Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-4970
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ABSTRACT |
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The administration of selective
1 (phenylephrine)-,
(isoproterenol)-, or mixed
(epinephrine) adrenergic agonists induces a marked Mg2+
extrusion from perfused rat livers. In the absence of extracellular Ca2+, phenylephrine does not induce a detectable
Mg2+ extrusion, isoproterenol-induced Mg2+
mobilization is unaffected, and epinephrine induces a net
Mg2+ extrusion that is lower than in the presence of
extracellular Ca2+ and quantitatively similar to that
elicited by isoproterenol. In the absence of extracellular
Na+, no Mg2+ is extruded from the liver
irrespective of the agonist used. Similar results are observed in
perfused livers stimulated by glucagon or 8-chloroadenosine
3',5'-cyclic monophosphate. In the absence of extracellular
Na+ or Ca2+, adrenergic-induced glucose
extrusion from the liver is also markedly decreased. Together, these
results indicate that liver cells extrude Mg2+ primarily
via a Na+-dependent mechanism. This extrusion pathway can
be activated by the increase in cellular cAMP that follows the
stimulation by glucagon or a specific
-adrenergic receptor agonist
or, alternatively, by the changes in cellular Ca2+ induced
by the stimulation of the
1-adrenoceptor. In addition, the stimulation of the
1-adrenoceptor appears to
activate an auxiliary Ca2+-dependent Mg2+
extrusion pathway. Finally, our data suggest that experimental conditions that affect Mg2+ mobilization also interfere
with glucose extrusion from liver cells.
1-adrenoceptor;
-adrenoceptor; hepatocyte; glucose
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INTRODUCTION |
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IN THE LAST DECADE OUR UNDERSTANDING of cellular Mg2+ homeostasis and its role in regulating cytosolic or membrane-bound enzymes (6, 8, 35), ion channels (8, 35), and metabolic cycles (25, 42) has improved significantly. The concept that cellular Mg2+ content remains relatively constant under varying metabolic conditions has been largely reevaluated because several experimental reports indicate that major fluxes of Mg2+ can cross the plasma membrane of mammalian cells in either direction within minutes of the application of various hormonal or metabolic stimuli (see Refs. 10, 29, and 35 for review).
Despite increasing evidence for the operation of Mg2+
transporters in the cell membrane, the structure and nature of the
transporters remain to be elucidated. The data available in the
literature support the idea that two distinct Mg2+
transport mechanisms operate in the plasma membrane of mammalian cells.
A Na+-dependent mechanism, tentatively identified as a
Na+/Mg2+ exchanger (7, 13), likely
represents the most abundant Mg2+ extrusion pathway in
cardiac myocytes (30, 41), hepatocytes (18,
31), thymocytes (15), and other cell types as well. This exchanger specifically requires Na+ as counterion for
Mg2+ extrusion (11, 13, 30, 31) and appears to
operate in either direction based on the ion gradient across the cell
membrane (11, 30, 31). Under conditions in which the
operation of this exchanger is prevented by the absence of
extracellular Na+ (30, 31) or by the presence
of the Na+ transport inhibitors amiloride (18,
41) or imipramine (5), Mg2+ is extruded
via an alternative pathway identified as a Na+-independent
mechanism (14). The extrusion of Mg2+ via this
second pathway appears to utilize divalent cations such as
Ca2+ (30, 31) or Mn2+ (4,
17) or anions such as HCO3 or Cl
(12). Recently, this laboratory (1, 2)
provided further evidence for the operation of distinct
Na+- and Ca2+-dependent Mg2+
extrusion mechanisms, located in the basolateral domain and apical portion, respectively, of the hepatocyte plasma membrane.
However, whether the Na+-dependent and -independent
Mg2+ extrusion mechanisms operate concomitantly or
alternatively under different stimulatory conditions remains undefined.
