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The effect of bretylium tosylate on the normal and digitalis-sensitized dog heart
Experimental and laboratory
reports
The effect of bretylium and digitalis-sensitized
tosylate on the normal dog heart
Janet I. Lipski, M.D. Ephraim Donoso, M.D. Charles K. Friedberg, M.D. New York, N. Y.
B
retylium tosylate, introduced as an antihypertensive agent, subsequently was found to have both a positive inotropic action and unique antiarrhythmic properties. It has been used in the treatment and prophylaxis of ventricular arrhythmias following myocardial infarction’ and openheart surgery.2p3 To further elucidate the mechanism of action of this drug, its effect on automatici ty , intra-atria1 conduction, intraventricular conduction, and sinus rate in the digitalis-sensitized and normal, intact dog heart was studied. Materials
and
methods
Adult mongrel dogs, weighing 20 to 2.5 kilograms, were anesthetized with chloralose and urethane intravenously. Artificial respiration with room air was maintained by a Harvard respirator pump. The right vagus was sectioned at its midcervical level and stimulating electrodes were attached to its distal end. A USC1 bipolar pacing catheter* introduced via the left femoral vein was passed blindly across the tricuspid valve and slowly withdrawn until a bi-
phasic bundle of His (H) deflection appeared between the atria1 and ventricular electrogram.4 Activity of the His bundle was recorded at low (120 c.p.s.) and high (500 c.p.s.) frequency settings on the electrocardiograph amplifier. The right atrium was paced at 180 beats per minute by an additional bipolar electrode catheter. Femoral artery pressures were measured through a polyethylene catheter by means of a Statham P23AA transducer. Continuous recordings of the Lead II surface electrocardiogram (ECG), intracardiac electrogram, and systemic blood pressure were made on an Electronics for Medicine multichannel oscilloscopic photographic recorder during sinus rhythm and atria1 pacing before and after drug administration. Atrioventricular conduction time was determined by measuring the interval between the beginning of the P wave of the ECG and the spike of the bundle of His on the electrogram (P-H). The presence of the atrioventricular node potential (A-V) at the termination of atria1 activity subdivided the P-to-His interval (the time of atrioventricular conduction) into two sub-
From
the Division of Cardiology, Department of Medicine, Mount Sinai School of Medicine of the City University of New York. New York, N. Y. 10029. This work was supported by United States Public Health Service Grant HE 09416-05. Received for publication July 29, 1971. Reprint requests to: Janet Lipski. M.D., Department of Medicine, Fifth Avenue and 100th Street, New York, N. Y. 10029. *U. S. Catheter & Instrument Corp., Glens Falls. N. Y.
Vol. 83, No. 6, pfi. 769-776
June, 1972
American Heart Journal
769
770
Lipski,
Dowoso, onct I;ridbcrg
Effect
Bretylwm
AcS
Fig. 1. The effect drop in rate after
on Heart
of acetylstrophanthidin and bretylium on heart rate AcS was given to a dog pretreated with bretylium.
Rate B+AcS
in one experiment.
Note
the precipitous
intervals, namely, the P-A-V and the A-V-H subintervals. Atrioventricular conduction during atria1 pacing was determined by the interval from stimulus artifact to the His potential. Intraventricular conduction was measured as the interval between the His potential and the end of the QRS complex (H-S). A right bundle branch potential was occasionally observed after the His potential and shortly before ventricular activation. Records of atrioventricular and intraventricular conduction were taken at a paper speed of 200 mm. per second. Cardiac arrest was produced by a Schwartz-Medtronic carotid sinus nerve stimulator (CSN) transmitter (Model 40416A). Vagal threshold to produce a cardiac arrest was determined before and after bretylium. The interval between onset of asystole and the ventricular escape beat defined ventricular escape time (VET), a measure of ventricular automaticity. Ventricular automaticity and conduction times during sinus rhythm and atria1 pacing were determined at 2 to 10 minute intervals throughout the entire experiment. After control values were recorded, digitalis toxicity was produced by a single intravenous injection of 7.5 pg per kilogram of acetylstrophanthidin* followed by
a continuous infusion of the drug at a rate of 2.0 to 3.0 fig per kilogram per minute. Infusion was terminated with the appearance of a stable ventricular tachycardia. One to 1% hours after the signs of digitalis toxicity disappeared, and when control values were reached, bretylium tosylate* (5 mg. per kilogram) was given intravenously over 3 to 5 minutes and recordings made every 5 to 10 minutes for 2 hours. At this time, acetylstrophanthidin was again given as previously described until a stable ventricular tachycardia appeared. In this manner each dog served as its own control. Standard statistical analysis was performed using the Student t test for paired samples.
*Supplied through the courtesy of G. C. Chiu. Research Laboratories, Indianapolis, Ind.
“Supplied through the courtesy of Dr. S. T. Bloomfield, roughs Wellcome and Co. (U.S.A.), Inc.. Tuckahoe.
M.D.,
Eli Lilly
Results
Heart rate. Both acetylstrophanthidin and bretylium decreased heart rate. Acetylstrophanthidin (AcS) decreased the heart rate an average of 18 per cent (from 182.5 to 150.8 beats per minute). Bretylium alone decreased the heart rate 27 per cent (from 180 to 132.3 beats per minute). AcS given for a second time to a dog having received bretylium produced a 36 per cent decrease (from 183.6 to 116.9 beats per minute). The effects of AcS and bretylium in one representative experiment are shown in Fig. 1. BurN. Y.
