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The areca nut, popularly known as the betel nut, is
almost symbolic of oriental culture, and is one of the oldest
known masticatories in Asia. The composition of the betel
quid varies regionally. In general, betel quid is composed of
betel leaf, areca nut, catechu and lime, to which tobacco is
sometimes added[1]. Betel nut is the endosperm of the fruit
of the Areca catechu tree. It contains several alkaloids, of
which arecoline is the most abundant[2,3]
. The pharmacological effects of betel nut include addiction, euphoria, excessive salivation and tremors, which are attributable to
the cholinergic effects of arecoline, the major alkaloid of the
betel nut[4].
Molinengo and coworkers found that lower doses of
arecoline caused neither modification of acetylcholine (ACh)
levels nor mouse motility, but higher doses of arecoline
caused a reduction in motility and an increase in the ACh
levels in the subcortical structures of the mouse central
nervous system[5]. It has also been shown that arecoline causes
a reduction in levels of ACh in the cortex and subcortex of
mice at the limit of statistical significance, but a statistically
significant reduction in levels of
norepinephrine[5]. The major constituent of betel nut, arecoline, may aggravate
bronchial asthma[6] and change urine volume and urinary
electrolyte excretion[7]. Arecoline has been used to treat patients
with Alzheimer¡¯s presenile dementia[8]. In such patients, it
has been shown to improve verbal memory and performance
in picture memory tasks[9]. In experimental models, arecoline
prevented scopolamine-induced impairment in task
acquisition[10], and restored passive avoidance
performance[11], indicating that certain kinds of memory depend, at least in
part, on cholinergic activity.
Arecoline has also been considered an
M1/M3 partial agonist, with a peak effect of approximately half the
maximum obtained with pilocarpine in rat brain
slices[12,13]. However, arecoline appears to be a full agonist in membranes
prepared from rat cortical slices, regardless of guanosine
5¡¯-O-(3-thiotriphosphate)
concentrations[14]. Recently, it has been suggested that the underlying mechanism by which
phosphoinositide turnover is inhibited in rat cortical slices
is arecoline-induced receptor
sequestration[15]. Yang and colleagues reported that arecoline exerted its excitatory
action by binding M2-muscarinic receptors on the cell
membrane of neurons of the locus
coeruleus[16].
It has been concluded that the pressor effects brought
about by quaternary compounds can be attributed to the
stimulation of nicotinic and muscarinic receptors in the
sympathetic ganglia of both pithed and anesthetized
rats[17]. Moreover, Polinsky and coworkers found that the increased
plasma epinephrine levels following arecoline treatment in
normal subjects and patients with multiple system atrophy
might result from nicotinic adrenal
stimulation[18]. It has also been reported that betel chewing increases plasma
concentrations of norepinephrine and
epinephrine[19]. However, the mechanism underlying the pressor effect and increased
plasma catecholamine (CA) concentration remains poorly
understood. Therefore, the present study was designed to
investigate the effects of arecoline on catecholamine
secretion in an isolated perfused model of the rat adrenal gland,
and to clarify its mechanism of action.
Materials and methods
Experimental procedure Male Sprague-Dawley rats,
weighing 200-300 g, were anesthetized with thiopental
sodium (50 mg/kg) intraperitoneally. Adrenal glands were
isolated by modification of the methods described
previously[20]. The abdomen was opened by a midline incision, and the left
adrenal gland and surrounding area were exposed by the
placement of three-hook retractors. The stomach, intestine
and a portion of the liver were not removed, but pushed over
to the right side and covered with saline-soaked gauge pads
while urine in the bladder was removed, in order to obtain
enough working space for tying blood vessels and carrying
out the cannulations. A cannula, which was used for
perfusion of the adrenal gland, was inserted into the distal end of
the renal vein after all branches of the adrenal vein (if any),
vena cava and aorta were ligated. Heparin (400 IU/mL) was
injected into the vena cava to prevent blood coagulation
before ligating the vessels and carrying out the cannulations.
