Dual effect of nitric oxide on cytosolic Ca2+concentration and insulin secretion in rat pancreatic β-cells

2003 ◽  
Vol 284 (5) ◽  
pp. C1215-C1222 ◽  
Author(s):  
Yukiko Kaneko ◽  
Tomohisa Ishikawa ◽  
Satoshi Amano ◽  
Koichi Nakayama
Keyword(s):  
Nitric Oxide ◽  
Insulin Secretion ◽  
Kinase Inhibitor ◽  
Soluble Guanylate Cyclase ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Dual Effect ◽  
Independent Manner ◽  
No Donor ◽  
Isolated Rat

In isolated rat pancreatic β-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 N G-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 β-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 ofl-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 β-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.

scholarly journals Nitric oxide interacts with cholinoceptors to modulate insulin secretion by pancreatic β cells

2020 ◽  
Vol 472 (10) ◽  
pp. 1469-1480
Author(s):  
Bashair M. Mussa ◽  
Ankita Srivastava ◽  
Abdul Khader Mohammed ◽  
Anthony J. M. Verberne
Keyword(s):  
Nitric Oxide ◽  
Insulin Secretion ◽  
Cell Viability ◽  
Combined Treatment ◽  
No Production ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Tnf Α ◽  
Ifn Γ

Abstract Dysfunction of the pancreatic β cells leads to several chronic disorders including diabetes mellitus. Several mediators and mechanisms are known to be involved in the regulation of β cell secretory function. In this study, we propose that cytokine-induced nitric oxide (NO) production interacts with cholinergic mechanisms to modulate insulin secretion from pancreatic β cells. Using a rat insulinoma cell line INS-1, we demonstrated that β cell viability decreases significantly in the presence of SNAP (NO donor) in a concentration- and time-dependent manner. Cell viability was also found to be decreased in the presence of a combined treatment of SNAP with SMN (muscarinic receptor antagonist). We then investigated the impact of these findings on insulin secretion and found a significant reduction in glucose uptake by INS-1 cells in the presence of SNAP and SMN as compared with control. Nitric oxide synthase 3 gene expression was found to be significantly reduced in response to combined treatment with SNAP and SMN suggesting an interaction between the cholinergic and nitrergic systems. The analysis of gene and protein expression further pin-pointed the involvement of M3 muscarinic receptors in the cholinergic pathway. Upon treatment with cytokines, reduced cell viability was observed in the presence of TNF-α and IFN-γ. A significant reduction in insulin secretion was also noted after treatment with TNF-α and IFN-γ and IL1-β. The findings of the present study have shown for the first time that the inhibition of the excitatory effects of cholinergic pathways on glucose-induced insulin secretion may cause β cell injury and dysfunction of insulin secretion in response to cytokine-induced NO production.

scholarly journals Role of Hck in the Pathogenesis of Encephalomyocarditis Virus-Induced Diabetes in Mice

2001 ◽  
Vol 75 (4) ◽  
pp. 1949-1957 ◽  
Author(s):  
K. S. Choi ◽  
H. S. Jun ◽  
H. N. Kim ◽  
H. J. Park ◽  
Y. W. Eom ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Low Dose ◽  
Kinase Inhibitor ◽  
Src Kinase ◽  
Encephalomyocarditis Virus ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Necrosis Factor Alpha ◽  
Diabetes In Mice ◽  
Tnf Α

