Electrophysiologic atrioventricular Jeremy Antonio Masood William Anthony
effects conduction
of tolamolol in man
on
N. Ruskin, M.D. R. Caracta, M.D. Akhtar, M.D. P. Batsford, M.D. N. Damato, M.D.
Staten Island, N. Y.
Tolamolol is a beta-adrenergic blocking agent with the following chemical designation: 4- [2(hydroxy-3-0-toloyloxy-propylamino) ethoxy] benzamide-hydrochloride. The drug is an effective antagonist of isoproterenol-induced tachycardia and has been shown to be equipotent to propranolol and fifty times more potent than proctolol in antagonizing exercise-induced tachycardia in animals.‘, 2 Like proctolol, tolamolol has been shown to possess considerable selectivity for cardiac tissue in experimental animals** 3 and in man.“. 4 In experiments on papillary muscle and guinea pig atria, tolamolol demonstrated condiserably less cardiac depressant activity than equivalent doses of propranolo12 Although preliminary hemodynamic studies in man have demonstrated some negative inotropic effect with intravenous tolamolol,” controlled comparisons with equivalent doses of propranolo have not been carried out in man. Recent work has suggested that tolamolol may be as effective as propranolol in the treatment of angina pectoris,6-8 and, in addition, is effective in the treatment of a variety of supraventricular tachyarrhythmias and certain digitalis-induced arrhythmias.“. lo The purpose of this study was to evaluate the effects of tolamolol on the electrophysiologic properties of the S-A node, A-V node, and HisFrom the Cardiopulmonary Service Hospital, Staten
Laboratory, Island, N. Y.
Received
Oct. 21, 1974.
for publication
Reprint requests: Jeremy N. Ruskin, tory. United States Public Health N. Y. 10304.
December,
United
M.D., Service
States
Public
Health
Cardiopulmonary Hospital, Staten
LaboraIsland,
1975, Vol. 90, No. 6, pp. 755-766
Purkinje system in man, by means of intracardiac electrograms and the extrastimulus method. Materials
and methods
Thirteen patients underwent right heart catheterization in the nonsedated, postabsorptive state after informed consent had been obtained. They were studied for known or suspected disorders of cardiac rhythm or conduction. All patients were in sinus rhythm, and no patient had received cardioactive medication for at least 1 week prior to the time of catheterization. With the use of local anesthesia, a quadripolar catheter was percutaneously introduced into an antecubital vein and, under fluorscopic guidance, positioned against the lateral wall of the high right atrium. The distal two electrodes were used for atria1 pacing, and the proximal two electrodes for recording a high right atria1 electrogram. A tripolar catheter was percutaneously introduced into the femoral vein and positioned across the tricuspid value to record electrical activity from the bundle of His, as previously described.” A bipolar pacing catheter was percutaneously introduced into another arm vein and positioned at the right ventricular apex for ventricular stimulation. Atria1 pacing was performed with a programmed digital stimulator which delivered rectangular impulses of 15msec. duration at twice diastolic threshold. Ventricular pacing was carried out in a similar manner, with the lowest milliamperage that permitted reliable ventricular capture. Studies of the refractory period were performed by the extrastimulus method.“, I3 Studies of sinus node suppression
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Heart Journal
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Ruskin et al.
were carried out by pacing the right atrium for 1 minute at each of 4 fixed cycle lengths (600, 550, 500, and 460 msec.).14 Sinus node escape time was then measured (see definition of terms) after cessation of pacing at each cycle length. Intracardiac electrograms, standard ECG Leads I, II, III, and V,, and time lines generated at intervals of 10 and 100 msec. were simultaneously displayed on a multichannel oscilloscope and recorded on magnetic tape. Recordings were subsequently reproduced on photographic paper at a speed of 150 mm. per second. Care was taken to insure adequate grounding of all equipment. After completion of control studies, tolamolol was infused intravenously at a rate of 4 mg. per minute, with the total dose ranging from 4 to 30 mg. (mean, 17 mg. or 0.24 mg./Kg.). Because of the experimental nature of the drug, incremental doses were administered to the 13 patients studied. Repeat electrophysiologic studies were initiated 5 minutes after infusion of the drug and completed within 45 minutes. Five patients subsequently received a small dose (0.5 or 1.0 mg.) of intravenous atropine 45 minutes after receiving tolamolol. Repeat electrophysiologic studies were initiated 2 minutes after the administration of atropine and completed within 20 minutes. Heart rate and supine blood pressures were carefully monitored throughout each study. Results were analyzed by means of the Student’s t test for paired data. In addition, a separate group of 5 patients was studied in the supine resting position in order to evaluate the effects of incremental doses of tolamolol on sinus rate. Three subjects had mild hypertension controlled with diuretics, and 2 had arteriosclerotic heart disease. All cardioactive medications were discontinued at least 1 week prior to the time of study, and none of the patients had evidence of congestive heart failure, atria1 arrhythmias, or sinus node dysfunction. A slow intravenous drip of 5 per cent dextrose in water was started in’ each patient, and a 30minute control period was observed. Tolamolol was then administered intravenously as a 2-mg. bolus every 10 minutes up to a total dose of 20 mg. Heart rate was monitored by standard ECG (Lead II) recorded at 5-minute intervals during the control period and at intervals of 1,5, and 10 minutes after each 2-mg. bolus of tolamolol. Blood pressure was simultaneously monitored
766
with a sphygmomanometer. Control sinus cycle length was calculated as the average of 20 consecutive sinus beats recorded 1 minute prior to the administration of tolamolol. Sinus cycle length for each incremental dose of tolamolol was calculated as the average of 20 consecutive sinus beats recorded 5 minutes after each 2-mg. injection. Definition
of terms
S,, A,, H,, V, represent the stimulus artifact, atria1 electrogram, His bundle electrogram, and ventricular electrogram of the basic drive beat. S,, A,, HP, V2 represent the stimulus artifact, atria1 electrogram, His bundle electrogram, and ventricular electrogram of the premature beat. A - V nodal conduction time is approximated by the A-H interval, which is measured from the onset of the low right atria1 electrogram to the onset of the His bundle deflection (normal values for this laboratory, 60 to 140 msec.). His-Purkinje conduction time is approximated by the H-V interval, which is measured from the onset of the His bundle deflection to the onset of ventricular activation (normal values for this laboratory, 30 to 55 msec.). Sinus escape time (SET) is defined as the interval between the last paced atria1 beat and the first sinus escape beat as verified by P-wave morphology and a high to low atria1 activation sequence and was measured from the high right atria1 electrogram recordings. Effective refractory period (ERP) of the atrium is defined as the longest S,S, interval at which S, fails to depolarize the atrium. Effective refractory period of the A-V node is defined as the longest A,A, interval at which A, fails to depolarize the His bundle. Functional refractory period (FRP) of the A-V node is defined as the shortest H,H, interval that results from any A,A,, provided that A-V conduction is not limited by atria1 refractoriness. ERP of the His-Purkinje system (HPS) is defined as the longest H,H, interval at which H, fails to conduct to the ventricles. Relative refractory period (RRP) of the HPS is the longest H,H, at which H, conducts to the ventricles with a longer H-V interval than that of the basic drive beat or with a QRS of aberrant configuration. The limitations of this definition have been discussed previously.‘“* I6 ERP of the ventricle is defined as the longest
December, 1975,Vol. 90, No. 6
Electrophysiologic
Table
I. Clinical
2
75 62
M M
3 4
61 66
M M
5 6
59 67
M M
7 8 9
56 56 69
M F M
10 11
56 58
M M
12
24
F
13
25
M
1
(MSEC)
700 2
4
DOSE
8 OF
I3
10
11
TOLAMOLOL
14
lb
18
sb
hf%)
Fig. I, The effect of incremental doses of tolamolol on sinus rate (5 patients). Sinus cycle length (msec.) is plotted as a function of the cumulative dose of tolamolol administered. Little or no additional prolongation of sinus cycle length occurred as the total dose exceeded 10 mg. intravenously.
