the stellate ganglion and norepinephrine infusion will be referred to as ~adrenergic enhancement."

RESULTS Sympathetic Stimulation and Idioventricular Rhythm The control idioventricular r a t e in 16 animals was 48.8 +_ SE 1.9 beats/min. One minute stimulation of the left stellate ganglion at 1/sec increased the systolic blood pressure by 9.2%, while th e idioventricular r a t e r e m a i n e d unchanged except for a small increase in one dog. Stimulation at 5/sec increased the systolic blood pressure by 18.7% and the idiovent r i c u l a r r a t e by 3.9 _+ 1.4% (P < 0.001). Stimulation at 20/sec increased the systolic blood pressure by 26.6% and the idioventri-

cular r a t e by 10 _+ 2.1% (P < 0.001). T he idiovent ri cul ar r a t e a t t a i n e d with this m a x i m a l sympathetic stimulation is similar to values reported before (see Fig. 8 in Ref. 12). Sympathetic stimulation induced a shift in pacem a k e r site in 32 runs in 11 experiments. The faster t h e r a t e of s y m p a t h e t i c stimulation, the earlier t he shift in p a c e m a k e r site and t he faster the spontaneous rat e of discharge of t he new rhyt hm . In contrast to t he "physiological" acceleration reported above, s y m p a t h e t i c stimulation at 20/sec resulted in an abrupt tachycardia in 10 runs in five animals. T he m a x i m a l average rate of the tachycardia was 173.7 _+ 29.6 beats/min. The t achycardi a continued t h r o u g h o u t t he sym pat het i c stimulation and ceased abrupt l y at different intervals after cessation of stimulation.

Induction of a New Rhythm by Drive During Sympathetic Stimulation The induction of a fast r h y t h m by drive during sympathetic stimulation is illustrated in Fig. 1. Sympathetic stimulation was started at t h e downward arrow (first trace). When t h e idoventricular rat e had increased from a control value of 37 to 43 beats/min two driven beats at 120/min induced a new r h y t h m discharging at a rate of 88 beats/min (third trace and first curve in graph). Shortly t hereaft er, t hree driven beats at 180/min induced a temp o r a r y acceleration to 125 beats/min (fifth trace and second curve in the graph). While the idioventricular rat e was still faster t h a n t h a t prior to t he first drive, four beats at 180/min induced an acceleration to 150/min (seventh trace and t hi rd curve in the graph). At the u p r i g h t arrow (bottom trace), sympathetic stimulation was t e r m i n a t e d and the induced r h y t h m ceased s h o r t l y t h e r e a f t e r . The cessation of fast r h y t h m was followed by a period of p a c e m a k e r suppression. Electrical drive was carried out before, during, and after sym pat het i c stimulation in 15 dogs. The drive was at 180/min for five seconds, but drives at 30, 60, 120, and 240/min for various periods of t i m e were also carried out. D uri ng sympathetic stimulation (20/sec), drive did not result in a r r h y t h m i a s in four, was followed by extrasystoles in two and by a fast r h y t h m in nine animals. In t he last group of nine animals, the average m a x i m a l r a t e of discharge during the fast rhythm was 142 _+ 7.9 beats/min, an i n c r e m e n t of 93 --- 8.8 beats/min over t h e pre-drive rate. The induced r h y t h m began i m m edi at el y after t he cessation of fast drive and t he rat e of discharge was highest soon after t he drive. If t h e drive was slow, t he induced r h y t h m began d u r i n g t h e drive and overcam e t he d r i v e n beats. The faster t he drive, t he faster t he initial rat e of the induced r h y t h m . If t he drive J. ELECTROCARDIOLOGY, VOL. 9, NO. 4, 1976

SYMPATHETIC SYSTEM AND OVERDRIVE

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'I Fig. 1. Induction of a fast rhythm by drive during sympathetic stimulation. The first, third, fifth and seventh traces are bipolar electrograms recorded from the distal portion of the anterior wall of the left ventricle, and the other traces are Lead H. Each driven beat is labelled with a dot and the rate of drive is indicated above the driven beats. The ordinate of the graph shows the reciprocal of the cycle length in seconds and the abscissa the successive beats. The height of the columns indicates the rate of drive and the small vertical lines on top of the columns the number of driven beats. Control = 0.69 sec: reciprocal of the cycle length in seconds of the idioventricular rhythm prior to the first drive of 2 beats at 120/min. SYMP STIM Of IO/Ser