Activation of -adrenergic receptors by isoproterenol (Iso)
(21, 41), epinephrine (Epi) (22), or
norepinephrine (18, 30, 31, 34) in isolated cardiac
(30, 33, 41) or liver (18, 31, 34) cells, perfused heart (33, 41) or liver (18, 31,
34), or anesthetized animals (15, 21) results in a
marked mobilization of cellular Mg2+ into the extracellular
compartment and ultimately into the bloodstream via a
Na+/Mg2+ exchanger. The stimulatory effect of
cell-permeant cAMP analogs or forskolin (18, 30, 33, 34)
and the inhibitory effect of Rp-cAMP (43) strongly support
the idea that the Na+/Mg2+ exchanger becomes
active after phosphorylation by cAMP (15). In contrast,
relatively little is known about hormonal activation of the
Na+-independent mechanism. Our laboratory reported
previously that a physiological extracellular Ca2+
concentration ([Ca2+]o) is required to
observe a Mg2+ extrusion from cardiac (30) or
liver cells (31) stimulated by norepinephrine, which
supports the idea that the Na+-independent transport
mechanism is involved, to some extent, in hormonal mobilization of
cellular Mg2+. Furthermore, Jakob et al. (20)
and, more recently, Keenan et al. (22) provided evidence
for a role of the
1-adrenergic receptor in mediating an
extrusion of Mg2+ from liver cells after phenylephrine
(Phe) administration through an uncharacterized transport mechanism.
Hence, in the present study we investigated the possibility that
1-adrenoceptor-induced Mg2+ extrusion
specifically occurs via the Na+-independent
(Ca2+-dependent) mechanism. The results reported here
indicate for the first time that the stimulation of the
1-adrenoceptor results in an extrusion of
Mg2+ from liver cells primarily via a
Na+-dependent pathway and only marginally via a
Ca2+-dependent mechanism. By contrast, the specific
stimulation of the
-adrenergic receptor results in the selective
activation of a Na+-dependent Mg2+ extrusion
mechanism. The administration of a mixed adrenergic agonist (e.g., Epi)
results in a Mg2+ extrusion that is larger than that
attained by the administration of a selective
1- or
-adrenergic agonist alone.
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MATERIALS AND METHODS |
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Chemicals. Collagenase (CLS-2) was from Worthington (Lakewood, NJ). Enzymatic kits for glucose and lactate dehydrogenase (LDH) determinations in the perfusate and all other reagents were from Sigma (St. Louis, MO).
Perfused livers.
Fed male Sprague-Dawley rats (250-300 g body wt) were anesthetized
by intraperitoneal injection of pentobarbital sodium (50 mg/kg). The
abdomen was opened, and the liver was perfused via the portal vein with
a medium containing (mM) 120 NaCl, 3 KCl, 1.2 CaCl2, 12 NaHCO3, 1.2 KH2PO4, 15 glucose, and
10 HEPES, pH 7.2 at 37°C, equilibrated with an
O2-CO2 (95:5 vol/vol) gas mixture (regular
perfusion medium). The liver was quickly removed from the abdomen,
placed on a platform for a 20-min washout period, and perfused at a
flow rate of 3.5-4
ml · g1 · min
1. Aliquots of
the perfusate were collected at 30-s intervals, and Mg2+
content was measured by atomic absorbance spectroscopy (AAS) in
a Perkin-Elmer 3100 atomic absorbance flame spectrophotometer. The first 10 min after the washout period provided a baseline for
subsequent adrenergic agent addition. Phe (5 µM), Iso (10 µM), or
Epi (5 µM) was dissolved directly into the perfusion medium. The
concentration of Mg2+ present as contaminant in the buffer
was measured by AAS and found to be
3 µM. For simplicity, this
value was not subtracted from the curves of efflux reported in the figures.
Na+- or
Ca2+-free medium.
To determine the dependence of Mg2+ extrusion on the
presence of extracellular Na+ and
Ca2+, livers were perfused with a medium similar
to the perfusion medium described in Perfused livers but
devoid of Na+ (NaCl and NaHCO3 were replaced
with equiosmolar concentrations of choline chloride and
KHCO3, respectively, pH 7.4 with KOH) or
Ca2+ (CaCl2 omitted from the buffer).