ABSTRACT Soluble mediators such as interleukin-1β, tumor necrosis factor alpha (TNF-α), and inducible nitric oxide synthase (iNOS) produced from activated macrophages play an important role in the destruction of pancreatic β cells in mice infected with a low dose of the D variant of encephalomyocarditis (EMC-D) virus. The tyrosine kinase signaling pathway was shown to be involved in EMC-D virus-induced activation of macrophages. This investigation was initiated to determine whether the Src family of kinases plays a role in the activation of macrophages, subsequently resulting in the destruction of β cells, in mice infected with a low dose of EMC-D virus. We examined the activation of p59/p56Hck, p55Fgr, and p56/p53Lynin macrophages from DBA/2 mice infected with the virus. We found that p59/p56Hck showed a marked increase in both autophosphorylation and kinase activity at 48 h after infection, whereas p55Fgr and p56/p53Lyn did not. The p59/p56Hck activity was closely correlated with the tyrosine phosphorylation level of Vav. Treatment of EMC-D virus-infected mice with the Src kinase inhibitor, PP2, resulted in the inhibition of p59/p56Hck activity and almost complete inhibition of the production of TNF-α and iNOS in macrophages and the subsequent prevention of diabetes in mice. On the basis of these observations, we conclude that the Src kinase, p59/p56Hck, plays an important role in the activation of macrophages and the subsequent production of TNF-α and nitric oxide, leading to the destruction of pancreatic β cells, which results in the development of diabetes in mice infected with a low dose of EMC-D virus.

scholarly journals Effects of nitroglycerin/L-cysteine on soluble guanylate cyclase: evidence for an activation/inactivation equilibrium controlled by nitric oxide binding and haem oxidation

2005 ◽  
Vol 390 (2) ◽  
pp. 625-631 ◽  
Author(s):  
Antonius C. F. Gorren ◽  
Michael Russwurm ◽  
Alexander Kollau ◽  
Doris Koesling ◽  
Kurt Schmidt ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Soret Band ◽  
Flavin Mononucleotide ◽  
Independent Manner ◽  
No Donor ◽  
No Release ◽  
Glycerol Trinitrate ◽  
Haem Protein

GTN (nitroglycerin; glycerol trinitrate) causes dilation of blood vessels via activation of nitric oxide (NO)-sensitive sGC (soluble guanylate cyclase), a heterodimeric haem protein that catalyses the conversion of GTP into cGMP. Activation of sGC by GTN requires enzymatic or non-enzymatic bioactivation of the nitrate. Based on insufficient NO release and lack of spectroscopic evidence for formation of NO–sGC, the cysteine (Cys)-dependent activation of sGC by GTN was proposed to occur in an NO-independent manner. This extraordinary claim is questioned by the present findings. First, the effect of GTN/Cys was blocked by the NO scavenger oxyhaemoglobin, the superoxide-generating compound flavin mononucleotide and the haem-site sGC inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one). Secondly, at equi-effective concentrations, GTN/Cys and the NO donor 2,2-diethyl-1-nitroso-oxyhydrazine released identical amounts of NO. Finally, at sufficiently high rates of NO release, activation of sGC by GTN/Cys was accompanied by a shift of the Soret band from 431 to 399 nm, indicating formation of NO–sGC. In the absence of Cys, GTN caused haem oxidation, apparent as a shift of the Soret band to 392 nm, which was accompanied by inactivation of the NO-stimulated enzyme. These results suggest that the effect of GTN/Cys is the result of an activation/inactivation equilibrium that is controlled by the rate of NO release and haem oxidation.

scholarly journals A Neuronal Isoform of Nitric Oxide Synthase Expressed in Pancreatic β-Cells Controls Insulin Secretion

Diabetes ◽  
2001 ◽  
Vol 50 (6) ◽  
pp. 1311-1323 ◽  
Author(s):  
Anne-Dominique Lajoix ◽  
Hubbert Reggio ◽  
Thierry Chardès ◽  
Sylvie Péraldi-Roux ◽  
Florence Tribillac ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Insulin Secretion ◽  
Nitric Oxide Synthase ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Oxide Synthase

Involvement of stretch-activated cation channels in hypotonically induced insulin secretion in rat pancreatic β-cells

2006 ◽  
Vol 291 (6) ◽  
pp. C1405-C1411 ◽  
Author(s):  
Miki Takii ◽  
Tomohisa Ishikawa ◽  
Hidetaka Tsuda ◽  
Kazumitsu Kanatani ◽  
Takaaki Sunouchi ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Membrane Depolarization ◽  
Ruthenium Red ◽  
Cell Swelling ◽  
Cation Channels ◽  
Channel Blockers ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Voltage Dependent ◽  
Isolated Rat