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Sympathetic Stimulation, Overdrive Excitation and Overdrive Suppression O v e r d r i v e of cardiac p a c e m a k e r s c a u s e s a s u b s e q u e n t s u p p r e s s i o n . 1;4-9'13 I t h a s n o t b e e n d e t e r m i n e d w h e t h e r a l o n g o v e r d r i v e supp r e s s e s a f a s t r h y t h m in t h e p r e s e n c e of s y m p a t h e t i c s t i m u l a t i o n . I n F i g . 2, s y m pathetic stimulation was initiated at the b e g i n n i n g of t h e top t r a c e at t h e d o w n w a r d

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arrow and was continued throughout the recording shown. The idioventricular rate was 31 beats/min before the drive at 180/min for five sec and increased to 100 beats/min immediately after the drive (top trace). In the bottom trace, overdrive at 240/min for 15 sec not only abolished the induced r h y t h m but also was followed by a period of marked suppression: this in spite of the fact that sympathetic stimulation was continued. The experiment shows that overdrive suppression can prevail not only upon overdrive excitation but also upon the stimulatory action of the s y m p a t h e t i c system on normal p a c e m a k e r activity. In the light of these results, it was of interest to find out whether overdrive suppression is antagonized by the sympathetic stimulation during the drive. A test of this kind is shown in Fig. 3. In the top trace, overdriving the ventricles at 240/min for two min was followed by a marked suppression. In the bottom trace, the 240/min drive was repeated and the stellate ganglion was stimulated at 20/sec during the second minute of drive. Drive and s y m p a t h e t i c s t i m u l a t i o n were t e r m i n a t e d simultaneously. Instead of overdrive suppression, a fast (150 beats/min) s p o n t a n e o u s rhythm appeared. The pause aider this fast rhythm was shorter and the subsequent idioventricular activity faster t h a n in the top trace. Similar results were obtained in 12 runs in seven animals. Thus, sympathetic stimulation induced an initial overdrive excitation and counteracted the inhibition of the normal pacemaker activity by drive.

Driving During Sympathetic Stimulation and Sympathetic Stimulation During Drive If driving during sympathetic stimulation can induce a new rhythm, it should be possible to obtain the same result by stimulating the sympathetic nerves while driving. An experiment of this kind is illustrated in Fig. 4. In the top trace, the first panel shows the control idioventricular r h y t h m and the beginning of sympathetic stimulation. In the second panel, as a result of sympathetic stimulation, the idioventricular rate had increased from the control rate of 50 (first panel) to 67 beats/min just prior to the beginning of drive (second panel). The very first driven beat (labelled w i t h a dot) i n i t i a t e d a fast r h y t h m (136 beats/min) which outlasted both t h e sympathetic stimulation and overdrive as shown in the third panel. In the bottom trace, the drive was initiated first (beats labelled with a dot, first panel). When sympathetic stimulation was superimposed on the drive, the spontaneous activity became faster than the driven beats (second panel). A driven beat (labelled with a dot) initiated abruptly a fast rhythm (122 beats/min) which outlasted both

the ventricular drive and sympathetic stimulation (third panel). Similar results were obtained in four experiments of this type. The experiments show that while drive or sympathetic stimulation singly m a y not induce an a b n o r m a l r h y t h m , f a s t r h y t h m s c a n be precipitated by the combination of these two factors. Furthermore, these findings indicate that it is unimportant whether the drive is superimposed on sympathetic stimulation or vice versa.

