Department of Pharmacology, University of Lund, S-223 62 Lund, Sweden
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ABSTRACT |
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Nitric oxide (NO)
produced by islet constitutive NO synthase (cNOS) is a putative
modulator of islet hormone secretion. We show here for the first time
that the release of insulin induced by
L-arginine or
L-homoarginine is inhibited and
that of glucagon stimulated in parallel with the rate of islet NO
production. It was found that
L-homoarginine was
25-30% less potent than
L-arginine as an insulin
secretagogue but equally potent as a glucagon secretagogue. Biochemical
determination of islet cNOS activity revealed that the NO production
with L-homoarginine as substrate
was only
40% of that of
L-arginine. Selective inhibition
of islet cNOS potentiated insulin release during amino acid
stimulation. Moreover, inhibition of cNOS suppressed glucagon release,
more so with L-arginine than with L-homoarginine as
secretagogue, reflecting the relative rates of their NO production. In
K+-depolarized islets, inhibition
of cNOS enhanced the insulin response to
L-arginine by 50% and that to
L-homoarginine by 23%, largely corresponding to their relative NO production. The intracellular NO
donor hydroxylamine dose dependently inhibited insulin but increased
glucagon secretion in
K+-depolarized and amino
acid-stimulated islets. We conclude that both amino acids have a dual
action on insulin release, since their stimulatory effects are reduced
in parallel with the rates of their NO production. Furthermore, the
greater NO production induced by
L-arginine relative to
L-homoarginine corresponds to NO-mediated increases in glucagon release. These NO effects are mainly
exerted independently of membrane depolarization events.
islets of Langerhans; L-arginine; L-homoarginine; nitric oxide synthase activity; insulin secretion; glucagon secretion; nitric oxide synthase inhibitors
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INTRODUCTION |
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L-ARGININE STIMULATES insulin release. Three different
mechanisms have been suggested to account for this stimulation (6, 38):
1) -cell uptake of the positively
charged L-arginine molecule followed by depolarization of the plasma membrane;
2)
L-arginine metabolism through
the action of arginase
(L-arginine is thereby hydrolyzed to urea and ornithine, and ornithine is then further metabolized, ending up in the citric acid cycle); and
3) stimulation by nitric oxide (NO)
derived from the metabolism of
L-arginine through the action of
a constitutive NO synthase (cNOS). The metabolism of
L-arginine through this latter
pathway yields equimolar concentrations of NO and
L-citrulline (23, 36, 38).
Exactly how NO influences islet hormone secretion is still rather
controversial, however, and both stimulatory (26, 38) and inhibitory
(2, 3, 17, 21, 31-33, 36) effects on insulin release have been
reported. Already in 1992, we observed that the NO synthase (NOS)
inhibitor NG-nitro-L-arginine
potentiated L-arginine-induced
insulin release from isolated mouse islets (33). These data prompted us
to suggest that NO, evolved from
L-arginine-induced islet cNOS
activity, restrained insulin secretion stimulated by
L-arginine and thus that
L-arginine had a dual action on
insulin release (33). Later on we found that NO, in contrast, exerted a
stimulatory effect on glucagon secretion (31).
It has been our aim in the present study to further investigate the
complex influence of NO within the islets of Langerhans with special
regard to its action on
L-arginine-induced hormone release. Because L-homoarginine,
a close analog to L-arginine, is
known to be poorly metabolized by NOS activities in other tissues (22),
we have compared the effects of
L-arginine with those of
L-homoarginine concerning islet
NO production in relation to the relative potency of the amino acids to
induce insulin and glucagon secretion. A new microtechnique for NOS
assay in small tissue samples (11, 36) was used to perform a direct
biochemical determination of cNOS activity in islet homogenates.
