(Circulation. 1995;91:462-470.)
© 1995 American Heart Association, Inc.
Articles |
Sympatholytic Action of Intravenous Amiodarone in the Rat Heart
From the Alfred and Baker Medical Unit, Baker Medical Research Institute and Alfred Hospital, Melbourne, Australia.
Correspondence to Dr X-J Du, Alfred and Baker Medical Unit, Baker Medical Research Institute, Commercial Rd, Prahran, Victoria 3181, Australia.
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Abstract |
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Background Amiodarone is a commonly used antiarrhythmic agent with complex pharmacological effects. Although ventricular arrhythmias can be suppressed soon after intravenous amiodarone, the mechanisms responsible for this action are unclear. We studied the effects of acute treatment with amiodarone on the metabolism and release of norepinephrine (NE) in intact rats and in perfused rat hearts.
Methods and Results Experiments were performed in anesthetized rats and in perfused, innervated hearts with amiodarone administered intravascularly. NE release was induced by electrical stimulation of the sympathetic ganglion. Concentrations of NE and its intraneuronal metabolite dihydroxyphenylglycol (DHPG) in hearts, plasma, and coronary venous effluent were measured by high-performance liquid chromatography. Acute administration of amiodarone induced dose-dependent increases in DHPG concentrations in plasma (5 mg/kg, +48%; 15 mg/kg, +84%; and 50 mg/kg, +467%) and in coronary venous effluent (1 µmol/L, +37%; 3 µmol/L, +510%; and 10 µmol/L, +1100%) together with an unchanged basal overflow of NE. In perfused hearts, NE release evoked by nerve stimulation was inhibited by infusion of amiodarone (1 µmol/L, -16%; 3 µmol/L, -24%; and 10 µmol/L, -64%) or by intravenous amiodarone (50 mg/kg) given 1 hour before heart perfusion (-70%), and the extent of this suppression correlated well with levels of DHPG overflow present immediately before nerve stimulation. When given in vitro and in vivo, amiodarone also significantly reduced NE and increased DHPG content in the heart, leading to a raised DHPG/NE ratio. All these effects of amiodarone were similar to those found with reserpine but less potent. In contrast, oral amiodarone produced none of these effects.
Conclusions Acute administration of amiodarone in perfused hearts or intact rats induces partial NE depletion in the heart by interfering with vesicular NE storage and enhancing intraneuronal NE metabolism, effects associated with an impaired NE release during sympathetic activation. Oral dosing with amiodarone has no such effect. Further study is required to test whether this novel sympatholytic effect of amiodarone contributes to its antiarrhythmic action after intravenous administration.
Key Words: amiodarone • dihydroxyphenylglycol • norepinephrine • reserpine • nervous system
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Introduction |
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Amiodarone is a potent antiarrhythmic agent with complex pharmacological properties. Enthusiasm for intravenous use of this drug is increasing after many clinical studies showing that an intravenous dosing regimen with amiodarone is particularly effective in abolishing resistant ventricular arrhythmias in heterogeneous clinical situations.1 2 3 4 5 6 7 8 9 10 11 Animal experiments in different species have also documented a similar antiarrhythmic activity.12 13 14 15 16 17 18 In the clinic, high-dose oral amiodarone has been reported to suppress resistant ventricular arrhythmias within a few days.19 20 21 22 The mechanisms for such protection, however, are incompletely known. Although defined as a class III antiarrhythmic agent,23 amiodarone possesses, to differing degrees, activities of other drug classes, including sodium and calcium channel blockade23 24 25 26 and adrenergic antagonism.23 27 28 There is convincing evidence that sympathetic activation is an important factor for the genesis of ventricular arrhythmias.15 29 30 31 However, the effect of amiodarone on sympathetic neurotransmission, especially in the heart, has been little studied.