Induction of Fast Ventricular Rhythms by Drive in the Presence of Norepinephrine Sympathetic stimulation enhances the induction of new rhythms by drive presumably by releasing norepinephrine. Therefore, it should be possible to reproduce the effects of sympathetic stimulation by administration of norepinephrine. In Fig. 5, first trace, the idiov e n t r i c u l a r rate i n c r e a s e d from a control value of 23 (first panel) to 30 beats/min after the two min infusion of norepinephrine. A short drive (second panel) precipitated a fast r h y t h m (maximal value of 115 beats/min, second trace). The infusion of norepinephrine was terminated at the arrow, b u t the fast r h y t h m continued in the third and fourth traces which were recorded in part at a reduced speed. The relatively abrupt cessation of the fast r h y t h m was followed by suppression and by the s u b s e q u e n t resumption of normal p a c e m a k e r activity (fourth trace). During norepinephrine infusion, drive was not followed by a r r h y t h m i a s in one experiment, w a s followed r e p e a t e d l y by extrasystoles in another experiment, and by a fast r h y t h m in eight experiments. In the eight experiments, the control idioventricular rate was 53 +_ 3.2 beats/min. Norepinephrine was infused at the average rate of 0.97 _ 0.2 ng/ kg/min and drive was usually at a rate of 180/min for five seconds. Other frequencies and durations of drive were used and as few as two beats intiated a fast rhythm. The average r a t e of t h e s e i n d u c e d r h y t h m s w a s 145.8 • 8.6 beats/min and the duration averaged 69.5 • 8.4 sec. In four animals, norepinephrine infusion caused a fast r h y t h m ( a v e r a g e v a l u e 149 beats/min) in the absence of drive as occasionally seen with the s t i m u l a t i o n of t h e splanchnic nerves to the adrenal medulla. 14 The occurrence of a spontaneous r h y t h m and its suppression by drive is illustrated in Fig. 6. The first panel shows t h e control idioventricular r h y t h m at 28 beats/rain. After two minutes of norepinephrine infusion, the idioventricular rate had accelerated to 100 beats/min (beginning of the second panel). While t h e infusion of norepinephrine was continued, driving the ventricles at 180/min for one min resulted in the suppression of the J. ELECTROCARDIOLOGY, VOL. 9, NO. 4, 1976

SYMPATHETIC

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fast r h y t h m and a m a r k e d t r a n s i t o r y inhibition. Thus, overdrive prevails upon the excitatory action of norepinephrine as it prevails upon the excitatory action of sympathetic stimulation (see Fig. 2).

Potentiation of Drive-Induced Rhythms by Calcium Both an increase in the rate of d i s c h a r g e 15,16 a n d t h e a d m i n i s t r a t i o n of norepinephrine 1~ increase calcium influx in cardiac cells in unit of time, and this could play a role in the induction of new rhythms. If this is the case, the infusion of calcium might potentiate the arrhythmogenic effect of drive. In fact, it was found t h a t drive during calcium infusion was followed by extrasystoles and fast r h y t h m s in 37 runs in seven animals. To study the combined effects of adrenergic enhancement and calcium infusion on overdrive excitation, these procedures first were carried out singly at a level that gave minimal effects a n d t h e n t h e drive was r e p e a t e d d u r i n g simultaneous adrenergic e n h a n c e m e n t and calcium administration. In Fig. 7, first trace, drive was followed by a slight slowing (68 before and 63 beats/min aider the drive). ]n the second trace, sympathetic stimulation had increased the ventricular rate to 86/min prior to drive. Drive was followed by a short acceleration (three beats) and then by a slight slowing (79 beats/min at the end of the trace). During calcium administration (third trace), drive was followed by a slowing of the idiov e n t r i c u l a r r h y t h m (65 b e f o r e a n d 52 beats/min after drive). During a continuous