Volume Number
53 6
Bretylkm
P-H P-AY N-H
Fig. 2. The effect on atrioventricular potential; H = His-bundle potential;
conduction time with atria1 RB = Right bundle branch
tosylate
771
202.5 77.8 12s
pacing at a constant rate. A Ir = A-V node potential. Paper speed 200 mm. per second.
EFFECT ON INTRA ATRIAL CONDUCTION TIME (Wilh atria1 pacing)
90
90
P-H
80
SO
AV-H
I 70 I z' 60 :
50
z ; 40 5 .\" 30 20 IO 0
Fig. 3. The subinterval
average change
percentage increase was not statistically
in P-H and A-V-H significant.
Table I summarizes the effect on heart rate in 17 experiments. At&ventricular conduction time. In order to eliminate the effects of changing rate on the P-R interval, the atria were paced at a constant rate. Conduction times with and without atria1 pacing were investigated. The effect on atrioventricular conduction with atria1 pacing in one representative experiment is shown in Fig. 2. In 17 experiments the average percentage increase in P-H and A-V-H with atria1 pacing is shown in Fig. 3.
with
atria1
pacing
is summarized
here.
The
P-A-V
With atria1 pacing (Table II A) AcS increased the average P-H interval 2.5 per cent (from 110 to 137.7 msec.). Bretylium increased the atrioventricular conduction time 36 per cent (from 103.7 to 141.7 msec.), whereas AcS given 2 hours after bretylium was administered increased the P-H interval 111 per cent (from 100.3 to 211.1 msec.). The greatest latency was at the A-V-H subinterval which showed a 197 per cent increase (from 32.1 to 9.5.3 msec.). The P-A-V subinterval was also increased with both drugs but the increase
772
Lipski,
Am. Heart
Donoso, and Fuiedbeug
JuJtc,
J. 192
I b TIME
Lmin)
Fig. 4. The effect on automaticity or the ventricular escape time in one representative experiment. Note the decrease in the VET immediately after bretylium was given. From a control value of 2.75 sec. the VET decreased to 1 sec. before increasing to 25 sec. at 60 minutes. Pretreatment with bretylium attenuated the response to A& given the second time.
Table I. Effect of drugs on heart rate
%:’ 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mean S.E.M. P
1 lvnlrol~
AcS
1 &t$,
IBali
161 190 200 163 170 131 200 190 207 152 163 157 204 190 163 197 190
151 163 168 143 139 104 184 168 187 136 158 80 139 130 144 150 165
150 121 158 118 139 150 150 139 130 113 173 106 100 131 128
95 163 104 118 148 146 130 134 66 133 101 63 113 123
182.5 ==5.0
150.8 *6.7
132.3 +5.7
116.9 ~7.8
was not statistically significant. Also, the effect on intraventricutar conduction was not statistically significant. In the absence of pacing there was a similar increase in
P-H and A-V-H interval. Table II summarizes the effect of drugs on atrioventricular conduction time with and without atria1 pacing. In 4 dogs, the experiment was terminated when long periods of asystole and advanced degrees of A-V block precluded further administration of AcS. Ventricular automaticity (VET). The effects of A& and bretylium on automaticity in a representative experiment are shown in Fig. 4. AcS increased automaticity by decreasing the VET an average of 80.5 per cent (from 11.24 to 2.19 sec.). Bretylium increased automaticity for 10 to 15 minutes after injection, after which time automaticity was profoundly depressed. The average VET increased 190 per cent (from 6.78 to 19.69 sec.), at 83 minutes. AcS given after bretylium caused only a 50 per cent decrease in VET (from 7.11 to 3.54 sec., Table III). Following bretylium 7 of 17 animals showed brief spontaneous bursts of ventricular premature systoles and ventricular tachycardia. This coincided with the period of increased automaticity that was noted immediately following the administration of bretylium. Two dogs died in ventricular tachycardia following the administration
Bretylizrm
Tuble II A, Part 1. Effect of drugs on atrioventriczrlar conduction with pacing (P-H [msec.])
1
2-3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mean S.E.M. P
132.5 161 105 157.5 127.5 87.5 9.5 112 100 1.50 125 97.5 107.5 85 95 110 =+=5.9
126.5
200
-
-
-
195 120 165
132.5 -
12 152.5 147.5 110 285 165 177.5 112.5 135 105
130 137.5 131.5 120 295 130 142.5 165 117.5 165
140 255 135 202.5 140 265 235 245 150 260 157.5
137.7 ~8.4 <0.025
141.7 b8.6 <0.005
211 * 19.7
105
of bretylium. One dog, not included in the study, received bretylium only 15 min. after A& induced ventricular tachycardia. RSR was present at the time bretylium was given in both cases.
773
tosylate
Tuble II A, Part 2. Efect of drugs on atrioventricular conduction with pacing (P-A-V [msec.])
1
2-3-4-5 6 7 8 9 10 11 12 13 14 15 16 17 Mean S.E.M. P
100
-
-
-
90 60 70
-
-
70 72.5
77.5 57.5
7’1.5 74.5 97.5 67.5 56 62.5
77.5 72.5 167.5 75 67.5
77,s 71.5 80 97.5 90
77.5 71 85 87.5
79.3 *4.6
84.7 h10.7 >0.5
82.4 h4.2 >O.lOO
76.0 b4.4 >0.200
100
125 89 65 80
82.5
Table II A, Part 3. E$ect of drugs on at&ventricular conduction with pacing
(A - V-H [msec.])