We report here results from a study in rats showing that acute treatment with amiodarone produces a pronounced sympatholytic action, an effect that probably contributes to the antiarrhythmic property of amiodarone given intravenously. Since the effects of amiodarone suggested a "reserpine-like" action, we also examined the effects of reserpine in similar experimental protocols to give insight into the mechanism of action of amiodarone.
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Methods |
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Preparations
Male Sprague-Dawley rats (270 to 450 g) anesthetized with pentobarbitone (60 mg/kg IP) were used. Experiments were carried out either ex vivo in in situ perfused hearts or in anesthetized rats. For the in vitro experiments, the chest was opened, and after injection with heparin (200 U IV), a metal cannula was inserted into the ascending aorta to start coronary perfusion in situ.32 The perfusate was a modified Krebs-Henseleit solution containing (in mmol/L) NaCl 126, KCl 4.0, CaCl2 1.85, MgCl2 1.05, NaHCO3 25, Na2HPO4 0.5, glucose 11, and EDTA 0.027. The buffer was continuously gassed with 95% O2/5% CO2 (pH 7.4) and warmed to 37°C. Perfusion flow rates were controlled by a peristaltic pump and set at about 5 mL/g per minute by the heart weight estimated from body weight. The right atrium was cannulated for the collection of coronary venous effluent, with 85% to 100% recovery rate. In some experiments, a Millar microtip transducer catheter was positioned in the left ventricle through the apex to record the ventricular pressure and its first derivative (dP/dt).32 A 20-minute stabilizing period was allowed before experiments were started. Drugs were infused through a side arm of the perfusion line into the perfusion fluid with a model 22 pump (Harvard Apparatus). The left cervicothoracic stellate ganglion, with the cardiac nerves attached, was separated and mounted on a pair of bipolar electrodes for subsequent electrical stimulation with a model SD9 stimulator (Grass Instrument Co). The nerves were constantly superfused with warm and oxygenated buffer except when stimulated. Stimuli had a pulse width of 2 ms and a current of 0.8 mA. For experiments with anesthetized rats, the left femoral artery and the right femoral vein were cannulated for arterial blood sampling and infusion, and rats were allowed to recover for 20 minutes before experiments. Blood was collected (1 mL) at scheduled times, and plasma was separated. The separated red blood cells were resuspended in 0.5 mL Haemoccel and returned to the animals.
Catecholamine Assay
Samples of coronary venous effluent (from
in vitro experiments)
or plasma (from in vivo experiments) were immediately frozen on dry ice
and stored at -80°C until assay with high-performance liquid
chromatography.33 This method allowed simultaneous
determination of norepinephrine (NE), 3,4-dihydroxyphenylglycol (DHPG),
and epinephrine. Catecholamines and DHPG were adsorbed with activated
alumina, separated by high-performance liquid chromatography, and
quantified by electrochemical detection. Concentrations of epinephrine
in coronary effluent were very low (0 to 20 pg/mL) and therefore were
not included in the data analysis. Hearts from in vivo and in vitro
preparations were blotted dry, weighed, and stored at -80°C. They
were then homogenized in 0.4 mol/L perchloric acid (5 mL per heart),
and the catechols were assayed chromatographically.
Drugs Used
The amiodarone used was either a product of Sigma
Chemical Co or a commercial preparation, Cordarone, from Winthrop
Laboratories. Other agents used were desipramine, polysorbate 80 (Tween
80), reserpine, and DHPG, all obtained from Sigma.
Experimental Protocols
The experimental protocols in this
study were approved by the
Alfred Hospital and Baker Medical Research Institute Animal
Experimentation Committee and were consistent with guidelines of the
American Physiological Society.
To minimize the confounding influence of the neuronal reuptake mechanism on the issues investigated, a neuronal reuptake inhibitor, desipramine (final concentration of 0.3 µmol/L), was added to the perfusate in all experiments with perfused hearts.
Experiment 1
Effects of intravenous amiodarone on plasma and cardiac
levels of catechols were examined in anesthetized rats (n=6 per group).
