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259
Original Contributions
Central 3-Adrenergic Mechanisms May
Modulate Ischemic Ventricular Fibrillation
in Pigs
Gerald W. Parker, Lloyd H. Michael, Craig J. Hartley,
James E. Skinner, and Mark L. Entman
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A central noradrenergic process may permit expression of the stress-related increase in cardiac
vulnerability to ventricular fibrillation (VF). Thus, the effect of central j8-adrenergic receptor
blockade with L-propranolol (0.01 and 0.05 mg/kg) on ischemia-induced VF vulnerability was
evaluated in the psychologically stressed pig model and compared with Ringer's solution and
D-propranolol (0.05 mg/kg). The ischemia of a maximum 15-minute left anterior descending
coronary artery occlusion was used since we previously determined that pigs surviving 15
minutes usually do not fibrillate. Time to the onset of VF was analyzed by time-to-event analysis
and ranged from 0.75 to 13.8 minutes in vulnerable pigs. Intracerebroventricular administration of L-propranolol (0.05 mg/kg) prolonged the time to VF compared with Ringer's solution
and D-propranolol (p<0.05). The high dose of L-propranolol also reduced the incidence of VF
(7/15 fibrillated) compared with Ringer's solution (12/12 fibrillated) and D-propranolol (6/7
fibrillated). The lower dose of L-propranolol was without effect on VF vulnerability (7/9
fibrillated). The plasma concentration resulting from central administration of 0.05 mg/kg
L-propranolol was found to be 9.05+±3.25 ng/ml, which is significantly below therapeutic
antiarrhythmic blood levels. We conclude that the reduced vulnerability to ischemia-induced
VF after intracerebroventricular administration of propranolol is due to alteration of a central
P-adrenergic receptor-mediated phenomenon as opposed to an effect on the heart directly or
to nonspecific membrane stabilization. (Circulation Research 1990;66:259-270)
V arious psychological risk factors have been
related epidemiologically to cardiac rhythm
disturbances in the presence and absence of
coronary artery disease.1-6 These rhythm disturbances include ventricular tachycardia and ventricular fibrillation (VF), the underlying mechanisms of
sudden cardiac death. Although some of the psychological stressors are clearly related to acute phasic
stress and imminent emotional distress accompanied
by hemodynamic alterations consistent with autonomic imbalance, many are related to more tonic
From the section of Cardiovascular Sciences (G.W.P., L.H.M.,
M.L.E., C.J.H.) and Division of Neurophysiology (J.E.S.), Departments of Medicine (G.W.P., L.H.M., M.L.E., C.J.H.), Physiology
(G.W.P., L.H.M., M.L.E., JE.S.), and Neurology (J.E.S.), Baylor
College of Medicine and the Methodist Hospital, Houston, Texas.
Supported by National Institutes of Health grants 1-PO1-HL31164-03 and 1-RO1-HL-23161-10.
Address for reprints: Mark L. Entman, MD, Section of Cardiovascular Sciences, Baylor College of Medicine, One Baylor Plaza,
Houston, TX 77030.
Address for correspondence: Gerald W. Parker, Pathophysiology Division, United States Army Medical Research Institute for
Infectious Diseases, Fort Detrick, Frederick, MD 21701.
Received August 23, 1988; accepted July 24, 1989.
psychosocial factors that are often imperceptible.1"5'7
Because the response may be temporally distant from
the provocative event, causality of central nervous
system-mediated arrhythmias associated with tonic
psychosocial stress in humans is often difficult to
discern.
Our laboratory has developed a unique pig model
of sudden cardiac death in which operationally
defined tonic psychological stress is associated with
the development of ischemia-induced VF. Specifically, lack of behavioral adaptation to the novel
laboratory environment is associated with the development of VF in most cases within 15 minutes after
occlusion of the left anterior descending (LAD)
coronary artery. Reduction of psychological stress by
behavioral adaptation to the laboratory (learned
adaptation), however, significantly reduces the vulnerability of the pig heart to ischemia-induced
fibrillation.8 Furthermore, cryogenic blockade of a
specific frontocortical brain stem pathway is also
effective in preventing VF.9 Despite the increased
vulnerability observed in the laboratory-unadapted
pig, there were no overt signs of stress nor differences
in basal heart rate in the unadapted compared with
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Circulation Research Vol 66, No 2, February 1990
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the adapted state.10 Together, these studies indicate
that specific cortical influences on the brain stem and
autonomic nervous system modulate myocardial vulnerability to ischemia-induced VF evoked by tonic
psychological stress associated with the novel laboratory environment.
The cerebral neurochemical mechanisms mediating
the increased myocardial vulnerability to psychological
stress are unknown. Several neurophysiological studies
have suggested a central catecholaminergic synaptic
mechanism associated with the cerebral response to
environmental stimuli. Central catecholaminergic mechanisms are associated with responses to new, noxious,
or meaningful stimuli that invoke event-related slow
potentials. The event-related slow potentials are characterized by slow membrane potential shifts caused by
inactivation of a specific potassium current and are
modulated by norepinephrine release and subsequent
stimulation of cyclic AMP formation.1112 Additionally, other experiments have suggested a relation
between ,3-adrenergic receptor stimulation and synaptic plasticity involved in neurophysiological models
of learning.13 Because the concept of environmental
stress implies cognition of meaningful stimuli, we
hypothesized that central noradrenergic 13-receptormediated mechanisms contribute to the cerebral
cortex's influence on autonomic regulation of the
heart, which in turn mediates increased sensitivity to
ischemia-induced VF.
The purpose of the present study was to evaluate
myocardial vulnerability to VF in the laboratoryunadapted psychologically stressed pig after central
,/-adrenergic receptor blockade. We demonstrate
that administration of L-propranolol into the lateral
cerebral ventricles exerts a specific potent effect on
vulnerability to ischemic VF.
