(Circulation. 1997;96:4044-4049.)
© 1997 American Heart Association, Inc.
Articles |
Intrapericardial Delivery of L-Arginine Reduces the Increased Severity of Ventricular Arrhythmias During Sympathetic Stimulation in Dogs With Acute Coronary Occlusion
Nitric Oxide Modulates Sympathetic Effects on Ventricular Electrophysiological Properties
From the Krannert Institute of Cardiology and the Endocrine Division, Department of Medicine, Indiana University School of Medicine, and the Roudebush Veterans Administration Medical Center, Indianapolis, Ind.
Correspondence to Douglas P. Zipes, MD, Distinguished Professor of Medicine, Pharmacology and Toxicology, Krannert Institute of Cardiology, Indiana University Medical Center, 1111 West 10th St, Indianapolis, IN 46202-4800.
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Abstract |
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Background Nitric oxide (NO) modulates autonomic effects on myocardial contractility and sinus and atrioventricular nodal function of the heart. Whether NO influences autonomic actions on ventricular electrophysiological properties and arrhythmogenesis is not known.
Methods and Results Four groups consisting of 43 autonomically denervated dogs were studied. To "superfuse" sympathetic nerves innervating the ventricles, test drugs were introduced into the pericardial sac for 30 minutes, and their effects on ventricular effective refractory period (ERP) and arrhythmia development were assessed before and during sympathetic stimulation (SS). In group 1 (n=12), ventricular ERPs showed no significant difference between control and superfusion with L-arginine, a NO precursor (222±20 versus 222±19 ms, P=.485). However, L-arginine significantly reduced SS-induced ERP shortening compared with control (9±7 versus 13±7 ms, P<.001). Simultaneous administration of NG-monomethyl-L-arginine (2 mg/mL) abolished the inhibitory effects of L-arginine (13±7 versus 13±7 ms, P=.885). In group 2 (n=15), the severity of ventricular arrhythmias significantly increased during SS. L-Arginine reduced this increase caused by SS. In group 3 (n=8), plasma norepinephrine spillover measured from the coronary sinus significantly increased during SS and was reduced by pericardial superfusion with L-arginine compared with control (6005.2±1525.6 versus 8503.4±2044.5 pg/min, P=.012). In group 4 (n=8), L-arginine pericardial superfusion significantly increased NO overflow measured from the coronary sinus during SS (93.25±59.20 versus 114.82±74.92 nmol/min, P=.043).
Conclusions Pericardial L-arginine reduces ERP shortening and increased severity of ischemic ventricular arrhythmias during SS in dogs. NO-induced reduction of norepinephrine release in the heart may be one of the underlying mechanisms.
Key Words: arrhythmia • nervous system, autonomic • electrophysiology • norepinephrine
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Introduction |
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Substantial evidence indicates that heightened sympathetic activity can increase the prevalence and severity of life-threatening ventricular arrhythmias in both animals and humans. Because NO inhibits the positive inotropic response of the heart to ß-adrenergic stimulation,1 perhaps by increasing production of cGMP via guanylyl cyclase,1,2 and modulates the autonomic responses of the sinus and atrioventricular nodes,3 we hypothesized that NO might influence the autonomic actions that modulate electrophysiological properties of ventricular myocardium and influence the pathogenesis of some ventricular arrhythmias produced by increased sympathetic activity. The purpose of this study was to test this hypothesis and to determine a potential mechanism by investigating the impact of NO on norepinephrine release from cardiac sympathetic nerves.
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Methods |
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Animals
Forty-three adult mongrel dogs, weighing 20 to 30 kg, were allocated into four groups in which we measured ventricular ERP (group 1), ventricular arrhythmia (group 2), norepinephrine release (group 3), and NO production (group 4). The ERP group was further divided into two subgroups to assess the effects of L-arginine on autonomic modulation of ventricular ERP in the absence (group 1a) and presence of L-NMMA (group 1b), respectively. The experimental protocol was approved by the Indiana University Animal Experimentation Committee.
Surgical Preparation
All dogs were anesthetized with 5% pentobarbital sodium
(30 mg/kg IV), and additional doses of 1 mL were given as needed
to maintain anesthesia during experiments. Dogs were
intubated and ventilated with room air using a constant volume-cycled
respirator (Harvard Apparatus). The left femoral artery and
vein were cannulated to monitor blood pressure via a transducer (model
p-23Db, Statham) and to administer fluids and pentobarbital sodium,
respectively. The heart was exposed through a median sternotomy. The
left and right stellate ganglia were isolated and decentralized. The
cervical vagi were also isolated, doubly ligated, and transsected. A
small hole (2x2 cm) was made in the anterior surface of the
pericardium as we previously reported.4–6 A
thermistor (model 400, Yellow Springs Instruments) was put into the
pericardial sac and used to monitor epicardial temperature. With a
heating pad underneath the animal and an operating lamp above the
opened chest, body temperature was maintained between 36° and 37°C.