Discussion
Bretylium tosylate, an adrenergic neuronal blocking agent, was introduced as an antihypertensive agent.6 Like guanethidine, it blocks the peripheral sympathetic nervous system without antagonizing the effects of released or injected epinephrine or norepinephrine and without depressing the parasympathetic nervous system.6 Leveque’ first reported its antiarrhythmic properties in 1965 when he showed its protective effect in experimentally induced atrial fibrillation. Bacaner8 subsequently reported bretylium to be uniquely effective in raising the ventricular fibrillation threshold and producing the spontaneous defibrillation phenomenon. More recently, its therapeutic value in abolishing ventricular premature systoles after myocardial infarction and in the prevention of arrhythmias
1
23--4--5 6 7 8 9-10 11 12 13 14 15 16 17 Mean S.E.M. P
42.5
50
-
75
-
-
-
32.5 38.5 22.5 40
75 36 30
41 25.5 52.5 40 29 32.5
90 37.5 117.5 32.5 37.5
36.9 A3.4
59.5 bl1.1 = 0.05
z 35 62.5 56.5 48.5 100 85 iii 63.4 h5.8
z 62.5 150 125 69 65 70 95.3 *17.7 <0.025
774
Lipski,
lhble II B, Part 1. Effect of drugs on at&ventricular conduction with no pacing (P-H [msec.])
%f. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mean S.E.M. P
/ io,ltm~
AcS
1 B:::1-
/ B i3AcS
105 82.5 90 94 96.5 99 72.5 82.5 77.5 79 78.5 87.5 78 60 80 85 80
92.5 135 130 125 182.5 152.5 100 135 101 100 115 135 135 95 117.5 82.5
125 155 125 137.5 94 97.5 110 87.5 95 160 120 80 92.5 90 110
235 120 192.5 110 100 105 145 200 110 -195 110
83.5 =‘=2.6
120.8 h6.4
111.9 b6.4
151.3 f 15.7 <0.005
-
Table II B, Part 2. E$ect of drugs on atrioventricular conduction with no pacing (A - V-H [msec.])
1 2 3 4 5 6 7 8 9 10 11 12 13
37.5 30
30 75
40 32 21.5 50 15 23.5 40 -
26 40 70 95 45 29 30 57.5 -
14 15 16 17
40 31
62.5 32.5
32.8 *3.0
51.5 h6.1 <0.050
Mean S.E.M. P
Am. Heart J. June, 1972
Donoso, and Friedberg
57.5 79 -~
-
55 37.5 29 27.5 100 -
52.5 127.5
4Y.5 35
1 35
51.4 ==8.2 <0.05
67.5 +17..5
40 32.5 85 -
Table II B, Part 3. E$ect of drugs on at&ventricular conduction with no pacing (P-A-V [msec.])
%: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mean S.E.M. P
~ Contra' 72.5 52.5 56.5 zi.5 50 64 55 47.5 40 49 52.4 b2.5
AcS 65 61.5 55 86.5 5.5 55 75 70 57.5 32.5 50 60.3 k5.2 >0.200
~ Bi::" 80 52.5 -
/ B &AcS
-
-
-
39 60 70 67.5 60
70 65 -60 72.5 60
-
50 75 61.6 A4.3 >O.lOO
66.0 =+=2.3 <0.025
following open-heart surgery has been reported.3sg Because other commonly used antiarrhythmic agents (quinidine, procainamide, lidocaine, diphenylhydantoin, and propranolol) have negative inotropic actions and were judged to be without effect in suppressing electrically induced ventricular fibrillation,2 bretylium tosylate offered the unique combination of a positive inotropic effect in addition to its antiarrhythmic properties. Previous investigators have shown that bretylium has a negative chronotropic effect in both human and animal experiments.6s10 Though both AcS and bretylium given alone decreased heart rate, the addition of the glycoside to a dog having received bretylium further potentiated this effect. Potentially useful, therefore, in sinus tachycardia, bretylium should be used with caution in bradyarrhythmias, especially in those receiving digitalis. When the atria were paced at a constant rate to eliminate effects of a changing rate on the P-R interval, atrioventricular con-
Bretylium
Table III. Effect of automaticity escape time in seconds)
(ventricular
Table IV. Acetylstrophanthidin rep&red to produce ventricular tachycardia Mg. Exp.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mean S.E.M. P
38.9 7.97 5.25 2.44 33.0 11.25 19.8 1.50 2.62 24.5 4.9 2.18 29.0 17.0 11.0 2.5 5.0
4.25 0.5 2.13 1.25 3.50 1.50 1.0 0.5 0.33 11.0 0.75 1.2 6.25 1.0 1.5
11.24 ~2.76
2.19 AO.74
1.5
0.5
19.3 8.0 20.0 56.0 1.75 28.13 2.5 7.75 10.0 19.25 32.0 25.0 25.25 3.5
0.50 3.75 4.25 1.5 0.75 0.25 3.5 1.5 3.0 19.0 1.0
19.69 =!=4.05 <0.025
3.54 k1.60
duction time (the P-H interval) increased moderately with either bretylium or A&. When the glycoside was given to a dog having received bretylium a marked increase in atrioventricular conduction time was noted. The greatest delay was noted in the A-V-H subinterval which suggests that both drugs exert an appreciable effect on the A-V node. In 2 patients with second degree A-V block and Wenckebach periods secondary to an acute myocardial infarction, bretylium was reported to have eliminated the Wenckebach periods but first degree A-V block persisted.g In light of both the negative chronotropic effect and the prolongation of conduction primarily at the A-V node observed in our experiments, it is difficult to attribute the conversion of this second degree A-V block to the bretylium. In one other patient with an acute myocardial infarction and possible digitalis toxicity manifested by atria1 tachycardia with 2 : 1 block, bretylium increased the A-V block. However, a second dose of bretylium was followed by restoration of sinus rl~ythm.s In our studies bretylium had no appreciable effect on intraventricu-
No.