Materials and Methods
Experimental Animal
Chronically instrumented, conscious Yorkshire-cross
pigs (20-25 kg) were used for the study. The pig was
selected for several reasons. First, since an individual's
response to psychological stressors is a factor contributing to the etiology of sudden cardiac death, it was
critical to select an animal model in which vulnerability
is similarly modulated by a behavioral response to
environmental stimuli. The pig represents an appropriate animal model since operationally defined psychological stressors are known to increase the vulnerability
of the pig heart to arrhythmogenesis.81415 Second,
since behavior is a variable in this study, which implies
that interpretive responses to sensory stimuli need to be
controlled, it was necessary to obtain experimental
animals having a uniform psychosocial background
and thus uniform behavioral response to the laboratory and personnel. Pigs were obtained from a single
agricultural source located near our facility. The pigs
were raised under identical conditions, transported
to our lab in the same vehicle, and housed in the
same environment during boarding and while in our
laboratory. In addition, it was often possible to obtain
littermates to serve as additional controls. A similar
constancy of experimental animals is not easily
obtained from other commonly used large animal
models. These two factors, a constant psychosocial
background and vulnerability to psychosocial stressors, made the pig an ideal model for the study.
Surgical Preparation
Pigs underwent aseptic brain cannula implantation
to facilitate drug infusion as well as left lateral
thoracotomy for implanting instrumentation. Anesthesia was induced with 15 mg/kg i.m. ketamine and
10 mg/kg i.v. methohexital. After tracheal intubation,
anesthesia was maintained with methoxyflurane and
oxygen. The pigs were ventilated with a tidal volume
of 10-20 ml/kg and a respiratory rate of 10-15
breaths/min by use of an oxygen-flushed anesthetic
machine and ventilator.
Two 25-gauge stainless steel spinal needles cut to a
length of 50 mm were implanted into the lateral
cerebral ventricles of the brain. One needle was
inserted into the left ventricle, and the second needle
was placed in the right ventricle. The needles were
implanted under stereotaxic control at a location 22.5
mm rostral to bregma. Each cannula was inserted to
depth of 21.5 mm so that the tip was positioned in the
anterior horn of the left and right lateral cerebral
ventricle. The needles were permanently secured to
the cranium by a cranial acrylic crown attached to the
skull with stainless steel screws. Cannula placement
in the cerebral ventricles was confirmed at autopsy by
observing fluorescein dye in the cerebrospinal fluid,
which had been injected into the cannula before
death. Placement was also confirmed histologically.
Thoracotomy in the fourth left intercostal space
exposed the pericardium, which was then opened.
The internal mammary artery was cannulated with
polyethylene tubing (PE-100) to facilitate arterial
blood gas analysis during surgery. One group of pigs
was instrumented for measurement of various hemodynamic indexes; a second group assigned to the
myocardial vulnerability protocol was instrumented
further with a hydraulically activated ligatureoccluding device capable of effecting reversible myocardial ischemia at a later time in the conscious
state.8 The occluder was positioned on the proximal
LAD coronary artery 1 cm distal to its bifurcation
with the circumflex coronary artery. A pulsed Doppler blood flow velocity probe was placed distal to the
occluder. Doppler ultrasonic wall-thickening probes
for evaluating regional myocardial function were
sutured to the epicardial surface in the region to be
rendered ischemic (anterior wall) as well as in the
nonischemic region (posterior wall) of the left ventricle. A high fidelity pressure transducer (model P7,
Konigsberg) was positioned in the chamber of the left
ventricle via a stab incision in the apex in those pigs
assigned to the hemodynamic protocol. Stainless
steel wire electrodes were sutured through the skin
on all four extremities for monitoring standard lead
Parker et al Central f3-Adrenergic Modulation of Ischemic VF
electrocardiograms. The distal end of the lead wires,
catheter, and occluder were exteriorized caudal to
the scapula and secured to the animal with a waterproof bandage. A chest tube was placed in the
thoracic cavity before closing the thoracotomy and
was removed postoperatively on evacuation of the
pneumothorax. The animals were allowed 7-10 days
postoperative recovery before beginning experimental manipulations. The animals were afebrile, eating
well, and gaining weight by this time.
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Behavioral Protocol
The behavioral response to experimental handling
of the pig is known to be a critical factor influencing
myocardial vulnerability to ischemia-induced VF.
Therefore, the psychological state of the animal was
experimentally controlled by providing consistent
care in handling of the animals. The pigs were
transported from their home cage in the vivarium to
the laboratory on a portable cart. Minimal restraint
was effected by taping the legs together in an
extended position. In the laboratory, the pigs were
placed in right lateral recumbency in a specially
designed study chamber. This exposure to the unfamiliar laboratory, in effect, constitutes a set of novel
stimuli that is associated with increased vulnerability to
ischemia-induced arrhythmias. Behavioral adaptation,
however, occurs after 6-8 daily experiences in the
laboratory, and VF no longer occurs during identical
ischemic insults.8 Thus, evaluation of VF latency after
central administration of propranolol in this study was
conducted in the laboratory-unadapted state, when pigs
are known to manifest VF within 15 minutes after LAD
coronary artery occlusion.
Experimental Protocol
Hemodynamic alterations as a function of laboratory
adaptation. Pigs were transported to the laboratory as
described above on a daily basis for 8 days to assess
hemodynamics as a function of laboratory adaptation. This was done to more fully evaluate hemodynamic status in this paradigm of tonic psychosocial
stress in the pig. The Konigsberg pressure transducer, previously calibrated in vitro, measured left
ventricular systolic and end-diastolic pressures. The
first derivative of left ventricular pressure (dP/dt) was
obtained by electronic differentiation. A triangular
wave signal with known rate of change was used to
provide direct calibration of the differentiator amplifier. A cardiotachometer triggered by the electrocardiogram provided instantaneous and continuous
record of heart rate. LAD coronary artery blood flow
velocity and regional myocardial wall thickening (left
ventricular systolic thickening fraction) were
recorded by their respective ultrasonic Doppler
probes.16-18 The initial onset of the upstroke of left
ventricular systolic pressure and peak negative dP/dt
were used for timing the beginning and end of systole
necessary for calculating systolic thickening fraction.