S,S, interval at which S, fails to depolarize the ventricle during ventricular stimulation. Ventriculo-atria1 (V-A) conduction time is defined as the interval from the stimulus artifact to the onset of the low right atria1 electrogram as observed during right ventricular pacing.” In these patients, latency between the stimulus artifact and the onset of ventricular activation as seen on standard ECG was not observed. Criteria for retrograde conduction and activation of the atria have been described previously.‘s Retrograde ERP of the A-V node is defined as the longest S,H, interval at which the retrograde His bundle deflection of the premature beat (H,) is not followed by retrograde atria1 depolarization. Because the retrograde His bundle deflection of the basic drive beat (H,) is usually obscured by the ventricular electrogram (V,), and because the S,H, interval usually remains constant,” S,H, may be used in place of the H,H, interval in retrograde studies in man. Results Dose-response studies (Fig. 1). Maximal longation of sinus cycle length (SCL) by molol occurred after a total dose of 8 mg. in patients, 10 mg. in 1 patient, and 14 mg. patient. Subsequent 2-mg. increments of
American
Heart
Journal
protola3 of 5 in 1 tola-
effects of tolamolol
data and drugs administered
ASHD (VPBs) ASHD (LBBB, VPBs) ASHD (VPBs) ASHD (RBBBI LAD and 1” AVB) ASHD (LBBB) ASHD (ASMI, VPBs) HHD (LVH) NHD (RBBB) ASHD (DMI, VPBs) WPW-A Mitral prolapse (VPBs) Mitral prolapse (STTW Ab) NHD (Normal)
12 (0.151 8 (0 11)
IO 0.5
12 (0.16) 16 10 “3)
0 1
20 (0.21) 30 (0.45, 20 (0.27)
0
20 (0.28) 30 (0.53)
0 1
16 (0.27)
0
25 (0.34)
0
1 1
‘Numbers do not designate the temporal sequence in which patients were studied. Abbreviations: ASHD = arteriosclerotic heart disease; HHD = hypertensive heart disease; NHD = no heart disease; LBBB = left bundle branch block; RBBB = right bundle branch block; LAD = left axis deviation; 1” AVB = first-degree A-V block; WPW-A = WolffParkinson-White syndrome-type A; VPBs = ventricular premature beats; ASMI = anteroseptal myocardial infarction; DMI = diaphragmatic myocardial infarction; LVH = left ventricular hypertrophy; STTW Ab = S-T and T-wave abnormalities.
molol up to a total dose of 20 mg. produced little or no additional sinus slowing in these patients (Fig. 1). The effect of each 2-mg. increment on sinus rate was maximal within 5 minutes after infusion of the drug. In all patients, nearly maximal prolongation of sinus cycle length ( > 75 per cent of peak SCL) persisted for at least 90 minutes, and significant sinus slowing ( > 50 per cent of peak SCL) persisted for at least 3 hours, after a total dose of 20 mg. of tolamolol. No significant changes in supine blood pressure were observed. Two patients experienced transient postural hypotension after completion of the study. All subsequent results pertain to the group of 13 patients studied with intracardiac electrograms. The essential clinical data for this group are presented in Table I. Sinus
node
Sinus
cycle length
function
(Table
II).
(SCL). Administration
of
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Ruskin et al.
II. Antegrade conduction studies and sinus escape times before and after tolamolol (msec.)
Table
Sinus cycle length Patient No.
Sinus
A-H interval
Before
After
Before
1 2 3 4 5
595 700 670 1,050 530
680 840 685 1,060 1,ooo
85 105 100 210 60
6 7 8 9 10
so0 800 760 760 830
990 850 780 820 850
80 115 90 so 90
11 12 13 Mean P value
960 1,140 560 700 670 740 752 +- 43 856 + 41 P < 0.01
Ill.
Refractory ERP
Patient No.
Before
1 2 3 4 5 6 7 8 9
260 245 285 320 260 290 300 300 240
10 11 12 13 Mean P value
$ 285 210 250 270 f 9
After
interval
escape time
PCL at onset Wenchebach
of
Before
After
Before
100 110 115 230 70
40 75 40 60 70
40 75 40 60 70
770 1,074 1,100 1,205 1,193
980 1,287 1,187 1,290 1,203
310 330 370 750 +
370 460 460 850 *
so 130 loo 120 so
55 50 45 55 t
55 50 45 55
1,120 954 1,170 1,004 947
1,124 1,034 1,170 1,280 1,090
430 300 460 370 *
460 500 460 500 *
45 50 40 52
45 50 40 52
so 100 so 100 70 so 98 k 10 111 f 10 P < 0.001
‘Wenckebach block not observed during atria1 pacing. tHis bundle deflection preceded by onset of ventricular PCL = paced cycle length.
Table
H-V
activation
t
After
1,184 1,277 854 944 760 1,m 1,025 + 43 1,143 + 34 P < 0.001
Before
After
370 460 300 400 330 430 392 f 38 486 k 38 P < 0.001
(WPW).
period data before and after tolamolol (msec.) ERP
of atrium* After 250 265 255 280 275 280 260 295 240 $ 270 210 270 263 + 6 P > 0.1
of A-V
node*
FRP
Before
After
Before
t 280 330 600 t 365 375 385 295
320 350 380 620 t 430 395 420 420
330 395 485 770
$ $ 350 435 220 260 260 340 346 _’ 32 405 -c 29 P < 0.001
t 453 515 463 430 $ 430 373 370 455 5
of A-V
node*
ERP
After
Before
380 468 518 810 t 500 553 483 575 t 510 433 440 35 515 * 33 P < 0.001
of ventricle* After
300 220
280 240
250
230
256 -+ 23 250 f 15 P > 0.1
*Each value represents an average of results obtained at multiple comparable cycle lengths (see Results). tElectrophysiologic studies limited by atria1 refractoriness. SElectrophysiologic studies limited by induction of atria1 fibrillation during atria1 vulnerable period.
tolamolol resulted in prolongation of SCL in all patients (mean + 104 msec., p < 0.01). This corresponds to a 14 per cent increase in SCL or a mean decrease in heart rate of 10 beats per minute. The effects of tolamolol on SCL are presented in Table II. Sinus escape time (SET). Administration of
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tolamolol resulted in prolongation of SET in 11 of 13 patients, and no change in 2 patients (mean + 118 msec., p < 0.001). Sinus escape times presented in Tables II and IV represent an average of values determined at 4 comparable cycle lengths (460, 500, 550, and 600 msec.) for each patient. When average escape times were
December,
1975,
Vol. 90, No. 6
Electrophysiologic
effects of tolumolol
Fig. 2. Effect of tolamolol on effective refractory period of the A-V node (Patient No. 11). In all panels the basic atria1 cycle length is constant at 600 msec. In panel A (control) an atria1 premature depolarization (A,) coupled to basic drive beat (A,) at an interval of 390 msec. is conducted with an A,H, interval of 170 msec. Inpanel B the A,AI coupling interval is reduced to 380 msec., and the premature depolarization (A,) is blocked in the A-V node. This is the longest A,A, interval (380 msec.) at which A, fails to propagate to the HPS. thus defining the effective refractory period (ERP) of the A-V node during the control period. In panel C (after tolamolol :10 mg. intravenously) an atria1 premature depolarization (A,) coupled to the basic drive (A,) at an A,A, interval of 470 msec. is conducted with an A,H, interval of 260 msec. In panel D the A,A, coupling interval is reduced to 460 msec., and the premature depolarization (A,) is blocked in the A-V node, thus defining the ERP of this tissue after tolamolol. When panels B and D are compared, it is apparent that tolamolol has prolonged the ERP of the A-V node by 80 msec. The presence of a drug effect is further substantiated by an increase in A-V nodal conduction time during the basic drive beats (A,H,) from 120 msec. during control studies (panels A and B) to 155 msec’. after tolamolol (panels C and D).
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Heart Journal
759
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Table
et al.
IV. Effects of atropine
on tolamolol-induced
Sinus cycle kxgth Patient No. 4 6 7 9 11 Mean P value
c
T
1,050 900 800 760 960 8945 52
changes in antegrade
A-H interval A
1,060 960 990 680 850 700 820 820 1,140 860 9725 804+ 60 60 P < 0.05
C
TACTA
210 80
230 90
115 90 90 117 + 24
c 60 55
60 55
60 55
130 95 120 100 100 80 134 k 117 f 25 25 P < 0.05
50 55 45 53
50 55 45 53
50 55 45 53
(msec.)
Sinus escape time
H-V interval
220 90
conduction
T * *
Paced CL at onset of Wenckebach A
* *
C * *
954 1,034 830 1,004 1,280 1,034 1,184 1,277 1,155 1,047 f 1,197 -r- 1,006 -t 70 81 94 P < 0.005
750 430 300 370 370 444 -c 79
T
A
850 750 460 400 500 310 500 420 460 430 554 -c 462 +74 75 P < 0.05
*Sinus escape times not studied after z&opine. P values compare poet-atropine with poet-tolamolol values only. Abbreviations: C = control; T = tolamolol; A = atropine; CL = cycle length.
compared with results determined at any single cycle length, no significant difference in the magnitude of change was observed and the statistical significance achieved by these changes was the same. Antegrade
conduction
(Table
II).
