Download Intrinsic sympathomimetic activity and the effects of beta

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J AM COLL CARDIOL
1983.1(6) 1442- 6
Intrinsic Sympathomimetic Activity and the Effects of Beta-Adrenergic
Blocking Drugs on Vulnerability to Ventricular Fibrillation
ERNST A. RAEDER , MD, RICHARD L. VERRIER, PhD, FACC, BERNARD LOWN , MD, FACC
Boston, Massachusetts
Beta-adrenergic blocking agents differ considerably in
their effects on myocardial excitable properties. The possibility that intrinsic sympathomimetic activity might
contribute to such differences has not been adequately
explored. This study examined the influence of intrinsic
sympathomimetic activity on the electrophysiologic effects of three agents with vary ing degr ees of such activity. Intravenous propranolol (0.5 mglkg), oxprenolol (0.5
mg/kg) and pind olol (0.05 mglkg) were administered in
16 anesthetized dogs. The effects of the drugs on ventr icular vulnera bility were studied over a 2 hour period.
A growing number of beta-ad renocep tor blocking drugs are
becoming avai la ble for the treat ment of cardiac arrhythmias
(1-5) . Whereas so me of these age nts have been dem onstrated to reduce myocard ial infarction and pre vent sudden
ca rdiac death , the mechani sm for the se actions remains undefined (2- 5). Individual age nts, how ever, differ con sidera bly with regard to their card ioselectivity, extra-adrenergic effects and intrinsic sympathomimetic activity (6-8) .
The latter is of particular impo rta nce in light of experimental
and clinical evidence strongly implicating sympathetic neural
traffic in the ge nesis of life-threaten ing arrhythmias (9- 11).
The deg ree to whic h part ial ago nist activ ity of beta-adrenergic blocki ng dru gs modul ates their antifibrillatory influence rema ins to be defined.
The objectives of the present study were to: I) exami ne
the effects of beta-adren ergic block ing agen ts with differin g
From the Cardiovascular Research Laboratones, Department of Nutrition. Harvard Schoo l of Public Health, and the Cardiovascular Division,
Departme nt of Medicine, Brigham and Women 's Hospual, Harvard Medical School, Boston, Massach usetts. Th is study was suppo rted in part by
Gra nts HL-07776 and HL-28387 from the National Heart , Lung, and Blood
Institute , Natio nal Institutes of Health, U.S Public Health Services, Bethesda, Mary land. Manuscript received Augu st 3 1, 1982, revised manuscnpt received Jan uary 3, 1983, accep ted Janua ry 5, 1983.
Address for reprints: Bernard Lown, MD, Professor of Card iology,
Department of Nutrition , Harv ard School of Public Health, 665 Huntington
Avenue , Boston, Massachusetts 021 15
© 1983 by the American College of Cardiology
Pr opranolol and oxprenolol raised the ventr icular fibrillation threshold by 42 and 56% , respectively. In contra st, pindolol resulted in an elevation of only 25 %. After
depletion of endogenous norepinephrine stores using reserpine, pindolol led to a decr ease of the ventricular
fibrillation threshold, which was reversed by propranolol. These data indicate that intrinsic sympathomimetic
activity of beta-adrenergic blocking agents substantially
alters their ultimate effect on myocardial excitable
properties.
degrees of parti al agonist activity on vulnerability to ventricular fibrillatio n, and 2) exp lore the ro le of intr insic sympathom imetic activ ity in ca techolami ne-depleted animals.
Methods
Experimental preparation. Th e investigations we re
carried out in 16 healthy adult mon grel dogs of either sex
weighin g between 8 and 22 kg. Th e animals were an esth etized with intravenous alpha -chloralose (100 mg/kg , 10%
weig ht in vo lume) and additio nal doses of 50 rng/kg were
given as required to maintain a co nsta nt level of anes thes ia .
Ventilation with a mixt ure of room air and 100% oxygen
was mai ntai ned by a cuffed endo trac hea l tube att ach ed to a
Har vard res pirator which was adj uste d to keep art erial pH
bet ween 7.35 and 7 .50 and parti al press ure of oxygen (Po 2 )
at greater than 90 mm Hg. A femo ra l artery and ve in were
can nulated with a polyeth ylene ca theter for art er ial blood
. sampling, blood pressure monitoring and drug administration.