To minimize recent phasic stress-induced hemodynamic alterations associated with moving the pig
261
from the vivarium to the laboratory, data were not
collected for 30 minutes after arrival in the laboratory and attachment to the physiograph preamplifier
patient cables. Heart rate, left ventricular systolic
and end-diastolic pressure, maximum rate of left
ventricular pressure development, left ventricular
systolic wall thickening, and LAD coronary artery
blood flow were continuously recorded on an eightchannel recorder (Gould, Cleveland, Ohio). The
above indexes were measured three times at 10minute intervals while the pig was in a quiescent
state. Once it was determined that significant differences did not exist among the three measurements
(repeated analysis of variance, p=NS), the mean was
used to represent baseline hemodynamic status on a
given day in the laboratory.
Effect of centrally administered propranolol on
hemodynamics. These same pigs were then used to
evaluate the effect of centrally administered Lpropranolol on the chronotropic and inotropic state
of the heart. Once these baseline recordings had
been obtained, either 0.01 mg/kg L-propranolol or
Ringer's solution (vehicle control) was slowly infused
into the lateral cerebral ventricles via the brain
cannula. The volume administered was held constant
(250-300 ,ll) among the pigs and was given by slow
infusion over a 10-minute period. The presentation
of drug treatment was alternated with respect to
laboratory day exposure so that Ringer's solution was
given on lab days 1, 3, 5, and 7 and L-propranolol was
given on lab days 2, 4, 6, and 8. The data were initially
analyzed for propranolol-induced changes with
respect to the number of days of accrued laboratory
adaptation. The number of daily experiences in the
laboratory, however, was found not to be a factor in
the observed hemodynamic alterations. Thus, the
values from all the days within each drug treatment
were pooled. A separate set of pigs was similarly
instrumented and studied with a higher dose of
L-propranolol (0.05 mg/kg i.c.v.) and the dextrorotatory isomer, D-propranolol (0.05 mg/kg i.c.v.).
VF latency determinations. Initial handling of the
pigs and data collection were performed in an identical manner as described above. Once baseline
hemodynamic indexes were recorded, pigs were given
either 0.01 or 0.05 mg/kg L-propranolol, 0.05 mg/kg
D-propranolol, or Ringer's solution (vehicle control)
infused slowly into the lateral cerebral ventricles over
a 10-minute period. LAD coronary artery occlusion
was effected 10 minutes after completion of the drug
infusion. Completeness of coronary occlusion was
verified by the LAD blood flow velocity signal, electrocardiographically, and by observing paradoxical
left ventricular systolic wall thinning in the ischemic
region.19 The time to the development of VF (VF
latency) of a maximum 15-minute coronary artery
occlusion was determined. A maximum 15-minute
occlusion was selected because earlier studies demonstrated that VF will occur within 14 minutes after
complete occlusion of the LAD coronary artery in
unadapted pigs.8 Furthermore, adapted pigs not sus-
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Circulation Research Vol 66, No 2, February 1990
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ceptible to VF remained so for at least 24 hours.8
Thus a 15-minute occlusion provided sensitivity for
detecting antifibrillatory efficacy while minimizing
the occurrence of occlusion/reperfusion-associated
myocardial damage. If VF occurred, the occlusion
was released, and the animal was electroconverted
(200-250 Wsec extrathoracic shock) while unconscious. Reperfusion was also instituted if fibrillation
did not occur after 15 minutes of ischemia. Some pigs
were additionally used in a within-subject control
protocol. These pigs were used on a subsequent
occlusion trial only if recovery from occlusion/
reperfusion-induced regional myocardial dysfunction could be prospectively documented by the ischemic zone wall-thickening data and if animals were
free of electrocardiographic abnormalities. Gross,
histochemical (triphenyl tetrazolium chloride stain),
and histological examinations of the hearts were also
performed to confirm the prospective characterization of these pigs. In the within-subject experimental
design, presentation of drug treatment was randomized with respect to laboratory day exposure or
occlusion trial.
Pharmacokinetics of centrally administered propranolol. Cerebrospinal fluid and plasma levels of propranolol were determined at 5 and 10 minutes after intracerebral ventricular administration of 0.05 mg/kg Lpropranolol in a separate group of pigs. The samples
were obtained under anesthesia (ketamine, sodium
methohexital, and methoxyflurane) to facilitate cerebrospinal fluid collection at a site distant from drug
infusion. Otherwise, infusion of L-propranolol into the
right and left lateral cerebral ventricles was performed
in an identical manner as previously described for VF
latency determinations and hemodynamic evaluation.
Cerebrospinal fluid samples were obtained at the
level of the cisterna magna with a 20-gauge, 4-inch
spinal needle. Blood was simultaneously collected
from a femoral venous catheter. Intravenous infusion of 0.05 mg/kg L-propranolol via a lateral ear
vein was also performed in three pigs to allow
comparison of cerebroventricular versus intravenous administration. Plasma and cerebrospinal
fluid samples were stored at -70° C until analyzed.
Propranolol concentrations were determined by
high-performance liquid chromatography.20
Statistical Analysis
The time to the onset of VF subsequent to LAD
coronary artery occlusion (VF latency) was analyzed by
Kaplan-Meier time-to-event or survival-curve analysis
followed by Gehan's test of significance.21 Hemodynamic indexes within each treatment group and for
laboratory adaptation were analyzed by repeatedmeasure analysis of variance. When an overall treatment effect was detected, between-group analysis of
either percent change or absolute change from baseline
was used to isolate specific drug effects at individual
time points (analysis of variance followed by the Bonferroni multiple-comparison t test). The latter was
preceded by evaluating the homogeneity of baseline
values between the four treatment groups (analysis of
variance).22 Data are expressed as mean±+SD.