A - Vnode. Administration of tolamolol resulted in a statistically significant increase in A-V nodal conduction time during sinus rhythm in 12 of 13 patients (mean + 13 msec., p < 0.001’). In 1 patient with WPW-type A pre-excitation there was no change in A-H interval after tolamolol. Onset of A-V nodal Wenckebach block during atria1 pacing occurred at longer paced cycle lengths in 10 of 11 patients and was unchanged in 1 patient (mean + 94 msec., p < 0.001). In 2 patients, Wenckebach block did not occur with rapid atria1 pacing before or after tolamolol. His-Purkinje system (HPS). Conduction time within the HPS remained unchanged in all patients after tolamolol, both during sinus rhythm and during rapid atria1 pacing. Tolamolol had no effect on HPS conduction time in 3 patients who demonstrated prolonged H-V intervals during control studies (Table II). Refractory period studies (Table Ill). Refractory period data presented in Tables III and V represent values which were averaged from results obtained at multiple comparable cycle lengths (range, 600 to 900 msec.) for each patient. In view of the known effect of cycle length on refractory periods,19 these data were compared with refractory period data determined at a single
760
cycle length (600 msec.) before and after tolamolol in 8 patients. There were no significant differences in the magnitude of the changes observed and no differences in the degree of statistical significance achieved by these changes when averaged data were compared with results obtained at a single cycle length in this group of patients. Atrium. Tolamolol exerted variable and statistically insignificant effects on the effective refractory period (ERP) of the atrium. This parameter was shortened in 7 patients, prolonged in 3 patients, and unchanged in 2 patients (mean-13 msec., p > 0.1). A-V node. Tolamolol prolonged the effective refractory period of the A-V node in 10 of 10 patients in whom this parameter could be measured (mean + 59 msec., p < 0.001). Fig. 2 illustrates prolongation of the ERP of the A-V node after tolamolol. Tolamolol significantly prolonged the functional refractory period (FRP) of the A-V node in 11 of 11 patients (mean + 60 msec., p < 0.001). His-Purkinje system. During control studies, the relative refractory period (RRP) of the HPS was reached in 4 patients, and the ERP of the HPS was reached in 1 patient. Because of the delay in A-V nodal conduction time and the marked increase in A-V nodal refractoriness induced by tolamolol, comparable H,H, intervals could not be attained in any patient after the drug. The effects of tolamolol on the A-V node thus prevented assessment of any possible effects
December,
1975, Vol. 90, No. 6
Fig. 3. Effect of tolamolol on retrograde A-V nodal conduction and refractoriness (Patient No. 8). Pnnel A demonstrates control, and panels B and C demonstrate post-tolamolol retrograde refractory period studies. The right ventricle is paced at a basic cycle length (S,S,) of 600 msec., and premature ventricular beats (S:) are coupled to every eighth drive beat. The longest S,H, interval which fails to depolarize the atrium defines the retrograde ERP of the A-V node (see definitions). InpaneZA (control) a premature beat (S,) is delivered at a coupling intrrvxl of 320 msec., resulting in an S,H, interval of 440 msec. and a retrograde A-V nodal conduction time (H,A.) of IO5 msec. During control studies, progressively early premature ventricular beats continued to conduct retrogradely to the atria, and the retrograde ERP of the A-V node was not encountered. In panel B (after tolamolol), an S delivered at a coupling interval of 360 msec. results in an S,H, interval of 460 msec., thus arriving at the A-V node 20 msec. later than the S, displayed in panel A. Despite its later arrival and because of the effects of tolamolol. the premature beat in panel B encounters a longer retrograde A-V nodal conduction time (HIA, = 120 msec.) than the premature beat in panel A. Comparison of panels A and B thus confirms prolongation of retrograde A-V nodal conduction time by tolamolol in this patient. Inpanel C (after tolamolol) an S, introduced at a coupling interval of 350 msec. results in an S,H, interval of 450 msec. which fails to depolarize the atria (i.e., is blocked in the A-V node), thus defining the retrograde ERP of the A-V node. During control studies the shortest S,H, interval observed prior to the atria was observed. Tolamolol, to encountering the ERP of the ventricle was 415 msec., and conduction therefore, prolonged the retrograde ERP of the A-V node by more than 35 msec. in this patient, but the precise magnitude of prolongation could not be determined because of failure to reach the retrograde ERP of the A-V node during control studies.
American
Heart Journal
761
Ruskin
et al.
Fig. 4. Effect of atropine on the ERP of the A-V node (Patient No. 11). This patient received atropine (1.0 mg. intravenously) immediately after completion of electrophysiologic studies with tolamolol (30 mg. intravenously). The ERP of the A-V node was prolonged from 380 msec. during control studies to 460 msec. after tolamolol (see Fig. 2). At the same basic atria1 cycle length (600 msec.) after atropine, an atria1 premature depolarization, A,. introduced at a coupling interval (A,A;) of 380 msec. conducts with an AIH, interval of 170 msec. (panel A). In panel I3, the A,A, coupling interval is reduced to 370 msec., and A, is blocked in the A-V node, thus defining the ERP of this tissue after atropine. When compared with the ERP of the A-V node after tolamolol (460 msec.), as shown in Fig. 2 (panel D), it is apparent that atropine has shortened the ERP of the A-V node by 90 msec. The presence of a drug (atropine) effect is further substantiated by a decrease in A-V nodal conduction time during the basic drive beats A,H, from 155 msec. after tolamolol (Fig. 2,paneZs C and D) to 110 msec. after atropine @an&A and B above).
on the relative or effective refractory the HPS. Retrograde
periods of
studies.
Ventriculo-atria1 ( V-A) conduction time. Retrograde conduction studies were performed in 5 patients. In 2 patients (Nos. 1 and 5), V-A conduction time at comparable paced ventricular rates did not change after tolamolol, and retrograde A-V nodal Wenckebach block did not occur before or after the drug in either patient. In 2 patients (Nos. 4 and 8), V-A conduction time was prolonged at comparable paced rates (mean + 10 msec.), and retrograde A-V nodal Wenckebach block occurred at longer paced cycle lengths after tolamolol (mean + 180 msec.). Because of the few patients involved, these changes did not achieve statistical significance. In 1 patient (No. 13), consistent V-A conduction was observed during
762
control studies, whereas, after tolamolol, V-A dissociation was observed at all ventricular paced rates in spite of concomitant sinus deceleration. Retrograde ERP of the A-V node. Tolamolol caused insignificant prolongation (+ 10 msec.) of the retrograde ERP of the A-V node in 1 patient (No. 5) in whom this parameter could be determined at a comparable cycle length before and after the drug. In a second patient (No. 8), the retrograde ERP of the A-V node was not reached during control studies because this parameter was exceeded by the ERP of the ventricle. After tolamolol, the retrograde ERP of the A-V node was significantly prolonged and was, therefore, encountered prior to the ERP of the ventricle. Pig. 3 illustrates prolongation of V-A conduction time and prolongation of the retrograde ERP of the A-V node in this patient. In 2 additional
December,
1975, Vol. 90, No. 6
Electrophysiologic
Table
V.
Effects of atropine on tolamolol-induced ERP of atrium*
Patient NO. 4 6 7 9 11 Mean P value
C 320 290 300 240 285 287 t 13
T
changes in refractory
periods (msec.)
ERP of A-V node* A
280 300 280 260 260 270 240 240 270 260 266 t 7 266 + 9 P > 0.1
c 600 365 375 295 350 397 k 52
T
effects of fol~molol
A
620 550 430 340 395 0.1). A small decrease in calculated mean blood pressure in the supine position was observed in 6 of 13 patients after tolamolol, and no change was seen in 7 of 13 patients (mean - 3 mm. Hg, p < 0.025). No untoward side effects were observed. Electrophysiologic bles IV and V).
studies
after
atropine
(Ta-
The following changes were observed in 5 patients who received atropine (0.5 or 1.0 mg. intravenously) immediately upon completion of electrophysiologic studies with tolamolol (data compare post-atropine with posttolamolol values for each parameter): (1) sinus cycle length shortened significantly in 4 of 5 patients (mean - 168 msec., p < 0.05); (2) sinus escape time shortened significantly in 3 of 3 patients (mean - 191 msec., p < 0.05); (3) A-V nodal conduction time during sinus rhythm decreased significantly in 4 of 5 patients (mean - 17 msec., p < 0.05); (4) HPS conduction time was unchanged in 5 of 5 patients; (5) the ERP of the atrium was not significantly altered in 5 of 5 patients; (6) the ERP and FRP of the
American
Heart Journal
A-V node shortened significantly in 5 of 5 patients (mean -87 and - 91 msec., respectively, p < 0.05). Fig. 4 illustrates the effect of atropine in shortening the ERP of the A-V node after this parameter was prolonged by tolamolol (see Fig. 2). Discussion
In this study, tolamolol, adminisbered to 13 patients in a dose range of 4 to 30 mg. intravenously, significantly prolonged spontaneous sinus cycle length, sinus escape time, -4-V nodal conduction time, and the effective and functional refractory periods of the A-V node. Tolamolol did not affect His-Purkinje conduction time in any patient, including 3 subjects who manifested prolonged H-V intervals during control studies (Table II). This latter observation is consistent with the findings in most previous reports in which it has been shown that conduction in the HPS is insensitive to adrenergic stimulation or blockade.“‘-‘” In addition, no consistent or significant effects on atria1 and ventricular refractoriness were observed. Because of the increase in A-V nodal conduction time and refractoriness induced by tolamolol, the HPS was, in a sense, “protected” by the drug. Thus, conduction delay or block within the A-V node consistently precluded assessmentof the relative and effective refractory periods of the HPS by preventing attainment of critically short H,H, intervals after tolamolol. A similar situation existed in previous studies with propranolol” and digoxin.” The findings in this study are in close agreement with preliminary observations in open-chest dogs which demonstrated a 20 per cent increase in
763
Ruskin
et al.
