Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In addition to its functions as a neuronal messenger molecule, nitric oxide (NO) has also been implicated in playing a major role in ischemic damage and glutamate neurotoxicity. Using primary cortical cultures from transgenic neuronal NO synthase (NOS) null (nNOS-) mice, we definitively establish NO as a mediator of NMDA and hypoxic neurotoxicity. Neurotoxicity elicited by NMDA is markedly attenuated in nNOS- cortical cultures compared with wild-type cultures. The NOS inhibitor nitro-L-arginine is neuroprotective in wild-type but not nNOS-cultures, confirming the role of nNOS-derived NO in glutamate neurotoxicity. Confirming that the nNOS- cultures lack NMDA-stimulated nNOS activity, NMDA did not stimulate the formation of cGMP in nNOS- cultures, but markedly elevates cGMP in wild-type cultures. Both wild-type and nNOS- cultures are sensitive to toxicity induced by NO donors, indicating that pathways stimulated by NO that result in neuronal cell death are still intact in the transgenic mice. Superoxide dismutase is neuroprotective against NMDA and NO neurotoxicity in both wild-type and nNOS- cultures, highlighting the importance of superoxide anion in subsequent neuronal damage. The unknown cellular factors that endow differential resistance to NMDA neurotoxicity and differential susceptibility to quisqualate neurotoxicity remain intact in the nNOS- cultures, because the response of somatostatin-immunopositive neurons in nNOS- cultures to high-dose NMDA and low-dose quisqualate is identical to the response of NOS-immunopositive neurons in the wild-type cultures. There is no difference in susceptibility to kainate neurotoxicity between nNOS- and wild-type cultures and only a modest resistance to quisqualate neurotoxicity, confirming observations that NO-mediated neurotoxicity is associated primarily with activation of the NMDA receptor. The nNOS- cultures are markedly protected from 60 min of combined oxygen-glucose deprivation neurotoxicity compared with wild-type cultures. Wild-type cultures are protected from neuronal cell death by the NMDA receptor antagonist MK-801 and the NOS inhibitor L-nitroarginine methyl ester, but not its inactive stereoisomer D-nitroarginine methyl ester. nNOS- cultures were not additionally protected. These data confirm that activation of NMDA receptors and production of NO are primary mediators of neuronal damage after ischemic insult.
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PMID:Resistance to neurotoxicity in cortical cultures from neuronal nitric oxide synthase-deficient mice. 878 24

We have previously demonstrated that endothelin-1 (ET-1) increases plasma insulin and decreases blood glucose. The present study was designed to determine if ET-1-induced hypoglycemia occurs in the presence of the insulin secretion inhibitor, somatostatin, and whether ET-1-induced insulin secretion is affected by the nitric oxide synthase I inhibitor, NG-methyl-L-arginine (NMLA), in the anesthetized rat. ET-1 increased plasma insulin and decreased blood glucose in all protocols. Somatostatin alone decreased blood glucose and plasma insulin. Somatostatin blocked ET-1-induced plasma insulin release but did not completely block ET-1-induced hypoglycemia. NMLA alone decreased blood glucose and plasma insulin. NMLA also blocked ET-1-induced insulin release but not ET-1-induced hypoglycemia. The present study confirms our previous finding that ET-1 decreases blood glucose and increases plasma insulin. Because hypoglycemia occurs during insulin inhibition with somatostatin, the present study suggests that ET-1-induced hypoglycemia is partially caused by non-insulin-mediated mechanisms. Because insulin secretion is blocked by nitric oxide synthase I inhibitor, NMLA, the present study suggests that ET-1-induced insulin release may be mediated by production of nitric oxide.
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PMID:NG-methyl-L-arginine and somatostatin decrease glucose and insulin and block endothelin-1 (ET-1)-induced insulin release but not ET-1-induced hypoglycemia. 878 19