The sinus node was crushed if the sinus rate remained >130 bpm after
autonomic denervation.
Bipolar electrodes (0.5 to 1 cm apart) hooked in the right atrial
appendage were used to record and stimulate the right atrium, and
two bipolar electrodes (
1 cm apart) were inserted into the right and
left ventricular anterior walls for ventricular
recording. The hook electrodes were made from Teflon-coated
wires, insulated except for their tips. Standard lead II ECG, bipolar
right atrial and right and left ventricular epicardial
electrograms, and arterial blood pressure were recorded
simultaneously using a multiple-channel
physiological recorder (Honeywell VR16). In
animals of group 1, eight hook electrodes were inserted into basal and
apical right and left ventricular walls, respectively, to
serve as the cathode for unipolar stimulation to determine ERPs (Fig 1
). An anodal electrode was placed in the
abdominal wall. In animals of group 2, the left anterior descending
coronary artery was dissected between the first and second
diagonal branches, with care taken to not damage the perivascular
nerves during this procedure. A silk suture, passed through a plastic
tube, was placed around the isolated coronary artery for
repeated occlusions.
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In groups 3 and 4, a balloon catheter (Arrow) was inserted into the
right internal jugular vein, and its tip was passed deep into the
coronary sinus. The balloon catheter was fixed onto the lateral
wall of the superior vena cava with a suture to prevent its slipping
out of the coronary sinus. The position of the catheter was
confirmed visually during and after completion of experiments. During
collection of blood, the balloon was inflated, and coronary
sinus blood flow was determined by the volume of blood withdrawn within
a minute during very gentle pulling on the plunger of a syringe. The
catheter was flushed with normal saline containing heparin after each
collection. The heart rate was held constant (150 bpm) by pacing the
right atrium during coronary sinus blood sampling. Heparin (a
loading dose of 3000 U followed by 500 U/h IV) was
administered to prevent blood clotting. In group 3, desipramine
hydrochloride (1 mg/kg) was administered
intravenously before coronary sinus sampling to
block the neuronal reuptake of norepinephrine released from
sympathetic nerve endings. Each blood sample was placed in a tube
containing EDTA and heparin. The plasma, which was separated by
centrifugation (6000 rpm) at a temperature of -10°C
for 10 minutes, was stored in a freezer at a temperature of -77°C
for 
24 hours until norepinephrine or NO
concentrations was measured. Norepinephrine was determined
by radioenzymatic assay using phenylethanolamine
N-methyltransferase.7
Analysis for NOx was performed using an established
method8 by running samples through a NO
analysis system (NOA 280, Sievers). Briefly, plasma samples
were frozen at -77°C for 24 hours before
analysis.9 On the day of the NOx assay,
all samples were deproteinized by the addition of 2 µL of 10 N NaOH
to 200 µL of plasma followed by the addition of 120 µL of 0.15
mol/L ZnSO4. Tubes were vortexed and
placed on ice for 15 minutes and then centrifuged at 12,000 rpm
for 10 minutes. The supernatant was used for analysis. A
standard calibration curve for NOx measurement was generated at each
assay with a standard solution of nitrate. Four microliters of
supernatant/standard solution were injected quickly with a microliter
syringe (Hamilton) through a silicone septum into a purge vessel
containing vanadium chloride in hydrochloride and kept at 95°C. In
the purge vessel, NOx was reduced to NO, which was transferred to the
NO analysis system by a vacuum pump (model E2M5, Edwards). The
amount of NO produced was determined by the luminescence generated in
the presence of ozone in the NO analysis system. The
luminescence measured is directly proportional to the amount of NO
produced and, in turn, to the NOx content of the samples. Each sample
and standard solution were measured in duplicate during all analytical
runs.
Sympathetic Stimulation
Shielded bipolar electrodes were placed on the left and right
stellate ganglia near the exit of the ansae subclaviae to stimulate the
efferent cardiac sympathetic nerves through separate constant voltage
isolators from a programmable two-channel stimulator (S88, Grass).
Stimuli were 4 ms in duration at a frequency of 4 Hz. The output to the
right stellate ganglia was adjusted to increase the heart rate to
140 bpm. The level of output to the left stellate ganglia was
initially the same as that for the right one and adjusted to shorten
left ventricular ERP by 10 to 20 ms.