Furthermore, two different NOS inhibitors (7, 35),
NG-monomethyl-L-arginine
(L-NMMA) and
NG-nitro-L-arginine methyl ester
(L-NAME), were employed when we studied the consequences of inhibition of cNOS activity on islet hormone release. Aside from its NOS inhibitory properties,
L-NAME, at least in high
concentrations, has recently been reported to induce closure of
ATP-sensitive K+ channels in the
-cells (25). It was therefore important to compare the effects of
L-NAME with those of
L-NMMA, since
L-NMMA has not been reported to
exert this effect. To avoid interference by membrane depolarization
events, some experiments were performed with islets exposed to
diazoxide, a known K+-channel
opener (27), in combination with a depolarizing concentration of
K+ (14) in the absence and
presence of L-NAME or
L-NMMA. In addition, we tested
the effects of the intracellular NO donor hydroxylamine on insulin and
glucagon secretion from
K+-depolarized islets.
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MATERIALS AND METHODS |
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Animals. Female mice of the NMRI strain (B&K, Sollentuna, Sweden) weighing 25-30 g were used in all studies. They were fed a standard pellet diet (B&K) and tap water ad libitum. The experiments were approved by the Ethical Committee for Animal Research at Lund University.
Drugs and chemicals. Collagenase (CLS4) was obtained from Worthington Biochemicals (Freehold, NJ). L-NMMA, L-NAME, and hydroxylamine as well as L-arginine and L-homoarginine were from Sigma (St. Louis, MO). BSA was from ICN Biochemicals (High Wycombe, UK). All other chemicals were from Merck (Darmstadt, Germany). The RIA kits for insulin and glucagon determination were obtained from Diagnostika (Falkenberg, Sweden) and Euro-Diagnostica (Malmö, Sweden), respectively.
Assay of islet NOS.
Preparation of isolated pancreatic islets from the mouse was performed
by retrograde injection of a collagenase solution via the
bile-pancreatic duct (16). Islets were then isolated and handpicked
under a stereomicroscope at room temperature. The freshly isolated
islets were then thoroughly washed and collected in ice-cold buffer
(200 islets in 840 µl buffer) containing 20 mM HEPES, 0.5 mM EDTA,
and 1 mM DL-dithiothreitol, pH
7.2, and immediately frozen at 20°C. On the day of assay,
the islets were sonicated on ice, and the buffer solution containing
the islet homogenate was supplemented to also contain 0.45 mM
CaCl2, 2 mM NADPH, 25 U
calmodulin, and 0.2 mM
L-arginine or 0.2 mM
L-homoarginine in a
total volume of 1 ml. The buffer composition is essentially the same as
previously described for assay of NOS in brain tissue using
radiolabeled L-arginine (10).
The homogenate was then incubated at 37°C under constant air
bubbling, 1.0 ml/min, for 3 h. It was ascertained that under these
conditions, the reaction velocity was linear for at least 6 h. Aliquots of the incubated homogenate (200 µl) were then passed
through a 1-ml Amprep CBA cation-exchange column for HPLC analysis. The
amount of L-citrulline (or
L-homocitrulline) formed was
then measured in a Hitachi F 1000 fluorescence spectrophotometer (Merck) as previously described (36). NO and citrulline are produced in
equimolar concentrations. The methodology has been described in detail
earlier (11, 36), the only difference being that the incubation was now
performed at 37°C instead of at room temperature (36). Protein was
determined according to Bradford (9) on samples from the original
homogenate.
Hormone secretion. Freshly isolated islets were preincubated for 30 min at 37°C in Krebs-Ringer bicarbonate buffer (24), pH 7.4, supplemented with 10 mM HEPES, 0.1% BSA, and 1 mM glucose. Each incubation vial contained 10 islets in 1.0 ml of buffer solution and was gassed with 95% O2-5% CO2 to obtain constant pH and oxygenation. After preincubation, the buffer was changed to a medium containing 7 mM glucose plus or minus the different test agents, and then the islets were incubated for 60 min. All incubations were performed at 37°C in a shaking water bath (30 cycles/min). Immediately after incubation, aliquots of the medium were removed and frozen for subsequent assay of insulin and glucagon (1, 18, 34).
Statistics. Statistical significance between sets of data was assessed using unpaired Student's t-test or, where applicable, ANOVA followed by Tukey-Kramer's multiple comparisons test. Results are expressed as means ± SE.
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RESULTS |
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cNOS activity in islet homogenates with
L-arginine or
L-homoarginine as substrate.