In 3 groups, after collection of a control blood sample,
amiodarone (Winthrop Laboratories) diluted in 5% glucose
solution was infused intravenously, over a period of 2 minutes, at
doses of 5, 15, and 50 mg/kg. Blood samples were then taken at 13, 30,
and 60 minutes after the injection. Another 6 rats served as controls,
receiving an intravenous injection with 5% glucose solution, and blood
samples were taken before and 30 minutes after the injection. In 6 more
rats, reserpine (dissolved in DMSO) was injected intraperitoneally at 5
mg/kg, and blood samples were obtained at 13, 30, and 60 minutes after
the injection. At the end of the experiments, hearts were excised,
washed, and weighed.
The commercial preparation of amiodarone contains 100 mg Tween 80 per 50 mg amiodarone. Tween 80 possesses certain hemodynamic and electrophysiological effects.24 To examine the effect of Tween 80 on the issue studied, a supplementary experiment was undertaken that involved intravenous injection of anesthetized rats with Tween 80 at 100 mg/kg (n=6), and arterial blood was collected immediately before and 13, 30, and 60 minutes after the injection. Plasma concentrations of catecholamines and DHPG were measured.
Experiment 2
Effects of intravenous treatment with
amiodarone
(Winthrop Laboratories) given in vivo on subsequent nerve
stimulation-induced NE release in vitro (perfused hearts) and the
reversibility of such effects were studied. Two groups of rats (n=7
each) were injected through the tail vein with amiodarone at 50
mg/kg over a 2-minute period. Heart perfusion and nerve stimulation
experiments were carried out 1 hour (1 group) or 8 days (1 group) after
the treatment. Arterial blood was collected immediately before heart
perfusion. Sympathetic nerves were stimulated three times at 2, 4, and
8 Hz (in random order, 1-minute duration each at 10-minute intervals),
and effluent was collected for 1 minute immediately before nerve
stimulation and for a period of 2 minutes starting with nerve
stimulation. Another 7 rats were injected with 5% glucose solution
(controls), and heart perfusion and nerve stimulation experiments were
performed 8 days after the injection according to the protocol
described above.
Experiment 3
Effects of amiodarone
and reserpine on basal
overflow of NE and DHPG and on NE release in response to sympathetic
nerve stimulation were studied in perfused hearts. Amiodarone (Sigma)
was dissolved in 20% ethanol in water.13 Reserpine was
dissolved in DMSO. They were infused into the perfusion flow with final
concentrations of ethanol <.02% and of DMSO <.1%.
In 4 groups, hearts were treated with either amiodarone at 1, 3, or 10 µmol/L (equal to 0.68, 2.04, and 6.8 mg/L, respectively; 3 groups of 6 or 7 hearts) or vehicle (1 group, n=10). Ten minutes after infusion with amiodarone or vehicle, the sympathetic ganglion was stimulated at 5 Hz for 30 seconds. Coronary effluent was collected for a 1-minute period immediately before drug infusion, 3 and 10 minutes after drug infusion, and during nerve stimulation. For comparison, another 5 groups of hearts were treated with reserpine (final concentrations, 0.03, 0.3, 1, and 10 µmol/L, respectively; 4 groups of 6 hearts) or vehicle (DMSO 0.1%, 1 group, n=8). The same protocol as described above was followed. Furthermore, the possibility that a high DHPG level per se might interfere with NE release in response to nerve stimulation was tested in another group (n=6) by nerve stimulation applied twice (5 Hz for 1 minute) in the absence and presence of DHPG in the perfusate at a concentration of 2100 pg/mL (12.5 µmol/L).
To examine the effect of amiodarone versus reserpine on cardiac concentrations of catecholamines and DHPG, particularly NE and DHPG, three groups of hearts (n=6 per group) were subjected to 20-minute perfusion with amiodarone (10 µmol/L), reserpine (10 µmol/L), or vehicle, respectively. At the end of the 20-minute period, hearts were excised, weighed, and stored at -80°C for catechol assay.