Results
VF Latency Determination
The latency to the onset of VF subsequent to
complete occlusion of the LAD coronary artery in the
psychologically unadapted pig was determined after
intracerebroventricular administration of 0.05 and
0.01 mg/kg L-propranolol, 0.05 mg/kg D-propranolol,
and Ringer's solution. Survival curve analysis revealed
that L-propranolol at a dose of 0.05 mg/kg was an
effective pharmacological intervention in prolonging
the time to the development of VF as well as reducing
the incidence of VF after acute occlusion of the LAD
coronary artery (Figure 1). Ischemia-induced VF
occurred in all 12 occlusion trials in the Ringer's
solution treatment group with VXF latencies ranging
from 0.75 to 12.5 minutes. L-Propranolol (0.05 mg/kg
i.c.v.), however, prolonged the time to VF compared
with Ringer's solution (p<0.01) and D-propranolol
(p<0.05). The incidence of ischemia-induced VF was
also reduced to 47% (7/15 fibrillated) compared with
Ringer's solution (12/12 fibrillated) and D-propranolol
(6/7 fibrillated). VF latencies in the vulnerable pigs
ranged from 1.5 to 13.8 minutes. There were no
significant differences between the lower dose Lpropranolol (7/9 fibrillated) and D-propranolol (6/7
fibrillated) treatment groups compared with the Ringer's group.
A within-subject experimental design was also used
to minimize between-subject variability.23 LPropranolol (0.05 mg/kg i.c.v.) prolonged the time to
the onset of VF compared with Ringer's solution and
D-propranolol in all cases (Figure 2). VF latencies
after randomized presentation of L-propranolol and
Ringer's solution were 12.72±1.42 and 6.18+1.42
minutes, respectively (p =0.016; one-tail paired t test).
A similar randomized presentation of L-propranolol
and D-propranolol resulted in VF latencies of
9.75+3.21 and 7.29±2.43 minutes (p=0.0432). In
these nine pigs in which experimental presentation of
drug treatment was randomized with respect to laboratory day exposure, only four (44%) developed VF
subsequent to LAD coronary artery occlusion after
central administration of 0.05 mg/kg L-propranolol.
Ischemia-induced VF occurred in all nine of those
same pigs after central administration of either Dpropranolol or Ringer's solution.
Hemodynamic Effect of Centrally
Administered Propranolol
Hemodynamics were also evaluated at 5, 10, 15, 20,
and 30 minutes after intracerebroventricular administration of 0.05 and 0.01 mg/kg L-propranolol, 0.05
mg/kg D-propranolol, and Ringer's solution (vehicle
control) in a separate group of pigs. Data for each
treatment are summarized in Table 1 and Figure 3
and indicate the following: 1) Baseline heart rate, left
ventricular systolic pressure, maximum left ventricu-
Parker et al Central f3-Adrenergic Modulation of Ischemic VF
263
FIGURE 1. Graph showing latency to the onset of
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
LL.
0
z
0
-'
.0
0
CL
ventricularfibrillation (VF) subsequent to complete
occlusion of the left anterior descending coronary
artery in the psychologically stressed pig. Pigs were
given either Ringer's solution (vehicle control), 0.05
mg/kg D-propranolol (d-P on figure), or 0.05 mg/kg
and 0.01 mg/kg L-propranolol (I-P on figure)
infused slowly into the lateral intracerebral ventricles
10 minutes before coronary artery occlusion. VF
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
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TIME (min)
lar dP/dt and dP/dt per developed pressure, and left
ventricular systolic wall thickening were similar
between the four treatment groups (p=NS by analysis of variance). 2) L-Propranolol (0.05 and 0.01 mg/
kg) induced a moderate decrease in heart rate,
maximum left ventricular dP/dt, and maximum left
ventricular dP/dt per developed pressure (p<0.0005
by repeated-measure analysis of variance). The peak
heart rate decrease after 0.05 mg/kg i.c.v. Lpropranolol was 27 beats/min and after 0.01 mg/kg
i.c.v. L-propranolol was 13 beats/min. The maximum
decrease in left ventricular dP/dt after 0.05 and 0.01
mg/kg i.c.v. L-propranolol was 19% and 16%, respec-
latencies for the treatment groups were analyzed by
the Kaplan-Meier survival curve analysis in which
estimated probabilities for not developing VF (ordinate) are plotted against time (abscissa). VF
occurred in all 12 occlusion trials in the Ringer's
treatment group and in six out of seven occlusion
trials in D-propranolol-treated pigs. VF latencies
ranged from 0. 75 to 12.5 minutes. L-Propranolol
(0.05 mg/kg), however, prolonged the time to VT
compared with both Ringer's solution ( p <0. 01) and
D-propranolol ( p<O.OS). The incidence of VT was
reduced to 47% (7/15 fibrillated) in the 0.05 mg/kg
L-propranolol-treated pigs. The lower dose of Lpropranolol and D-propranolol were not significantly
different from Ringer's solution. *p <0.05 compared
with Ringer's solution or D-propranolol.
tively. Maximum left ventricular dP/dt per developed
left ventricular systolic pressure achieved a maximum
decline from baseline of 16% and 13%. The above
hemodynamic effects were observed as early as 5
minutes after completion of drug infusion, but peak
responses were not achieved until 15-25 minutes in
individual animals. Between-group analysis of either
absolute change or percent change from baseline at
individual time points revealed a dose-dependent
L-propranolol effect on heart rate but not on maximum left ventricular dP/dt or dP/dt per developed
pressure (Figure 3). 3) L-Propranolol (0.05 mg/kg)
was associated with a slight reduction in systolic wall
FIGURE 2. Bar chart showing ventricular fibrillation (VF) latency in the psychologically stressed pig
subsequent to complete occlusion of the left anterior
descending coronary artery (within-subject experimental design). Pigs were given either 0.05 mg/kg
L-propranolol (1-prop on figure), 0. 05 mg/kg Dpropranolol (d-prop on figure), or Ringer's solution
infused slowly into the lateral intracerebral ventricles
10 minutes before coronary artery occlusion. Each
bar represents the VF latency of an individual pig.
Successive experiments in the same pig are connected by a common baseline. Drug treatments were
randomized with respect to laboratory day exposure
and paired within each animal. In these nine pigs,
only four (44%) given L-propranolol developed VF
5
0
M
I-prop
(o.OS mg/Kg)
10
VF LATENCY (min)
C
Cl
15
CDZ d-prop (0.05n
to left anterior descending coronary
artery occlusion. Ischemia-induced VF occurred in
all nine of these same pigs when given either Dpropranolol or Ringer's solution.