In the first series of experiments, we analyzed the production of NO
(measured as L-citrulline or
L-homocitrulline) in mouse islet
homogenates after incubation with the different NOS substrates at
enzyme-saturated conditions. At 37°C, the islet cNOS enzyme with
L-arginine as substrate
displayed an activity of 29.6 ± 0.90 pmol
L-citrulline · mg
protein1 · min
1
(n = 6). When
L-arginine was replaced by
L-homoarginine as substrate, the
NO production was only 11.3 ± 0.83 pmol
L-homocitrulline · mg
protein
1 · min
1
(n = 5), i.e., only
40% of that of
L-arginine. In the absence of
Ca2+/calmodulin or substrate, the
islet homogenates were almost devoid of cNOS activity.
Dose-response relationship for
L-arginine and
L-homoarginine on islet hormone release.
Figure
1A
illustrates a dose-response curve showing the stimulatory effect of
L-arginine and
L-homoarginine on insulin
release. The maximal stimulatory concentration for insulin release was reached at 15 mM for
L-arginine (20 mM giving the
same response; data not shown in the graph) and at
10 mM for
L-homoarginine. At concentration
levels of 5 and 10 mM,
L-homoarginine was
25% less
potent than L-arginine. At a 15 mM concentration, the
L-homoarginine-induced release
was 40% less than that induced by
L-arginine. Glucagon secretion
(Fig. 1B) was also dose dependently
stimulated by L-arginine and
L-homoarginine. In this case,
the two amino acids showed exactly the same potency, and a maximal
stimulation was achieved at a concentration of 10 mM for both of them.
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Effects of L-NAME and
L-NMMA on islet hormone release
stimulated by L-arginine or
L-homoarginine.
The first set of experiments was designed to study the effects of the
NOS inhibitors L-NAME and
L-NMMA on the secretion of insulin and glucagon from isolated islets at a basal physiological glucose concentration (7 mM). The two NOS inhibitors showed
no effects at all either on basal insulin or on basal glucagon
secretion at a 5 mM concentration in the presence of 7 mM glucose
[i.e., insulin controls 0.33 ± 0.020 ng
insulin · islet1 · h
1
(n = 12) vs. 0.28 ± 0.044 (n = 8) in the presence of
L-NAME and 0.33 ± 0.045 (n = 8) in the presence of
L-NMMA]. The results for glucagon were as follows: glucagon controls 26.0 ± 1.81 pg
glucagon · islet
1 · h
1
vs. 21.2 ± 2.12 (L-NAME) and
25.0 ± 2.50 (L-NMMA). A
concentration of 5 mM of the inhibitors was chosen, since previous
dose-response studies (32) showed that this was the highest
concentration of L-NAME that did
not per se affect insulin release.
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Effects of L-NAME and L-NMMA on islet hormone release stimulated by L-arginine or L-homoarginine in the presence of diazoxide and a depolarizing concentration of K+. Figure 3 shows a strong stimulatory effect by KCl (30 mM) in the presence of diazoxide (250 µM) on basal insulin and glucagon secretion at 7 mM glucose. No significant effects on insulin release were found when either L-NAME or L-NMMA was added (Fig. 3A). In contrast, we observed a modest suppressive action by both NOS inhibitors on glucagon release (Fig. 3B).
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Influence of the intracellular NO donor hydroxylamine on islet hormone release induced by L-arginine or L-homoarginine in the presence of diazoxide, L-NAME, and a depolarizing concentration of K+. Figure 5 illustrates the dose-response pattern induced by the intracellular NO donor hydroxylamine on insulin and glucagon release stimulated by L-arginine (Fig. 5, A and B) or L-homoarginine (Fig. 5, C and D) in the presence of diazoxide, L-NAME, and a depolarizing K+ concentration. The NO donor, at 0.003-3.0 mM, dose dependently inhibited insulin release induced by both amino acids (Fig 5, A and C). In contrast, glucagon secretion was potentiated. Only concentrations of 0.003 and 0.03 mM of the drug increased glucagon secretion (Fig. 5, B and D).