Experiment 4
Effects of oral dosing
with amiodarone (Sigma) on plasma
and cardiac concentrations of catecholamines and metabolites and NE
release in response to sympathetic nerve stimulation were investigated.
Amiodarone was dissolved in water preheated to 50°C to 60°C and
sonicated.34 In 2 groups (n=8 each), rats received gavage
once daily with amiodarone (75 mg/kg) or water (controls) for 3
weeks. For comparison, another 8 rats were treated with reserpine
(dissolved in DMSO, 0.5 mg/kg IP every second day) for 2 weeks. At the
end of the treatment, rats were anesthetized and arterial blood samples
were taken. Hearts were then perfused in situ, and sympathetic nerves
were stimulated at 2, 4, and 8 Hz (in random order, 1-minute duration
each at 10-minute intervals). Coronary effluent was collected for 1
minute immediately before and for a period of 2 minutes starting with
each nerve stimulation. Concentrations of catecholamines and DHPG in
plasma, coronary effluent, and hearts were analyzed. To test whether a
high-dose loading regimen might have effects similar to those seen with
intravenous amiodarone, 5 rats received gavage every 8 hours
for 3 days with amiodarone at a daily dose of 450 mg/kg.
Another 5 rats were gavaged similarly with water and served as
controls. Rats were anesthetized 2 hours after the last dosing, and
arterial blood was collected to measure plasma levels of
catecholamines.
Statistical Analysis
Results are expressed as
mean±SEM. Differences between groups
were tested for statistical significance by one- or two-way ANOVA or by
unpaired or paired Student's t test. When applicable, a
simultaneous multicomparison test (Scheffé) was applied only if
the F statistical analysis indicated an overall statistical
significance between group means. The probability values from multiple
comparisons by Student's t test between two groups were
corrected by Bonferroni's method. A value of P<.05 (after
Bonferroni correction when applicable) was considered statistically
significant. The least-squares method was used for linear regression
and correlation between selected variables.
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Results |
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There was no difference in the coronary perfusion flow for heart perfusion experiments (combined data from groups of control, 4.87±0.14 mL/g per minute; amiodarone, 4.86±0.06 mL/g per minute; and reserpine, 5.07±0.14 mL/g per minute) or in body weight for in vivo experiments (control, 389±14 g; amiodarone, 382±7 g; and reserpine, 368±18 g).
Effects of Amiodarone and Reserpine on Plasma Concentrations of
Catechols In Vivo
In anesthetized rats, intravenous injection of
amiodarone
induced a dose-dependent increase in plasma DHPG, which was
statistically significant in all 3 groups at each time point examined
(Fig 1
). Amiodarone at 5 mg/kg increased plasma DHPG by
about 47%. At the highest dose, 50 mg/kg, there was an approximately
6-fold increase in plasma DHPG level 13 minutes after injection.
Similarly, treatment with reserpine resulted in a more than 10-fold
increase in plasma DHPG concentration at 13, 30, and 60 minutes
(5520±831, 7763±186, and 6513±509 pg/mL versus
664±23 pg/mL at 0
minute, all P<.01). In all groups, plasma levels of NE were
unchanged over the experimental period (Fig 1), but progressive
increase in plasma concentrations of epinephrine was observed. In
control rats injected with glucose solution, all parameters remained
stable over the 30-minute period examined (data not shown).
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Tween 80 at 100 mg/kg showed no effect on plasma concentrations of DHPG measured at 13, 30, and 60 minutes (592±37, 640±31, and 656±16 versus 597±20 pg/mL, P=NS). Thus, these data do not indicate a confounding influence of Tween 80.
Effects of Amiodarone on DHPG Overflow and Neural NE Release in
Perfused Hearts
DHPG overflow per minute was similar between groups
before
treatment with amiodarone (359 to 424 pg/g, P=NS).
