Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka City, Shizuoka 422-8526, Japan
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ABSTRACT |
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In
isolated rat pancreatic -cells, the nitric oxide (NO) donor NOC-7 at
1 µM reduced the amplitude of the oscillations of cytosolic
Ca2+ concentration ([Ca2+]c)
induced by 11.1 mM glucose, and at 10 µM terminated them. In the
presence of NG-nitro-L-arginine
(L-NNA), however, NOC-7 at 0.5 and 1 µM increased the
amplitude of the [Ca2+]c oscillations,
although the NO donor at 10 µM still suppressed them. Aqueous NO
solution also had a dual effect on the
[Ca2+]c oscillations. The soluble guanylate
cyclase inhibitor LY-83583 and the cGMP-dependent protein kinase
inhibitor KT5823 inhibited the stimulatory effect of NO, and
8-bromo-cGMP increased the amplitude of the
[Ca2+]c oscillations. Patch-clamp analyses in
the perforated configuration showed that 8-bromo-cGMP inhibited whole
cell ATP-sensitive K+ currents in the isolated rat
pancreatic
-cells, suggesting that the inhibition by cGMP of
ATP-sensitive K+ channels is, at least in part, responsible
for the stimulatory effect of NO on the
[Ca2+]c oscillations. In the presence of
L-NNA, the glucose-induced insulin secretion from isolated
islets was facilitated by 0.5 µM NOC-7, whereas it was suppressed by
10 µM NOC-7. These results suggest that NO facilitates
glucose-induced [Ca2+]c oscillations of
-cells and insulin secretion at low concentrations, which effects
are mediated by cGMP, whereas NO inhibits them in a cGMP-independent
manner at high concentrations.
islets of Langerhans; calcium oscillations; guanosine 3',5'-cyclic monophosphate; NOC-7; glucose
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INTRODUCTION |
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NITRIC OXIDE (NO)
produced from L-arginine by NO synthase (NOS) is an
important regulator of various physiological and pathological functions
in various types of cells. In pancreatic islets, a large amount of NO
generated by inducible NOS (iNOS) has been postulated to be involved in
-cell degeneration in the process of insulin-dependent diabetes
mellitus (1, 6, 22). On the other hand, recent immunostaining studies clearly demonstrated the presence of
constitutive NOS (cNOS), which is activated by Ca2+ and
calmodulin, in rat and mouse pancreatic islet cells, i.e., neuronal NOS
in
-,
-, and
-cells (3, 25) and endothelial NOS
in
-and
-cells (37). Furthermore, direct biochemical
evidence for the cNOS enzyme activity was obtained from isolated islets of mice (33). These findings suggest a physiological
involvement of NO in the regulation of the hormone secretion from
pancreatic islet cells.
By binding to iron in the heme at the active site of soluble guanylate
cyclase (sGC), NO activates the enzyme, which results in elevation of
the cGMP level. Given that the enzyme activities of guanylate cyclase
(16) and cGMP-dependent protein kinase have been
demonstrated in pancreatic islets (23), it is plausible that NO exerts its effect partly through the elevation of cGMP level.
Several studies have shown that a rise in the cGMP level in -cells
stimulates insulin secretion (15, 26). We previously reported that an aqueous NO solution as well as 8-bromo-cGMP elevates the cytosolic Ca2+ concentration
([Ca2+]c) at 7.0 mM glucose in isolated rat
-cells (29). Thus NO is predicted to facilitate
glucose-induced insulin secretion via the stimulation of cGMP formation.
However, the physiological role of NO produced by cNOS in insulin
secretion from -cells is now a matter of controversy. For instance,
nonselective NOS inhibitors, such as
NG-nitro-L-arginine
(L-NNA) and
NG-nitro-L-arginine methyl ester
(L-NAME), have been shown to inhibit insulin secretion
induced by L-arginine, which is a substrate of NOS, or by 3 mM glucose in the HIT-T15
-cell line (10, 34) and in
isolated rat islets (27, 37), suggesting a stimulatory effect of NO on insulin secretion. In contrast, several other groups
have reported that NOS inhibitors increase the L-arginine- or glucose-induced insulin secretion from isolated islets of mice (2, 18, 31, 33) and rats (38). Moreover,
controversial data showing stimulatory (10, 24, 27, 34,
41) and inhibitory (4, 9, 31, 35, 38) effects of
aqueous NO solution or NO donors, such as 3-morpholinosydnonimine
(SIN-1), sodium nitroprusside, and hydroxylamine, on insulin secretion
have also been presented.