2 3 4 5 6 7 8 9 10 11
12 13 14 1.5 16 17 Mean S.E.M. P
AcS before bretylium 0.810 1.328 1.925 1.53 2.145 2.421 1.832 1.321 2.047 1.441 1.750 1.203 1.096 2.90 1.454 1.009 1.631 *O. 132
775
tosylute
(mg.)
Mg.
AcS ajter bretylium
1.488 1.992 1.53 3.079 2.299 1.434 3.264 1.708 0.867 2.53 1.920 1.017 1.973 *0.228 <0.20
lar conduction, which is unique for an antiarrhythmic agent. Bretylium had an interesting effect on ventricular automaticity, as manifested by the ventricular escape time. It initially increased automaticity before profoundly decreasing it. During the period of increased automaticity, frequent ventricular premature systoles and short bursts of ventricular tachycardia have been noted in several dogs. This arrhythmia may be due to the transient release of intrinsic catecholamine produced by bretylium.6 Bretylium offers long-term protection to the normal and the digitalis-sensitized heart in that a longer time and a greater dose of the glycoside was required to produce ventricular tachycardia. Bretylium’s therapeutic vaIue is based on its lack of effect on intraventricular conduction time, so that a digitalis-induced arrhythmia secondary to increased automaticity may be aborted provided the initial period of increased automaticity is safely passed. Our present study confirms the observations that bretylium tosylate decreases the sinus rate and increases atrioventricular
776
Lifiski,
AWL. Heal? I. June. 1972
Donoso, und l+iedberg
(P-H) conduction time. This conduction delay is significantly accentuated in the digitalis-sensitized heart as compared to the normal heart, so that the use of bretylium in the presence of bradyarrhythmias and advanced degrees of A-V block appears to be contraindicated. The propensity of bretylium to produce ventricular premature systoles and ventricular tachycardia for an initial short period may limit its potential clinical use. Nevertheless, bretylium remains unique as an antiarrhythmic agent in that it is a positive inotropic agent, it decreases ventricular automaticity, and it has no appreciable effect on intraventricular conduction. Summary Investigations were made of the effect of bretylium tosylate, an antiarrhythmic drug, on automaticity, atrioventricular conduction time, intraventricular conduction time, and sinus rate in the digitalis-sensitized and normal, intact dog heart. Bretylium and acetylstrophanthidin decreased sinus rate 27 and 18 per cent, respectively. Acetylstrophanthidin given after bretylium pretreatment caused a 36 per cent decrease in sinus rate. Bretylium and acetylstrophanthidin each increased atrioventricular conduction time (P-H interval). With right atria1 pacing at a constant rate, bretylium increased atrioventricular conduction time 36 per cent while acetylstrophanthidin increased this time by 25 per cent. Together, bretylium and acetylstrophanthidin increased conduction time 111 per cent, chiefly in the A-V-H subinterval. Bretylium initially increased then subsequently decreased automaticity. The average ventricular escape time increased 190 per cent by bretylium. Acetylstrophanthidin, given after bretylium, de-
creased ventricular escape time 50 per cent, as compared to 80 per cent when given alone. Bretylium produced ventricular premature systoles and ventricular tachycardia in 7 of 17 dogs during the short period of increased automaticity. This finding as well as the effect to decrease sinus rate and to increase atrioventricular conduction time may limit the clinical usefulness of bretylium. for
The authors her valuable
wish to thank Miss Maureen technical assistance.
Baker
REFERENCES 1. Richards, A. M., and Jerde, 0. M.: Bretylium tosylate and electroshock as combined therapy for intractable ventricular fibrillation and arrhythmias in myocardial infarction, Am. J. Cardiol. 23:134, 1969. (Abst.) 2. Bacaner, M.: Quantitative comparison of bretylium with other antifibrillatory drugs, Am. J. Cardiol. 21:504, 1968. 3. Castaneda, A. R., and Bacaner, M.: Prophylactic suppression of postoperative arrhythmias with bretylium tosylate in open heart surgery, Am. J. Cardiol. 23:107, 1969. (Abst.) 4. Scherlag, B. J., Helfant, R. H., and Damato, A. N.: Catheterization technique for His bundle stimulation and recording in the intact dog, J. Appl. Physiol. 25:425, 1968. A. L. A., Green, A. F., McCoubrey, A., 5. Boura, Laurence, D. R., Moulton, R., and Rosenheim, M. L.: Darenthin: Hypotensive agent of new type, Lancet 2:17, 1959. A. L. A., and Green, A. F.: The actions 6. Boura, of bretylium: Adrenergic neurone blocking and other effects, Br. J. Pharmacol. 14:536, 1959. 7. Leveque, P.: Anti-arrhythmic action of bretylium, Nature 207:203, 196.5. 8. Bacaner, M.: Bretylium tosylate for suppression of induced ventricular fibrillation, Am. J. Cardiol. 17:.528, 1966. 9. Bacaner, M.: Treatment of ventricular fibriliation and other acute arrhythmias with bretylium tosylate, Am. J. Cardiol. 21:.530, 1968. W. M., and Wilson, W. R.: Phar10. Kirkendall, macodynamics and clinical use of guanethidine, bretylium and methyldopa, Am. J. Cardiol. 9:107. 1962.
reports
The effect of bretylium and digitalis-sensitized
tosylate on the normal dog heart
Janet I. Lipski, M.D. Ephraim Donoso, M.D. Charles K. Friedberg, M.D. New York, N. Y.