Measurement of Ventricular ERP
Ventricular ERP was measured by a single
extrastimulus (S2) delivered in decrements of 1
ms after every eight basic ventricular drives
(S1) at a basic cycle length
(S1S1) of 400 ms.
S1 and S2 (2-ms duration
and twice-diastolic pacing threshold) were delivered from a
Medtronic stimulator (model 5325). The output of stimuli was kept
constant throughout the entire study. The longest
S1S2 coupling interval at
which S2 did not evoke a ventricular
depolarization and confirmed twice was defined as the
ventricular ERP.
Cardiac sympathetic nerves were superfused4–6 by
the introduction of normal Tyrode's solution (40 to 80 mL)
containing either L-arginine (the
physiological precursor of NO; 100
mmol/L, Sigma Chemical) or L-arginine and
L-NMMA (a NO synthase inhibitor; 2
mg/mL, Sigma). The millimolar composition of normal Tyrode's
solution was MgCl2 0.5,
NaH2PO4 0.9,
CaCl2 2.0, NaCl 137.0,
NaHCO3 12.0, KCl 4.0, and glucose 5.0. This
resulted in pH 7.35.6 The test solutions were
prepared by the addition of substances into normal Tyrode's solution
before it was put into the pericardial sec. All the solutions were
prewarmed to 37°C and gassed with 95% O2 and
5% CO2.
Experimental Protocol
Baseline data were determined 30 minutes after the Tyrode's
solution was put into the pericardial sac. The Tyrode's solution was
replaced by the Tyrode's solution containing L-arginine or
L-NMMA. Each parameter was measured again 30
minutes later. Then the Tyrode's solution containing drugs was
carefully washed out at least three times using the Tyrode's solution
without any drugs. Data collection was repeated 30 minutes later.
Group 1: Ventricular ERP
ERPs were measured in the presence of pericardial superfusion
with L-arginine (n=7) or L-arginine and
L-NMMA (n=5) before and during SS. The mean value of ERPs
in the presence of pericardial superfusion with Tyrode's solution
before and after superfusion with L-arginine was taken as
control.
Group 2: Ventricular Arrhythmia
Ventricular arrhythmias were induced
by repeated 7-minute occlusions of the left anterior descending
coronary artery between the first and second diagonal branches
during constant atrial pacing (cycle length, 400 ms) (n=15). The latter
was begun 90 sec before coronary occlusion and continued for 90
sec after release of occlusion. SS, when applied, was started 60 sec
before coronary artery occlusion and was continued for 60 sec
after reperfusion. The first coronary artery occlusion was
performed 30 minutes after normal Tyrode's solution was put into the
pericardial sac. Because intramyocardial conduction delay and
ventricular arrhythmias are usually more
exaggerated during the first occlusion than subsequent
ones,5 possibly due to the effects
of preconditioning,10 results from this first
occlusion were discarded and the second occlusion was used as control.
The second coronary occlusion was performed 15 minutes after
the first occlusion (Table 1). The third
occlusion was performed 15 minutes later in the presence of SS. Then,
the Tyrode's solution containing L-arginine was put into
the pericardial sac to replace normal Tyrode's solution, and the
fourth coronary artery occlusion was performed 30 minutes
later. The fifth coronary artery occlusion was performed after
superfusion with normal Tyrode's solution for 30 minutes (washout).
Both the fourth and the fifth coronary occlusions were
performed in the presence of SS.
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Groups 3 and 4: Norepinephrine Release and NO
Overflow
Five-milliliter samples from coronary sinus blood were
obtained during pericardial superfusion with (1) Tyrode's solution,
(2) Tyrode's solution and L-arginine, and (3) washout with
Tyrode's solution after atrial pacing at 150 bpm for 3 minutes. These
were repeated during SS for 3 minutes. The concentration of
norepinephrine in coronary sinus blood reaches
steady state within a minute of SS in normal dog hearts.11
Norepinephrine spillover (group 3; n=8) and NO overflow (group 4; n=8)
was defined as the product of norepinephrine or NO
concentration and blood flow from the coronary sinus.
Statistical Analysis
All data are expressed as mean±SD. Paired t test,
one-way ANOVA, Friedman's test, and Wilcoxon's signed rank
test were used where appropriate. A two-tailed p value of
<.05 was considered statistically significant.