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DISCUSSION |
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In the present study, we found that the NO evolution when
L-homoarginine was used as a
substrate was only 40% of that produced by
L-arginine. This is in good
agreement with measurements in other tissues (19, 22, 30) and thus
suggests, together with our previous data (36), that islet cNOS shares
the properties described for the
Ca2+/calmodulin-regulated isoforms
in the brain and in the vascular endothelium (23). It should be noted
that the recorded cNOS activity with
L-arginine as a substrate in our
present investigation was approximately four times higher compared with
our previous experiments, in which the homogenate incubations were
performed at room temperature (36).
Insulin secretion.
Equimolar concentrations of
L-arginine and
L-homoarginine (10 mM; being
maximal with regard to islet hormone release for the latter amino acid)
induced exactly the same response with regard to glucagon release,
whereas the insulin response to
L-arginine was 25-30%
greater than that to
L-homoarginine. The insulin
response to L-arginine has been
attributed to intracellular accumulation of this positively charged
amino acid, whereby the plasma membrane is depolarized and
Ca2+ influx is initiated (21).
This property is shared by
L-homoarginine, which is taken
up by the same transport system, (y)+, and also carries a net positive
charge equal to that of
L-arginine (6, 20, 37). Thus
quantitative differences in the insulin-releasing action between these
amino acids cannot be accounted for by the cationic charge.
L-Homoarginine is
reportedly not metabolized by arginase within islet tissue (28), and
because L-arginine metabolism is
another proposed mechanism for the stimulatory effect of this amino
acid on insulin release (28), the more efficient "fuel
properties" of L-arginine, as
well as its ability to increase cAMP (32), may explain why
L-arginine is a more potent
insulin secretagogue than its close analog
L-homoarginine. This hypothesis is further strengthened by our present finding that the
insulin-releasing effect of
L-homoarginine was almost
abolished in depolarized islets, thus indicating that the main
mechanism of action of
L-homoarginine to stimulate
insulin release is intimately coupled to membrane depolarization
events. Our observation that
L-arginine is a more efficient
insulin secretagogue than
L-homoarginine at an amino acid
concentration of 10 mM (being maximal for
L-homoarginine) is at variance
with previous data from rat islets, where no such difference was found
(6). The explanation for this discrepancy is presently unclear.
Glucagon secretion. L-Arginine and L-homoarginine were equally potent in stimulating glucagon secretion. Hence, the effect of L-arginine to stimulate glucagon release is probably independent of any "fuel effect" exerted by this amino acid in the glucagon cell. Therefore, depolarization with subsequent Ca2+ influx is conceivably responsible for the main glucagon-releasing action of both amino acids. Furthermore, in contrast to their effects on insulin release, both NOS inhibitors, i.e., L-NMMA and L-NAME, did not stimulate but inhibited glucagon release induced by both L-arginine and L-homoarginine. Moreover, this inhibition was quantitatively the same irrespective of whether L-NMMA or L-NAME was used. This is in accordance with the notion that the glucagon-producing cells are lacking KATP channels (5). Thus L-NAME was found to inhibit L-arginine-stimulated glucagon secretion by 27% compared with the effect of L-NMMA (being 31%). Regarding glucagon secretion stimulated by L-homoarginine, the corresponding values were 18% reduction (L-NAME) and 21% reduction (L-NMMA). The greater inhibition of cNOS activity by the two NOS inhibitors in the presence of L-arginine than in the presence of L-homoarginine corresponded to the comparatively greater NO evolution derived from L-arginine than from L-homoarginine.