infusion of calcium chloride, s y m p a t h e t i c stimulation was repeated and again resulted in the same shift in pacemaker site and acceleration to 75 beats/min (beginning of fourth trace, experimental). However, d u r i n g the s i m u l t a n e o u s calcium a d m i n i s t r a t i o n and sympathetic stimulation, the same drive induced a fast r h y t h m of 188 beats/min for 24 sec. [n the bottom trace, the induced r h y t h m slowed somewhat before ending abruptly. The r h y t h m present before the drive reappeared at a slower rate (60/min). During the infusion of calcium, norepinephrine should also potentiate the arrhythmogenic effect of drive (Fig. 8). In the first trace, overdriving the ventricles at 180/min was followed by a degree of inhibition of pacemaker activity (56 before and 44 beats/min after the drive, see graph). In the second trace, overdrive was r e p e a t e d 2.5 rain after the beg i n n i n g of n o r e p i n e p h r i n e i n f u s i o n a n d caused only a slight slowing. In the third trace, overdrive was carried out two min after the beginning of calcium infusion and caused a decrease in rate from 49 to 40 beats/min. In the fourth trace, (NE + Ca + Drive), overdrive was repeated two min after the i n i t i a t i o n of s i m u l t a n e o u s i n f u s i o n of norepinephrine and calcium. This time, the cessation of overdrive was not followed by slowing but, on the contrary, by the abrupt onset of a fast r h y t h m (maximal rate of 150/ min) which lasted 33 sec. The fast r h y t h m e v e n t u a l l y slowed and s h o r t l y t h e r e a f t e r ceased abruptly (see also graph). The r h y t h m J. ELECTROCARDIOLOGY, VOL. 9, NO. 4, 1976

SYMPATHETIC SYSTEM AND OVERDRIVE

present before the drive reappeared at a markedly slower rate. P o t e n t i a t i o n of the arrhythmogenic effect of drive by calcium and adrenergic e n h a n c e m e n t was demonstrated in 23 runs in six animals.

DISCUSSION The present results suggest the following conclusions: (1) adrenergic enhancement m a y cause m a r k e d ventricular tachycardias instead of the usual physiological acceleration; (2) adrenergic enhancement potentiates overdrive excitation; (3) overdrive suppression and overdrive excitation act antagonistically during adrenergic enhancement, and, under suitable conditions, one or the other prevails; and (4) the enhancement of the inward calcium current m a y be important in the onset of a r r h y t h m i a s d u r i n g drive, a d r e n e r g i c enhancement and calcium administration. It is well known t h a t the enhancement of the adrenergic system has a positive chronotropic effect on idioventricular pacemakers. However, the present results and earlier findings ( ~ ' ~ see ~) make it clear t h a t such an increase in automatic discharge involves normal as well as abnormal mechanisms. Both in vitro TM and in vivo ~ ' ~ the ~'physiological" acceleration is characterized by a gradual onset, a t t a i n m e n t of a maximal rate rarely in excess of 80 beats/min and gradual return to DRIVE

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control rate as soon as the adrenergic enh a n c e m e n t ceases. In contrast, the abnormal acceleration is characterized by an abrupt onset, a t t a i n m e n t of a fast rate usually in excess of 120 beats/min, continuation for a time after t h e t e r m i n a t i o n of t h e a d r e n e r g i c enhancement, and a relatively abrupt cessation. ~='~ The difference b e t w e e n t h e maximal rate during normal and the m i n i m a l r a t e d u r i n g a b n o r m a l r h y t h m s has been t e r m e d " c a t e c h o l a m i n e r a t e g a p " to emphasize t h a t the mechanism responsible for the normal r h y t h m is different from t h a t of abnormal rhythms. 14 C a t e c h o l a m i n e s physiologically increase t h e r a t e of d i s c h a r g e of cardiac P u r k i n j e fibers by steepening the slope of diastolic depolarization2 s The mechanism of the enh a n c e m e n t of diastolic depolarization is a shift in the steady state activation curve for t h e p a c e m a k e r c u r r e n t in a d e p o l a r i z i n g direction2 ~'~~ The mechanisms for the catecholamine-induced ventricular tachycardias are not known. The present findings point to the fact t h a t ventricular drive during adrenergic enhancement precipitates fast r h y t h m s w i t h c h a r a c t e r i s t i c s s i m i l a r to t h o s e occasionally found with adrenergic enhancement alone. Thus, the fast r h y t h m s induced by drive during adrenergic enhancement initiate abruptly, a t t a i n a rate far in excess of the m a x i m a l "physiological" rate, last beyond