We could not rule out that a part of the controversial data hitherto
reported concerning the effect of NO on the glucose-induced insulin
secretion is due to differences in the concentration of glucose or NO
used: In most studies showing an inhibitory effect of NO on the insulin
secretion, high concentrations of glucose such as 11.1, 16.7, and 20 mM
or millimolar concentrations of NO donors were used for the analyses
(4, 5, 9, 12, 35). A large amount of NO could be produced
by high concentrations of glucose in -cells (34);
however, the endogenously produced NO has been ignored in all the
studies that investigated the effect of exogenously applied NO on the
insulin secretion. The aim of the present study was to resolve the
controversy by focusing on the concentration of exogenously applied NO
and on endogenous NO produced by glucose. Our results provide evidence
for a concentration-dependent dual effect of NO, i.e., a stimulatory
effect at low concentrations and an inhibitory one at high
concentrations, on the [Ca2+]c of
-cells
and insulin secretion.
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METHODS |
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Drugs. The following drugs were used: 8-bromo-cGMP, KT5823, L-NNA, and tolbutamide (Sigma, St. Louis, MO); LY-83583 (6-anilino-5,8-quinolinedione; Affinity Bioreagents, Golden, CO); streptomycin and penicillin (Meiji Seika, Tokyo, Japan); thapsigargin (Wako, Osaka, Japan); and fura 2-acetoxymethyl ester (fura 2-AM) and NOC-7 (1-hydroxy-2-oxo-3-[N-methyl-3-aminopropyl]-3-methyl-1-triazene; Dojindo Laboratories, Kumamoto, Japan).
LY-83583 and NOC-7 were first dissolved in ethanol as a 20 mM stock solution and in 1 M NaOH as a 1 M solution, respectively, and were stored atMeasurements of
[Ca2+]c.
Pancreatic -cells were isolated from male Wistar rats (9-12 wk
old, 200-300 g; SLC, Hamamatsu, Japan) by the collagenase digestion technique as described previously (29). The
dispersed
-cells were plated on coverslips and cultured for 1 day in
RPMI-1640 medium (Sigma) supplemented with 10% fetal bovine serum, 100 µg/ml streptomycin, and 100 U/ml penicillin.
Measurements of ion currents.
Whole cell currents in isolated rat pancreatic -cells were measured
in the perforated configuration of the patch-clamp technique as
described previously (20). Patch pipettes were pulled from borosilicate glass capillaries and fire-polished before use. The pipette resistance (when filled with the pipette solution) was 1-2
M
, and the current recording was performed when the series resistance was <10 M
. The bathing solution contained (in mM) 135 NaCl, 5 KCl, 1.2 CaCl2, 1.2 MgCl2, 5.5 glucose,
and 10 HEPES (pH 7.4 with NaOH). The pipette solution contained (in mM)
100 K-aspartate, 40 KCl, 10 HEPES, and 270 µg/ml amphotericin B (pH 7.2 with KOH). Macroscopic currents were recorded using a patch-clamp amplifier (Axopatch 1-D; Axon Instruments, Foster City, CA). Data were
filtered at 1 kHz, digitized at 2 kHz, and stored in a computer by
using pCLAMP 6.0 software with an analog-to-digital converter (TL-1;
Axon Instruments). The holding potential was
80 mV, and currents were
evoked by 200-ms voltage ramps from
120 to
20 mV. The experiments
were performed at room temperature.
Measurements of insulin secretion.
Rat pancreatic islets isolated by the collagenase digestion technique
were cultured for 1-2 days in RPMI 1640 medium supplemented with
10% fetal bovine serum, 100 µg/ml streptomycin, and 100 U/ml penicillin. Next, the islets were preincubated for 30 min at 37°C in
HK solution containing 11.1 mM glucose and 5 mM L-NNA, and then batches of 10 islets were incubated for 10 min in 1 ml of the same
solution with 0, 0.5, or 10 µM NOC-7. At the end of the incubation,
700 µl of the incubation medium were collected and kept at 70°C
for later assay. Insulin released into the medium was measured by use
of an enzyme immunoassay kit for rat insulin (Amersham Pharmacia
Biotech, Amersham, UK) and was expressed as nanograms per islet.
Statistics. Data are expressed as means ± SE. The effects of treatment were analyzed with paired or unpaired Student's t-test as appropriate. A probability of P < 0.05 was accepted as the level of statistical significance.
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RESULTS |
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Effects of NO on
[Ca2+]c of -cells.