B
retylium tosylate, introduced as an antihypertensive agent, subsequently was found to have both a positive inotropic action and unique antiarrhythmic properties. It has been used in the treatment and prophylaxis of ventricular arrhythmias following myocardial infarction’ and openheart surgery.2p3 To further elucidate the mechanism of action of this drug, its effect on automatici ty , intra-atria1 conduction, intraventricular conduction, and sinus rate in the digitalis-sensitized and normal, intact dog heart was studied. Materials
and
methods
Adult mongrel dogs, weighing 20 to 2.5 kilograms, were anesthetized with chloralose and urethane intravenously. Artificial respiration with room air was maintained by a Harvard respirator pump. The right vagus was sectioned at its midcervical level and stimulating electrodes were attached to its distal end. A USC1 bipolar pacing catheter* introduced via the left femoral vein was passed blindly across the tricuspid valve and slowly withdrawn until a bi-
phasic bundle of His (H) deflection appeared between the atria1 and ventricular electrogram.4 Activity of the His bundle was recorded at low (120 c.p.s.) and high (500 c.p.s.) frequency settings on the electrocardiograph amplifier. The right atrium was paced at 180 beats per minute by an additional bipolar electrode catheter. Femoral artery pressures were measured through a polyethylene catheter by means of a Statham P23AA transducer. Continuous recordings of the Lead II surface electrocardiogram (ECG), intracardiac electrogram, and systemic blood pressure were made on an Electronics for Medicine multichannel oscilloscopic photographic recorder during sinus rhythm and atria1 pacing before and after drug administration. Atrioventricular conduction time was determined by measuring the interval between the beginning of the P wave of the ECG and the spike of the bundle of His on the electrogram (P-H). The presence of the atrioventricular node potential (A-V) at the termination of atria1 activity subdivided the P-to-His interval (the time of atrioventricular conduction) into two sub-
From
the Division of Cardiology, Department of Medicine, Mount Sinai School of Medicine of the City University of New York. New York, N. Y. 10029. This work was supported by United States Public Health Service Grant HE 09416-05. Received for publication July 29, 1971. Reprint requests to: Janet Lipski. M.D., Department of Medicine, Fifth Avenue and 100th Street, New York, N. Y. 10029. *U. S. Catheter & Instrument Corp., Glens Falls. N. Y.
Vol. 83, No. 6, pfi. 769-776
June, 1972
American Heart Journal
769
770
Lipski,
Dowoso, onct I;ridbcrg
Effect
Bretylwm
AcS
Fig. 1. The effect drop in rate after
on Heart
of acetylstrophanthidin and bretylium on heart rate AcS was given to a dog pretreated with bretylium.
Rate B+AcS
in one experiment.
Note
the precipitous
intervals, namely, the P-A-V and the A-V-H subintervals. Atrioventricular conduction during atria1 pacing was determined by the interval from stimulus artifact to the His potential. Intraventricular conduction was measured as the interval between the His potential and the end of the QRS complex (H-S). A right bundle branch potential was occasionally observed after the His potential and shortly before ventricular activation. Records of atrioventricular and intraventricular conduction were taken at a paper speed of 200 mm. per second. Cardiac arrest was produced by a Schwartz-Medtronic carotid sinus nerve stimulator (CSN) transmitter (Model 40416A). Vagal threshold to produce a cardiac arrest was determined before and after bretylium. The interval between onset of asystole and the ventricular escape beat defined ventricular escape time (VET), a measure of ventricular automaticity. Ventricular automaticity and conduction times during sinus rhythm and atria1 pacing were determined at 2 to 10 minute intervals throughout the entire experiment. After control values were recorded, digitalis toxicity was produced by a single intravenous injection of 7.5 pg per kilogram of acetylstrophanthidin* followed by
a continuous infusion of the drug at a rate of 2.0 to 3.0 fig per kilogram per minute. Infusion was terminated with the appearance of a stable ventricular tachycardia. One to 1% hours after the signs of digitalis toxicity disappeared, and when control values were reached, bretylium tosylate* (5 mg. per kilogram) was given intravenously over 3 to 5 minutes and recordings made every 5 to 10 minutes for 2 hours. At this time, acetylstrophanthidin was again given as previously described until a stable ventricular tachycardia appeared. In this manner each dog served as its own control. Standard statistical analysis was performed using the Student t test for paired samples.
*Supplied through the courtesy of G. C. Chiu. Research Laboratories, Indianapolis, Ind.
“Supplied through the courtesy of Dr. S. T. Bloomfield, roughs Wellcome and Co. (U.S.A.), Inc.. Tuckahoe.
M.D.,
Eli Lilly
Results
Heart rate. Both acetylstrophanthidin and bretylium decreased heart rate. Acetylstrophanthidin (AcS) decreased the heart rate an average of 18 per cent (from 182.5 to 150.8 beats per minute). Bretylium alone decreased the heart rate 27 per cent (from 180 to 132.3 beats per minute). AcS given for a second time to a dog having received bretylium produced a 36 per cent decrease (from 183.6 to 116.9 beats per minute). The effects of AcS and bretylium in one representative experiment are shown in Fig. 1. BurN. Y.