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Results |
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Effects of NO on Ventricular ERPs (Group 1)
In the baseline state without SS in 7 dogs (group 1a), there was no significant difference in ventricular ERP during pericardial superfusion with Tyrode's solution (control) and during pericardial superfusion with L-arginine (222±20 versus 222±19 ms, P=.485). SS significantly shortened ventricular ERPs by 13±7 ms during pericardial superfusion with Tyrode's solution (P<.001), whereas during superfusion with Tyrode's solution containing L-arginine, SS shortened ventricular ERP by 9±7 ms (P<.001) (Fig 2
, top). Thus,
L-arginine reduced the SS-induced shortening of
ventricular ERPs by 31% (P<.001).
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In an additional 5 dogs (group 1b), during simultaneous
pericardial superfusion with L-NMMA and
L-arginine, there was no significant difference in
SS-induced change in ERPs compared with controls (13±7 versus 13±7
ms, P=.885) (Fig 2
, bottom).
Effects of NO on Ischemic Ventricular
Arrhythmias (Group 2)
Ventricular arrhythmias were classified into
five categories of increasing severity5: (1) no
ventricular arrhythmias, (2)
isolated ventricular ectopic beats, (3) couplets, (4)
nonsustained ventricular tachycardia (3
consecutive beats but <15 sec), and (5) ventricular
fibrillation. The highest category of ventricular
arrhythmias was scored for each occlusion. Data from 7 dogs
were eliminated because they had no ventricular
arrhythmias before and during SS. The severity of
ventricular arrhythmia significantly increased
during SS in the remaining 8 dogs (Fig 3). L-Arginine significantly
reduced this increase in ventricular arrhythmias caused by SS
(P=.018). There was no significant difference in the
severity of ventricular arrhythmia after washout of
L-arginine using normal Tyrode's solution compared with
that before pericardial superfusion with L-arginine
(P=.600).
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Effects of NO on Release of Norepinephrine From
Sympathetic Nerves of the Heart (Group 3)
The coronary sinus blood flow was increased during
superfusion with L-arginine compared with control before
(control, 12.2±2.8; L-arginine, 13.7±3.0 mL/min,
P=.012) and during SS (control, 14.3±2.9;
L-arginine, 15.8±2.9 mL/min, P=.068). Before
SS, there were no significant changes in both
norepinephrine concentration (control, 113.1±26.2;
L-arginine, 114.8±25.8 pg/mL, P=.674)
and spillover (control, 1347.0±456.7; L-arginine,
1470.4±407.8 pg/min, P=.161) during superfusion with
L-arginine compared with controls (Fig 4). During SS, both
norepinephrine concentration (control, 682.9±204.9;
L-arginine, 436.1±155.3 pg/mL, P=.012)
and spillover (control, 8503.4±2044.5; L-arginine,
6005.2±1525.6 pg/min, P=.012) were significantly
decreased during superfusion with L-arginine compared with
controls. Thus, L-arginine reduced both the
norepinephrine concentration and spillover by 36.1%
and 29.4%, respectively, during SS, despite an increase in
coronary blood flow.
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Coronary Sinus NO Overflow During Superfusion of the Heart
With L-Arginine (Group 4)
In group 4, the coronary sinus blood flow was
significantly increased during L-arginine superfusion
before (from 10.50±1.76 to 12.75±1.78 mL/min, P=.020) and
during SS (from 11.67±1.99 to 14.03±2.53 mL/min, P=.042).
NO overflow was significantly increased during L-arginine
superfusion compared with control during SS (from 93.25±26.47 to
114.82±33.51 nmol/min, P=.043). NO overflow was
also greater during superfusion with L-arginine without SS
(from 91.69±27.80 to 100.26±28.77
nmol/min), but the difference did not reach statistical
significance (P=.225). The difference in NO concentrations
between superfusion with L-arginine and control was not
statistically significant (Fig 5).