In isolated rat pancreatic
-cells, [Ca2+]c
was low and stable at 2.8 mM glucose. Elevating the glucose
concentration to 7.0 mM, which is known to cause a slight release of
insulin, induced an initial decrease and subsequent transient increase
in the [Ca2+]c, followed by a sustained,
moderate elevation of the [Ca2+]c, as
described previously (29). At 11.1 mM glucose, which is
known to stimulate insulin secretion, most of the
-cells showed [Ca2+]c oscillations (Fig.
1). These
[Ca2+]c oscillations were completely
abolished by the Ca2+ channel blocker nicardipine (1 µM;
data not shown), suggesting that they were caused by Ca2+
influx through L-type voltage-operated Ca2+ channels. The
exposure to 1 µM NOC-7 for 30 min decreased the amplitude of the
[Ca2+]c oscillations in about 55% of the
-cells tested (Fig. 1A). Only 15% of the
-cells
responded to 1 µM NOC-7 with an increase in the amplitude of the
[Ca2+]c oscillations (data not shown). On the
other hand, 10 µM NOC-7 almost terminated the
[Ca2+]c oscillations at 11.1 mM glucose in
all of the
-cells tested (Fig. 1B).
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Effects of NO on
[Ca2+]c of -cells in the
presence of L-NNA.
It had been shown previously (10, 34, 39) that glucose
could stimulate endogenous NO production in rat pancreatic islets and
in the HIT-T15
-cell line. Thus endogenously released NO might
inherently affect the [Ca2+]c response to
exogenously applied NO. Therefore, we reexamined the effects of NOC-7
on the [Ca2+]c oscillations in the presence
of the NOS inhibitor L-NNA. After the treatment with 1 mM
L-NNA for longer than 30 min, 11.1 mM glucose still evoked
[Ca2+]c oscillations. Under this condition,
0.5 and 1 µM NOC-7 significantly increased the amplitude of the
[Ca2+]c oscillations in about 50% of the
-cells tested (Figs. 2A and 3A) and caused no apparent
changes in the rest of the
-cells (data not shown). The frequency of the
[Ca2+]c oscillations was not affected by
NOC-7 (Fig. 3B). In contrast, 10 µM NOC-7 still suppressed
the [Ca2+]c oscillations even in the presence
of 1 mM L-NNA in all of the
-cells tested (Fig.
2B). The decomposed products of NOC-7, which were prepared
by incubating NOC-7 in the HK solution at 37°C for 1 h, showed
no apparent effects on the [Ca2+]c
oscillations (data not shown). When 0.5, 1, and 10 µM NOC-7 solutions
were superfused, the concentration of NO in the chamber on the stage of
the microscope was in the range of 10-30, 30-50, and
160-200 nM, respectively.
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Mechanism for the dual effect of NO on
[Ca2+]c of -cells.
The involvement of cGMP in the dual effect of NOC-7 was investigated.
The stimulatory effect of 0.5 µM NOC-7 on the
[Ca2+]c oscillations in the presence of
L-NNA was abolished by LY-83583 (3 µM), an inhibitor of
sGC (Fig. 5A). In contrast,
the inhibition by 10 µM NOC-7 of the
[Ca2+]c oscillations was not affected by
LY-83583 (3 µM; Fig. 5B). 8-Bromo-cGMP (1 mM; Fig.
5C) increased the amplitude of the
[Ca2+]c oscillations without affecting their
frequency (Fig. 3). Furthermore, KT5823 (0.5 µM), an inhibitor of
cGMP-dependent protein kinase (PKG), abolished the stimulatory effect
of 0.5 µM NOC-7 on the [Ca2+]c oscillations
in the presence of L-NNA (Fig. 5D). These
results suggest that cGMP and PKG are involved in the stimulatory
effect of NO, whereas the inhibitory effect is cGMP-independent.
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Effects of NO on insulin secretion.
We finally examined how the concentration-dependent dual effect of NO
on the [Ca2+]c of -cells acted on the
insulin secretion from
-cells. It is well established that glucose
induces biphasic insulin secretion, i.e., the first phase, where the
insulin secretion rapidly increases and decreases during the first
5-10 min, and the second phase, which characteristically shows a
sustained increase in insulin secretion (11). For
comparison with the effects of NOC-7 on the
[Ca2+]c oscillations, we investigated effects
of the NO donor on the second phase of the insulin secretion induced by
11.1 mM glucose. In the presence of 5 mM L-NNA, 0.5 µM
NOC-7 significantly facilitated the insulin secretion induced by 11.1 mM glucose, whereas 10 µM NOC-7 suppressed the hormone secretion
(Fig. 7).