A small slit was cut into the adrenal cortex just opposite the
entrance of the adrenal vein. Perfusion of the gland was
started, making sure that no leakage occurred, and the
perfusion fluid escaped only from the slit made in the adrenal
cortex. Then the adrenal gland, along with the ligated blood
vessels and the cannula, was carefully removed from the
animal and placed on a platform in a leucite chamber. Water
heated to 37±1 °C was continuously circulated in the chamber.
Drugs and their sources The following drugs were used:
arecoline hydrobromide, acetylcholine chloride,
1.1-dimethyl-4-phenyl piperazinium iodide (DMPP), (-) nicotine,
norepinephrine bitartrate,
methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5-carboxylate
(Bay-K-8644) (Sigma, USA), cyclopiazonic acid,
3-(m-choloro-phenyl-carbamoyl-oxy)-2-butynyl trimethyl ammonium chloride
(McN-A-343) (RBI, USA). Drugs were dissolved in distilled
water (stock) and added to the normal Krebs solution as
required except Bay-K-8644, which was dissolved in 99.5%
ethanol and diluted appropriately (final concentration of
alcohol was less than 0.1%). Concentrations of all drugs used
are expressed in terms of molar base.
Perfusion of adrenal gland The adrenal glands were
perfused by means of an ISCO pump (WIZ Co) at a rate of
0.33 mL/min. The perfusion was carried out with Krebs
bicarbonate solution of the following composition (mmol/L):
NaCl, 118.4; KCl, 4.7; CaCl2, 2.5;
MgCl2, 1.18; NaHCO3, 25;
KH2PO4, 1.2; glucose, 11.7. The solution was constantly
bubbled with 95% O2+5% CO2 and the final pH of the
solution was maintained in the range of 7.4-7.5. The solution
contained disodium ethylenediamine tetraacetic acid (EDTA)
(2.97×10-5 mol/L) and ascorbic
acid (5.68×10-4 mol/L) to prevent oxidation of CA.
Drug administration The perfusions of DMPP
(1×10-4 mol/L) and McN-A-343
(1×10-4 mol/L) for 2 min, and a single
injection of ACh (5.32 mmol/L) and KCl (5.6 mmol/L) in a
volume of 0.05 mL were made into the perfusion stream via a
three-way stopcock, respectively. Bay-K-8644
(1×10-5 mol/L) and cyclopiazonic acid
(1×10-5 mol/L) were also perfused for
4 min, respectively.
In the preliminary experiments, it was found that after
administration of these drugs, secretory responses to ACh,
KCl, McN-A-343, Bay-K-8644 and cyclopiazonic acid returned
to pre-injection levels in approximately 4 min, but the
responses to DMPP took 8 min.
Collection of perfusate Prior to stimulation with various
secretagogues, the perfusate was collected for 4 min to
determine the spontaneous secretion of CA (background
sample). Immediately after these samples were taken,
collection of the perfusates was continued in another tube as soon
as the perfusion medium containing the stimulatory agent
reached the adrenal gland. These samples were collected for
4-8 min. The amounts secreted in the background sample
were subtracted from those secreted in the stimulated sample
to obtain the net secretion value of CA.
To study the effect of arecoline on spontaneous and
evoked secretion, adrenal glands were perfused with Krebs
solution containing arecoline for 60 min. Then the perfusate
was collected for a certain period as a background sample.
The medium was changed to the one containing the
stimulating agent along with arecoline, and the perfusates were
collected for the same period as the background sample.
The adrenal gland perfusates were collected in chilled tubes.
Measurement of catecholamines CA content of
perfusate was measured directly by using the fluorometric method
of Anton and Sayre[21], without the intermediate purification
alumina for the reasons described
earlier[20], using a
fluorospectrophotometer (Kontron, Milan, Italy). A volume
of 0.2 mL of the perfusate was used for the reaction. The CA
content in the perfusate of the stimulated glands achieved
by using secretagogues used in the present work was high
enough to obtain readings several times greater than the
reading of control samples (unstimulated). The sample blanks
were also lowest for perfusates of stimulated and
non-stimulated samples. The content of CA in the perfusate was
expressed in terms of norepinephrine (base) equivalents.