Volume Number
53 6
Bretylkm
P-H P-AY N-H
Fig. 2. The effect on atrioventricular potential; H = His-bundle potential;
conduction time with atria1 RB = Right bundle branch
tosylate
771
202.5 77.8 12s
pacing at a constant rate. A Ir = A-V node potential. Paper speed 200 mm. per second.
EFFECT ON INTRA ATRIAL CONDUCTION TIME (Wilh atria1 pacing)
90
90
P-H
80
SO
AV-H
I 70 I z' 60 :
50
z ; 40 5 .\" 30 20 IO 0
Fig. 3. The subinterval
average change
percentage increase was not statistically
in P-H and A-V-H significant.
Table I summarizes the effect on heart rate in 17 experiments. At&ventricular conduction time. In order to eliminate the effects of changing rate on the P-R interval, the atria were paced at a constant rate. Conduction times with and without atria1 pacing were investigated. The effect on atrioventricular conduction with atria1 pacing in one representative experiment is shown in Fig. 2. In 17 experiments the average percentage increase in P-H and A-V-H with atria1 pacing is shown in Fig. 3.
with
atria1
pacing
is summarized
here.
The
P-A-V
With atria1 pacing (Table II A) AcS increased the average P-H interval 2.5 per cent (from 110 to 137.7 msec.). Bretylium increased the atrioventricular conduction time 36 per cent (from 103.7 to 141.7 msec.), whereas AcS given 2 hours after bretylium was administered increased the P-H interval 111 per cent (from 100.3 to 211.1 msec.). The greatest latency was at the A-V-H subinterval which showed a 197 per cent increase (from 32.1 to 9.5.3 msec.). The P-A-V subinterval was also increased with both drugs but the increase
772
Lipski,
Am. Heart
Donoso, and Fuiedbeug
JuJtc,
J. 192
I b TIME
Lmin)
Fig. 4. The effect on automaticity or the ventricular escape time in one representative experiment. Note the decrease in the VET immediately after bretylium was given. From a control value of 2.75 sec. the VET decreased to 1 sec. before increasing to 25 sec. at 60 minutes. Pretreatment with bretylium attenuated the response to A& given the second time.
Table I. Effect of drugs on heart rate
%:’ 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mean S.E.M. P
1 lvnlrol~
AcS
1 &t$,
IBali
161 190 200 163 170 131 200 190 207 152 163 157 204 190 163 197 190
151 163 168 143 139 104 184 168 187 136 158 80 139 130 144 150 165
150 121 158 118 139 150 150 139 130 113 173 106 100 131 128
95 163 104 118 148 146 130 134 66 133 101 63 113 123
182.5 ==5.0
150.8 *6.7
132.3 +5.7
116.9 ~7.8
was not statistically significant. Also, the effect on intraventricutar conduction was not statistically significant. In the absence of pacing there was a similar increase in
P-H and A-V-H interval. Table II summarizes the effect of drugs on atrioventricular conduction time with and without atria1 pacing. In 4 dogs, the experiment was terminated when long periods of asystole and advanced degrees of A-V block precluded further administration of AcS. Ventricular automaticity (VET). The effects of A& and bretylium on automaticity in a representative experiment are shown in Fig. 4. AcS increased automaticity by decreasing the VET an average of 80.5 per cent (from 11.24 to 2.19 sec.). Bretylium increased automaticity for 10 to 15 minutes after injection, after which time automaticity was profoundly depressed. The average VET increased 190 per cent (from 6.78 to 19.69 sec.), at 83 minutes. AcS given after bretylium caused only a 50 per cent decrease in VET (from 7.11 to 3.54 sec., Table III). Following bretylium 7 of 17 animals showed brief spontaneous bursts of ventricular premature systoles and ventricular tachycardia. This coincided with the period of increased automaticity that was noted immediately following the administration of bretylium. Two dogs died in ventricular tachycardia following the administration
Bretylizrm
Tuble II A, Part 1. Effect of drugs on atrioventriczrlar conduction with pacing (P-H [msec.])
1
2-3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mean S.E.M. P
132.5 161 105 157.5 127.5 87.5 9.5 112 100 1.50 125 97.5 107.5 85 95 110 =+=5.9
126.5
200
-
-
-
195 120 165
132.5 -
12 152.5 147.5 110 285 165 177.5 112.5 135 105
130 137.5 131.5 120 295 130 142.5 165 117.5 165
140 255 135 202.5 140 265 235 245 150 260 157.5
137.7 ~8.4 <0.025
141.7 b8.6 <0.005
211 * 19.7
105
of bretylium. One dog, not included in the study, received bretylium only 15 min. after A& induced ventricular tachycardia. RSR was present at the time bretylium was given in both cases.
773
tosylate
Tuble II A, Part 2. Efect of drugs on atrioventricular conduction with pacing (P-A-V [msec.])
1
2-3-4-5 6 7 8 9 10 11 12 13 14 15 16 17 Mean S.E.M. P
100
-
-
-
90 60 70
-
-
70 72.5
77.5 57.5
7’1.5 74.5 97.5 67.5 56 62.5
77.5 72.5 167.5 75 67.5
77,s 71.5 80 97.5 90
77.5 71 85 87.5
79.3 *4.6
84.7 h10.7 >0.5
82.4 h4.2 >O.lOO
76.0 b4.4 >0.200
100
125 89 65 80
82.5
Table II A, Part 3. E$ect of drugs on at&ventricular conduction with pacing
(A - V-H [msec.])