To exclude that a reduced Mg2+ extrusion in the absence of
extracellular Na+ or Ca2+ could be ascribed to
an altered sensitivity of an 1- or
-adrenergic receptor, pharmacological doses of adrenergic agonists were used under
all experimental conditions.
Estimation of total Mg2+ extrusion. To estimate the total amount of Mg2+ extruded in the perfusate, the Mg2+ concentrations of the last five points before the addition of adrenergic agonist were averaged and then subtracted from each of the subsequent time points under the curve of efflux. The net Mg2+ concentration (nmol/ml) was then expressed as micromoles, taking into account perfusion rate and collection intervals (37).
Glucose and LDH determination. Aliquots of perfusate were collected every minute, and glucose content was determined with an enzymatic kit (Sigma) monitoring the variations in NADH+ content at 340 nm. The absence of cell damage was assessed by measuring LDH release in aliquots of the perfusate with an NADH+-coupled enzymatic kit (Sigma).
Collagenase-dispersed cells. Collagenase-dispersed rat hepatocytes were isolated according to the procedure of Seglen (36). After isolation, hepatocytes were resuspended (final concentration 1 × 106 cells/ml) in a medium containing (mM) 120 NaCl, 3 KCl, 1.2 KH2PO4, 12 NaHCO3, 1.2 CaCl2, 1.2 MgCl2, 10 HEPES, and 10 glucose, pH 7.2, at 37°C under O2-CO2 (95:5 vol/vol) flow and kept at room temperature until used. Cell viability was 88 ± 3% (n = 5) as assessed by trypan blue exclusion test and did not significantly change over the course of 3-4 h (85 ± 2%, n = 5).
Mg2+ determination in cell
suspensions.
To determine Mg2+ extrusion, 1 ml of cell suspension was
transferred in a microfuge tube, and the cells were rapidly sedimented at 600 g for 30 s. After the supernatant was removed,
the cells were washed with 1 ml of a medium having a composition
similar to that mentioned in Collagenase-dispersed cells but
devoid of Mg2+ (incubation medium). The concentration
of Mg2+ present as contaminant was measured by AAS
and found to be 3 µM. After the washing, the cells were transferred
to 10 ml of incubation medium, prewarmed at 37°C, and incubated under
continuous stirring and O2-CO2 flow. After 3 min of equilibration, the reported doses of adrenergic agonist were
added to the incubation system. Ca2+ channel blockers or
Na+ transport or glucose transport inhibitors were added to
the incubation system together with the cells. At the time points
indicated in Figs. 5A and 6A, 700-µl aliquots
of the incubation mixture were withdrawn in duplicate and the cells
were sedimented in microfuge tubes (3,500 g × 30 s). The supernatants were removed, and the Mg2+
content was measured by AAS. For the experiments in the absence of
Na+ or Ca2+, isolated hepatocytes were washed
and incubated in the Na+- or Ca2+-free buffers.
The net Mg2+ extrusion was estimated as follows. The
Mg2+ content in the supernatant at the two time points
before adrenergic agonist administration was averaged and then
subtracted from each of the subsequent time points. The net
Mg2+ content in the supernatant (nmol/mg protein) at the
latest time point of incubation (time = 6 min after agonist
addition) was then plotted in Figs. 5B, 6B, and
7.
Other procedures. Protein content was measured using the procedure of Lowry et al. (24).
Statistical analysis. Data are reported as means ± SE. Data were first analyzed by one-way ANOVA. Multiple means were then compared by Tukey's multiple-comparison test performed with a q value established for significance of P < 0.05.
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RESULTS |
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Rat livers perfused with regular medium in the absence of any
stimulatory agent maintained a stable Mg2+ baseline in the
perfusate over 35 min of perfusion (Fig.