20 subsequent
e99)
--,
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Circulation Research Vol 66, No 2, Februaty 1990
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TABLE 1. Hemodynamic Response After Intracerebroventricular Administration of L-Propranolol, D-Propranolol, and Ringer's Solution
After drug administration
n
Baseline
5 min
10 min
15 min
20 min
30 min
p
Heart rate (beats/min)
L-Propranolol (0.05 mg/kg) 14 142.6±10.6
123.2±7.9
121.4±7.4
118.9±6.6
113.4+6.5
115.7±9.4
<0.0005
L-Propranolol (0.01 mg/kg) 16 130.1±19.6
124.3±23.5
120.6±20.3
118.9+19.3
116.7±18.3
117.2±18.7 <0.0005
D-Propranolol (0.05 mg/kg) 8 129.8±16.3
128.8±15.7
128.2+12.8
129.4+16.3
128.4±16.7
127.2±15.5
NS
Ringer's solution
14 131.3±17.9
132.2±22.9
129.4±18.0 126.4+19.8
129.4±18.0
132.6±20.2
NS
LVSP (mm Hg)
L-Propranolol (0.05 mg/kg) 9 112.1±8.17
107.1±6.9
107.8+7.4
107.5+6.2
108.1±5.5
109.2+4.8
NS
L-Propranolol (0.01 mg/kg) 16 103.2±5.6
100.8+7.1
101.2±7.9
101.5+7.2
101.9+7.9
102.9+6.8
NS
D-Propranolol (0.05 mg/kg) 5 107.6±2.7
109.5±5.6
108.4±1.6
110.2±3.3
109.3±5.9
110.8±3.1
NS
Ringer's solution
14 102.1+5.7
101.2±8.7
101.2+7.1
102.6±7.9
102.8+7.9
105.0±8.8
NS
LVEDP (mm Hg)
L-Propranolol (0.05 mg/kg) 9
5.9+3.8
7.0+3.8
7.4±3.6
7.6+3.6
8.0±4.5
7.0±3.5
NS
L-Propranolol (0.01 mg/kg) 16
8.0±3.4
8.9+4.0
9.9±4.5
9.4+4.2
9.2+3.1
9.9±3.5
NS
D-Propranolol (0.05 mg/kg) 5
4.6+3.7
5.3+5.6
4.8+3.6
6.4±3.5
6.7+4.8
5.8+1.8
NS
Ringer's solution
14
8.2+3.3
8.9+4.8
8.1+4.1
8.7+4.5
8.8+4.2
9.5+5.1
NS
LV+dP/dt
L-Propranolol (0.05 mg/kg) 9 3,551±575
2,967+301
2,999±528
2,861+397 <0.0005
2,903+469
2,835+421
L-Propranolol (0.01 mg/kg) 16 3,518+522
3,024+502
2,947+546
3,072+446
2,946+474
2,995-+547 <0.0005
D-Propranolol (0.05 mg/kg) 5 2,916±250
2,972±215
2,962+222 3,070+251
NS
2,961+209
2,921+199
Ringer's solution
14 3,479±553
3,392+534
3,346±542
3,423±459
3,571+580
NS
3,426+440
LV+dP/dt/P
L-Propranolol (0.05 mg/kg) 9
33.3+3.7
29.6±2.9
29.8+4.1
28.9±3.7
28.1+3.7
28.0+3.2
<0.0005
L-Propranolol (0.01 mg/kg) 16
36.8±4.4
33.4+4.1
33.1+2.4
31.9±4.6
31.7±3.9
32.0+4.5
<0.0005
D-Propranolol (0.05 mg/kg) 5
30.9+2.3
31.0+2.5
31.1±2.4
32.2±3.3
31.4+2.5
30.2+3.2
NS
Ringer's solution
14
36.9+3.9
36.7+3.8
35.8±4.1
36.4±3.2
36.5+2.9
37.2+4.3
NS
LV systolic TF (%)
L-Propranolol (0.05 mg/kg) 7
28.6+9.4
26.1+6.6
25.9±7.0
27.3+7.5
27.0±7.7
27.0±7.7
<0.05
L-Propranolol (0.01 mg/kg) 13
26.7±9.9
25.8+9.1
25.5±9.8
25.9+9.7
25.8±10.1
25.7±10.5
NS
D-Propranolol (0.05 mg/kg) 5
33.1±8.2
32.3±7.7
32.4+7.7
32.5±8.4
31.7+7.8
31.5±7.5
NS
Ringer's solution
11
29.1±8.9
29.8±9.9
28.6±8.5
29.4±9.1
29.0+9.3
29.0±9.4
NS
Values are mean±SD. Values of p are by repeated-measure analysis of variance. LVSP, left ventricular systolic pressure; LVEDP, left
ventricular end-diastolic pressure; LV+dP/dt, maximum left ventricular dP/dt; LV+dP/dt/P, LV+dP/dt per developed left ventricular
pressure; LV systolic TF, left ventricular systolic wall thickening fraction; NS, not significant.
thickening (p<0.05), but statistical significance was
only marginal. Furthermore, analysis of percent change
from baseline between the four treatment groups at
individual time points did not reveal a significant
between-group effect. 4) Left ventricular systolic and
end-diastolic pressures were not significantly affected
by any of the four treatment regimens (p=NS). 5) DPropranolol and Ringer's solution after intracerebral
infusion were not associated with significant alterations
in the measured hemodynamic indexes.
Heart Rate Response to LAD
Coronary Artery Occlusion
Baseline heart rate in the quiescent state was
similar in the L-propranolol (0.05 mg/kg and 0.01
mg/kg), D-propranolol, and Ringer's solution treatment groups (Table 2; p=NS by analysis of variance).