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Discussion |
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Main Findings of the Present Study
In this study, we tested the hypothesis that NO is involved in the autonomic modulation of ventricular electrophysiological properties in canine hearts. We found that pericardial superfusion with L-arginine reduced the extent of sympathetically induced ERP shortening and the increased severity of ventricular arrhythmias produced during coronary occlusions. The fact that the specific NO synthase inhibitor L-NMMA prevented the action of L-arginine on ventricular ERPs during SS suggests that the underlying mechanism is through a NO pathway. In fact, we demonstrated that superfusion of the heart with L-arginine increased NO production in the heart in this experimental preparation. We found that these results can be explained by decreased norepinephrine spillover in the coronary sinus, presumably by reducing norepinephrine release from sympathetic nerves in the heart, and are consistent with the observations from our previous study.3
Potential Mechanisms Underlying NO-Mediated Modulation of Autonomic
Effects on Ventricular Electrophysiological
Properties
NO, produced by either constitutive or inducible isoforms of NO
synthase, influences myocardial inotropic and
chronotropic responses. The NO pathway has been studied using NO donors
or NO synthase inhibitors.12 Basal NO
production seems to exert little tonic inhibition of
ß-adrenergic responses.13 Because cGMP is
associated with the negative effects of muscarinic cholinergic
stimulation of the heart,14 NO-mediated
intracellular production of cGMP via guanylyl
cyclase2 may account for many of the observed
physiological actions of NO. NO has been shown to
be an important modulator of ß-adrenergic effects on slow inward
calcium currents through cGMP-dependent protein
kinase.15 Mohan et al16
recently reported that cGMP is involved in the NO-induced biphasic
contractile response in a concentration-dependent manner. This effect
of NO is modulated by the status of endocardial
endothelium and by concomitant autonomic
stimulation.13
The potential sites of NO-mediated changes in ventricular electrophysiological properties during SS may be ventricular myocytes, cardiac neurons, or both. Horackova et al17 recently reported that NO did not directly affect cultured adult guinea pig myocytes. The beating rate of such myocytes could be indirectly affected when they were cultured with intrinsic or stellate ganglia neurons. In consideration that there was a significant L-arginine–mediated effect on ventricular ERPs during SS in our study but no significant change without SS, a likely location of the effects of NO is the signaling between cardiac neurons and ventricular myocardium. This is consistent with the finding in the study of Horackova et al17 that the effect of NO on the beating rates of ventricular myocytes depended on neuronal activation. Several investigators18–21 reported that nonadrenergic and noncholinergic actions may be involved in certain physiological responses to NO. Our finding that norepinephrine release in the heart was decreased in response to SS makes nonadrenergic and noncholinergic actions of NO less important in the NO-mediated autonomic modulation of ventricular electrophysiology.
Because NO is involved in the modulation of coronary blood flow,22,23 the decrease in the incidence of ventricular arrhythmias in the presence of L-arginine may be caused by improvement of myocardial perfusion in addition to changes in ventricular electrophysiological properties. Several studies24–27 have demonstrated that NO donors and L-arginine ameliorate ischemia/reperfusion injury and improve postischemic mechanical function, whereas NO synthase inhibitors are associated with a significantly poorer recovery. The fact that protection of NO donors and L-arginine has been demonstrated in subvasodilatory doses25,28 suggests that dilation of coronary vessels and increase of coronary blood flow are not the only mechanisms responsible for the protective action of NO. In addition, although changes in coronary blood flow can account for the influence of NO on ventricular arrhythmias, they cannot account for the modulating effects of NO on ventricular ERPs or norepinephrine spillover in this study. NO-induced alteration of norepinephrine release from the heart and of autonomic modulation of the electrophysiological properties of the ventricles may play a more important role in the reduction of the severity of ventricular arrhythmias during coronary artery occlusion and SS.
Potential Study Limitations
Because a higher concentration of L-arginine may cause
nonspecific negative inotropic effect on papillary
muscles,13 the use of a relatively high
concentration of L-arginine in this study may also result
in nonspecific changes in
electrophysiological properties of
ventricular myocardium. However, the finding
that the electrophysiological effects of
L-arginine could be abolished by L-NMMA
suggests the NO pathway is the underlying mechanism. On the other hand,
the concentration of L-arginine reached at the
myocardium might be much less than that in the pericardial
sac. Although every effort was made to maintain the experimental
conditions stable, it was difficult to eliminate minor changes with
time in cardiac function and electrophysiology during the entire
experiment. These changes with time should be compensated by taking the
average value between the baseline and washout. However, we could not
eliminate a potential residual effect of L-arginine after
washout.
To maintain the pericardial sac intact, we were unable to secure the cannula around the coronary sinus close to its ostium to collect blood samples; instead, we used a balloon catheter advanced deep in the coronary sinus. Thus, coronary sinus blood flow measured in this manner may be originating mostly from left ventricle and various parts of the right ventricle. This may explain the fact that coronary sinus blood flow was lower than that reported in the literature.11 It should be pointed out the method used to measure coronary sinus blood flow is not as accurate as other methods, such as thermodilution. Furthermore, the vasodilation effects of NO cannot be excluded in this study.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study is supported in part by the Herman C. Krannert Fund and by grants HL-52322 and DK-42469 from the National Heart, Lung, and Blood Institute of the National Institutes of Health. We thank Dzung D. Nguyen, MSc, and Claude Arnett, BSc, for surgical preparation; Judith A Eudaly, BSc, for measurement of plasma norepinephrine; Yonggang Wu, MD, for measurement of plasma NO; and Naomi Fineberg, PhD, for statistical help.
Received June 19, 1997; revision received July 29, 1997; accepted August 27, 1997.
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