1A). The administration of the
selective -adrenergic agonist Iso (10 µM), the
1-adrenergic agonist Phe (5 µM), or Epi (5 µM), an
endogenous catecholamine that stimulates both
- and
-adrenergic
receptors, resulted in a significant extrusion of cellular
Mg2+ into the perfusate (Fig. 1A). The
Mg2+ extrusion was detectable within 1-2 min of the
agonist addition and became maximal by 8 min before returning toward
baseline despite the persistence of the agonist in the perfusion
medium. The Mg2+ extrusion was not associated with LDH
release into the perfusate (not shown), thus excluding that the process
depended on a nonspecific alteration of cell membrane integrity. The
total amount of Mg2+ released into the perfusate, estimated
as described in MATERIALS AND METHODS, accounted for
~1.09, 1.42, and 2.64 µmol of Mg2+ after Iso, Phe, or
Epi administration, respectively (Fig. 1B). These values
correspond to 2.8, 3.6, and 6.8% of total liver Mg2+
content, respectively.
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Previous reports from this laboratory (30, 31) and other
laboratories (18, 41) indicate that the stimulation of
-adrenergic receptor by catecholamine or Iso via increase in the
cytosolic cAMP level induces an extrusion of Mg2+ from
cardiac and liver cells through the operation of an
Na+/Mg2+ exchanger (7, 13, 18, 30, 31,
41). Under conditions in which the operation of this transport
pathway is inhibited by amiloride (41) or imipramine
(5) or by the removal of extracellular Na+
(30, 31), Mg2+ is extruded through a
Na+-independent (Ca2+-dependent) mechanism
(14, 30, 31). However, the modality of activation of this
alternative mechanism is still undefined.
To investigate the possibility that the Mg2+ extrusion
induced by Phe occurs via activation of the Na+-independent
(Ca2+-mediated) pathway, livers were perfused with a
Ca2+-free medium. The results, reported in Fig.
2A, indicate that, in the
absence of a physiological [Ca2+]o, Phe was
ineffective at inducing a Mg2+ extrusion from perfused
livers (inhibition ~90%). In contrast, under the same experimental
conditions, the Mg2+ extrusion induced by Iso was
unaffected (Fig. 2A), whereas that prompted by Epi was
inhibited ~60%. The estimation of the net amount of Mg2+
extruded by the liver after Iso or Epi administration in the absence of
extracellular Ca2+ accounted for ~1 and 0.9 µmol
Mg2+, respectively.
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When similar perfusion experiments were carried out with a medium devoid of extracellular Na+, no Mg2+ extrusion from liver cells was observed (Fig. 2B) regardless of the adrenergic agonist and the dose used. Qualitatively similar results were also obtained when 0.1 mM imipramine was used as an inhibitor of Na+ transport. The administration of imipramine to livers perfused in the presence of physiological extracellular Na+ concentration ([Na+]o) and [Ca2+]o 5 min before the addition of 5 µM Phe resulted in a 60% inhibition of Phe-induced Mg2+ extrusion (net Mg2+ extrusion was ~0.60 vs. 1.88 µmol). A similar inhibitory effect was also observed in livers pretreated with imipramine and stimulated by 10 µM Iso or 5 µM Epi (not shown). Under these experimental conditions, doses of Phe or other adrenergic agonists larger than those reported here were ineffective at eliciting a Mg2+ extrusion (not shown). A similar inhibitory effect was also exerted by 500 µM amiloride (not shown), another agent able to significantly reduce Mg2+ extrusion from liver cells (37).
It is well documented that the stimulation of both 1-
and
-adrenergic receptors results in activation of glycogenolysis (26) and glucose extrusion from liver cells
(39). We recently reported (32) that
insulin-stimulated Mg2+ accumulation in cardiac cells
appears to be associated with and dependent on glucose transport. To
investigate whether a similar association also exists for glucose and
Mg2+ extrusion from liver cells and to determine whether
changes in extracellular ion composition affect glucose extrusion in
addition to Mg2+ mobilization, the amount of glucose
extruded from the liver into the perfusate after adrenergic agonist
administration was measured enzymatically. Figure
3 shows that, in the absence of
physiological [Na+]o or
[Ca2+]o in the perfusion medium, the
administration of Phe, Iso, or Epi resulted in the extrusion of a
negligible amount of hepatic glucose into the perfusate compared with
the amount mobilized from stimulated livers perfused with a medium
containing physiological [Na+]o or
[Ca2+]o. Glucose output was also reduced by
~50% in livers pretreated with imipramine and stimulated by Phe
(13.9 ± 1.8 vs. 27 ± 2 µmol glucose/ml, n = 4; P < 0.05) or other adrenergic agonists (not shown).