the P-R interval and a 10 per cent increase in the FRP of the A-V node after tolamolol (0.3 to 0.4 mg./Kg. intravenously). 28 In addition, the study reported no effect on conduction or excitability within the HPS, and a tenfold or greater increase in ventricular fibrillation threshold after tolamo101.= The electrophysiologic effects observed after the administration of tolamolol were qualitatively identical to those previously observed with propranolol in this laboratory.24 The fact that the drugs were evaluated in different patient populations precludes any valid comparison with regard to relative potency of the two agents in altering various properties of the cardiac conduction system. No consistent relationship between the effects of tolamolol on antegrade and retrograde conduction was observed in this study. Propranolo1 has been reported to have a greater effect on retrograde than on antegrade A-V nodal conduction and refractoriness in dogs.29 In this study, complete V-A block without antegrade block was observed in 1 patient (No. 13) after tolamolol, whereas consistent V-A conduction was present at all ventricular paced rates during control studies. A similar phenomenon after propranolol has been reported in man.3o The effect of incremental doses of tolamolol on sinus cycle length reached a peak at or near a dose of 10 mg. in the 5 patients studied. At higher doses, little or no additional depression of resting sinus rate was observed. No statement can be made, however, with regard to the possible effect of larger doses of tolamolol on ambulatory heart rate or exercise-induced tachycardia. There appeared to be a trend in both groups of patients toward greater degrees of sinus slowing in subjects with faster resting sinus rates, regardless of the dose of tolamolol administered. This may reflect a relationship between the degree of sympathetic tone and the magnitude of sinus depression produced by tolamolol. Further studies are necessary to properly assess the significance of this relationship. Atropine (0.5 or 1.0 mg. intravenously) reversed the effects of tolamolol on the sinoatrial node and A-V conducting system. The observed effects of atropine on automaticity, conduction, and refractoriness have been described previously31-34 and are thought to result primarily from parasympatholytic activity in this dose range.“5 The possi-
764
bility that tolamolol possesses vagomimetic as well as beta-adrenergic blocking properties cannot be excluded. However, it seems more likely that the electrophysiologic effects of tolamolol and atropine are dissociated and result from distinct action on separate parts of the autonomic nervous system. The changes observed after atropine in this study are consistent with the elimination of a normal degree of resting vagal tone by the drug. These observations suggest that atropine could serve as an effective alternative to isoproterenol in reversing the effects of tolamolol on the electrophysiologic properties of the sinus and A-V nodes. None of the patients in this study was receiving digitalis at the time of catheterization. We have subsequently used tolamolol (10 mg. intravenously) in 2 patients with atria1 fibrillation in whom the ventricular response was inadequately controlled with digoxin alone. The combination of tolamolol and digoxin produced effective slowing of the ventricular response in both patients. In conclusion, tolamolol is a potent betaadrenergic blocking agent which produces moderate depression of sinus node automaticity and significant prolongation of A-V nodal conduction time and refractoriness. These latter properties explain the efficacy of the drug in controlling the ventricular response in patients with atria1 flutter or fibrillation, and in the termination of A-V nodal reentrant supraventricular tachycardias.“. lo The lack of effect on HPS conduction time renders the drug safe in patients with infra-His bundle conduction disturbances. Summary
The electrophysiologic effects of tolamolol (UK-6558-Ol), a beta-adrenergic blocking agent, were studied in 13 patients by means of intracardiac electrograms and the extrastimulus method. Tolamolol(4 to 30 mg. intravenously) resulted in: (1) prolongation of sinus cycle length (SCL) in all patients (p C 0.01); (2) prolongation of sinus escape time (SET) in 11 of 13 patients (p < 0.001); (3) prolongation of A-V nodal conduction time during sinus rhythm in 12 of 13 patients (p < 0.001); (4) onset of A-V nodal Wenckebach block at longer paced cycle lengths in 10 of 11 patients (p < 0.001); (5) prolongation of the functional refractory period (FRP) of the
December,
1975, Vol. 90, No. 6
Electrophysiologic
A-V node in 11 of 11 patients (p < 0.001); and (6) prolongation of the effective refractory period (ERP) of the A-V node in 10 of 10 patients (P < 0.001). Tolamolol had no effect on HisPurkinje system (HPS) conduction time in any patient, including 3 patients with abnormal H-V intervals. Because of the marked increase in A-V nodal conduction time encountered by premature atria1 depolarizations, the relative and effective refractory periods of the HPS could not be determined in any patient after tolamolol. Atropine (0.5 or 1.0 mg. intravenously) significantly reversed the effects of tolamolol on: sinus cycle length (4 of 5 patients); sinus escape time (3 of 3 patients); A-V nodal conduction time (4 of 5 patients); and A-V nodal refractoriness (5 of 5 patients).
11.
12.
13.
14.
15.
16.
17. We wish to acknowledge the assistance David Berr,v, and Anne Mazzella.
of Mary
Vecchione,
18.
REFERENCES 1.
2. 3.
4.
I5
6.
7.
8.
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10.
Adam, K. R., Pullman, L. G., and Scholfield, P. C.: Isoprenaline and exercise-induced tachycardia in the assessment of beta-adrenoreceptor blocking drugs; a comparison between tolamolol, practolol and proprano101, Br. J. Pharmacol. 49:560, 1973. Pfizer Central Research: Investigator’s Brochure UK6558-01, 1971. Adam, K. R., Baird, J. R. C., Burges, R. A., and Linnell, J.: The beta blocking potency and cardioselectivity of tolamolol and its isomers in rodents, Eur. J. Pharmacol. 25:170. 1974. Briant, R. H., Dollery, C. T., Fenyvest, T., and George, C. F.: Assessment of selective beta adrenoreceptor blockade in man, Br. J. Pbarmacol. 49:106, 1973. Hillis, W. S., Hutton, I., Lawrie, T. D. V., Lorimer, A. R., and Reid, J. M.: The effect of a new beta-adrenoreceptor blocking compound, tolamolol, on haemodynamics and myocardial function in man, Br. J. Pharmacol. In press. Denes, P., Anastacio, R., and Goldbarg, A. N.: Effects of placebo and beta blockade on two exercise protocols in angina pectoris, (Abst.) Circulation (Suppl. II), 45, 1972. Sood, N. K., and Havard, C. W. H.: Effects of a new cardioselective beta-adrenergic blocker (tolamolol) on exercise tolerance in patients with angina pectoris, Thorax 28:331, 1973. Kappenberger, L., Fellman, H., and Nager, F.: Therapy of angina pectoris with beta blockers and isosorbiddinitrate in slow-release form. Schweiz. Med. Wochenschr. 103:1789, 1973. Aronow, W. S., Harding, P. R., Nelson, W. H., Vangrow, J. S., Johnson, L. L., and Khursheed, M.: Treatment of arrhythmias with tolamolol. Clin. Pharmacol. Ther. 13:856, 1972. Aronow, W. S., Johnson, L. L., Vangrow, J. S., Nelson, W. H., Kursheed, M., and Harding, P. R.: Treatment of acute arrhythmias with orally administered tolamolol, Chest 63:917, 1973.