Amiodarone induced a concentration-dependent increase in DHPG overflow
that was evident at 3 minutes and continued until at least 20 minutes
after drug administration (Fig 2). The basal overflow of
NE per minute was low and was not affected by amiodarone at
lower doses (control, 165±22 pg/g; 1 µmol/L, 101±18 pg/g;
and 3
µmol/L, 129±12 pg/g; all P=NS) but increased at 10
µmol/L (to 361±60 pg/g, P<.05).
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NE overflow per
minute into the effluent was low in hearts treated with
reserpine at 0.03 µmol/L (10-minute value versus control, 273±33
versus 255±24 pg/g, P=NS) but increased slightly at
higher
doses (0.3 µmol/L, 473±27 pg/g; 1 µmol/L, 520±43 pg/g;
and 10
µmol/L, 525±53 pg/g; all P<.05 versus control).
Reserpine markedly enhanced DHPG overflow; 3 minutes (data not shown)
after drug administration, DHPG overflow had already reached levels
similar to those measured at 10 minutes for all doses tested (Fig
3).
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In both control groups, nerve stimulation (5 Hz for
30 seconds)
induced NE release of about 6000 pg/g (after the basal overflow was
subtracted), and there was no significant difference between the two
groups. In hearts treated with amiodarone or reserpine,
quantities of evoked NE release were lower than the control values, and
such reduction tended to be dose-dependent (Fig 3
). Further
analysis of the grouped data showed that there was a significant
negative correlation between DHPG overflow measured immediately before
nerve stimulation and evoked NE release in response to nerve
stimulation (Fig 4). DHPG overflow was not affected by
nerve stimulation in any of the groups (data not shown). Increasing
perfusate DHPG concentration to 2100 pg/mL had no influence on evoked
NE release (6524±851 versus 6588±1011 pg/g, P=NS
by paired
t test).
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)
indicates amiodarone groups; (
), reserpine groups.
Effects of Intravenous Amiodarone on Evoked NE Release in Perfused
Hearts
There was a marked increase, compared with controls, in plasma
levels of DHPG and epinephrine 1 hour after intravenous
amiodarone at 50 mg/kg (both P<.01;
Table). Eight days after the injection, these
differences disappeared (all P=NS versus control and
P<.01 versus 1-hour amiodarone groups). Plasma
levels of NE were similar in all 3 groups.
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In perfused hearts, there
was a fivefold increase, after the 20-minute
stabilizing period, in DHPG overflow into coronary effluent in those
hearts in which perfusion started 1 hour after the injection
(P<.01 versus either control or 8-day amiodarone
groups). Such differences were no longer apparent in hearts perfused 8
days after amiodarone injection (Fig 5). Basal
NE overflow was not significantly different between these groups.
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In
hearts of control rats, nerve stimulation induced
frequency-dependent increases in NE overflow. In hearts in which
perfusion started 1 hour after amiodarone injection, NE release
induced by higher frequencies was suppressed by about 70%
(P<.01 versus controls, Fig 5). Eight days after
intravenous amiodarone, there was a significant recovery in the
capacity for NE release during nerve stimulation (P<.05
versus 1-hour amiodarone group), but quantities of NE released
were still about 30% to 40% lower than control values
(P<.05).
Effects of Oral Amiodarone
Plasma concentrations of catechols
and DHPG were similar between
control rats and rats orally dosed for 3 weeks with amiodarone
at 75 mg/kg (Table). A 3-day oral dosing with high-dose
amiodarone (450 mg/kg) did not induce any change in plasma
concentrations of DHPG, NE, or epinephrine (Table). In rats
treated
with reserpine for 2 weeks, plasma concentrations of NE and DHPG were
reduced (82±12 and 329±30 pg/mL, respectively, P<.05
versus control), whereas those of epinephrine increased (545±57 pg/mL,
P<.05), with a raised DHPG/NE ratio (4.71±1.01,
P<.05).