The regulation of clonal rat insulinoma (RINm5F) cell proliferation and hormone accumulation was investigated with the aim of identifying putative compounds capable of inducing differentiation, i.e. decreased growth and increased insulin accumulation, by the tumor cells. In particular, interest was focused on the role of a number of peptides as well as pharmacological probes modulating various signal transduction systems and which have been shown to regulate normal beta-cell proliferation and insulin accumulation. Growth hormone stimulated insulin accumulation and inhibited DNA synthesis, whereas galanin and insulin-like growth factor I caused a moderate suppression of insulin accumulation but did not affect proliferation, while epidermal growth factor, transforming growth factor beta, platelet-derived growth factor, acidic and basic fibroblast growth factor, bradykinin and somatostatin were virtually inactive on all parameters tested. Exogenous prostaglandins E2 and F1 alpha were inactive, while the cycloxygenase inhibitor indomethacin slightly suppressed insulin accumulation. The cytokine IL-1 beta caused a significant decrease in both beta-cell mitogenesis and insulin accumulation, effects that were mediated through nitric oxide generation. The vitamin A derivative retinyl acetate slightly inhibited serum-stimulated DNA synthesis, but did not affect insulin accumulation. The vitamin E alpha-tocopherol significantly enhanced insulin release but did not affect mitogenesis. By contrast, gamma-tocopherol was inactive on both these parameters. The alpha-adrenergic agonist clonidine evoked a slight inhibition of serum-stimulated DNA synthesis, without influencing insulin accumulation, whereas phenylephrine did not affect any of these parameters. Carbamylcholine increased insulin accumulation, but not cell proliferation, whereas the adenylyl cyclase activator forskolin suppressed mitogenesis but did not affect insulin accumulation. Inhibition of protein kinase C with staurosporine or prolonged treatment with phorbol ester suppressed DNA synthesis, as did the tyrosine kinase inhibitor genistein. Stimulating Ca2+ influx by closing ATP-dependent K+ channels with glibenclamide enhanced DNA synthesis, while opening of these channels with diazoxide suppressed cell growth. Conversely, preventing Ca2+ influx by the Ca2+ channel antagonist D-600, chelating intracellular Ca2+ by fura-2 AM or inhibiting the Ca2+/calmodulin-dependent protein kinase by calmidazol resulted in a decreased DNA synthesis. On the other hand, uncontrolled influx or mobilization of Ca2+ by ionomycin or thapsigargin resulted in an arrested DNA synthesis. The present paper shows that RINm5F insulinoma cell proliferation and insulin accumulation can be modulated by various peptidergic and pharmacological agents regulating certain signal transduction pathways. However, mitogenesis in the insulinoma cells seemingly is controlled in a vastly different manner in comparison to that in normal beta-cells. The most spectacular finding in this screening study, i.e. that growth hormone, contrarily to its effect on normal beta-cells, suppresses insulinoma cell growth, merits further elucidation of the underlying mechanisms. Possibly the hormone might become of utility in a clinical setting in the treatment of patients with insulin-producing tumors.
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PMID:Regulation of insulinoma cell proliferation and insulin accumulation by peptides and second messengers. 880 83

The localization and distribution of nitric oxide synthase in the hypothalamus have been studied with an immunohistochemical technique using antibodies to neuronal rat nitric oxide synthase. Subsequent double-labeling experiments examined the colocalization patterns of nitric oxide synthase and several peptides. Our results demonstrate a widespread occurrence of nitric oxide synthase-immunoreactive nerve cell bodies and processes throughout the hypothalamus, especially in various parts of the preoptic region, in the supraoptic and paraventricular nuclei, the lateral hypothalamic area, the ventromedial and dorsomedial nuclei, the arcuate nucleus and various parts of the mammillary region. Double labeling experiments showed that nitric oxide synthase-like immunoreactivity coexists with substance P-like immunoreactivity in the medial preoptic area, with oxytocin-, cholecystokinin-and galanin message-associated peptide-like immunoreactivity in the supraoptic nucleus, with enkephalin, oxytocin- and corticotropin releasing factor-like immunoreactivity in the paraventricular nucleus and with enkephalin-like immunoreactivity in the arcuate nucleus. Furthermore, in the ventromedial nucleus, nitric oxide synthase-like immunoreactivity coexisted with enkephalin-, substance P-, and somatostatin-like immunoreactivity, and in the dorsomedial nucleus with enkephalin-, galanin message-associated peptide-and substance P-like immunoreactivity. In the mammillary region nitric oxide synthase-like immunoreactivity coexisted with enkephalin-, cholecystokinin-, and substance P-like immunoreactivity. Among these neuropeptides, enkephalin and substance P were most frequently found in nitric oxide synthase-immunoreactive neurons. We conclude that nitric oxide synthase-immunoreactive neurons contain neuropeptides in various parts of the hypothalamus, and that nitric oxide in the hypothalamus may be involved in a variety of neuroendocrine and autonomic functions.
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PMID:Immunohistochemical mapping of nitric oxide synthase in the rat hypothalamus and colocalization with neuropeptides. 881 20