Cardiac Testing
Electr ica l stimulation. Electrical stim ulatio n was accom plished through an intracavitary electrode sys tem co nsisting of a transvenous bipolar pac ing catheter (Medtronic
no . 58 19 platinum electrodes with an interelectrode distance
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of 1.5 em and a width of 3 mm) and an electrographic
recording catheter (4F semifloating bipolar temporary pacing catheter; USCI). The recording catheter was bound to
the pacing catheter with silk ligatures, approximately 3 cm
proximal to the tip of the latter, and positioned at the right
ventricular apex by way of a jugular vein. The current was
set at twice the value of the mid-diastolic threshold. The
distal pole of the pacemaker catheter was made cathodal
with reference to the proximal pole. Heart rate was maintained constant at 210 beats/min by right ventricular pacing
during all determinations. Testing impulses were generated
by a constant current Grass S 44 square wave pulse generator
(Grass Instrument Company) in conjunction with an optically isolated constant current source of our own manufacture. The constant current source used voltage-controlled
voltage-source circuitry to generate constant current pulses
directly proportional to the voltage input pulses. The output
of the device has a voltage compliance of 300 V direct
current. Current output of the optically isolated constant
current source can be verified by taking the voltage across
a variety of dummy load resistors (10 0 to 10 kO) and
employing Ohm's law. Current output, under actual operating conditions, can be verified by taking the voltage across
a small resistor (approximately 10 0) with an oscilloscope
equipped with a differential input amplifier and again using
Ohm's law. The timing of stimuli was controlled by a digital
timer with a crystal-controlled time base having an accuracy
of ± 0.01 % or better. Timing synchronization was from
the pacemaker stimulus. The stimulation system is equipped
with appropriate circuitry to inhibit the output of the pacemaker from I to 5 seconds after delivery of the test stimulus.
The test stimuli were delivered after every 10th to 15th paced
beat.
Determination of ventricular fibrillation thresholds,
mid-diastolic thresholds and the effective refractory period. Ventricular fibrillation thresholds were determined by
scanning electrical diastole in 5 ms intervals with constant
current cathodal pulses of 5 ms duration. Scanning began
at the boundary of the effective refractory period and terminated beyond the T wave. The current was increased in
2 rnA steps until ventricular fibrillation occurred. The lowest
stimulus strength necessary to elicit ventricular fibrillation
defined the ventricular fibrillation threshold. Defibrillation
was accomplished within 5 seconds by a direct current 200
to 300 W-s discharge from a Lown cardioverter and delivered through a pair of copper plates previously fastened to
the thorax.
The excitable properties of the heart were determined by
setting a test stimulus of 0.1 rnA intensity and 2 ms duration
in mid-diastole and increasing stimulus intensity in 0.1 rnA
steps until a propagated response was evoked. The minimal
current required to elicit this response defined the diastolic
threshold.
The refractory period was determined by scanning the
RR interval with a test impulse of 2 ms duration and 3, 5
and 7 rnA intensity. The longest R to stimulus interval that
did not result in a propagated response marked the refractory
period.
Between defibrillations and isoproterenol tests, the animals were allowed to recover for at least 5 minutes to avoid
undue adrenergic influences.
Experimental Interventions
Oxprenolol, propranolol and pindolol were selected for
two reasons. First, the dose necessary to elicit beta-adrenergic blockade is well below the membrane-stabilizing dose.
Second, these agents differ considerably in their intrinsic
beta-stimulating properties (1,7,8,12,13). Specifically, pindolol exerts strong beta-agonist effects, whereas oxprenolol
has only mild intrinsic sympathomimetic activity. Propranolol is devoid of beta-agonist effects.
Oxprenolol. This group comprised nine dogs that were
given oxprenolol, 0.5 mg/kg body weight intravenously.
Electrophysiologic determinations were initiated 20, 40,60,
80, 100 and 120 minutes after drug administration. At 30,
50, 70, 90 and 110 minutes, the effectiveness of beta-receptor blockade was tested by measuring peak increment in
heart rate and peak decrement in arterial blood pressure after
a bolus injection of isoproterenol, I jLg/kg.