Statistical analysis The statistical difference between
the control and pretreated groups was determined by using
Student¡¯s t-test and ANOVA. A P-value of less than 0.05
was considered to represent statistically significant changes
unless specifically noted in the text. Values given in the text
refer to the means and the standard errors of the mean (SEM).
The statistical analysis of the experimental results was done
by the computer program described by Tallarida and
Murray[22].
Results
Effect of arecoline on CA secretion evoked by ACh,
excess K+, DMPP and McN-A-343 from the perfused rat
adrenal glands After perfusion with oxygenated Krebs
bicarbonate solution for 1 h, basal CA release from the isolated
perfused rat adrenal glands amounted to 23.1±2.2 ng per 2
min (n=6). Because the addition of arecoline in rat brain
cortical slices inhibited the carbachol-stimulated
phosphoinositide breakdown[15], we initially attempted to
examine the effects of arecoline itself on CA secretion from
the perfused model of the rat adrenal glands. However, in
the present study, arecoline
(1×10-4-1×10-3 mol/L) by itself
did not produce any effect on basal CA output of the
perfused rat adrenal glands (data not shown). Therefore, it was
decided to investigate the effects of arecoline on cholinergic
receptor stimulation, as well as membrane
depolarization-mediated CA secretion. Secretagogues were given at 15 min
intervals. Arecoline was present 15 min before initiation of
stimulation.
When ACh (5.32×10-3 mol/L) in a volume of 0.05 mL was
injected into the perfusion stream, the amount of CA
secreted was 283±36 ng for 4 min. Pretreatment with arecoline
for 60 min at concentrations ranging from
1×10-4 to 1×10-3 mol/L inhibited ACh-stimulated CA secretion in 6 adrenal
glands in a time-dependent manner. As shown in Figure 1
(upper panel), in the presence of arecoline, CA-releasing
responses were inhibited to 88%-30% of the corresponding
control release. It has also been found that depolarizing
agents such as KCl markedly stimulate CA secretion (128±16
ng for 0-4 min). Excess K+
(5.6×10-2 mol/L)-stimulated CA
secretion, after pretreatment with a lower concentration of
arecoline (1×10-4 mol/L), was not affected as compared with
its corresponding control secretion (100%) (Figure 1, lower
panel). However, following pretreatment with higher
concentrations of arecoline (3×10-4
mol/L and 1×10-3 mol/L), excess
K+ (5.6×10-2 mol/L)-stimulated CA secretion was
significantly inhibited. When perfused through the rat adrenal
gland, DMPP (1×10-4 mol/L), which is a selective nicotinic
receptor agonist in autonomic sympathetic ganglia, evoked
a sharp and rapid increase in CA secretion (512±24 ng for
0-8 min). However, as shown in Figure 2 (upper panel),
DMPP-stimulated CA secretion after pretreatment with arecoline was
significantly reduced to a maximum of 16% of the control
release (100%) in 6 rat adrenal glands. McN-A-343
(1×10-4 mol/L), which is a selective muscarinic
M1-agonist[23], when perfused into an adrenal gland for 4 min, caused increased
CA secretion (79±8 ng for 0-4 min) from 6 glands. However,
McN-A-343-stimulated CA secretion in the presence of
arecoline was markedly depressed to 75%-0% of the
corresponding control secretion (100%) as depicted in Figure 2
(lower panel).
Effect of arecoline on CA secretion evoked by
Bay-K-8644 and cyclopiazonic acid from perfused rat adrenal
glands Because Bay-K-8644 is known to be a calcium
channel activator that enhances basal
Ca2+ uptake[24] and CA
release[25], it was of interest to determine the effects of arecoline
on Bay-K-8644-stimulated CA secretion from isolated
perfused rat adrenal glands. As shown in Figure 3 (upper panel),
Bay-K-8644 (1×10-5 mol/L)-stimulated CA secretion in the
presence of arecoline was significantly blocked to 85%-33%
as compared with the control release (92±7 ng for 0-4 min).