The present data showing that the NOS inhibitors greatly reduced glucagon release stimulated by L-arginine and L-homoarginine in depolarized islets suggest that this effect is largely independent of membrane depolarization events and thus probably exerted at a later step in the stimulus-secretion coupling. Such an assumption was moreover evidenced by our observation that the intracellular NO donor hydroxylamine could further increase glucagon release already stimulated by maximal doses of both amino acids in depolarized islets in the presence of L-NAME. These data thus suggest that NO may serve as an important messenger of glucagon release. Incidentally, as mentioned above, a maximal glucagon-releasing dose of L-homoarginine induced the same response as a maximal dose of L-arginine, yet the rate of NO production from L-homoarginine was only 40% of that of L-arginine. Thus L-arginine would be expected to bring about a greater glucagon release than L-homoarginine. It is not inconceivable that this greater NO-mediated glucagon release induced by L-arginine could have been counteracted, and thus masked, by an inhibitory fuel effect of this arginase-metabolized amino acid. That would be in line with the well-known "fuel"-induced inhibition of glucagon release exerted by glucose. Concerning the NO effects vs. the electrogenic effects induced by the two amino acids on the secretory processes of both insulin and glucagon, available evidence indicates that cNOS activity is fully saturated at a concentration of 0.2 mM for both amino acids (Refs. 11 and 36 and unpublished data), whereas concentrations of 3-5 mM are required to stimulate islet hormone secretion (cf. Fig. 1). Hence, the NO-mediated effects are apparently exerted at an approximately ten times lower concentration of the cationic amino acids than their major hormone-releasing action, which evidently is exerted through membrane depolarization and Ca2+ influx. In addition, the question arises as to whether the effects of NO are elicited solely within the cell of origin or are also exerted through the paracrine route. There is a general agreement that cNOS activity is located at the insulin-producingConclusion. We conclude that NO is produced within the islets of Langerhans and that L-arginine is a much better substrate for islet cNOS than its analog L-homoarginine. Both amino acids have a dual action on insulin release, since their stimulatory actions are reduced in relation to the rate of their NO production. Moreover, the stimulatory electrogenic action of the two amino acids on glucagon release is further increased by the relative rates by which they produce NO. The intracellular NO donor hydroxylamine inhibited insulin and stimulated glucagon release in K+-depolarized islets, thus mimicking the effects of islet endogenous NO production. Hence NO is a negative modulator of insulin release and a positive modulator of glucagon release induced by L-arginine or L-homoarginine. These NO effects are mainly exerted independently of membrane depolarization events.
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ACKNOWLEDGEMENTS |
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The skillful technical assistance of Elsy Ling and Britt-Marie Nilsson is gratefully acknowledged.
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FOOTNOTES |
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This study was supported by the Swedish Medical Research Council (14X-4286), the Swedish Diabetes Association, and the Albert Påhlsson and Åke Wiberg Foundations.
Address for reprint requests: R. Henningsson, Dept. of Pharmacology, Sölvegatan 10, S-223 62 Lund, Sweden.
Received 14 November 1997; accepted in final form 10 June 1998.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Ahrén, B.,
and
I. Lundquist.
Glucagon immunoreactivity in plasma from normal and dystrophic mice.
Diabetologia
22:
258-263,
1982[Medline].
2.
Åkesson, B.,
and
I. Lundquist.
Modulation of the nitric oxide system and sulphonylurea-induced insulin secretion.
Diabetes Res.
31:
91-99,
1996.
3.
Åkesson, B.,
H. Mosén,
G. Panagiotidis,
and
I. Lundquist.
Interaction of islet nitric oxide system with L-arginine induced secretion of insulin and glucagon in mice.
Br. J. Pharmacol.
119:
758-764,
1996[Abstract].
4.
Antoine, M.-H.,
R. Ouedraogo,
J. Sergooris,
M. Hermann,
A. Herchuelz,
and
P. Lebrun.
Hydroxylamine, a nitric oxide donor, inhibits insulin release and activates K+ATP channels.
Eur. J. Pharmacol.
313:
229-235,
1996[Medline].
5.
Berts, A.,
E. Gylfe,
and
B. Hellman.
Ca2+ oscillations in pancreatic islet cells secreting glucagon and somatostatin.
Biochem. Biophys. Res. Commun.
208:
644-649,
1995[Medline].
6.
Blachier, F.,
A. Mourtada,
A. Sener,
and
W. J. Malaisse.
Stimulus-secretion coupling of arginine-induced insulin release. Uptake of metabolized and nonmetabolized cationic amino acids by pancreatic islets.
Endocrinology
124:
134-141,
1989[Abstract].
7.
Bogle, R. G.,
S. Moncada,
J. D. Pearson,
and
G. E. Mann.
Identification of inhibitors of nitric oxide synthase that do not interact with the endothelial cell L-arginine transporter.
Br. J. Pharmacol.