The aim of the study was to characterize the gastric and mesenteric vascular changes induced by diabetes and the implication of endothelial [nitric oxide (NO) and prostaglandins] and humoral (glucagon) factors in such changes. Diabetes was induced in rats by a single streptozotocin injection. Four weeks later, gastric mucosa, left gastric artery, and superior mesenteric artery blood flows were measured using hydrogen gas clearance and perivascular ultrasonic flowmeter techniques, respectively, in anesthetized and fasted diabetic and control rats. Blood pressure, hematocrit, blood volume, and blood viscosity were also measured. Left gastric (41 +/- 6 vs. 25 +/- 4 ml.min-1.100 g-1) and superior mesenteric artery blood flows (83 +/- 8 vs. 65 +/- 4 ml.min-1.100 g-1) were significantly higher in diabetic than in control rats. The increased blood flow in the left gastric artery was distributed to a hypertrophic mucosa in diabetic rats; therefore, the blood flow per 100 g tissue in the gastric mucosa was not significantly different in diabetic compared with control rats. Pretreatment with indomethacin reduced both increase gastric and mesenteric flows of the diabetic rats to the same levels as in control rats. NG-nitro-L-arginine methyl ester decreased gastric blood flow in a dose-dependent manner and to a similar extent in diabetic and control rats. In contrast, an increased sensitivity to the higher doses of the NO inhibitor was observed in the mesenteric vascular bed of diabetic rats. Glucagon reduction achieved by somatostatin infusion did not influence either gastric or mesenteric blood flow in diabetic rats. In summary, the present study revealed an increase in gastric and mesenteric arterial blood flows in streptozotocin-induced diabetic rats. The gastrointestinal hyperemia seems to be due, at least in part, to the increased demand of a hypertrophic mucosa and is mediated primarily by endogenous prostaglandins. Increased vascular sensitivity to NO may also contribute to the mesenteric vasodilation.
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PMID:Role of prostaglandins and nitric oxide in gastrointestinal hyperemia of diabetic rats. 892 99

The release of somatostatin-like immunoreactivity was studied in isolated synaptosomes. A significant release of somatostatin-like immunoreactivity was observed in the presence of vasoactive intestinal polypeptide (VIP) (10(-6) M: 53.0 +/- 12.4 pg/mg, basal: 14.3 +/- 1.7 pg/mg, n = 5, P < 0.05), secretin (10(-6) M: 56.1 +/- 3.8 pg/mg, basal: 25.8 +/- 1.6 pg/mg, n = 6, P < 0.01) and isoproterenol (10(-5) M: 54.0 +/- 13.4 pg/mg, basal: 20.0 +/- 3.4 pg/mg, n = 8, P < 0.05). Forskolin, an unspecified activator of the adenylate cyclase, caused a significant release of somatostatin-like immunoreactivity (10(-6) M: 57.3 +/- 13.2 pg/mg, basal: 30.0 +/- 5.8 pg/mg, n = 13, P < 0.01) which was further augmented in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX 10(-4) M) (77.0 +/- 17.8 pg/mg, n = 13, P < 0.01). 3-Isobutyl-l-methylxanthine and N6, 2'-O-dibutyryladenosine-3',5'-cyclic monophosphate mimicked at effect of forskolin and VIP. The release of somatostatin was paralleled by an increase of cAMP immunoreactivity in the presence of VIP (10(-6) M: 37.1 +/- 9.4 pmol/mg, basal: 19.8 +/- 4.2 pmol/mg, n = 10, P < 0.05), isoproterenol (10(-5) M: 42.4 +/- 9.8 pmol/mg basal: 16.7 +/- 2.4 pmol/mg, n = 12, P < 0.01) and forskolin (10(-6) M: 47.1 +/- 12.4 pmol/mg, basal: 19.8 +/- 4.2 pmol/mg, n = 10, P < 0.01). The effect of nitric oxide (NO) which acts as an inhibitory neurotransmitter in the enteric nervous system was studied. NO is known to activate guanylate cyclase to induce transmitter release. The NO-generating compound sodium nitroprusside and bromoguanosine-3',5'-cyclic monophosphate (8-Br-cGMP) had no effect on the release of somatostatin-like immunoreactivity. These data demonstrate the stimulatory effect of VIP, secretin and isoproterenol on release of somatostatin-like immunoreactivity from enteric synaptosomes, which is presumably mediated by cAMP-dependent mechanisms. cGMP-dependent mechanisms seem to be of minor relevance.
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PMID:Presynaptic modulation by VIP, secretin and isoproterenol of somatostatin release from enriched enteric synaptosomes: role of cAMP. 895 33