The only exception to this decrease was the first 4 min,
during which an increase occurred.
Cyclopiazonic acid, a mycotoxin from
Aspergillus and Penicillium, has been described as a highly selective
inhibitor of Ca2+-ATPase in skeletal muscle sarcoplasmic
reticulum[26,27]. The inhibitory action of arecoline on cyclopiazonic
acid-evoked CA secretory response was observed as shown
in Figure 3 (lower panel). However, in the presence of
arecoline in 6 rat adrenal glands, cyclopiazonic acid
(1×10-5 mol/L)-evoked CA secretion was not altered in comparison
with the control response (52±4 ng for 0-4 min).
Effect of nicotine on CA secretion evoked by ACh,
excess K+, DMPP, and McN-A-343 from the perfused rat
adrenal glands It has been reported that arecoline increases
plasma epinephrine levels in normal subjects and patients
with multiple system atrophy, which may result from
nicotinic adrenal stimulation[18]. Therefore, in order to compare the effects of nicotine with those of arecoline, it was of
interest to examine the effect of nicotine on CA secretion from
isolated perfused rat adrenal glands evoked by ACh, high
K+, and DMPP. In order to test the effect of nicotine on
cholinergic receptor-stimulated CA secretion as well as
membrane depolarization-mediated secretion, when nicotine
(3×10-5 mol/L) was loaded into the adrenal medulla, the
released CA amounted to 40±10 ng (0-4 min) and 24±6 ng
(15-19 min) without any more release after 30 min (Figure 4). In
the present experiment, ACh
(5.32×10-3 mol/L)-evoked CA release, before perfusion with nicotine, was 358±39 ng (0-4
min). In the presence of nicotine
(3×10-5 mol/L) for 60 min, ACh-evoked CA release initially increased to 149% of the
control in the first 4 min period. As time elapsed, this CA
release gradually reduced to 46% of the control (Figure 5,
upper panel). High K+
(5.6×10-2 mol/L)-evoked CA release,
in the presence of nicotine, was significantly enhanced to
260% in the first 4 min, and then gradually changed to 131%
of the control secretion (120±14 ng, 0-4 min). Only in the
last period (98%±9%, 60-64 min) did the secretions return to
the control level, as shown in Figure 5 (lower panel). In 8 rat
adrenal glands, DMPP (1×10-4 mol/L) perfused into the
adrenal gland evoked a marked CA secretion of 537±59 ng (0-8
min) before loading with nicotine. Following perfusion with
the nicotine, the secretion was considerably diminished to a
maximum of 19% of the corresponding control release (Figure
6, upper panel). Moreover, in the presence of nicotine,
McN-A-343 (10-4 mol/L)-evoked CA secretory responses were also
time-dependently inhibited to 23% of the control secretion
(81±9 ng, 60-64 min) from 6 glands, as shown in Figure 6
(lower panel).
Discussion
The present study shows that arecoline dose- and
time-dependently inhibits CA secretory responses from the
perfused rat adrenal gland evoked by ACh, DMPP, and
McN-A-343. Arecoline in lower doses did not affect CA secretion
induced by high K+; however, higher doses greatly reduced
CA secretion of high K+. Furthermore, in adrenal glands
loaded with arecoline, CA secretory responses evoked by
Bay-K-8644, an activator of L-type Ca2+ channels, was
markedly inhibited, whereas CA secretion evoked by
cyclopia-zonic acid, an inhibitor of cytoplasmic
Ca2+-ATPase, was not affected. In contrast to arecoline exposure, exposure of the
adrenal gland to nicotine (30 µmol/L) for 60 min initially
enhanced the ACh-evoked CA secretory responses. These
responses were inhibited as time elapsed, whereas the
initially enhanced high K+-evoked CA release was time-depen
dently diminished. CA secretion evoked by DMPP and
McN-A-343 was significantly depressed in the presence of
nicotine. Taken together, these results suggest that arecoline
greatly inhibits CA secretion evoked by the activation of
cholinergic (both nicotinic and muscarinic) receptors. At
lower doses arecoline does not inhibit CA secretion by
membrane depolarization, but at larger doses it does. We
suggest that this inhibitory effect of arecoline may be mediated
by blocking the calcium influx into the rat adrenal medullary
chromaffin cells without the inhibition of
Ca2+ release from the cytoplasmic calcium store. It seems that there is a
difference in the mode of action between nicotine and arecoline in
rat adrenomedullary CA secretion.