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t$ect,s of tolcrmolol
Scherlag, B. J., Lau, S. H., Helfant, Ii. H., Stein, E., Berkowitz, W. D., and Damato, A. N.: Catheter technique for recording His bundle activity in man, Circulation 39:13, 1969. Krayer, O., Mandoki, J. J., and Mendez. C.: Studies on veratrum alkaloids. XVI. The action of epinephrine and of veratramine on the functional refractory period of the atrioventricular transmission in the heart-lung preparation of the dog, J. Pharmacol. Exper. Ther. 103:412, 1951. Goldreyer, B. N., and Bigger, J. T.: Spontaneous and induced reentrant tachycardia, Ann. Inttsrn. Med. 70:87, 1969. Mandel, W., Hayakawa, H., Danzig, R.. and Marcus, H. S.: Evaluation of sinoatrial node function in man by overdrive suppression, Circulation 44:59. 1971. Wit, A. L., Weiss, M. B., Berkowitz, W. D., Rosen, K. M., Steiner, C., and Damato, A. N.: Patterns of atrioventricular conduction in the human heart. Cirr. Res. 27:345, 1970. Josephson, M. E., Caracta, A. R., Lau, S. H., Gallagher, cJ. J., and Damato, A. N.: Effects of lidocaine on refractory periods in man, Am. Heart J. 84:778. 1972. Akhtar, M., Damato, A. N., Caracta, A. R., Batsford, W. P., and Lau, S. H.: The gap phenomena during retrograde conduction in man. Cimulation 49:811, 1974. Castillo, C. A., and Castellanos, A., Jr.: Retrograde activation of the His bundle during intermittent paired ventricular stimulation in the human heart, Circulation 42:1079, 1970. Denes, P., Wu, D., Dhingra, R.. Pietras. R. H., and Rosen, K. M.: The effects of cycle length on cardiac refractory periods in man, Circulation 49:32, 1974. Priola, D. V.: Effects of beta receptor stimulation and blockade on A-V nodal and bundle branch conduction in the canine heart, Am. J. Cardiol. 31:35, 1973. Berkowitz, W. D., Wit, A. L., Lau, S. H., Steiner, C., and Damato, A. N.: The effects of propranolol on cardiac conduction, Circulation 40855, 1969. Smithen. C. S.. Balcon. , R.. and Sowton. E.: Use of bundle of His potentials to assess changes in atrioventricular conduction produced by a series of beta-adrenergic blocking agents. Br. Heart J. 33:955, 1971. Damato. A. N.. Lau. S. H.. Helfant.. R. H.. Stein. E.. Berkowitz, W. D., and Cohen, S. I.: Stidy of atrioventricular conduction in man using electrode catheter recordings of His bundle activity, Circulation 39:287, 1969. Seides, S. F., Josephson, R. E., Batsford, W. P., Weisfogel, G. M., Lau, S. H., and Damato, A. N.: The electrophysiology of propranolol in man, Am. Heart d. 88:733, 1974. Vargas, G., Akhtar, M., and Damato, A. N .: Electrophysiological effects of isoproterenol on the cardiac conduction system in man. In press. Dhingra, R. C., Winslow, E., Pouget, J. M.. Rahimtoola, S. H., and Rosen, K. M.: The effect of isoproterenol on atrioventricular and intraventricular conduction, Am. .J. Cardiol. 32:629, 1973. Pryzybyla, A. C., Paulay, K. P., St.ein, E.. and Damato, A. N.: Effects of digoxin on atrioventricular conduction patterns in man, Am. J. Cardiol. 33:344. 1974. Svenson. R. M.. Gambetta. M.. and Childers, R.: Antifibrillatory and electrophysiologic effects of UK-6558-01, a new beta adrenergic blocking agent, i Abst.) Chest 62:379, 1972. Zipes, D. P., Cobb, F. R., and Wallace, A. G.: Differential effects of propranolol on antegrade and retrograde
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31.
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conduction and refractoriness of the A-V node, (Abst.) Circulation (Suppl. VI) 38:212, 1968. Maytin, O., Castillo, C. A., and Castellanos, A.: Complete V-A block (without impairment of forward conduction) produced by propranolol, Am. J. Cardiol. 27:687, 1971. Averill, K. H., and Lamb, L. E.: Less commonly recognized actions of atropine, Am. J. Med. Sci. 237:304, 1959. Dauchot, P., and Gravenstein, J. S.: Effects of atropine on the electrogram in different age groups, Clin. Pharmacol. Ther. 12:274, 1971. Linhart, J. W., Braunwald, E., and Ross, J., Jr.: Deter-
34.
35.
minants of the duration of the refractory period of the atrioventricular nodal system in man, J. Clin. Invest. 44:883, 1965. Akhtar, M., Damato, A. N., Caracta, A. R., Batsford, W. P., Josephson, M. E., and Lau, S. H.: Electrophysiologic effects of atropine on atrioventricular conduction studied by His bundle electrogram, Am. J. Cardiol. 33:333, 1974. Goodman, L. S., and Gilman, A.: Antimuscarinic or atropinic drugs. The Pharmacologic Basis of Therapeutics, New York, 1970, Macmillan Publishing Co., Inc., p. 530.
December,
1975,
Vol.
90, No.
6
effects conduction
of tolamolol in man
on
N. Ruskin, M.D. R. Caracta, M.D. Akhtar, M.D. P. Batsford, M.D. N. Damato, M.D.
Staten Island, N. Y.
Tolamolol is a beta-adrenergic blocking agent with the following chemical designation: 4- [2(hydroxy-3-0-toloyloxy-propylamino) ethoxy] benzamide-hydrochloride. The drug is an effective antagonist of isoproterenol-induced tachycardia and has been shown to be equipotent to propranolol and fifty times more potent than proctolol in antagonizing exercise-induced tachycardia in animals.‘, 2 Like proctolol, tolamolol has been shown to possess considerable selectivity for cardiac tissue in experimental animals** 3 and in man.“. 4 In experiments on papillary muscle and guinea pig atria, tolamolol demonstrated condiserably less cardiac depressant activity than equivalent doses of propranolo12 Although preliminary hemodynamic studies in man have demonstrated some negative inotropic effect with intravenous tolamolol,” controlled comparisons with equivalent doses of propranolo have not been carried out in man. Recent work has suggested that tolamolol may be as effective as propranolol in the treatment of angina pectoris,6-8 and, in addition, is effective in the treatment of a variety of supraventricular tachyarrhythmias and certain digitalis-induced arrhythmias.“. lo The purpose of this study was to evaluate the effects of tolamolol on the electrophysiologic properties of the S-A node, A-V node, and HisFrom the Cardiopulmonary Service Hospital, Staten
Laboratory, Island, N. Y.
Received
Oct. 21, 1974.
for publication
Reprint requests: Jeremy N. Ruskin, tory. United States Public Health N. Y. 10304.
December,
United
M.D., Service
States
Public
Health
Cardiopulmonary Hospital, Staten
LaboraIsland,
1975, Vol. 90, No. 6, pp. 755-766
Purkinje system in man, by means of intracardiac electrograms and the extrastimulus method. Materials
and methods
Thirteen patients underwent right heart catheterization in the nonsedated, postabsorptive state after informed consent had been obtained. They were studied for known or suspected disorders of cardiac rhythm or conduction. All patients were in sinus rhythm, and no patient had received cardioactive medication for at least 1 week prior to the time of catheterization. With the use of local anesthesia, a quadripolar catheter was percutaneously introduced into an antecubital vein and, under fluorscopic guidance, positioned against the lateral wall of the high right atrium. The distal two electrodes were used for atria1 pacing, and the proximal two electrodes for recording a high right atria1 electrogram. A tripolar catheter was percutaneously introduced into the femoral vein and positioned across the tricuspid value to record electrical activity from the bundle of His, as previously described.” A bipolar pacing catheter was percutaneously introduced into another arm vein and positioned at the right ventricular apex for ventricular stimulation. Atria1 pacing was performed with a programmed digital stimulator which delivered rectangular impulses of 15msec. duration at twice diastolic threshold. Ventricular pacing was carried out in a similar manner, with the lowest milliamperage that permitted reliable ventricular capture. Studies of the refractory period were performed by the extrastimulus method.“, I3 Studies of sinus node suppression
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Heart Journal
755
Ruskin et al.