Propranolol. The effects of propranolol, 0.5 mg/kg, were
studied in seven dogs. Three of these animals also underwent
testing with oxprenolol on the preceding day and four on
the following day. The study protocol was the same as for
oxprenolol.
Pindolol. In a group of seven dogs, we examined the
electrophysiologic effects of pindolol, 0.05 mg/kg. This
investigation was carried out in two steps. On day I, the
action of pindolol was studied adhering to the same protocol
for oxprenolol and propranolol. The second part of the investigation was designed to expose the intrinsic sympathomimetic activity of pindolol by pretreating the dogs with
reserpine, 0.3 mg/kg intramuscularly, which has been shown
to deplete endogenous catecholamine stores (14). After 24
hours, the electrophysiologic studies were repeated at 20,
40, 60 and 80 minutes after administration of pindolol. The
degree of beta-adrenergic blockade was determined at 30,
50 and 70 minutes as described. In four dogs, we attempted
to block the sympathomimetic activity of pindolol by administration of propranolol, 0.5 mg/kg, 90 minutes after the
animals had received pindolol. The measurements were then
repeated.
Statistical analysis. The data were analyzed by analysis
of covariance on an IBM 4341 computer using a General
Linear Models Procedure (Statistical Analysis System). Differences between drugs were estimated by computation of
the least square (LS) means and the probability values for
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J AM COLL CARDIOL
RAEDER ET AL
1983;1(6) : 1442-6
the null hypothesis (H") (LS mean [I] = LS mean [J]).
Data were normalized to percent change from control and
are reported as mean ± standard error of the mean.
100
< 0.02 VI. Control
Results
Suppression of isoproterenol-induced tachycardia.
All drugs achieved a comparable peak reduction in heart
rate response 30 minutes after test injections of isoproterenol, I J,Lg/kg. Oxprenolol reduced the tachycardia and hypotension by 78 and 80%, respectively. Similar results were
obtained using propranolol and pindolol (Fig. I). The betaadrenergic blocking action of oxprenolol and propranolol
gradually subsided over the course of the experiment, while
that of pindolol persisted after 90 minutes.
Effects on myocardial excitable properties in normal
animals. Mid-diastolic threshold. Oxprenolol raised the
excitability threshold to 43 ± 10% (probability [p] < 0.03)
and propranolol to 41 ± 8% (p < 0.02) above the control
value. Pindolol elevated the mid-diastolic threshold by 57
± 15% (p < 0.02), a value significantly different from that
induced by the other two agents (Fig. 2).
Effective refractory period. Administration of oxpren0101 and propranolol resulted in a comparableand significant
prolongation of ventricular refractoriness (8 ± 3 and 10 ±
2%, respectively; p < 0.001 versus control). By contrast,
pindolol shortened the refractory period duration by 4 ±
1% (p = 0.01 ; Fig. 3).
The maximal change of ventricular refractoriness indicated was obtained at stimulus intensities of 3 rnA (propranolol and pindolol) and 5 rnA (oxprenolol). However,
statistical analysis of differences between the drugs was
performed separately for each of the stimulus intensities
employed. At 3, 5 and 7 rnA, the difference between the
effects of oxprenolol and propranolol on the one hand and
pindolol on the other was highly significant (p < 0.0001).
Figure 1. Peak inhibition of isoproterenol-induced tachycardia by
oxprenolol, propranolol and pindolol in 16 normal dogs. The results indicate that these drugs produce comparable levels of betareceptor blockade.
~-::;:::I~'"
80
40
TIM E
pc 0.025
120
VI. Control
160
(minutes)
Figure 2. Effects of the beta-adrenergic blocking drugs on the
mid-diastolic threshold. The interrupted line in this and succeeding figures represents pindolol at a dose of 0.5 mg/kg.
The peak prolongation of the refractory period achieved by
oxprenolol was 7 ± 5%, as determined using a 3 rnA
stimulus intensity.
Ventricular fibrillation threshold . The vulnerable period
threshold was significantly elevated by all three drugs (oxprenolol +56 ± 26%; propranolol + 42 ± 15% and pindolol + 25 ± 8%). However, the effect of pindolol was
less than that of oxprenolol (p < 0.004; Fig. 4), and the
difference between propranolol and pindolol failed to achieve
significance (p = 0.115).