In perfused hearts of control and 75-mg/kg
amiodarone–treated
rats, basal overflow of NE and DHPG was similar. Nerve stimulation
induced a frequency-dependent release of NE, which was also similar
between the two groups (Fig 6). Nerve stimulation did
not affect the overflow of DHPG in any of the groups (data not shown).
Treatment with reserpine reduced basal overflow of NE and DHPG by about
70% to 80% and almost totally abolished NE release in response to
nerve stimulation (Fig 6).
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Functional Response to Sympathetic Nerve Stimulation in Relation to
NE Release
The left ventricular peak dP/dt at basal status was between
1500
and 1700 mm Hg/second and did not differ between drug-treated and
control groups of experiments 2 and 4 (data not shown). In control
hearts, dP/dt was increased by nerve stimulation in a
frequency-dependent manner. With oral amiodarone treatment, the
increase in inotropic response by sympathetic nerve stimulation was not
significantly affected (Fig 7A, P=.10 by
ANOVA). In contrast, in hearts of rats administered intravenous
amiodarone, the increase in dP/dt produced by nerve stimulation
was markedly inhibited during the acute phase (Fig 7B,
P<.01). This was largely but not totally reversed 8 days
afterward (P<.05 versus control). Chronic treatment with
reserpine almost totally prevented the inotropic response to nerve
stimulation (P<.01). There was a good correlation, on the
basis of group means, between quantities of NE release (data in Figs
5 and 6) and increases in dP/dt induced by nerve
stimulation at different
frequencies (Fig 7).
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dP/dt) in response to sympathetic nerve stimulation at
various frequencies in perfused hearts and the correlation between
Amiodarone, Reserpine, and Cardiac Content of Catechols and
DHPG
In hearts of rats treated with intravenous
amiodarone (50 mg/kg) or intraperitoneal reserpine (5 mg/kg),
the cardiac content of DHPG was increased and that of NE reduced
significantly compared with control values (both P<.01). As
a result, the DHPG/NE ratio was significantly increased (Fig 8,
top). These changes were more pronounced in
reserpine- than amiodarone-treated hearts (P<.05).
Compared with control values, amiodarone and reserpine both
significantly reduced epinephrine content (4.9±1.1 and 4.8±1.1
versus
12.5±2.8 ng/g, P<.01). In hearts perfused 8 days after the
injection, there was a 19% reduction in NE content (485.9±14.6 versus
588±60.4, P<.05) without significant change in DHPG
content (43.3±6.4 versus 49.4±4.0 ng/g), DHPG/NE ratio
(0.089±0.02
versus 0.086±0.01, P=NS), or epinephrine content
(10.0±1.6
versus 9.8±1.8 ng/g). Similar changes were observed in hearts perfused
for 20 minutes with amiodarone or reserpine (both at 10
µmol/L, Fig 8, middle). Epinephrine content was reduced by
reserpine
(6.6±0.8 versus 10.8±1.8 ng/g, P<.05) but not by
amiodarone (11.1±2.6 ng/g, P=NS versus
control).
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Three weeks after oral amiodarone at 75 mg/kg, cardiac
contents of DHPG, NE, and epinephrine (7.6±1.2 versus 7.3±1.3
ng/g,
P=NS) were basically unchanged compared with those of
control rats gavaged daily (Fig 8, bottom). In contrast, 2
weeks of
treatment with reserpine (0.5 mg/kg every second day) almost completely
depleted NE content in the heart, together with reduced DHPG and
epinephrine content (1.4±0.4 versus 7.3±1.3, P<.01)
and a
raised DHPG/NE (Fig 8).
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Discussion |
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This study demonstrates that acute administration of amiodarone, either injected intravenously or added to the perfusion medium, induces dose-dependent increases in the overflow to plasma or coronary effluent of DHPG, the intraneuronal metabolite of NE. Such increased DHPG overflow was associated with a reduced cardiac NE content and a raised DHPG/NE ratio both in vivo and in vitro. The functional consequence of this acute effect is suppressed NE release and inotropic response during sympathetic nerve stimulation in the heart. In contrast, oral dosing of amiodarone did not produce similar effects. So far as we are aware, this is the first report of such a sympatholytic action of amiodarone.