were carried out by pacing the right atrium for 1 minute at each of 4 fixed cycle lengths (600, 550, 500, and 460 msec.).14 Sinus node escape time was then measured (see definition of terms) after cessation of pacing at each cycle length. Intracardiac electrograms, standard ECG Leads I, II, III, and V,, and time lines generated at intervals of 10 and 100 msec. were simultaneously displayed on a multichannel oscilloscope and recorded on magnetic tape. Recordings were subsequently reproduced on photographic paper at a speed of 150 mm. per second. Care was taken to insure adequate grounding of all equipment. After completion of control studies, tolamolol was infused intravenously at a rate of 4 mg. per minute, with the total dose ranging from 4 to 30 mg. (mean, 17 mg. or 0.24 mg./Kg.). Because of the experimental nature of the drug, incremental doses were administered to the 13 patients studied. Repeat electrophysiologic studies were initiated 5 minutes after infusion of the drug and completed within 45 minutes. Five patients subsequently received a small dose (0.5 or 1.0 mg.) of intravenous atropine 45 minutes after receiving tolamolol. Repeat electrophysiologic studies were initiated 2 minutes after the administration of atropine and completed within 20 minutes. Heart rate and supine blood pressures were carefully monitored throughout each study. Results were analyzed by means of the Student’s t test for paired data. In addition, a separate group of 5 patients was studied in the supine resting position in order to evaluate the effects of incremental doses of tolamolol on sinus rate. Three subjects had mild hypertension controlled with diuretics, and 2 had arteriosclerotic heart disease. All cardioactive medications were discontinued at least 1 week prior to the time of study, and none of the patients had evidence of congestive heart failure, atria1 arrhythmias, or sinus node dysfunction. A slow intravenous drip of 5 per cent dextrose in water was started in’ each patient, and a 30minute control period was observed. Tolamolol was then administered intravenously as a 2-mg. bolus every 10 minutes up to a total dose of 20 mg. Heart rate was monitored by standard ECG (Lead II) recorded at 5-minute intervals during the control period and at intervals of 1,5, and 10 minutes after each 2-mg. bolus of tolamolol. Blood pressure was simultaneously monitored
766
with a sphygmomanometer. Control sinus cycle length was calculated as the average of 20 consecutive sinus beats recorded 1 minute prior to the administration of tolamolol. Sinus cycle length for each incremental dose of tolamolol was calculated as the average of 20 consecutive sinus beats recorded 5 minutes after each 2-mg. injection. Definition
of terms
S,, A,, H,, V, represent the stimulus artifact, atria1 electrogram, His bundle electrogram, and ventricular electrogram of the basic drive beat. S,, A,, HP, V2 represent the stimulus artifact, atria1 electrogram, His bundle electrogram, and ventricular electrogram of the premature beat. A - V nodal conduction time is approximated by the A-H interval, which is measured from the onset of the low right atria1 electrogram to the onset of the His bundle deflection (normal values for this laboratory, 60 to 140 msec.). His-Purkinje conduction time is approximated by the H-V interval, which is measured from the onset of the His bundle deflection to the onset of ventricular activation (normal values for this laboratory, 30 to 55 msec.). Sinus escape time (SET) is defined as the interval between the last paced atria1 beat and the first sinus escape beat as verified by P-wave morphology and a high to low atria1 activation sequence and was measured from the high right atria1 electrogram recordings. Effective refractory period (ERP) of the atrium is defined as the longest S,S, interval at which S, fails to depolarize the atrium. Effective refractory period of the A-V node is defined as the longest A,A, interval at which A, fails to depolarize the His bundle. Functional refractory period (FRP) of the A-V node is defined as the shortest H,H, interval that results from any A,A,, provided that A-V conduction is not limited by atria1 refractoriness. ERP of the His-Purkinje system (HPS) is defined as the longest H,H, interval at which H, fails to conduct to the ventricles. Relative refractory period (RRP) of the HPS is the longest H,H, at which H, conducts to the ventricles with a longer H-V interval than that of the basic drive beat or with a QRS of aberrant configuration. The limitations of this definition have been discussed previously.‘“* I6 ERP of the ventricle is defined as the longest
December, 1975,Vol. 90, No. 6
Electrophysiologic
Table
I. Clinical
2
75 62
M M
3 4
61 66
M M
5 6
59 67
M M
7 8 9
56 56 69
M F M
10 11
56 58
M M
12
24
F
13
25
M
1
(MSEC)
700 2
4
DOSE
8 OF
I3
10
11
TOLAMOLOL
14
lb
18
sb
hf%)
Fig. I, The effect of incremental doses of tolamolol on sinus rate (5 patients). Sinus cycle length (msec.) is plotted as a function of the cumulative dose of tolamolol administered. Little or no additional prolongation of sinus cycle length occurred as the total dose exceeded 10 mg. intravenously.
S,S, interval at which S, fails to depolarize the ventricle during ventricular stimulation. Ventriculo-atria1 (V-A) conduction time is defined as the interval from the stimulus artifact to the onset of the low right atria1 electrogram as observed during right ventricular pacing.” In these patients, latency between the stimulus artifact and the onset of ventricular activation as seen on standard ECG was not observed. Criteria for retrograde conduction and activation of the atria have been described previously.‘s Retrograde ERP of the A-V node is defined as the longest S,H, interval at which the retrograde His bundle deflection of the premature beat (H,) is not followed by retrograde atria1 depolarization. Because the retrograde His bundle deflection of the basic drive beat (H,) is usually obscured by the ventricular electrogram (V,), and because the S,H, interval usually remains constant,” S,H, may be used in place of the H,H, interval in retrograde studies in man. Results Dose-response studies (Fig. 1). Maximal longation of sinus cycle length (SCL) by molol occurred after a total dose of 8 mg. in patients, 10 mg. in 1 patient, and 14 mg. patient. Subsequent 2-mg. increments of
American
Heart
Journal
protola3 of 5 in 1 tola-
effects of tolamolol
data and drugs administered
ASHD (VPBs) ASHD (LBBB, VPBs) ASHD (VPBs) ASHD (RBBBI LAD and 1” AVB) ASHD (LBBB) ASHD (ASMI, VPBs) HHD (LVH) NHD (RBBB) ASHD (DMI, VPBs) WPW-A Mitral prolapse (VPBs) Mitral prolapse (STTW Ab) NHD (Normal)
12 (0.151 8 (0 11)
IO 0.5
12 (0.16) 16 10 “3)
0 1
20 (0.21) 30 (0.45, 20 (0.27)
0
20 (0.28) 30 (0.53)
0 1
16 (0.27)
0
25 (0.34)
0
1 1
‘Numbers do not designate the temporal sequence in which patients were studied. Abbreviations: ASHD = arteriosclerotic heart disease; HHD = hypertensive heart disease; NHD = no heart disease; LBBB = left bundle branch block; RBBB = right bundle branch block; LAD = left axis deviation; 1” AVB = first-degree A-V block; WPW-A = WolffParkinson-White syndrome-type A; VPBs = ventricular premature beats; ASMI = anteroseptal myocardial infarction; DMI = diaphragmatic myocardial infarction; LVH = left ventricular hypertrophy; STTW Ab = S-T and T-wave abnormalities.
molol up to a total dose of 20 mg. produced little or no additional sinus slowing in these patients (Fig. 1). The effect of each 2-mg. increment on sinus rate was maximal within 5 minutes after infusion of the drug. In all patients, nearly maximal prolongation of sinus cycle length ( > 75 per cent of peak SCL) persisted for at least 90 minutes, and significant sinus slowing ( > 50 per cent of peak SCL) persisted for at least 3 hours, after a total dose of 20 mg. of tolamolol. No significant changes in supine blood pressure were observed. Two patients experienced transient postural hypotension after completion of the study. All subsequent results pertain to the group of 13 patients studied with intracardiac electrograms. The essential clinical data for this group are presented in Table I. Sinus
node
Sinus
cycle length
function
(Table
II).
(SCL). Administration
of
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Ruskin et al.
II. Antegrade conduction studies and sinus escape times before and after tolamolol (msec.)
Table
Sinus cycle length Patient No.
Sinus
A-H interval
Before
After
Before
1 2 3 4 5
595 700 670 1,050 530
680 840 685 1,060 1,ooo
85 105 100 210 60
6 7 8 9 10
so0 800 760 760 830
990 850 780 820 850
80 115 90 so 90
11 12 13 Mean P value
960 1,140 560 700 670 740 752 +- 43 856 + 41 P < 0.01
Ill.
Refractory ERP
Patient No.
Before
1 2 3 4 5 6 7 8 9
260 245 285 320 260 290 300 300 240
10 11 12 13 Mean P value
$ 285 210 250 270 f 9
After
interval
escape time
PCL at onset Wenchebach
of
Before
After
Before
100 110 115 230 70
40 75 40 60 70
40 75 40 60 70
770 1,074 1,100 1,205 1,193
980 1,287 1,187 1,290 1,203
310 330 370 750 +
370 460 460 850 *
so 130 loo 120 so
55 50 45 55 t
55 50 45 55
1,120 954 1,170 1,004 947
1,124 1,034 1,170 1,280 1,090
430 300 460 370 *
460 500 460 500 *
45 50 40 52
45 50 40 52
so 100 so 100 70 so 98 k 10 111 f 10 P < 0.001
‘Wenckebach block not observed during atria1 pacing. tHis bundle deflection preceded by onset of ventricular PCL = paced cycle length.
Table
H-V
activation
t
After
1,184 1,277 854 944 760 1,m 1,025 + 43 1,143 + 34 P < 0.001
Before
After
370 460 300 400 330 430 392 f 38 486 k 38 P < 0.001
(WPW).
period data before and after tolamolol (msec.) ERP
of atrium* After 250 265 255 280 275 280 260 295 240 $ 270 210 270 263 + 6 P > 0.1
of A-V
node*
FRP
Before
After
Before
t 280 330 600 t 365 375 385 295
320 350 380 620 t 430 395 420 420
330 395 485 770
$ $ 350 435 220 260 260 340 346 _’ 32 405 -c 29 P < 0.001
t 453 515 463 430 $ 430 373 370 455 5
of A-V
node*
ERP
After
Before
380 468 518 810 t 500 553 483 575 t 510 433 440 35 515 * 33 P < 0.001
of ventricle* After
300 220
280 240
250
230
256 -+ 23 250 f 15 P > 0.1
*Each value represents an average of results obtained at multiple comparable cycle lengths (see Results). tElectrophysiologic studies limited by atria1 refractoriness. SElectrophysiologic studies limited by induction of atria1 fibrillation during atria1 vulnerable period.