Discussion
Bretylium tosylate, an adrenergic neuronal blocking agent, was introduced as an antihypertensive agent.6 Like guanethidine, it blocks the peripheral sympathetic nervous system without antagonizing the effects of released or injected epinephrine or norepinephrine and without depressing the parasympathetic nervous system.6 Leveque’ first reported its antiarrhythmic properties in 1965 when he showed its protective effect in experimentally induced atrial fibrillation. Bacaner8 subsequently reported bretylium to be uniquely effective in raising the ventricular fibrillation threshold and producing the spontaneous defibrillation phenomenon. More recently, its therapeutic value in abolishing ventricular premature systoles after myocardial infarction and in the prevention of arrhythmias
1
23--4--5 6 7 8 9-10 11 12 13 14 15 16 17 Mean S.E.M. P
42.5
50
-
75
-
-
-
32.5 38.5 22.5 40
75 36 30
41 25.5 52.5 40 29 32.5
90 37.5 117.5 32.5 37.5
36.9 A3.4
59.5 bl1.1 = 0.05
z 35 62.5 56.5 48.5 100 85 iii 63.4 h5.8
z 62.5 150 125 69 65 70 95.3 *17.7 <0.025
774
Lipski,
lhble II B, Part 1. Effect of drugs on at&ventricular conduction with no pacing (P-H [msec.])
%f. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mean S.E.M. P
/ io,ltm~
AcS
1 B:::1-
/ B i3AcS
105 82.5 90 94 96.5 99 72.5 82.5 77.5 79 78.5 87.5 78 60 80 85 80
92.5 135 130 125 182.5 152.5 100 135 101 100 115 135 135 95 117.5 82.5
125 155 125 137.5 94 97.5 110 87.5 95 160 120 80 92.5 90 110
235 120 192.5 110 100 105 145 200 110 -195 110
83.5 =‘=2.6
120.8 h6.4
111.9 b6.4
151.3 f 15.7 <0.005
-
Table II B, Part 2. E$ect of drugs on atrioventricular conduction with no pacing (A - V-H [msec.])
1 2 3 4 5 6 7 8 9 10 11 12 13
37.5 30
30 75
40 32 21.5 50 15 23.5 40 -
26 40 70 95 45 29 30 57.5 -
14 15 16 17
40 31
62.5 32.5
32.8 *3.0
51.5 h6.1 <0.050
Mean S.E.M. P
Am. Heart J. June, 1972
Donoso, and Friedberg
57.5 79 -~
-
55 37.5 29 27.5 100 -
52.5 127.5
4Y.5 35
1 35
51.4 ==8.2 <0.05
67.5 +17..5
40 32.5 85 -
Table II B, Part 3. E$ect of drugs on at&ventricular conduction with no pacing (P-A-V [msec.])
%: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mean S.E.M. P
~ Contra' 72.5 52.5 56.5 zi.5 50 64 55 47.5 40 49 52.4 b2.5
AcS 65 61.5 55 86.5 5.5 55 75 70 57.5 32.5 50 60.3 k5.2 >0.200
~ Bi::" 80 52.5 -
/ B &AcS
-
-
-
39 60 70 67.5 60
70 65 -60 72.5 60
-
50 75 61.6 A4.3 >O.lOO
66.0 =+=2.3 <0.025
following open-heart surgery has been reported.3sg Because other commonly used antiarrhythmic agents (quinidine, procainamide, lidocaine, diphenylhydantoin, and propranolol) have negative inotropic actions and were judged to be without effect in suppressing electrically induced ventricular fibrillation,2 bretylium tosylate offered the unique combination of a positive inotropic effect in addition to its antiarrhythmic properties. Previous investigators have shown that bretylium has a negative chronotropic effect in both human and animal experiments.6s10 Though both AcS and bretylium given alone decreased heart rate, the addition of the glycoside to a dog having received bretylium further potentiated this effect. Potentially useful, therefore, in sinus tachycardia, bretylium should be used with caution in bradyarrhythmias, especially in those receiving digitalis. When the atria were paced at a constant rate to eliminate effects of a changing rate on the P-R interval, atrioventricular con-
Bretylium
Table III. Effect of automaticity escape time in seconds)
(ventricular
Table IV. Acetylstrophanthidin rep&red to produce ventricular tachycardia Mg. Exp.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mean S.E.M. P
38.9 7.97 5.25 2.44 33.0 11.25 19.8 1.50 2.62 24.5 4.9 2.18 29.0 17.0 11.0 2.5 5.0
4.25 0.5 2.13 1.25 3.50 1.50 1.0 0.5 0.33 11.0 0.75 1.2 6.25 1.0 1.5
11.24 ~2.76
2.19 AO.74
1.5
0.5
19.3 8.0 20.0 56.0 1.75 28.13 2.5 7.75 10.0 19.25 32.0 25.0 25.25 3.5
0.50 3.75 4.25 1.5 0.75 0.25 3.5 1.5 3.0 19.0 1.0
19.69 =!=4.05 <0.025
3.54 k1.60
duction time (the P-H interval) increased moderately with either bretylium or A&. When the glycoside was given to a dog having received bretylium a marked increase in atrioventricular conduction time was noted. The greatest delay was noted in the A-V-H subinterval which suggests that both drugs exert an appreciable effect on the A-V node. In 2 patients with second degree A-V block and Wenckebach periods secondary to an acute myocardial infarction, bretylium was reported to have eliminated the Wenckebach periods but first degree A-V block persisted.g In light of both the negative chronotropic effect and the prolongation of conduction primarily at the A-V node observed in our experiments, it is difficult to attribute the conversion of this second degree A-V block to the bretylium. In one other patient with an acute myocardial infarction and possible digitalis toxicity manifested by atria1 tachycardia with 2 : 1 block, bretylium increased the A-V block. However, a second dose of bretylium was followed by restoration of sinus rl~ythm.s In our studies bretylium had no appreciable effect on intraventricu-
No.