In support of this idea, it has been found that arecoline
(10 mg/kg) injected subcutaneously caused a reduction in
levels of ACh in the mouse cortex and subcortex, and a great
reduction in levels of
norepinephrine[28]. However, higher doses (28.5 and 60 mg/kg per day) were found to cause a
reduction in mouse motility and an increase of the ACh
levels in the subcortical structure of the CNS of the
mouse[5]. However, Polinsky and colleagues have shown that increased
plasma epinephrine levels, following arecoline
administration in normal subjects and patients with multiple system
atrophy, may result from nicotinic adrenal
stimulation[18]. Recently, it has been found that chewing betel, which
contains arecoline, and Piper betel flower or leaf, which contain
aromatic phenolic compounds that have been found to
stimulate the release of catecholamine in in
vitro studies, also increase plasma concentrations of norepinephrine and
epinephrine in normal subjects[19]. However, in the present
study, our finding that arecoline greatly inhibited the CA
secretory responses evoked by ACh and DMPP, selective
neuronal nicotinic receptor agonists, clearly suggests that
arecoline can act as an antagonist of the nicotinic receptors
in rat adrenal medulla. Furthermore, at 1 mmol/L (the highest
concentration tested) arecoline completely blocked the CA
secretory responses that would have been evoked by
cholinergic stimulation. Therefore, the results of the present
experiments are not in agreement with those of previous
studies[18,19], in which plasma CA levels were elevated following
arecoline treatment or betel chewing. All concentrations (0.1-1.0 mmol/L) of arecoline used in these experiments failed
to evoke any secretions of CA. In terms of these findings, it
seems that arecoline at the concentrations used in the present
study does not act as a nicotinic receptor agonist in
perfused rat adrenal medulla.
Generally, arecoline has been considered as a
M1/M3 partial agonist with a peak effect of approximately half that
of the maximum obtained with pilocarpine in rat brain slices[12,13]. However, arecoline appears to be a full agonist
in membranes prepared from rat cortical slices regardless of
guanosine 5¡¯-O-(3-thiotriphosphate)
concentrations[14]. To assess the influence of arecoline treatment on muscarinic
receptor-associated phosphoinositide signaling pathways,
Lee and colleagues[15] investigated the effects of acute and
chronic administration of arecoline on muscarinic cholinergic
receptor-stimulated phosphoinositide turnover in rat brain
cortical slices. They found that administration of arecoline
inhibited carbachol-stimulated phosphoinositide turnover.
In terms of this finding, our finding that arecoline completely
abolishes the CA secretion evoked by McN-A-343, a
selective muscarinic M1-receptor agonist, suggests that arecoline
has an anti-muscarinic activity. In the present experiment,
more than 90% of the inhibitory response could also be
reversed by perfusion of the adrenal medulla with an
arecoline-free medium for 1.5 h after arecoline exposure. It would also
seem that this inhibition did not result from cytotoxicity.
In the present investigation, arecoline at higher
concentrations (0.3-1.0 mmol/L) greatly attenuated CA secretions
evoked by high K+, a direct membrane-depolarizing agent.