The effects of amiodarone demonstrated in this study were remarkably similar to those of reserpine. Reserpine is actively taken up by storage vesicles, where it interferes with catecholamine translocation through the amine transport carrier and dissociates the ATP-NE complex.35 36 This leads to an increase in free NE concentration in the axoplasm and subsequently to an increase in DHPG formation catalyzed by monoamine oxidase. As a highly lipophilic metabolite,37 DHPG diffuses easily across the axoplasmic membrane and appears in the circulation. In contrast, at physiological pH, NE is positively charged and largely retained within the axoplasm. A progressive rise in the plasma concentration of epinephrine after amiodarone injection can also be explained by the inhibition of amine transport in chromaffin granules.36 Being a more lipophilic and less charged molecule than NE,37 epinephrine in the axoplasm then diffuses into the circulation. DHPG can also be formed from the fraction of released NE recaptured by the Uptake1 carrier.38 39 The contribution of this mechanism to the observations in the perfused heart, however, was minimized by addition of the Uptake1 inhibitor desipramine.
A partial NE depletion with an increased DHPG content found in perfused hearts and hearts of anesthetized rats after treatment with amiodarone or reserpine can be explained by an impaired inward translocation of NE, NE leakage from vesicles, and blockade of NE synthesis after prevention of the inward transport of the precursor dopamine.35 36 This acute effect can be totally attributable to amiodarone per se, since the tissue level of its major metabolite, desethylamiodarone, is very low at this stage.40 41 42 43 44 Although the proposed mechanism of amiodarone action is likely, we have not excluded the possibility that amiodarone may be a vesicular H+-ATPase inhibitor. Catecholamine transport is driven by a H+ (acid inside) and potential (positive inside) gradient across the vesicular membrane, and NE inward transport is coupled with H+ outward transport.45 46 If amiodarone were to inhibit H+-ATPase and subsequently disrupt the H+-gradient, the process of catecholamine transport would be similarly impaired. This possibility requires further study.
Another similarity between the two agents is their long-lasting action after a single-dose injection. For reserpine, the induced depletion in tissue content of catecholamine may last several weeks because of persistent binding of reserpine to storage vesicles.35 A full recovery of neurotransmission after a single injection of reserpine is dependent on formation and transport of new storage vesicles down the axon and refilling of these vesicles with newly synthesized NE, processes that require 4 to 5 weeks.36 We observed a moderate reduction in cardiac NE content even 8 days after a single injection of amiodarone, although at this time an increased DHPG concentration in the heart, plasma, or coronary effluent was no longer evident. It is possible that a similar procedure holds for the recovery of neuronal function after amiodarone treatment. The finding in intact rats that even 10 days after a bolus injection amiodarone remains detectable in the heart supports this view.40
An interesting finding in the present study is a reduced ability of nerve stimulation to release NE in the perfused heart after acute treatment with amiodarone. The functional importance of such an effect is indicated by a depressed inotropic response of the ventricle to sympathetic activation. In hearts perfused with amiodarone, the extent of inhibition of NE release was related inversely to the levels of DHPG overflow, suggesting a partial depletion of vesicular NE storage as the underlying mechanism. Indeed, myocardial content of NE was reduced after a short period of treatment with amiodarone. In hearts exposed to amiodarone in vivo or in vitro, the degree of this depletion was about 25% to 40%, values much less than the 60% to 70% reduction in quantities of NE release induced by nerve stimulation. This discrepancy may be explained by a more profound depletion by amiodarone or reserpine of a "readily releasable NE pool" than that of a "storage pool," which contributes predominantly to the total NE content. The existence of two different NE storage pools has previously been postulated.47 48