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To exclude that changes in extracellular ion composition could affect
the responsiveness of the -adrenergic receptor, rat livers were
perfused with a Na+- or a Ca2+-free medium and
stimulated by the addition of glucagon (30 nM) or 8-chloroadenosine
3',5'-cyclic monophosphate (8-chloro-cAMP; 250 µM). We reported
previously (31, 34) that this cell-permeant cAMP analog
induces an extrusion of Mg2+ from liver cells comparable to
that elicited by
-adrenergic agonists. The administration of either
of these two agents resulted in an extrusion of Mg2+ that
accounted for
60% of that induced by Iso (Fig.
4A). This extrusion was
unaffected by the removal of Ca2+ from the perfusion medium
but was completely prevented in the absence of extracellular
Na+ (Fig. 4A). The amplitude of glucose
extrusion was also affected by Na+ but not by
Ca2+ removal (Fig. 4B).
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Qualitatively similar results were also obtained in
collagenase-dispersed hepatocytes. When incubated in the presence of
extracellular Na+ or Ca2+, nonstimulated
hepatocytes retained cellular Mg2+ for several minutes
(Fig. 5A). The addition of 10 µM Iso, 5 µM Epi, or 5 µM Phe resulted in a time-dependent
extrusion of Mg2+ from the cells into the extracellular
compartment, which reached the maximum (net Mg2+
extrusion 1.5 nmol/mg protein) within 6 min of the agonist addition (time = 8 min in Fig. 5A). Therefore, for
simplicity, the following data are expressed as the net amount of
Mg2+ released from the hepatocytes at 6 min after agonist
addition. In the absence of extracellular Ca2+ (Fig.
5B), the Mg2+ extrusion elicited by Iso, Epi, or
Phe was inhibited by ~60%, regardless of the agonist used. When
similar experiments were performed in hepatocytes incubated in
Na+-free medium, the Mg2+ extrusion elicited by
Iso was completely abolished and that induced by Phe or Epi was reduced
by ~80% (Fig. 5B).
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Isolated hepatocytes were also used to evaluate the efficacy of the
glucose transport inhibitor phloretin at inhibiting adrenergic-induced Mg2+ extrusion. When 15 µM phloretin was used to block
glucose transport, the amplitude of Iso-induced Mg2+
extrusion was reduced by ~50% (Fig. 6;
P < 0.05). The presence of 15 µM phloretin in the
incubation medium also reduced the amplitude of Phe- or Epi-induced
Mg2+ extrusion to a comparable extent (Fig. 6B).
A similar percent inhibition of Mg2+ and glucose extrusion
was observed in perfused livers stimulated by adrenergic agonist in the
presence of 15 µM phloretin in the perfusion medium (not shown).
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Consistent with the results reported in Fig. 4, the addition of 250 µM 8-chloro-cAMP to suspensions of isolated hepatocytes elicited a
Mg2+ extrusion comparable to that induced by isoproterenol
(compare Fig. 7 with Fig. 5). Also in
this experimental model, the cAMP-induced Mg2+ extrusion
was not affected by the removal of extracellular Ca2+ but
was significantly reduced in the absence of extracellular Na+ or in the presence of 15 µM phloretin (Fig. 7).