Although heart rate can fluctuate markedly after
LAD coronary artery occlusion in the conscious pig,
the general trend evoked by ischemia consisted of a
biphasic heart rate response in most pigs. Heart rate
increased in the early phase of ischemia (0-4 minutes) in all cases and in all treatment groups; this
increase was followed by a later decline in those
individual pigs with VF latencies greater than 4
minutes. The highest heart rate (peak) reached during the first 4 minutes of ischemia was lower in the
0.05 mg/kg L-propranolol group compared with the
Ringer's group (Table 2; p<O.05). However, there
was no difference in peak heart rate in the 0.05
mg/kg L-propranolol compared with both the Dpropranolol and low-dose L-propranolol treatment
groups, despite differences in VF vulnerability (Table
2; p=NS). Likewise, the heart rate measured at the
last period of sinus rhythm before VF (or at 15
minutes) was also moderately depressed in pigs
receiving 0.05 mg/kg L-propranolol compared with
pigs receiving Ringer's solution (p<0.05; Table 2)
but not compared with the other two groups (p=NS;
Table 2). Since heart rate may be a determinant of the
Parker et al Central f3-Adrenergic Modulation of Ischemic VF
265
10
WI
,:::z-,1,
\ -,
t-
'IA-1
1
1
-100
-
T
T
T
0
.L
I
0
E -20 1
U)
0
0
0
0
-30 1
0*
FIGURE 3. Graphs showing heart
rate and maximum left ventricular dPI
dt (MAX LV dP/dt) after cerebroventricular administration of 0.05 mg/kg
L-propranolol (I-prop on figure), 0.01
mg/kg L-propranolol, 0.05 mg/kg Dpropranolol (dprop on figure), and
Ringer's solution (vehicle control).
Heart rate is expressed as absolute
change from baseline in beats/min;
MAX LV dP/dt is expressed as percent
change from baseline. Values represent
mean ±+SEM. *p<O.01 compared with
Ringer's solution. **p<O.01 compared
with the lower dose of L-propranolol.
-40 I
-50
Downloaded from http://circres.ahajournals.org/ by guest on August 3, 2017
20
10
a10
~-J
fi
o
C
01
-10
0
0
c
0
-20
-30
-40
-50
0
*-* I-prp.05
30
20
TIME (min)
10
I-oPop.01
0-0
A
- -A
lbw
40
A-A
dprop
TABLE 2. Heart Rate After Intracerebroventricular Administration of L-Propranolol, D-Propranolol, Ringer's Solution, and Left Anterior
Descending Coronary Artery Occlusion
HR after drug administration
Treatment
n
L-Propranolol (0.05 mg/kg)
L-Propranolol (0.01 mg/kg)
D-Propranolol (0.05 mg/kg)
Ringer's solution
15
7
7
12
Baseline HR (beats/min)
1
2
3
143±15
140±14
140±14
145±14
141±14
145±15
136±14
134±18
132±14
137±20
137±19
132±20
(beats/min)
1 min
120±15
136±16
129±18
131±17
5 min
115±16
131±15
128±16
128±18
10 min
112±17
128±15
127±15
128±19
HR after LAD
occlusion (beats/min)
Phase 1
Phase 2
145±19*
130±18*
162±26
144±15
160±22
138±23
164±30
177±27
0.870t
F value
4.25:
5.23t
2.14t
2.71t
1.83t
0.626t
0.706t
Values are mean±SD. HR, heart rate; LAD, left anterior descending coronary artery; phase 1, peak HR during early phase of ischemia
(0-4 minutes); phase 2, stable HR within 1 minute of the onset of ventricular fibrillation or reperfusion. Three baseline measurements were
made before drug infusion. Resting HR is given for 1, 5, and 10 minutes after drug infusion and before ischemia. F values are by one-way
analysis of variance.
*p<0.01 compared with Ringer's solution by t test with Bonferroni correction.
tp=NS for the four treatment groups.
tp<O.Ol for the four treatment groups.
266
Circulation Research Vol 66, No 2, February 1990
250 r
*
O
A
A
A
A
200 F
A
A
0
I-:
I-
0
A
*
A
o
150 h
AA
U
11
I:
~~~~0
n
100
r = -0.29
0
6
3
9
VF LATENCY (min)
250
Downloaded from http://circres.ahajournals.org/ by guest on August 3, 2017
200
_A
A
A
LLi
,:
A
A
0
150 _
I-c
LI
100 F
0
*
50
L-
d-P (0.05mg/kg)
Ringers
A
A
W
I-P (0.05mg/kg)
I-P (0.01mg/kg)
0
0~~~~~~~~
0
FIGURE 4. Graphs showing relation between heart
rate and
ventricular fibrillation (VF) latency after
administration of L-propranolol (l-P), D-propranolol
(d-P), and Ringer's solution. Top panel: Relation
between peak heart rate in the first 4 minutes of
12
15 ischemia (ordinate) and VF latency (abscissa). Data
from all treatment groups were pooled and analyzed
by Pearson product-moment correlation coefficient;
however, individual data points from respective
* I-P (0.05mg/kg)
o l-P (0.01mg/kg)
treatment groups can be visualized as indicated in
A d-P (0.05mg/kg)
A Ringers
the figure legend. There was no correlation between
peak heart rate and VT latency (r= -0.29; p>0.05).
Bottom panel: Relation between sinus rhythm heart
rate nearest the onset of VF or at 15 minutes (ordinate)
and VF latency (abscissa). A relatively weak correlaA
tion was observed (r= -0.566; p<O0.05).
A
A
A
0
r = -0.57
50
0
3
6
9
12
15
VF LATENCY (min)
propensity to develop VF, the relation between peak
heart rate and VF latency from all the pigs was analyzed. A correlation between VF latency and peak
heart rate in the first 4 minutes of ischemia was not
observed (r= -0.296, p>O.05; Figure 4, top panel). A
relatively weak correlation, however, was observed
between VF latency and heart rate nearest the onset of
VF (r=-0.566, p<O.05; Figure 4, bottom panel).
Although heart rate may be one mechanism contributing to the differences observed in VF vulnerability, the
data suggest that other factors are involved.