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DISCUSSION |
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There is considerable controversy as to the effects of NO on
insulin secretion. Several research groups including ours have suggested that NO serves to increase insulin secretion (10, 24,
26, 29, 34, 41), whereas other researchers have proposed that
the main effect of NO is to suppress insulin secretion (5, 9, 31,
36, 39). The finding in the present study provides at least one
explanation for this controversy. The data shown here indicate a
concentration-dependent dual effect of NO on the
[Ca2+]c of isolated rat pancreatic -cells.
In the presence of L-NNA, the amplitude of the
[Ca2+]c oscillations induced by 11.1 mM
glucose was increased when 0.5 and 1 µM NOC-7 and 2 µM aqueous NO
solution were superfused. In contrast, the
[Ca2+]c oscillations were suppressed when 10 µM NOC-7 and 20 µM aqueous NO solution were superfused. These
results are in good agreement with the recent study showing that the NO
donor hydroxylamine has a concentration-dependent dual effect on
[Ca2+]c oscillations of -cells isolated
from ob/ob mice (13). There is an intimate
correlation between [Ca2+]c of
-cells and
insulin secretion (11, 17). It is also suggested that an
increase in the amplitude of the [Ca2+]c
oscillations induced by glucose results in the augmentation of insulin
secretion (7, 28). Hence, the present results obtained
with the [Ca2+]c measurement suggest that NO
stimulates insulin secretion at low concentrations, whereas it inhibits
the hormone secretion at high concentrations. This hypothesis was
supported by the direct measurement of insulin secretion in the present
study, which demonstrated that under the condition where NO production
was inhibited by L-NNA, the insulin secretion induced by
11.1 mM glucose was facilitated by 0.5 µM NOC-7, whereas it was
suppressed by 10 µM NOC-7. The concentration range of NO in the
chamber, which was measured with the NO sensor, was between 10 and 50 nM when 0.5 or 1 µM NOC-7 or 2 µM aqueous NO solution was
superfused and was higher than 60 nM when 10 µM NOC-7 or 20 µM
aqueous NO solution was superfused. It is suggested, therefore, that
low concentrations of NO, lower than 50 nM, facilitate glucose-induced
[Ca2+]c oscillations of
-cells and insulin
secretion, whereas high concentrations of NO, higher than 60 nM,
suppress them.
NO serves numerous biological functions, some of which are mediated by the ability of NO to activate sGC, resulting in cGMP formation (19, 30). The stimulatory effect of NOC-7 on [Ca2+]c was likely to have been mediated by cGMP, because similar [Ca2+]c responses were produced by 8-bromo-cGMP and the stimulatory effect of NOC-7 was abolished by the sGC inhibitor LY-83583. Furthermore, the facilitatory effect of NOC-7 was also eliminated by the PKG inhibitor KT5823, suggesting the involvement of PKG in the effect. Thus our data suggest that low concentrations of NO potentiate the glucose-induced insulin secretion via the production of cGMP followed by the activation of PKG. This is in good accordance with previous studies showing that cGMP stimulated insulin secretion from rat pancreatic islets (4, 15, 38).
The mechanism for the stimulatory effect of cGMP on
[Ca2+]c oscillations of -cells was further
investigated by the measurement of whole cell membrane currents. The
patch-clamp experiment clearly showed that 8-bromo-cGMP inhibited the
potassium-selective, voltage-independent currents activated by
diazoxide, a KATP channel opener. We confirmed that the
currents were also blocked by tolbutamide, a KATP channel blocker. These results suggest that cGMP inhibits KATP
channels of
-cells. In line with this, 8-bromo-cGMP has recently
been shown to decrease the activity of single KATP currents
recorded from cell-attached patches in mouse
-cells
(32). Inhibition of KATP channels would lead
to membrane depolarization, which is thought to be an important
mechanism for the potentiation of [Ca2+]c
oscillations. Thus our results support the idea that inhibition of
KATP channels is involved in the facilitation by cGMP of
insulin secretion from rat pancreatic islets.
Even in the presence of L-NNA, 10 µM NOC-7 caused an
appreciable inhibition of the glucose-induced
[Ca2+]c oscillations. This result is in good
agreement with those of previous studies showing that NO inhibited
insulin secretion (5, 9, 31, 36, 39). The inhibition by NO
of the glucose-induced [Ca2+]c responses
appeared to be independent of cGMP, because the inhibitory effect of
NOC-7 was not affected by the sGC inhibitor LY-83583 and 8-bromo-cGMP
had only stimulatory effects on the [Ca2+]c
oscillations. These results are also consistent with previous studies
suggesting that the inhibition of insulin secretion by NO donors such
as SIN-1 and sodium nitroprusside is independent of cGMP (8, 15,
38). This cGMP-independent mechanism appears to be relevant for
the inhibition by NO of islet function. One possible mechanism is that
NO hyperpolarizes the -cell membrane by opening KATP
channels, which is brought about by a reduction in the ATP/ADP ratio
through suppression of mitochondrial aconitase (40) or
phosphofructokinase (38), or through a depolarization of
the mitochondrial membrane potential (12).