In isolated rat pancreatic β-cells, hypotonic stimulation elicited an increase in cytosolic Ca2+ concentration ([Ca2+]c) at 2.8 mM glucose. The hypotonically induced [Ca2+]c elevation was significantly suppressed by nicardipine, a voltage-dependent Ca2+ channel blocker, and by Gd3+, amiloride, 2-aminoethoxydiphenylborate, and ruthenium red, all cation channel blockers. In contrast, the [Ca2+]c elevation was not inhibited by suramin, a P2 purinoceptor antagonist. Whole cell patch-clamp analyses showed that hypotonic stimulation induced membrane depolarization of β-cells and produced outwardly rectifying cation currents; Gd3+ inhibited both responses. Hypotonic stimulation also increased insulin secretion from isolated rat islets, and Gd3+ significantly suppressed this secretion. Together, these results suggest that osmotic cell swelling activates cation channels in rat pancreatic β-cells, thereby causing membrane depolarization and subsequent activation of voltage-dependent Ca2+ channels and thus elevating insulin secretion.

scholarly journals IL-1β reciprocally regulates chemokine and insulin secretion in pancreatic β-cells via NF-κB

2015 ◽  
Vol 309 (8) ◽  
pp. E715-E726 ◽  
Author(s):  
Susan J. Burke ◽  
Krisztian Stadler ◽  
Danhong Lu ◽  
Evanna Gleason ◽  
Anna Han ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Insulin Secretion ◽  
Transcriptional Activity ◽  
Cell Function ◽  
Inflammatory Responses ◽  
Cell Mass ◽  
Negative Regulator ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

Proinflammatory cytokines impact islet β-cell mass and function by altering the transcriptional activity within pancreatic β-cells, producing increases in intracellular nitric oxide abundance and the synthesis and secretion of immunomodulatory proteins such as chemokines. Herein, we report that IL-1β, a major mediator of inflammatory responses associated with diabetes development, coordinately and reciprocally regulates chemokine and insulin secretion. We discovered that NF-κB controls the increase in chemokine transcription and secretion as well as the decrease in both insulin secretion and proliferation in response to IL-1β. Nitric oxide production, which is markedly elevated in pancreatic β-cells exposed to IL-1β, is a negative regulator of both glucose-stimulated insulin secretion and glucose-induced increases in intracellular calcium levels. By contrast, the IL-1β-mediated production of the chemokines CCL2 and CCL20 was not influenced by either nitric oxide levels or glucose concentration. Instead, the synthesis and secretion of CCL2 and CCL20 in response to IL-1β were dependent on NF-κB transcriptional activity. We conclude that IL-1β-induced transcriptional reprogramming via NF-κB reciprocally regulates chemokine and insulin secretion while also negatively regulating β-cell proliferation. These findings are consistent with NF-κB as a major regulatory node controlling inflammation-associated alterations in islet β-cell function and mass.

scholarly journals Role for c-Jun N-Terminal Kinase in β-Cell Recovery from Nitric Oxide-Mediated Damage

Endocrinology ◽  
2003 ◽  
Vol 144 (8) ◽  
pp. 3415-3422 ◽  
Author(s):  
Anna L. Scarim ◽  
Sheri Y. Nishimoto ◽  
Sarah M. Weber ◽  
John A. Corbett
Keyword(s):  
Nitric Oxide ◽  
Insulin Secretion ◽  
Guanylate Cyclase ◽  
Recovery Process ◽  
Cell Recovery ◽  
Β Cells ◽  
Β Cell ◽  
No Donor ◽  
Aconitase Activity ◽  
Mitochondrial Aconitase