tolamolol resulted in prolongation of SCL in all patients (mean + 104 msec., p < 0.01). This corresponds to a 14 per cent increase in SCL or a mean decrease in heart rate of 10 beats per minute. The effects of tolamolol on SCL are presented in Table II. Sinus escape time (SET). Administration of
758
tolamolol resulted in prolongation of SET in 11 of 13 patients, and no change in 2 patients (mean + 118 msec., p < 0.001). Sinus escape times presented in Tables II and IV represent an average of values determined at 4 comparable cycle lengths (460, 500, 550, and 600 msec.) for each patient. When average escape times were
December,
1975,
Vol. 90, No. 6
Electrophysiologic
effects of tolumolol
Fig. 2. Effect of tolamolol on effective refractory period of the A-V node (Patient No. 11). In all panels the basic atria1 cycle length is constant at 600 msec. In panel A (control) an atria1 premature depolarization (A,) coupled to basic drive beat (A,) at an interval of 390 msec. is conducted with an A,H, interval of 170 msec. Inpanel B the A,AI coupling interval is reduced to 380 msec., and the premature depolarization (A,) is blocked in the A-V node. This is the longest A,A, interval (380 msec.) at which A, fails to propagate to the HPS. thus defining the effective refractory period (ERP) of the A-V node during the control period. In panel C (after tolamolol :10 mg. intravenously) an atria1 premature depolarization (A,) coupled to the basic drive (A,) at an A,A, interval of 470 msec. is conducted with an A,H, interval of 260 msec. In panel D the A,A, coupling interval is reduced to 460 msec., and the premature depolarization (A,) is blocked in the A-V node, thus defining the ERP of this tissue after tolamolol. When panels B and D are compared, it is apparent that tolamolol has prolonged the ERP of the A-V node by 80 msec. The presence of a drug effect is further substantiated by an increase in A-V nodal conduction time during the basic drive beats (A,H,) from 120 msec. during control studies (panels A and B) to 155 msec’. after tolamolol (panels C and D).
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Heart Journal
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Ruskin
Table
et al.
IV. Effects of atropine
on tolamolol-induced
Sinus cycle kxgth Patient No. 4 6 7 9 11 Mean P value
c
T
1,050 900 800 760 960 8945 52
changes in antegrade
A-H interval A
1,060 960 990 680 850 700 820 820 1,140 860 9725 804+ 60 60 P < 0.05
C
TACTA
210 80
230 90
115 90 90 117 + 24
c 60 55
60 55
60 55
130 95 120 100 100 80 134 k 117 f 25 25 P < 0.05
50 55 45 53
50 55 45 53
50 55 45 53
(msec.)
Sinus escape time
H-V interval
220 90
conduction
T * *
Paced CL at onset of Wenckebach A
* *
C * *
954 1,034 830 1,004 1,280 1,034 1,184 1,277 1,155 1,047 f 1,197 -r- 1,006 -t 70 81 94 P < 0.005
750 430 300 370 370 444 -c 79
T
A
850 750 460 400 500 310 500 420 460 430 554 -c 462 +74 75 P < 0.05
*Sinus escape times not studied after z&opine. P values compare poet-atropine with poet-tolamolol values only. Abbreviations: C = control; T = tolamolol; A = atropine; CL = cycle length.
compared with results determined at any single cycle length, no significant difference in the magnitude of change was observed and the statistical significance achieved by these changes was the same. Antegrade
conduction
(Table
II).
A - Vnode. Administration of tolamolol resulted in a statistically significant increase in A-V nodal conduction time during sinus rhythm in 12 of 13 patients (mean + 13 msec., p < 0.001’). In 1 patient with WPW-type A pre-excitation there was no change in A-H interval after tolamolol. Onset of A-V nodal Wenckebach block during atria1 pacing occurred at longer paced cycle lengths in 10 of 11 patients and was unchanged in 1 patient (mean + 94 msec., p < 0.001). In 2 patients, Wenckebach block did not occur with rapid atria1 pacing before or after tolamolol. His-Purkinje system (HPS). Conduction time within the HPS remained unchanged in all patients after tolamolol, both during sinus rhythm and during rapid atria1 pacing. Tolamolol had no effect on HPS conduction time in 3 patients who demonstrated prolonged H-V intervals during control studies (Table II). Refractory period studies (Table Ill). Refractory period data presented in Tables III and V represent values which were averaged from results obtained at multiple comparable cycle lengths (range, 600 to 900 msec.) for each patient. In view of the known effect of cycle length on refractory periods,19 these data were compared with refractory period data determined at a single
760
cycle length (600 msec.) before and after tolamolol in 8 patients. There were no significant differences in the magnitude of the changes observed and no differences in the degree of statistical significance achieved by these changes when averaged data were compared with results obtained at a single cycle length in this group of patients. Atrium. Tolamolol exerted variable and statistically insignificant effects on the effective refractory period (ERP) of the atrium. This parameter was shortened in 7 patients, prolonged in 3 patients, and unchanged in 2 patients (mean-13 msec., p > 0.1). A-V node. Tolamolol prolonged the effective refractory period of the A-V node in 10 of 10 patients in whom this parameter could be measured (mean + 59 msec., p < 0.001). Fig. 2 illustrates prolongation of the ERP of the A-V node after tolamolol. Tolamolol significantly prolonged the functional refractory period (FRP) of the A-V node in 11 of 11 patients (mean + 60 msec., p < 0.001). His-Purkinje system. During control studies, the relative refractory period (RRP) of the HPS was reached in 4 patients, and the ERP of the HPS was reached in 1 patient. Because of the delay in A-V nodal conduction time and the marked increase in A-V nodal refractoriness induced by tolamolol, comparable H,H, intervals could not be attained in any patient after the drug. The effects of tolamolol on the A-V node thus prevented assessment of any possible effects
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Fig. 3. Effect of tolamolol on retrograde A-V nodal conduction and refractoriness (Patient No. 8). Pnnel A demonstrates control, and panels B and C demonstrate post-tolamolol retrograde refractory period studies. The right ventricle is paced at a basic cycle length (S,S,) of 600 msec., and premature ventricular beats (S:) are coupled to every eighth drive beat. The longest S,H, interval which fails to depolarize the atrium defines the retrograde ERP of the A-V node (see definitions). InpaneZA (control) a premature beat (S,) is delivered at a coupling intrrvxl of 320 msec., resulting in an S,H, interval of 440 msec. and a retrograde A-V nodal conduction time (H,A.) of IO5 msec. During control studies, progressively early premature ventricular beats continued to conduct retrogradely to the atria, and the retrograde ERP of the A-V node was not encountered. In panel B (after tolamolol), an S delivered at a coupling interval of 360 msec. results in an S,H, interval of 460 msec., thus arriving at the A-V node 20 msec. later than the S, displayed in panel A. Despite its later arrival and because of the effects of tolamolol. the premature beat in panel B encounters a longer retrograde A-V nodal conduction time (HIA, = 120 msec.) than the premature beat in panel A. Comparison of panels A and B thus confirms prolongation of retrograde A-V nodal conduction time by tolamolol in this patient. Inpanel C (after tolamolol) an S, introduced at a coupling interval of 350 msec. results in an S,H, interval of 450 msec. which fails to depolarize the atria (i.e., is blocked in the A-V node), thus defining the retrograde ERP of the A-V node. During control studies the shortest S,H, interval observed prior to the atria was observed. Tolamolol, to encountering the ERP of the ventricle was 415 msec., and conduction therefore, prolonged the retrograde ERP of the A-V node by more than 35 msec. in this patient, but the precise magnitude of prolongation could not be determined because of failure to reach the retrograde ERP of the A-V node during control studies.
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Fig. 4. Effect of atropine on the ERP of the A-V node (Patient No. 11). This patient received atropine (1.0 mg. intravenously) immediately after completion of electrophysiologic studies with tolamolol (30 mg. intravenously). The ERP of the A-V node was prolonged from 380 msec. during control studies to 460 msec. after tolamolol (see Fig. 2). At the same basic atria1 cycle length (600 msec.) after atropine, an atria1 premature depolarization, A,. introduced at a coupling interval (A,A;) of 380 msec. conducts with an AIH, interval of 170 msec. (panel A). In panel I3, the A,A, coupling interval is reduced to 370 msec., and A, is blocked in the A-V node, thus defining the ERP of this tissue after atropine. When compared with the ERP of the A-V node after tolamolol (460 msec.), as shown in Fig. 2 (panel D), it is apparent that atropine has shortened the ERP of the A-V node by 90 msec. The presence of a drug (atropine) effect is further substantiated by a decrease in A-V nodal conduction time during the basic drive beats A,H, from 155 msec. after tolamolol (Fig. 2,paneZs C and D) to 110 msec. after atropine @an&A and B above).
on the relative or effective refractory the HPS. Retrograde
periods of
studies.