Hemodynamics as a Function of
Laboratoty Adaptation
Heart rate, left ventricular systolic and enddiastolic pressure, maximum rate of left ventricular
pressure development, left ventricular systolic wall
thickening, and coronary artery blood flow were
evaluated on a daily basis for 8 days (Figure 5). The
initial transport of the pig from the vivarium to the
laboratory is accompanied by acute hemodynamic
alterations. This acute phasic stress variable was
minimized by allowing 30 minutes to elapse before
beginning data collection. Significant differences
were not observed (repeated-measurement analysis
of variance) in the above hemodynamic indexes dur-
ing psychological adaptation to the unfamiliar environment. The lack of overt hemodynamic alterations
in the unadapted compared with the adapted pig
occurred despite the known increased myocardial
vulnerability to ischemia-induced VE associated with
initial exposure to a novel laboratory environment.8
Propranolol Pharmacokinetics
Cerebrospinal fluid and blood plasma analysis of
L-propranolol levels after intracerebral administration
of 0.05 mg/kg propranolol revealed concentrations of
1,201-5,991 ng/ml propranolol in the cerebrospinal
fluid as opposed to 4.9-13.7 ng/ml propranolol in the
plasma 10 minutes after completion of drug infusion
(Table 3). Intravenous administration of the same dose
of L-propranolol, on the other hand, produced cerebrospinal fluid levels of only 1.2-1.4 ng/ml, while 6.7-62.5
and 2-15.4 ng/ml were detected in the plasma at 5 and
10 minutes, respectively (Table 4).
Discussion
Ventricular tachycardia degenerating into VF is
the most consistently observed mechanism of sudden
cardiac death.4,24 Although myocardial ischemia and
infarction are known contributing factors in predisposing to VF, not all persons with ischemic heart
Parker et al Central 1-Adrenergic Modulation of Ischemic VF
170
12
150
10
8
L;R Ic 130
g
C)
0
-
0
z
6
W
1-
C 110
W
1-
T
A-
.0
I
-
A-
A&
j1
4
1
1
0
90 .
2
I
70
U
130
30
110
20
3
m
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V)
0I
3
J EE
I-
X
~0
10
90
TIl%.. T
..0
.1
1
70
l
100
v
4000
80
.
K,-,
10.0
0)
m
>
-JI
FIGURE 5. Graphs showing heart rate, left anterior
descending (LAD) coronary artery blood flow, left
ventricular systolic pressure (LVSP), left ventricular
end-diastolic pressure (LVEDP), maximum left ventricular dP/dt (MAXLVdP/dt), and left ventricular
(LV) systolic thickening fraction (%TF) as a function of laboratory adaptation in the conscious pig.
Values represent mean+±SEM.
0
5000
0
267
1
60
-<
)
:Eg
3000
-.1~
x.EE
2000
`- ,Lvvv
I.
20
Z
z
z
C)
1 000
1
2
3
4
5
0
6
7
8
LAB DAY
disease or infarction die unexpectedly. Furthermore,
acute pathological lesions of the coronary arteries
and myocardium are not observed or are inadequate
to account for the fatal event in 10-15% of the
cases.25 Thus, although ischemia is a major factor
triggering VF, other factors in addition to diffuse
coronary artery disease may mediate increased vulnerability in susceptible individuals.
This study provides further evidence in an animal
model that central nervous system input is one such
TABLE 3. Plasma and Cerebrospinal Fluid Propranolol Concentrations After Intracerebroventricular Administration
of 0.05 mg/kg L-Propranolol in the Pig
Cerebrospinal fluid
(ng/ml)
Plasma
(ng/ml)
Pig
41
41A
44
45
49
50
5
min
6.4
16.7
12.7
7.5
16.8
11.2
10 min
4.9
13.7
8.4
6.1
10.9
10.3
S
min
10 min
...
...
3,365.6
3,054.9
5,160.0
25,572.0
2,933.9
1,490.2
1,201.4
2,100.0
5,991.0
2,533.5
268
Circulation Research Vol 66, No 2, February 1990
TABLE 4. Plasma and Cerebrospinal Fluid Propranolol Concentrations After Intravenous Administration of 0.05 mg/kg LPropranolol in the Pig
Pig
42
44
45
5 min
62.5
6.7
56.9
Plasma
Cerebrospinal fluid
(ng/ml)
(ng/ml)
10 min
13.4
2.0
15.4
5 min
...
1.7
1.5
10 min
...
1.4
1.2
Downloaded from http://circres.ahajournals.org/ by guest on August 3, 2017
factor capable of influencing myocardial vulnerability. As has been shown previously, all pigs exposed to a
novel laboratory environment develop VF within 14
minutes after the onset of ischemia. Pretreatment with
direct intracerebral administration of L-propranolol,
however, significantly prolonged the time to the onset
of VF as well as reduced the incidence of ischemic VF
from 100% to 47%. The dextrorotatory isomer that has
less than 1% of the potency of the levorotatory isomer
in antagonizing ,8-adrenergic receptors, however, failed
to reduce the environmental stress-related vulnerability
to ischemia-induced VF. Thus, the major finding of this
study is that a central f3-adrenergic receptor-mediated
phenomenon appears to be involved in modulation of
myocardial vulnerability to environmental stressrelated arrhythmogenesis.