105:
768-770,
1992[Abstract].
8.
Bouwens, L.,
and
G. Klöppel.
Cytochemical localization of NADPH-daphorase in four types of pancreatic islet cell.
Histochemistry
101:
209-214,
1994[Medline].
9.
Bradford, M. M.
A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.
Anal. Biochem.
84:
309-312,
1978[Medline].
10.
Bredt, D. S.,
and
S. H. Snyder.
Nitric oxide mediates glutamate-linked enhancement of cGMP levels in cerebellum.
Proc. Natl. Acad. Sci. USA
86:
9030-9033,
1989[Abstract].
11.
Carlberg, M.
Assay of neuronal nitric oxide synthase by HPLC determination of citrulline.
J. Neurosci. Methods
52:
165-167,
1994[Medline].
12.
Corbett, J. A.,
J. L. Wang,
T. P. Misko,
W. Zhao,
W. F. Hickey,
and
M. L. McDaniel.
Nitric oxide mediates IL-1-induced islet dysfunction and destruction: prevention by dexamethasone.
Autoimmunity
15:
145-153,
1993[Medline].
13.
Drews, G.,
and
P. Krippeit-Drews.
NO synthase activity does not influence electrical activity of mouse pancreatic B-cells.
Biochem. Biophys. Res. Commun.
210:
914-920,
1995[Medline].
14.
Gembal, M.,
P. Gilon,
and
J.-C. Henquin.
Evidence that glucose can control insulin release independently from its action on ATP-sensitive K+ channels in mouse B cells.
J. Clin. Invest.
89:
1288-1295,
1992[Medline].
15.
Gerich, J. E.,
M. A. Charles,
and
G. M. Grodsky.
Characterization of the effects of arginine and glucose on glucagon and insulin release from the perfused pancreas.
J. Clin. Invest.
54:
833-841,
1974[Medline].
16.
Gotoh, M.,
T. Maki,
T. Kiyoizumi,
S. Satomi,
and
A. P. Monaco.
An improved method for isolation of mouse pancreatic islets.
Transplantation
40:
437-438,
1985[Medline].
17.
Gross, R.,
M. Roye,
M. Manteghetti,
D. Hillaire-Buys,
and
G. Ribes.
Alterations of insulin response to different cell secretagogues and pancreatic vascular resistance induced by N
-nitro-L-arginine methyl ester.
Br. J. Pharmacol.
116:
1965-1972,
1995[Abstract].
18.
Heding, L.
A simplified insulin radioimmunoassay method.
In: Labelled Proteins in Tracer Studies, edited by L. Donato,
G. Milhaud,
and J. Sirchis. Brussels: Euratom, 1996, p. 345-350.
19.
Hrabak, A.,
T. Bajor,
and
A. Temesi.
Comparison of substrate and inhibitor specificity of arginase and nitric oxide (NO) synthase for arginine analogues and related compounds in murine and rat macrophages.
Biochem. Biophys. Res. Commun.
198:
206-212,
1994[Medline].
20.
Inoue, Y.,
B. P. Bode,
D. J. Beck,
A. P. Li,
K. I. Bland,
and
W. W. Souba.
Arginine transport in human liver. Characterization and effects of nitric oxide synthase inhibitors.
Ann. Surg.
218:
350-363,
1993[Medline].
21.
Jansson, L.,
and
S. Sandler.
The nitric oxide synthase inhibitor II NG-nitro-L-arginine stimulates pancreatic islet insulin release in vitro, but not in the perfused pancreas.
Endocrinology
128:
3081-3085,
1991[Abstract].
22.
Knowles, R. G.,
M. Merrett,
M. Salter,
and
S. Moncada.
Differential induction of brain, lung and liver nitric oxide synthase by endotoxin in the rat.
Biochem. J.
270:
833-836,
1990[Medline].
23.
Knowles, R. G.,
and
S. Moncada.
Nitric oxide synthases in mammals.
Biochem. J.
298:
249-258,
1994[Medline].
24.
Krebs, H. A.,
and
K. Henseleit.
Untersuchungen Über die Harnstoffbildung im Tierkörper.
Hoppe Seylers Z. Physiol. Chem.