In contrast to the evident effects of amiodarone given intravenously, oral administration at the doses examined fails to achieve similar effects. One previous study observed unchanged cardiac NE content and evoked NE release in the dog heart in vivo after 3 weeks of oral amiodarone.50 The present study does not reveal the mechanism responsible for the differences between the two dosing regimens. Detailed pharmacokinetic studies in rats have shown that immediately after intravenous administration of amiodarone at doses of 50 to 100 mg/kg, the peak plasma level reached is up to 30 to 50 µg/mL, followed by a rapid accumulation of this drug in the myocardium, with a peak content of 100 to 300 µg/g, depending on dose and time of sampling.40 41 42 When given orally, bioavailability of amiodarone is low (about 35% to 40%). Latini et al50 reported the myocardial content of amiodarone to be 36 to 122 µg/g in rats with oral dosing at 75 to 150 mg/kg for 3 weeks. These values are lower than the maximum, although transient, cardiac content of amiodarone after intravenous injection, presumably because of lower plasma concentrations of amiodarone and continuous metabolism in the tissue. A similar difference in blood and tissue levels of amiodarone achieved by oral and intravenous regimens has also been observed in other species29 43 44 51 52 and in humans.1 51 53 Thus, the discrepancy in vesicular NE effects after different regimens seems to be due to higher tissue levels of amiodarone. However, this speculation cannot well explain the facts that intravenous amiodarone at lower doses, which would lead to lower tissue content of this drug, remains effective in inducing DHPG overflow while our high-dose oral dosing was ineffective. Thus, further study is needed to clarify whether intravenous and oral regimens of amiodarone are qualitatively different in regard to the effect on sympathetic neurons.
There is strong evidence that sympathetic activation is involved in the genesis of ventricular arrhythmias in a variety of cardiac disorders, such as myocardial ischemia and infarction and heart failure.30 31 32 54 Schwartz et al15 demonstrated in cats that intravenous amiodarone almost completely abolished ventricular tachyarrhythmias induced by a combination of acute ischemia and sympathetic ganglion stimulation. The striking difference in the rate of onset of antiarrhythmic activity between intravenous (minutes or hours) and oral (days or weeks) amiodarone is well known.1 24 Previous studies have indicated that different mechanisms may be responsible for the antiarrhythmic effects of intravenous and chronic oral amiodarone.14 15 16 17 23 55 56 The acute electrophysiological effects of intravenous amiodarone, especially prolongation of the action potential duration and effective refractory periods, are much less than those observed after long-term oral loading at conventional dosage.23 44 52 55 56 57 58 59 Conversely, intravenous amiodarone can achieve prompt blockade of slow channels and adrenergic receptors,1 16 17 23 although the ß-adrenergic blockade may also become apparent within a few days after oral loading at higher doses.60 Our data indicate a rapid onset of NE depletion and suppression of NE release by intravenous amiodarone, effects that may be, at least in part, responsible for the potent antiarrhythmic property seen after intravenous injection. This possibility remains to be examined.
In conclusion, the present study demonstrates a novel pharmacological action of amiodarone, specifically a partial depletion of NE in the sympathetic neuron and reduction in NE release during sympathetic activation. These effects can be achieved only by intravenous dosing. We speculate that this sympatholytic action possibly contributes to the potent antiarrhythmic property of amiodarone given intravenously. It is also possible that this action of amiodarone is involved in the hemodynamic changes after intravenous administration by lowering overall sympathetic tone in the cardiovascular system.8 23 61 However, caution is necessary when extrapolating the findings from this study in the rat into a clinical context, since we have not examined this aspect in other species and in humans.
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Acknowledgments |
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This study was supported by a postdoctoral fellowship grant (K.A.B. Smith Trust) from the Alfred Group of Hospitals Research Fund (Dr. Du) and by an Institute Grant to the Baker Medical Research Institute from the National Health and Medical Research Council of Australia. The authors wish to thank Helen Cox and Andrea Turner for technical assistance in performing catecholamine assays.
Received July 6, 1994; accepted August 2, 1994.
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