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DISCUSSION |
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In recent years, our laboratory (30, 31) and other
laboratories (15, 18, 41) have provided compelling
evidence for the operation of a Na+-dependent
Mg2+ extrusion mechanism in several tissues, including
liver (18, 31), after -adrenergic stimulation. Although
the transport mechanism has not been structurally characterized,
experimental results suggest that this Mg2+ is extruded
primarily through an Na+/Mg2+ exchanger, most
likely activated via phosphorylation (15) by the increase
in cellular cAMP level that follows the stimulation of
-adrenergic
receptor (28, 31, 34) or the administration of
cell-permeant cAMP analogs or forskolin (28, 31, 34). Under conditions in which the operation of the exchanger is prevented by the absence of extracellular Na+ or by agents that block
Na+ transport, namely amiloride (41) or
imipramine (5), Mg2+ extrusion can still occur
via a Na+-independent transport mechanism. The nature of
this alternative transporter is not fully characterized, because either
cations such as Ca2+ (30, 31) or
Mn2+ (4, 17) or anions such as
HCO3
or Cl
(12) have been
reported to favor Mg2+ extrusion. Recently, our laboratory
reported (1) that two distinct Mg2+ transport
mechanisms operate in purified rat liver plasma membranes. On the basis
of their characteristics, these transporters have tentatively been
identified as a Na+/Mg2+ and a
Ca2+/Mg2+ exchanger, respectively
(1). These transporters appear to be specifically
localized in the basolateral (the Na+/Mg2+
exchanger) and apical (the Ca2+/Mg2+ exchanger)
domains of the hepatocyte plasma membrane (2).
The present study was aimed at elucidating the possibility that the
stimulation of the 1-adrenergic receptor, which also induces Mg2+ extrusion from liver cells (20,
22), specifically activates the Na+-independent
(Ca2+-dependent) transport mechanism. The obtained results
indicate that this is not the case, in that
1-adrenergic
stimulation mobilizes cellular Mg2+ primarily via the
Na+-dependent mechanism and only marginally via the
Ca2+-dependent pathway.
Role of extracellular Na+ and
Ca2+ on
Mg2+ extrusion.
Perfused livers respond to the stimulation of 1- and/or
-adrenergic receptors by extruding a sizable amount of cellular Mg2+ into the perfusate, provided that a physiological
concentration of Na+ or Ca2+ is present
extracellularly. Some significant differences are observed. The
Mg2+ extrusion elicited via
1-adrenoceptor
by Phe requires both extracellular Na+ and Ca2+
to occur. In the absence of either of these two cations,
Mg2+ extrusion is reduced to a mere 10% in perfused organs
and to <50% in isolated hepatocytes. By contrast, Iso-induced
Mg2+ extrusion via
-adrenoceptor only requires
extracellular Na+, the absence of external Ca2+
being ineffective at preventing Mg2+ mobilization. The
mixed adrenergic agonist Epi also requires both extracellular
Na+ and Ca2+ to elicit maximal Mg2+
extrusion. However, Epi can still induce a sizable Mg2+
extrusion in the absence of extracellular Ca2+, the
amplitude of which is comparable to that elicited by Iso. These results
would suggest that the stimulation of
1- or
-adrenergic receptors ultimately results in the activation of a
Na+-dependent Mg2+ extrusion mechanism (most
likely the Na+/Mg2+ exchanger) via changes in
cellular Ca2+ signaling (3) or increase in
cellular cAMP (15, 18, 30, 31), respectively. Although the
effect of cAMP is likely mediated via phosphorylation
(15), whether the effect of Ca2+ is mediated
via calmodulin is not yet defined.
Concomitance of Mg2+ and glucose extrusion. Despite the large number of reports indicating that adrenergic agonist administration to anesthetized animals (16, 21), perfused organs (18, 30, 31, 41), or isolated cells (30, 31) results in an extrusion of Mg2+ into the extracellular compartment or in the circulation, the physiological significance of this phenomenon remains elusive.
We recently reported (32) that the administration of insulin to perfused rat hearts or isolated cardiac myocytes results in a parallel accumulation of glucose and Mg2+ in the cells. The stimulation of ![]() |
ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-18708, National Institute of Alcohol Abuse and Alcoholism Grant AA-R9AA11593A1, and Diabetes Association of Greater Cleveland Grant 397-A-97.
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. Romani, Dept. of Physiology and Biophysics, School of Medicine, Case Western Reserve Univ., 10900 Euclid Ave., Cleveland, OH 44106-4970 (E-mail: amr5{at}po.cwru.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 3 December 1999; accepted in final form 1 June 2000.
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