Since propranolol distribution into the blood compartment was expected to occur after intracerebroventricular administration, plasma and cerebrospinal
fluid levels of the drug were determined to firmly
establish the relative site of action (central vs. peripheral). Direct administration of 0.05 mg/kg Lpropranolol into the lateral cerebral ventricles did
result in measurable blood levels at 5 and 10 minutes
after drug infusion. Plasma concentrations of propranolol that are associated with therapeutic effects
are known to vary widely (20-1,000 ng/ml), particularly with reference to suppression of arrhythmic
activity. Intravenous infusion of 10 mg racemic propranolol (1 mg/min) suppressed spontaneous ventricular ectopy in eight out of 12 patients, whereas,
D-propranolol was without effect. Plasma levels associated with ectopy suppression following intravenous
administration were in the range of 40-85 ng/ml.26
This level is comparable with plasma concentrations
required to cause considerable cardiac ,B-adrenergic
receptor antagonism as evidenced by a 40-80%
inhibition of exercise-induced tachycardia.27 However, concentrations ranging from 100-800 ng/ml are
sometimes necessary to control ventricular arrhythmias in humans.28 Thus, the measured plasma concentration of 9+3.2 ng/ml observed after intracerebroventricular injection should be below therapeutic
antiarrhythmic blood levels. Cerebrospinal fluid levels, on the other hand, were on the order of 200300 -fold higher. Five minutes after the completion of
drug infusion, plasma concentration for intravenous
administration of L-propranolol was four times
higher than for intracerebral administration; at 10
minutes, the plasma concentration was similar for
intravenous and intracerebral propranolol. This further suggests that a plasma concentration in the 10
ng/ml range would not be associated with an antifibrillatory effect due to myocardial receptor antagonism since previously used intravenous doses of 0.2
mg/kg and 2 mg/kg racemic propranolol (4-40 times
the dose as used in the present study), which would
be associated with even higher plasma levels, were
not effective in preventing VF in this same pig
model.8 Moreover, propranolol was specifically evaluated for potential antifibrillatory efficacy in the pig,
and a plasma level of 600 ng/ml was without effect in
reducing the occurrence of VF after LAD coronary
occlusion.29
Baseline hemodynamic and cardiac function
before occlusion is also not expected to influence or
be predictive of increased myocardial vulnerability to
VF in this model since no significant changes were
observed in the measured indexes of cardiac inotropy
and chronotropy during an 8-day laboratory adaptation protocol. This observation extends a previous
finding that resting heart rates were similar in
laboratory-unadapted compared with laboratoryadapted pigs despite their known difference in vulnerability to ischemia-induced VF.10 The lack of
hemodynamic alterations and overt signs of stress
associated with exposure to a novel environment
confirm the utility of this paradigm in modeling the
influence of the often imperceptible tonic psychosocial stress associated with life-change events on myocardial vulnerability in man.1'5,7 It also points out the
need to recognize psychological variables, whether in
animals or man, when evaluating antiarrhythmic
efficacy.
Decreased vulnerability to ischemia-induced VF
after central administration of propranolol, however, is
associated with moderate hemodynamic alterations.
Both doses of L-propranolol resulted in a moderate, but
a significant, decrease in heart rate and maximum left
ventricular dP/dt but no effect on left ventricular systolic pressure and end-diastolic pressure. There were
no significant hemodynamic alterations after central
administration of D-propranolol and Ringer's solution.
After induction of ischemia, peak heart rate in the
first 4 minutes of ischemia and the stable heart rate
nearest the onset of VF were moderately depressed
in the high-dose L-propranolol-treated pigs compared with pigs receiving Ringer's solution. However,
both peak heart rate and heart rate nearest the onset
of fibrillation were not different in pigs receiving 0.05
mg/kg L-propranolol, 0.01 mg/kg L-propranolol, and
D-propranolol despite differences in VF vulnerability. Furthermore, there was no correlation between
VF latency and peak heart rate in the early phase of
ischemia and only a relatively weak correlation near
the onset of VF. The hemodynamic and heart rate
data, therefore, do not identify a specific physiological parameter that predicts antifibrillatory action.
Studies in other species have also reported a negative
chronotropic effect as well as a decrease in mean
arterial blood pressure after administration of pro-
Parker et al Central ,-Adrenergic Modulation of Ischemic VF
Downloaded from http://circres.ahajournals.org/ by guest on August 3, 2017
pranolol into the cerebroventricular system.30-32
Reduction of sympathetic nervous system activity33
and a decrease in plasma norepinephrine concentration34 accompany the physiological response after
cerebroventricular injection of propranolol. Thus,
there is no doubt that centrally administered propranolol alters autonomic tone and stimulation of the
heart by reducing (in all likelihood) sympathetic
outflow.
Several studies have demonstrated a reduction in the
incidence of ischemia-induced lethal ventricular
arrhythmias after myocardial 8-adrenergic blockade;
however, there are conflicting reports. Peripheral myocardial ,B-adrenergic receptor antagonism achieved by
the intravenous administration of /-blockers afforded
protection against VF during coronary artery occlusion
in the dog.35 Furthermore, 0.2 mg/kg i.v. propranolol
significantly reduced the incidence of ischemia-induced
VF with experimentally induced sympathetic hyperactivity in cats36; the cardioselective ,B-blocker tolamolol
(4 mg/kg i.v.), resulted in a 50% reduction in the
repetitive extrasystole VF threshold in a psychologically
stressed dog model.37 In contrast, peripheral administration of 0.2 and 2 mg/kg i.v. racemic propranolol in
the psychologically stressed pig was ineffective in providing protection against acute ischemia-induced VE8
The present study demonstrates in the same pig model
that central administration of 0.05 mg/kg L-propranolol
provides a salutary antifibrillatory effect. The reason for
the disparity of results in the pig compared with other
models concerning cardiac /3-adrenergic receptor
blockade is only speculative. However, it is known that
the pig is intrinsically sensitive to environmental
stressors.14,38,39 It may be that vulnerability to the
deleterious effects of environmental stress modulates
the observed differences. If so, this vulnerability is likely
shared by the pig and at least some patients.
The rationale for the present study stemmed from
observations that various operationally defined stressor events (novel stimulus, unexpected cutaneous
shock, and physical restraint) all appear to evoke a
cortical noradrenergic ,/-receptor process of which the
electrochemical correlates are known. These same
stressor events also increase the susceptibility to lethal
arrhythmias in pigs. The present study demonstrates
that antagonism of cerebral /3-adrenergic receptors
reduces the susceptibility to environmental stressrelated VF. The data suggesting that this is a centrally
mediated /3-adrenergic effect are 1) isomeric specificity of propranolol effect, 2) pharmacokinetic data
demonstrating negligible peripheral propranolol levels
with central administration, and 3) inability of peripheral (intravenous) administration to alter vulnerability
to ischemic VF.
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KEY WORDS * propranolol * ventricular fibrillation * pigs
psychological stress
Central beta-adrenergic mechanisms may modulate ischemic ventricular fibrillation in
pigs.
G W Parker, L H Michael, C J Hartley, J E Skinner and M L Entman
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Circ Res. 1990;66:259-270
doi: 10.1161/01.RES.66.2.259
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