The effects of NOC-7 on the [Ca2+]c oscillations were somewhat complicated. In the absence of L-NNA, 1 µM NOC-7 inhibited the [Ca2+]c oscillations. Conversely, in the presence of the NOS inhibitor, the dominant effect of 0.5 or 1 µM NOC-7 was rather stimulatory on the [Ca2+]c oscillations. Because glucose produces NO in pancreatic islets in a concentration-dependent manner (10, 34, 39), it can be estimated that glucose at 11.1 mM produces a large amount of NO. The NO produced by 11.1 mM glucose possibly induced both the cGMP-independent inhibitory and the cGMP-mediated stimulatory effects on the [Ca2+]c oscillations, and the former effect might have overwhelmed the latter one. Under this condition, it is likely that the exogenously applied NO inevitably acted in an inhibitory manner on the [Ca2+]c oscillations.
The concentration-dependent dual effect of NO on the
[Ca2+]c of -cells was further supported by
the experiments measuring insulin secretion. The present study clearly
demonstrates that in the presence of L-NNA, the insulin
secretion induced by 11.1 mM glucose is facilitated by 0.5 µM NOC-7,
whereas it is inhibited by 10 µM NOC-7. These results suggest that NO
has a dual effect on the insulin secretion, i.e., stimulation at low
concentrations and inhibition at high concentrations. Concerning the
effects of NO, NO donors, or NOS inhibitors on insulin secretion, a
number of conflicting data have been reported as described in the
Introduction. The controversy would be explained, at least in part, by
the concentration-dependent dual effect of NO on insulin secretion. In
most studies showing an inhibitory effect of NO on the insulin
secretion, a relatively high concentration of NO donors or aqueous NO
solution was used, e.g., 1 mM hydroxylamine (5, 9),
0.1-1 mM sodium nitroprusside (4), 0.1 or 1 mM SIN-1
(9, 35), and 20 µM aqueous NO solution (12). Here, it should also be noted that glucose by itself
produces NO in pancreatic islets (10, 39). Although
several researchers showed an inhibitory effect of NO on insulin
secretion in the presence of high concentrations of glucose such as
11.1, 16.7, and 20 mM, they did not consider the influence of NO
endogenously produced by such high concentrations of glucose on the
insulin secretion (4, 5, 9, 35, 39). As mentioned above, 11.1 mM glucose is likely to produce a large enough amount of NO to
inhibit insulin secretion.
It has been demonstrated that neuronal NOS, which is activated by
Ca2+ and calmodulin, resides in rat pancreatic -cells
(3, 25). Insulin secretagogues, such as acetylcholine and
glucagon-like peptide-1, elevate the [Ca2+]c
of
-cells, whereas exposure of
-cells to catecholamines, i.e.,
epinephrine and norepinephrine, or to somatostatin released from
pancreatic
-cells decreases their [Ca2+]c
(11). It is conceivable, therefore, that not only glucose but also numerous other substances contributing to insulin secretion participate in the regulation of NO production by increasing or decreasing [Ca2+]c of
-cells in vivo.
In summary, NO exerts both stimulatory and inhibitory effects on
[Ca2+]c and insulin secretion in rat
pancreatic -cells depending on its concentration. The dual effect of
NO was shown to be attributable to apparently different mechanisms: a
cGMP-mediated mechanism for the stimulatory effect and a
cGMP-independent one for the inhibitory effect. As a consequence, we
propose that endogenously released NO functions as a physiological
insulinotropic substance at concentrations lower than 50 nM, whereas it
takes part in the negative feedback system in insulin secretion at
higher concentrations.
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ACKNOWLEDGEMENTS |
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We thank E. Iwasaki for technical assistance.
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FOOTNOTES |
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This study was supported by a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science.
Address for reprint requests and other correspondence: T. Ishikawa, Dept. of Pharmacology, School of Pharmaceutical Sciences, Univ. of Shizuoka, 52-1 Yada, Shizuoka City, Shizuoka 422-8526, Japan (E-mail:ishikat{at}u-shizuoka-ken.ac.jp).
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.
First published January 15, 2003;10.1152/ajpcell.00223.2002
Received 16 May 2002; accepted in final form 8 January 2003.
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