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Fig. 8. Potentiation by calcium of the drive induced fast rhythms during norepinephrine infusion. Drive at 180/min for 5 sec was carried out alone (first trace), during norepinephrine infusion (second trace), during calcium infusion (third trace), and during the simultaneous infusion of norepinephrine and calcium (fourth trace). The fourth and fifth traces were recorded consecutively. The break in the traces indicates the omission of part of the recording during drive. In the graph, the ordinate shows the reciprocal of the cycle length and the abscissa the successive beats. The column indicates the drive. The curves are labelled with the same lettering as the strips from which they are derived. Part of the data for NE+Ca+Drive curve has been omitted, as indicated by the break in the curve. The dashed line connects the last beat of the fast rhythm with the first beat after the pause. The two beats labelled with an asterisk above the NE+Drive curve in the graph refer to the cycle length preceding the two beats of different configuration in the NE +Drive trace. J. ELECTROCARDIOLOGY, VOL. 9, NO. 4, 1976

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both drive and sympathetic stimulation, and cease abruptly. It is clear, then, that whatever the m e c h a n i s m by which a d r e n e r g i c enhancement induced fast rhythms, the simultaneous presence of drive facilitates the induction of such rhythms. The observation t h a t administration of calcium potentiates the arrhythmogenic effect of both drive and adrenergic enhancement bears on the mechanism of induction of these arrhythmias. One common characteristic of the three types of intervention (drive, adrenergic enhancement and calcium administration) is an increased calcium influx. This results from different mechanisms. Thus, overdrive increases calcium influx by increasing the number of the action potentials in the unit of time; catecholamines increase calcium inward current during the plateau of the action potential by increasing calcium conductance; 21 and a n increase in [Ca]o increases calcium influx by increasing the inward driving force for that ion. If each of the three factors is made small enough, no a r r h y t h m i a will be induced. However, these three factors acting simultaneously may increase the total calcium influx sufficiently to initiate repetitive discharge. The mechanism by which an increased calcium influx could be related to the onset of the fast rhythms is not clear. However, there are situations in which increasing [Ca]o provokes oscillations which steepen depolarization during diastole. 22'23 Also, cardiac glycosides (which presumably increase calcium influx, see 24) cause oscillations s u p e r i m p o s e d on diastolic depolarization 25'26 which also m a y result in repetitive discharge. 26 These oscillations are sensitive to changes in [Ca]o and to blockade of the slow calcium channel. 23 It is of interest in this regard that in clinical practice arrhythmias have been successfully treated with blockers of the slow inward c h a n n e l Y '28 The present findings do not permit one to decide w h e t h e r overdrive excitation results from an enhanced automatic discharge or reentry. In favor of a drive induced automatic discharge is the finding that in vitro driving Purkinje fibers exposed to low concentrations of catecholamines results in the induction of repetitive discharge caused by the developm e n t of p h a s e 4 diastolic depolarization. 2 These i n d u c e d r h y t h m s are fastest immediately after the end of the drive, continue for a while, exhibit a moderate degree of slowing before they cease abruptly, and are accelerated by short periods of drive. All these c h a r a c t e r i s t i c s a r e p r e s e n t a l s o in t h e r h y t h m s i n d u c e d in vivo in t h e p r e s e n t experiments. A reentry mechanism would be favored by adrenergic enhancement and calcium infusion for these interventions tend to enhance a slow response which underlies the

e s t a b l i s h m e n t of r e e n t r y rhythms. 29 However, a slow response originates from partially depolarized tissue such as m a y be found in an injured area. In the p r e s e n t experiments, no injury was caused to the myocardial tissues except that associated with the ligation of the His bundle. A reentry r h y t h m from the injured area of the His bundle would be expected to give a QRS complex of normal configuration and polarity, and this clearly was not the case. Overdrive excitation is not the only event induced by a fast drive in the presence or absence of adrenergic e n h a n c e m e n t . An increase in rate of discharge (however brought about) activates independently another process which is inhibitory in nature. Thus, a prolonged overdrive is usually followed by suppression and not excitation. The mechanism of overdrive suppression has been attributed to an increased sodium influx due to the higher rate of discharge: if the extrusion of this extra sodium load is electrogenic, suppression of pacemaker activity will follow the drive. 13 The magnitude of the suppression will be a function of the rate and duration of overdrive.lZ'Z~ If overdrive excitation and overdrive suppression can be induced independently, it can be shown that the two interact antagonistically. Thus, while a long overdrive is followed by suppression in most instances, occasionally it is followed by a few beats at slow rate (Fig. 2). This shows that both excitation and suppression have been induced by drive and that excitation occurs on a b a c k g r o u n d of suppression, a phenomenon which has been called inhibited excitation. 1 The simultaneous presence and antagonism between excitation and suppression can be demonstrated also by the interaction of effects of adrenergic enhancement and overdrive. The abolition of adrenergically-induced excitation by drive (Fig. 2 and 6) and the converse finding (Fig. 3) indicate that one intervention induced its effect on top of the b a c k g r o u n d established by the other intervention. Whether excitation or suppression will prevail depends on the sequence in which adrenergic enhancement and drive are applied.