2 3 4 5 6 7 8 9 10 11
12 13 14 1.5 16 17 Mean S.E.M. P
AcS before bretylium 0.810 1.328 1.925 1.53 2.145 2.421 1.832 1.321 2.047 1.441 1.750 1.203 1.096 2.90 1.454 1.009 1.631 *O. 132
775
tosylute
(mg.)
Mg.
AcS ajter bretylium
1.488 1.992 1.53 3.079 2.299 1.434 3.264 1.708 0.867 2.53 1.920 1.017 1.973 *0.228 <0.20
lar conduction, which is unique for an antiarrhythmic agent. Bretylium had an interesting effect on ventricular automaticity, as manifested by the ventricular escape time. It initially increased automaticity before profoundly decreasing it. During the period of increased automaticity, frequent ventricular premature systoles and short bursts of ventricular tachycardia have been noted in several dogs. This arrhythmia may be due to the transient release of intrinsic catecholamine produced by bretylium.6 Bretylium offers long-term protection to the normal and the digitalis-sensitized heart in that a longer time and a greater dose of the glycoside was required to produce ventricular tachycardia. Bretylium’s therapeutic vaIue is based on its lack of effect on intraventricular conduction time, so that a digitalis-induced arrhythmia secondary to increased automaticity may be aborted provided the initial period of increased automaticity is safely passed. Our present study confirms the observations that bretylium tosylate decreases the sinus rate and increases atrioventricular
776
Lifiski,
AWL. Heal? I. June. 1972
Donoso, und l+iedberg
(P-H) conduction time. This conduction delay is significantly accentuated in the digitalis-sensitized heart as compared to the normal heart, so that the use of bretylium in the presence of bradyarrhythmias and advanced degrees of A-V block appears to be contraindicated. The propensity of bretylium to produce ventricular premature systoles and ventricular tachycardia for an initial short period may limit its potential clinical use. Nevertheless, bretylium remains unique as an antiarrhythmic agent in that it is a positive inotropic agent, it decreases ventricular automaticity, and it has no appreciable effect on intraventricular conduction. Summary Investigations were made of the effect of bretylium tosylate, an antiarrhythmic drug, on automaticity, atrioventricular conduction time, intraventricular conduction time, and sinus rate in the digitalis-sensitized and normal, intact dog heart. Bretylium and acetylstrophanthidin decreased sinus rate 27 and 18 per cent, respectively. Acetylstrophanthidin given after bretylium pretreatment caused a 36 per cent decrease in sinus rate. Bretylium and acetylstrophanthidin each increased atrioventricular conduction time (P-H interval). With right atria1 pacing at a constant rate, bretylium increased atrioventricular conduction time 36 per cent while acetylstrophanthidin increased this time by 25 per cent. Together, bretylium and acetylstrophanthidin increased conduction time 111 per cent, chiefly in the A-V-H subinterval. Bretylium initially increased then subsequently decreased automaticity. The average ventricular escape time increased 190 per cent by bretylium. Acetylstrophanthidin, given after bretylium, de-
creased ventricular escape time 50 per cent, as compared to 80 per cent when given alone. Bretylium produced ventricular premature systoles and ventricular tachycardia in 7 of 17 dogs during the short period of increased automaticity. This finding as well as the effect to decrease sinus rate and to increase atrioventricular conduction time may limit the clinical usefulness of bretylium. for
The authors her valuable
wish to thank Miss Maureen technical assistance.
Baker
REFERENCES 1. Richards, A. M., and Jerde, 0. M.: Bretylium tosylate and electroshock as combined therapy for intractable ventricular fibrillation and arrhythmias in myocardial infarction, Am. J. Cardiol. 23:134, 1969. (Abst.) 2. Bacaner, M.: Quantitative comparison of bretylium with other antifibrillatory drugs, Am. J. Cardiol. 21:504, 1968. 3. Castaneda, A. R., and Bacaner, M.: Prophylactic suppression of postoperative arrhythmias with bretylium tosylate in open heart surgery, Am. J. Cardiol. 23:107, 1969. (Abst.) 4. Scherlag, B. J., Helfant, R. H., and Damato, A. N.: Catheterization technique for His bundle stimulation and recording in the intact dog, J. Appl. Physiol. 25:425, 1968. A. L. A., Green, A. F., McCoubrey, A., 5. Boura, Laurence, D. R., Moulton, R., and Rosenheim, M. L.: Darenthin: Hypotensive agent of new type, Lancet 2:17, 1959. A. L. A., and Green, A. F.: The actions 6. Boura, of bretylium: Adrenergic neurone blocking and other effects, Br. J. Pharmacol. 14:536, 1959. 7. Leveque, P.: Anti-arrhythmic action of bretylium, Nature 207:203, 196.5. 8. Bacaner, M.: Bretylium tosylate for suppression of induced ventricular fibrillation, Am. J. Cardiol. 17:.528, 1966. 9. Bacaner, M.: Treatment of ventricular fibriliation and other acute arrhythmias with bretylium tosylate, Am. J. Cardiol. 21:.530, 1968. W. M., and Wilson, W. R.: Phar10. Kirkendall, macodynamics and clinical use of guanethidine, bretylium and methyldopa, Am. J. Cardiol. 9:107. 1962.