210:
33-66,
1932.
25.
Krippeit-Drews, P.,
S. Welker,
and
G. Drews.
Effects of nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester on electrical activity and ion channels of mouse pancreatic B cells.
Biochem. Biophys. Res. Commun.
224:
199-205,
1996[Medline].
26.
Laychock, S. G.,
M. E. Modica,
and
C. T. Cavanaugh.
L-Arginine stimulates cyclic guanosine 3',5'-monophosphate formation in rat islets of Langerhans and RIN m5F insulinoma cells: evidence for L-arginine:nitric oxide synthase.
Endocrinology
129:
3041-3052,
1991.
27.
Lebrun, P.,
M.-H. Antoine,
and
A. Herchuelz.
K+ channel openers and insulin release.
Life Sci.
51:
795-806,
1992[Medline].
28.
Malaisse, W. J.,
F. Blachier,
A. Mourtada,
J. Camara,
A. Albor,
I. Valverde,
and
A. Sener.
Stimulus-secretion coupling of arginine-induced insulin release. Metabolism of L-arginine and L-ornithine in pancreatic islets.
Biochim. Biophys. Acta
1013:
133-143,
1989[Medline].
29.
Maruyama, H.,
A. Hisatomi,
L. Orci,
G. M. Grodsky,
and
R. H. Unger.
Insulin within islets is a physiologic glucagon release inhibitor.
J. Clin. Invest.
74:
2296-2299,
1984[Medline].
30.
Moncada, S.,
R. M. J. Palmer,
and
E. A. Higgs.
Nitric oxide: physiology, pathophysiology and pharmacology.
Pharmacol. Rev.
43:
109-142,
1991[Medline].
31.
Panagiotidis, G.,
B. Åkesson,
P. Alm,
and
I. Lundquist.
The nitric oxide system in the endocrine pancreas induces differential effects on secretion of insulin and glucagon.
Endocrine
2:
787-792,
1994.
32.
Panagiotidis, G.,
B. Åkesson,
E. L. Rydell,
and
I. Lundquist.
Influence of nitric oxide synthase inhibition, nitric oxide and hydroperoxide on insulin release induced by various secretagogues.
Br. J. Pharmacol.
229:
277-278,
1995.
33.
Panagiotidis, G.,
P. Alm,
and
I. Lundquist.
Inhibition of islet nitric oxide synthase increases arginine-induced insulin release.
Eur. J. Pharmacol.
229:
277-278,
1992[Medline].
34.
Panagiotidis, G.,
A. Salehi,
P. Westermark,
and
I. Lundquist.
Homologous islet amyloid polypeptide: effects on plasma levels of glucagon, insulin and glucose in the mouse.
Diabetes Res. Clin. Pract.
18:
167-171,
1992[Medline].
35.
Rees, D. D.,
R. M. J. Palmer,
R. Schulz,
H. F. Hodson,
and
S. Moncada.
Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo.
Br. J. Pharmacol.
101:
746-752,
1990[Abstract].
36.
Salehi, A.,
M. Carlberg,
R. Henningson,
and
I. Lundquist.
Islet constitutive nitric oxide synthase: biochemical determination and regulatory function.
Am. J. Physiol.
270 (Cell Physiol. 39):
C1634-C1641,
1996
37.
Schmidt, K.,
P. Klatt,
and
B. Mayer.
Characterization of endothelial cell amino acid transport systems involved in the actions of nitric oxide synthase inhibitors.
Mol. Pharmacol.
44:
615-621,
1993[Abstract].
38.
Schmidt, H. H. H. W.,
T. D. Warner,
K. Ishii,
H. Sheng,
and
F. Murad.
Insulin secretion from pancreatic B cells caused by L-arginine-derived nitrogen oxides.
Science
255:
721-723,
1992[Medline].
39.
Sener, A.,
F. Blachier,
J. Rasschaert,
A. Mourtada,
F. Malaisse-Lagae,
and
W. J. Malaisse.
Stimulus-secretion coupling of arginine-induced insulin release: comparison with lysine-induced insulin secretion.
Endocrinology
124:
2558-2567,
1989[Abstract].