Ventriculo-atria1 ( V-A) conduction time. Retrograde conduction studies were performed in 5 patients. In 2 patients (Nos. 1 and 5), V-A conduction time at comparable paced ventricular rates did not change after tolamolol, and retrograde A-V nodal Wenckebach block did not occur before or after the drug in either patient. In 2 patients (Nos. 4 and 8), V-A conduction time was prolonged at comparable paced rates (mean + 10 msec.), and retrograde A-V nodal Wenckebach block occurred at longer paced cycle lengths after tolamolol (mean + 180 msec.). Because of the few patients involved, these changes did not achieve statistical significance. In 1 patient (No. 13), consistent V-A conduction was observed during
762
control studies, whereas, after tolamolol, V-A dissociation was observed at all ventricular paced rates in spite of concomitant sinus deceleration. Retrograde ERP of the A-V node. Tolamolol caused insignificant prolongation (+ 10 msec.) of the retrograde ERP of the A-V node in 1 patient (No. 5) in whom this parameter could be determined at a comparable cycle length before and after the drug. In a second patient (No. 8), the retrograde ERP of the A-V node was not reached during control studies because this parameter was exceeded by the ERP of the ventricle. After tolamolol, the retrograde ERP of the A-V node was significantly prolonged and was, therefore, encountered prior to the ERP of the ventricle. Pig. 3 illustrates prolongation of V-A conduction time and prolongation of the retrograde ERP of the A-V node in this patient. In 2 additional
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Electrophysiologic
Table
V.
Effects of atropine on tolamolol-induced ERP of atrium*
Patient NO. 4 6 7 9 11 Mean P value
C 320 290 300 240 285 287 t 13
T
changes in refractory
periods (msec.)
ERP of A-V node* A
280 300 280 260 260 270 240 240 270 260 266 t 7 266 + 9 P > 0.1
c 600 365 375 295 350 397 k 52
T
effects of fol~molol
A
620 550 430 340 395 0.1). A small decrease in calculated mean blood pressure in the supine position was observed in 6 of 13 patients after tolamolol, and no change was seen in 7 of 13 patients (mean - 3 mm. Hg, p < 0.025). No untoward side effects were observed. Electrophysiologic bles IV and V).
studies
after
atropine
(Ta-
The following changes were observed in 5 patients who received atropine (0.5 or 1.0 mg. intravenously) immediately upon completion of electrophysiologic studies with tolamolol (data compare post-atropine with posttolamolol values for each parameter): (1) sinus cycle length shortened significantly in 4 of 5 patients (mean - 168 msec., p < 0.05); (2) sinus escape time shortened significantly in 3 of 3 patients (mean - 191 msec., p < 0.05); (3) A-V nodal conduction time during sinus rhythm decreased significantly in 4 of 5 patients (mean - 17 msec., p < 0.05); (4) HPS conduction time was unchanged in 5 of 5 patients; (5) the ERP of the atrium was not significantly altered in 5 of 5 patients; (6) the ERP and FRP of the
American
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A-V node shortened significantly in 5 of 5 patients (mean -87 and - 91 msec., respectively, p < 0.05). Fig. 4 illustrates the effect of atropine in shortening the ERP of the A-V node after this parameter was prolonged by tolamolol (see Fig. 2). Discussion
In this study, tolamolol, adminisbered to 13 patients in a dose range of 4 to 30 mg. intravenously, significantly prolonged spontaneous sinus cycle length, sinus escape time, -4-V nodal conduction time, and the effective and functional refractory periods of the A-V node. Tolamolol did not affect His-Purkinje conduction time in any patient, including 3 subjects who manifested prolonged H-V intervals during control studies (Table II). This latter observation is consistent with the findings in most previous reports in which it has been shown that conduction in the HPS is insensitive to adrenergic stimulation or blockade.“‘-‘” In addition, no consistent or significant effects on atria1 and ventricular refractoriness were observed. Because of the increase in A-V nodal conduction time and refractoriness induced by tolamolol, the HPS was, in a sense, “protected” by the drug. Thus, conduction delay or block within the A-V node consistently precluded assessmentof the relative and effective refractory periods of the HPS by preventing attainment of critically short H,H, intervals after tolamolol. A similar situation existed in previous studies with propranolol” and digoxin.” The findings in this study are in close agreement with preliminary observations in open-chest dogs which demonstrated a 20 per cent increase in
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et al.
the P-R interval and a 10 per cent increase in the FRP of the A-V node after tolamolol (0.3 to 0.4 mg./Kg. intravenously). 28 In addition, the study reported no effect on conduction or excitability within the HPS, and a tenfold or greater increase in ventricular fibrillation threshold after tolamo101.= The electrophysiologic effects observed after the administration of tolamolol were qualitatively identical to those previously observed with propranolol in this laboratory.24 The fact that the drugs were evaluated in different patient populations precludes any valid comparison with regard to relative potency of the two agents in altering various properties of the cardiac conduction system. No consistent relationship between the effects of tolamolol on antegrade and retrograde conduction was observed in this study. Propranolo1 has been reported to have a greater effect on retrograde than on antegrade A-V nodal conduction and refractoriness in dogs.29 In this study, complete V-A block without antegrade block was observed in 1 patient (No. 13) after tolamolol, whereas consistent V-A conduction was present at all ventricular paced rates during control studies. A similar phenomenon after propranolol has been reported in man.3o The effect of incremental doses of tolamolol on sinus cycle length reached a peak at or near a dose of 10 mg. in the 5 patients studied. At higher doses, little or no additional depression of resting sinus rate was observed. No statement can be made, however, with regard to the possible effect of larger doses of tolamolol on ambulatory heart rate or exercise-induced tachycardia. There appeared to be a trend in both groups of patients toward greater degrees of sinus slowing in subjects with faster resting sinus rates, regardless of the dose of tolamolol administered. This may reflect a relationship between the degree of sympathetic tone and the magnitude of sinus depression produced by tolamolol. Further studies are necessary to properly assess the significance of this relationship. Atropine (0.5 or 1.0 mg. intravenously) reversed the effects of tolamolol on the sinoatrial node and A-V conducting system. The observed effects of atropine on automaticity, conduction, and refractoriness have been described previously31-34 and are thought to result primarily from parasympatholytic activity in this dose range.“5 The possi-
764
bility that tolamolol possesses vagomimetic as well as beta-adrenergic blocking properties cannot be excluded. However, it seems more likely that the electrophysiologic effects of tolamolol and atropine are dissociated and result from distinct action on separate parts of the autonomic nervous system. The changes observed after atropine in this study are consistent with the elimination of a normal degree of resting vagal tone by the drug. These observations suggest that atropine could serve as an effective alternative to isoproterenol in reversing the effects of tolamolol on the electrophysiologic properties of the sinus and A-V nodes. None of the patients in this study was receiving digitalis at the time of catheterization. We have subsequently used tolamolol (10 mg. intravenously) in 2 patients with atria1 fibrillation in whom the ventricular response was inadequately controlled with digoxin alone. The combination of tolamolol and digoxin produced effective slowing of the ventricular response in both patients. In conclusion, tolamolol is a potent betaadrenergic blocking agent which produces moderate depression of sinus node automaticity and significant prolongation of A-V nodal conduction time and refractoriness. These latter properties explain the efficacy of the drug in controlling the ventricular response in patients with atria1 flutter or fibrillation, and in the termination of A-V nodal reentrant supraventricular tachycardias.“. lo The lack of effect on HPS conduction time renders the drug safe in patients with infra-His bundle conduction disturbances. Summary
The electrophysiologic effects of tolamolol (UK-6558-Ol), a beta-adrenergic blocking agent, were studied in 13 patients by means of intracardiac electrograms and the extrastimulus method. Tolamolol(4 to 30 mg. intravenously) resulted in: (1) prolongation of sinus cycle length (SCL) in all patients (p C 0.01); (2) prolongation of sinus escape time (SET) in 11 of 13 patients (p < 0.001); (3) prolongation of A-V nodal conduction time during sinus rhythm in 12 of 13 patients (p < 0.001); (4) onset of A-V nodal Wenckebach block at longer paced cycle lengths in 10 of 11 patients (p < 0.001); (5) prolongation of the functional refractory period (FRP) of the
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1975, Vol. 90, No. 6
Electrophysiologic
A-V node in 11 of 11 patients (p < 0.001); and (6) prolongation of the effective refractory period (ERP) of the A-V node in 10 of 10 patients (P < 0.001). Tolamolol had no effect on HisPurkinje system (HPS) conduction time in any patient, including 3 patients with abnormal H-V intervals. Because of the marked increase in A-V nodal conduction time encountered by premature atria1 depolarizations, the relative and effective refractory periods of the HPS could not be determined in any patient after tolamolol. Atropine (0.5 or 1.0 mg. intravenously) significantly reversed the effects of tolamolol on: sinus cycle length (4 of 5 patients); sinus escape time (3 of 3 patients); A-V nodal conduction time (4 of 5 patients); and A-V nodal refractoriness (5 of 5 patients).
11.
12.
13.
14.
15.
16.
17. We wish to acknowledge the assistance David Berr,v, and Anne Mazzella.
of Mary
Vecchione,
18.
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