Effects on myocardial excitable properties in catecholamine-depleted dogs. In five dogs, reserpine, 0.3 mgt
kg intramuscularly, was administered to depleteendogenous
catecholamine stores in order to evaluate the effect of pindolo!'s intrinsic sympathomimetic activity on vulnerability.
The drug increased the mid-diastolic threshold by 20 ±
13% and shortened the refractory period duration by 10 ±
2%. The threshold for ventricular fibrillation was lowered
by 43 ± 10%. In four reserpinized dogs, propranolol, 0.5
Figure3. Influence of the beta-adrenergic blocking agents on the
effective refractory period of thecanine ventricle.
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J AM cou, CARDlOl
BETA BLOCKERS AND VENTRICULAR FIBRIllATION
1445
1983.1(6).1442-6
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Figure 4. Differential effect of oxprenolol, propranolol and pindolol on the ventricular fibrillation (VF) threshold.
rug/kg, was injected subsequently. All the electrophysiologic changes elicited by pindolol were reversed (Fig. 5).
Dlscussion
This study examined the effects of diverse beta-receptor
blocking agents administered in doses to achieve comparable degrees of beta-adrenergic blockade on myocardial
excitableproperties. Our results indicatethat the drugs differ
considerably in their electrophysiologic actions. Specifically, propranolol and oxprenolol prolong the effective refractory period, diminish cardiac excitability and raise the
threshold for ventricular fibrillation. In contrast, pindolol
shortens the duration of ventricular refractoriness and elevates the mid-diastolicthreshold. Most notably, these agents
differ in their effects on the ventricularfibrillation threshold.
In particular, propranolol and oxprenolol exert a greater
action on this electrophysiologic property than does pindolol.
Mechanisms. What, then, is the basis for these diverse
electrophysiologic effects? Although all the drugs employed
in this study are known to exert membrane effects, extraadrenergic mechanisms such as membrane stabilization are
an unlikely cause because the doses required to produce
membrane stabilization are considerably greater than those
we administered. Specifically, the concentration of propranolol required for producing membrane effects is 50 to
100 times higher than that associated with inhibition of
exercise- or isoproterenol-induced tachycardia (15-18). The
membrane-stabilizing activity of oxprenolol is approximately half that of propranolol (19). Pindolol also exerts a
relatively minor influence on membrane stability (20).
A second possible mechanism that may account for the
differing antifibrillatory actionsof the drugs relates to their
partialagonistactivity. To explorethis question, we focused
on pindolol, which possesses substantial intrinsic sympathomimetic activity. In catecholamine-depleted dogs, pindolol decreased rather than increased the ventricular fibril-
90
50
TIME
140
174
(minutll8)
Figure5. Influence of pindolol ontheventricular fibrillation (VF)
threshold in five catecholamine-depleted dogs. Note that propranolol reversed the pindolol-induced decrease in the fibrillation
thresholds.
lation threshold and produced further shortening rather than
prolongation of the refractory period. The pindolol-induced
reduction in the ventricular fibrillation threshold was abolished by subsequent beta-adrenergic receptor blockade with
propranolol. These observations suggest that intrinsic sympathomimetic activity has an adverse effect on pindolol's
overall influence on ventricular vulnerability.
Clinical implications. Our study demonstrates significant differences in the effects of beta-receptor blockers on
the excitable properties of the heart. This effect relates, at
least in part, to an influence of intrinsic sympathomimetic
activity, which is contingent on the prevailing level of adrenergic tone. This is most evident under conditions of low
sympathetic tone.
Our results indicate that intrinsic sympathomimetic activity may significantly alter the antifibrillatory influence of
beta-adrenergic blocking agents. It remains unknown, however, whether this principle also applies to patients at risk
for sudden cardiac death. Further clinical studies will be
required to answer this question which carries important
therapeutic implications .
We express our appreciation to Jean M. Young, James P. Kiely and Dr.
Joseph Melmanfor theircapabletechnical assistanceandto MarianCordaro
for preparationof the manuscript. We also thankElizabeth Allredfor advice
as statistical consultant.
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