Abstract Treatment of rat islets with the cytokine IL-1 results in the inhibition of mitochondrial function and insulin secretion, events that are mediated by β-cell expression of iNOS [inducible nitric oxide (NO) synthase] and production of NO. β-Cells recover from the inhibitory actions of NO, produced following 24 h incubation with IL-1, on islet oxidative metabolism and insulin secretion if iNOS enzymatic activity is inhibited and the islets are cultured (in the presence of IL-1 and iNOS inhibitors) for a brief period of 8 h. Islet recovery from cytokine- and NO-mediated damage is an active process that requires new gene expression, and NO itself is one activator of this recovery process. In this study, the mechanism by which NO stimulates islet recovery has been examined. Incubation of rat islets or RINm5F cells with the NO donor compound, sodium (Z)-1(N,N-diethylamino) diazen-1-ium-1,2-diolate (DEA-NO) for 1 h results in a 60% inhibition of mitochondrial aconitase activity. β-Cells completely recover aconitase activity if the cells are washed to remove the NO donor compound and incubated for an additional 5 h in the absence of DEA-NO. The recovery of mitochondrial aconitase activity correlates with a 4-fold increase in cyclic GMP accumulation and is prevented by the inhibition of guanylate cyclase. The recovery of aconitase activity also correlates with the activation of members of the MAPKs, p38, c-Jun N-terminal kinase (JNK) and ERK, and the activation p38 and JNK is attenuated by inhibition of guanylate cyclase. ERK and p38 do not appear to participate in the recovery process as selective inhibition of these kinases fails to prevent recovery of aconitase activity; however, transduction of β-cells with a dominant negative mutant JNK prevents β-cell recovery from NO-mediated damage. These findings support a role for guanylate cyclase and JNK in the recovery of β-cells from NO-mediated damage.

Hypoxia-augmented constriction of deep femoral artery mediated by inhibition of eNOS in smooth muscle

2013 ◽  
Vol 304 (1) ◽  
pp. C78-C88 ◽  
Author(s):  
Jung-A. Han ◽  
Eun Yeoung Seo ◽  
Hae Jin Kim ◽  
Su Jung Park ◽  
Hae Young Yoo ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Nitric Oxide Synthase ◽  
Femoral Artery ◽  
Kinase Inhibitor ◽  
Soluble Guanylate Cyclase ◽  
Deep Femoral Artery ◽  
No Donor ◽  
Diphenylene Iodonium ◽  
Oxide Synthase

In contrast to the conventional belief that systemic arteries dilate under hypoxia, we found that α-adrenergic contraction of rat deep femoral artery (DFA) is largely augmented by hypoxia (HVCDFA) while hypoxia (3% Po2) alone had no effect. HVCDFA was consistently observed in both endothelium-intact and -denuded vessels with partial pretone by phenylephrine (PhE) or by other conditions (e.g., K+ channel blocker). Patch-clamp study showed no change in the membrane conductance of DFA myocytes by hypoxia. The RhoA-kinase inhibitor Y27632 attenuated HVCDFA. The nitric oxide synthase inhibitor [nitro-l-arginine methyl ester (l-NAME)] and soluble guanylate cyclase inhibitor [oxadiazole quinoxalin (ODQ)] strongly augmented the PhE-pretone, while neither of the agents had effect without pretone. NADPH oxidase type 4 (NOX4) inhibitors (diphenylene iodonium and plumbagin) also potentiated PhE-pretone, which was reversed by NO donor. No additive HVCDFA was observed under the pretreatment with l-NAME, ODQ, or plumbagin. Western blot and immunohistochemistry analysis showed that both NOX4 and endothelial nitric oxide synthase (eNOS) are expressed in smooth muscle layer of DFA. Various mitochondria inhibitors (rotenone, myxothiazol, and cyanide) prevented HVCDFA. From the pharmacological data, as a mechanism for HVCDFA, we suggest hypoxic inhibition of eNOS in myocytes. The putative role of NOX4 and mitochondria requires further investigation. The HVCDFA may prevent imbalance between cardiac output and skeletal blood flow under emergent hypoxia combined with increased sympathetic tone.

Dual effect of nitric oxide on ATP-sensitive K+ channels in rat pancreatic β cells

2008 ◽  
Vol 456 (3) ◽  
pp. 573-579 ◽  
Author(s):  
Takaaki Sunouchi ◽  
Kimiaki Suzuki ◽  
Koichi Nakayama ◽  
Tomohisa Ishikawa
Keyword(s):  
Nitric Oxide ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Dual Effect ◽  
K Channels
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