This result suggests that arecoline can block
voltage-sensitive Ca2+ channels. In support of this finding, our finding
that arecoline greatly attenuates the CA secretion evoked
by Bay-K-8644, an activator of L-type
Ca2+ channels, indicates that arecoline may act as a
Ca2+ channel antagonist in the rat adrenal medulla. Bay-K-8644 has been found to
enhance the release of CA by increasing
Ca2+ influx through L-type Ca2+ channels in cultured bovine chromaffin
cells[24]. Moreover, previous studies on primary cultures of bovine
chromaffin cells have shown that dihydropyridines can
partially inhibit CA secretion induced by depolarization with
ACh, nicotine or K+. The degree of inhibition varies
between studies depending on the dihydropyridine used, its
concentration, and the concentration of
agonist[29-31]. How-ever, at high concentrations
(³1 µmol/L), dihydropyridines block the nicotinic receptor-related ion channels, and at these
concentrations they also inhibit calcium uptake and CA
secretion induced by nicotinic agonists without comparable
effects on K+-evoked
responses[32]. Nitrendipine at a concentration of 1
mmol/L was found to be sufficient to reduce the contraction of pig coronary artery rings induced by 30
mmol/L K+ [33].
The most plausible explanation of this finding is that
arecoline also has a direct blocking effect on
Ca2+ channels. Therefore, the present experimental results imply that
arecoline itself blocks Ca2+ entry into the adrenomedullary
chromaffin cells by inhibiting voltage-dependent
Ca2+ channels and, as consequence, it inhibits the
Ca2+-dependent
release of CA evoked by cholinergic stimulation as well as
membrane-depolarization.
However, in the present work, arecoline did not inhibit
the increase in CA secretion evoked by cyclopiazonic acid.
Cyclopiazonic acid is a highly selective inhibitor of
Ca2+-ATPase in skeletal muscle sarcoplasmic
reticulum[26,27], and a valuable pharmacological tool for investigating intracellular
Ca2+ mobilization and ionic currents regulated by
intracellular Ca2+ [34]. In light of these facts, therefore, we think that the
inhibitory effect of arecoline on CA secretion evoked by
cholinergic stimulation as well as by
membrane-depolarization is not associated with the mobilization of intracellular
Ca2+ in chromaffin cells.
In the present study, nicotine (30 µmol/L) initially
enhanced the CA secretion evoked by ACh and high
K+, but later inhibited the secretion in a time-dependent manner. In
light of this finding, it appears that the mechanism by which
arecoline exerts its influence on the CA-releasing effects
evoked by cholinergic stimulation, as well as by membrane
depolarization, in the perfused rat adrenal medulla is quite
different from that of nicotine. In support of this idea, it has
been found that the arecoline-induced excitatory effects in
rat brain slices were not antagonized by
hexamethonium[16]. In contrast, the effect of nicotine (endogenous ACh,
splanchnic nerve stimulation) on CA secretion from the rat adrenal
gland was greatly reduced (75%) by hexamethonium
alone[35]. Based on these results, it seems that there is clearly
a large difference in the modes of action of arecoline and
nicotine, at least with respect to rat adrenomedullary CA
secretion. There do, however, exist controversial findings
that arecoline appears as a partial agonist in whole cells and
a full agonist in membranes prepared from rat cortical slices[14]. The data obtained here, that arecoline inhibits the
CA secretory responses evoked by cholinergic stimulation
(ACh and DMPP), imply that it has the properties of an
antagonist at the nicotinic ACh receptors, which mediate
nicotinic effects in adrenomedullary chromaffin cells.
In conclusion, the results of the present study using
isolated perfused rat adrenal glands demonstrate that
arecoline greatly inhibits the CA secretion evoked by
stimulation of cholinergic (both nicotinic and muscarinic)
receptors in a dose- and time-dependent fashion. However, at
lower doses, arecoline does not inhibit CA secretion by
membrane depolarization, but at larger dose it does. It seems that
this inhibitory effect of arecoline may be mediated by
blocking calcium influx into the rat adrenal medullary chromaffin
cells without the inhibition of Ca2+ release from the
cytoplasmic calcium store. These data indicate that nicotine and
arecoline have different modes of action with respect to rat adrenomedullary CA secretion.
Acknowledgement
We thank Ms Hye-Kyeong SHIN for technical
assis-tance.
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