The vascular effects of somatostatin (ST) and its mechanism of action are not well understood. In the present study, we investigated the direct effects of ST on the vascular tone of rat saphenous artery and vein using videomicroangiometry in situ. ST was administered either in superfusion or in infusion. We found opposite effects in arteries and veins: ST (10(-12)-10(-7) M) dilated the artery (outer diameter increased from 533 +/- 28 to 600 +/- 29 microns, administered in superfusion) and contracted the vein (from 709 +/- 26 to 640 +/- 26 microns and from 775 +/- 30 to 708 +/- 60 microns in superfusion and infusion, respectively). These effects of ST were completely abolished after deendothelization (air bolus maintained for 6 min in vessel lumen) and after local infusion of NG-nitro-L-arginine (L-NNA; 10(-4) M), a nitric oxide (NO) synthesis inhibitor. An NO-dependent basal vasodilator tone in the rat saphenous vein responsible for 10.9 +/- 0.3% of the total vessel diameter was found. After ST administration the venous diameter reduction was similar to that measured after deendothelization or L-NNA. We conclude that ST in situ induces NO release from endothelial cells of rat saphenous artery causing vasodilation, whereas, in contrast, it inhibits the basal NO-dependent vasodilator tone of the saphenous vein inducing vasoconstriction.
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PMID:Nitric oxide-dependent opposite effects of somatostatin on arterial and venous caliber in situ. 899 79

Direct vascular effects of somatostatin (ST) were investigated in cat superior mesenteric artery (SMA) segments in vitro. Changes of outer diameter were measured at constant axial length and perfusion pressure. SMA segments in the resting state were not affected by ST, regardless of endothelial integrity. Noradrenaline-preconstricted SMA segments were dilated concentration-dependently by ST (EC50 10(-13) mol/l). At maximal dilatation (by 10(-11) mol/l ST) the preconstriction was diminished to 45 +/- 9% (P<0.001). Perfusion with Triton X-100, or NG-nitro-L-arginine nearly abolished the ST-induced dilatation, while indomethacin treatment partially suppressed it. We conclude that ST dilates preconstricted cat SMA segments mainly via the endothelial release of nitric oxide, and additionally via prostaglandins.
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PMID:Somatostatin induces vasodilatation in the cat mesenteric artery via endothelium-derived nitric oxide and prostaglandins. 900 Apr 34

Nitric oxide synthase is co-localized with somatostatin and neuropeptide Y in a subpopulation of striatal interneurons that stain selectively for NADPH-diaphorase. We studied the ontogeny of diaphorase-positive neurons in striatal serum-free cultures derived from 15-16-day-old CD1 mice. NADPH-diaphorase staining was detected as early as embryological day 18 in vivo and day 5 in vitro. Over the next seven days the number of neurons staining for NADPH-diaphorase increased rapidly and then levelled off at about 0.5-1% of the total neuronal population both in vivo and in vitro. The cultured diaphorase neurons were also similar to their in vivo counterparts in terms of morphology and dendritic branching. Striatal neurons expressing NADPH-diaphorase exhibit similar ontogeny, morphology and neurochemical characteristics in vivo and in serum-free primary neuronal cultures. The culture system may represent a useful model for studying this important subgroup of striatal neurons.
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PMID:The ontogeny of NADPH-diaphorase neurons in serum-free striatal cultures parallels in vivo development. 914 14

The mechanisms of the vascular effects of somatostatin (ST) are not well known. This study compares the direct effect of ST in different vascular regions and species. Isolated perfused segments of the cat superior mesenteric artery in vitro did not exhibit a vascular response in the resting state, however, ST-induced vasodilatation was observed with norepinephrine preconstriction. In contrast, ST only slightly dilated superior mesenteric vein segments. In the artery, NG-nitro-L-arginine inhibited both ST and endothelium-dependent nitric oxide (NO) mediated response. No regular dose-response curves were found when ST was applied on the large mesenteric artery in the cat, but rings of small mesenteric artery from both cats and dogs exhibited dose-dependent relaxations. These effects were also NO-dependent. Local application of ST on the rat saphenous artery in situ elicited NO-mediated dose-dependent vasodilatation. However, ST constricted rat saphenous veins in the case of either adventitial or intraluminal application. It is concluded that ST exerts different actions on the arterial and the venous vessel wall. The major response in arteries is endothelium-mediated vasodilatation seen in various species and vascular beds. Large and small arteries respond differently to ST but these differences require further elucidation.
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PMID:Regional differences in nitric oxide-dependent vascular responses to somatostatin. 908 52


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