REFERENCES 1. VASSALLE, M, CUMMINS, M, CASTRO, C AND STUCKEY,J H: The relationship between over-

drive suppression and overdrive excitation in ventricular pacemakers. Circ Res 38:367, 1976 2. VASSALLE, M AND CARPENTIER, R: Overdrive excitation: the initiation of spontaneous activity in Purkinje fibers following a fast drive in the presence of norepinephrine. Pfh/gers Arch 332:198, 1971 J. ELECTROCARDIOLOGY, VOk. 9, NO. 4, 1976

SYMPATHETIC SYSTEM AND OVERDRIVE

3. NIKKI, P, TAKKI, S, TAMMISTO, T AND JAA TTELA, A: Effect of operative stress on plasma catecholamine levels. Ann Clin Res 4:146, 1972 4. LANGE, G: Action of driving stimuli from intrinsic and extrinsic sources on in situ cardiac pacemaker tissues. Circ Res 17:449, 1965 5. Lu, H H, LANGE, G AND BROOKS, C McC: Factors controlling pacemaker action in cells of the sinoatrial node. Circ Res 17:460, 1965 6. LINENTHAL,A J, ZOLL, P M, GARABEDIAN,G H AND HUBER, K: V e n t r i c u l a r s l o w i n g a n d standstill after spontaneous or electrically stimulated runs of rapid ventricular beats in a t r i o v e n t r i c u l a r block (abstr.) Circ 22:781, 1960 7. YORMAK, S S, KILLIP, T, LEVITT, B AND ROBERTS, J: Depression of ventricular pacemaker by induced tachycardia (abstr.). Clin Res 13:529, 1965 8. VASSALLE, M, VAGNINI, F J, GOURIN, A AND STUCKEY, J H: Suppression and initiation of idioventricular a u t o m a t i c i t y during vagal stimulation. Am J Physiol 212:1, 1967 9. ALAN]IS,J AND BEN~TEZ, D: The decrease in the automatism of the Purkinje pacemaker fibers provoked by high frequencies of stimulation. Jap J Physiol 17.'556, 1967 10. GROSSMAN, A AND FURCHGOTT, R F: Effect of various drugs on calcium exchange in isolated guinea-pig left auricle. J Pharmacol Exptl Therap 145:162, 1964 11. REUTER, H: Uber die Wirkung von Adrenalin auf den cellul~ren Ca-Umsatz des Meerschweinchenvorhofs. NaunynS c h m i e d e b e r g s Arch exp P a t h P h a r m a k 251:401, 1965 12. VASSALLE,M, LEVINE, M J AND STUCKEY, J H: On the sympathetic control of v e n t r i c u l a r automaticity. The effects of stellate ganglion stimulation. Circ Res 23:249, 1968 13. VASSALLE, M: Electrogenic suppression of automaticity in sheep and dog Purkinje fibers. Circ Res 27:361, 1970 14. VASSALLE,M, STUCKEY,J H AND LEVINE, M L: Sympathetic control of ventricular automaticity: role of the adrenal medulla. Am J Physiol 217:930, 1969 15. WINEGRAD,S AND SHANES, A M: Calcium flux and contractility in guinea pig atria. J Gen Physiol 45:371, 1962 16. GROSSMAN,A AND FURCHGOTT,R F: The effects of frequency of stimulation and calcium concentration on Ca 45 exchange and contractility

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