Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The central interactions between the sigma ligand, JO 1784, [(+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethylbut-3- en-1-ylamine hydrochloride], or neuropeptide Y (NPY) and corticotropin-releasing factor (CRF)-induced inhibition of gastric acid secretion were investigated in rats anaesthetized with urethane. Drugs were injected intracisternally (i.c.) or into specific hypothalamic nuclei. Gastric acid secretion was measured by the flushed technique under basal and pentagastrin (10 micrograms kg-1 h-1, i.v.) stimulated conditions. 2. Intracisternal injection of CRF (10 micrograms), bombesin (0.1 microgram) and human recombinant interleukin-1 beta (hIL-1 beta, 0.1 microgram) inhibited gastric acid response to pentagastrin by 72%, 56% and 62%, respectively. NPY (0.5 microgram) or JO 1784 (0.5 microgram) injected i.c. did not alter acid secretion but completely prevented the inhibitory effect of CRF. The antagonistic effect of NPY and JO 1784 against CRF was dose-related (0.01-0.5 microgram) and peptide-specific since NPY and JO 1784 did not alter the antisecretory action of bombesin or hIL-1 beta. 3. The putative sigma receptor antagonist, BMY 14802, (1 mg kg-1, s.c.) did not influence pentagastrin-stimulated acid secretion nor CRF-induced inhibition of gastric acid secretion; however, BMY 14802 administered s.c. 20 min before JO 1784 or NPY, abolished the antagonistic effect of both JO 1784 and NPY. 4. CRF (3 micrograms) microinjected into the hypothalamic paraventricular nucleus (PVN) and the lateral hypothalamus (LH) inhibited pentagastrin-stimulated gastric acid secretion by 61% and 51%; NPY (0.03 micrograms) or JO 1784 (0.03 micrograms) microinjected into the PVN had no effect by themselves but blocked CRF antisecretory action.There were more VPBs (220 +/- 75), a higher incidence of VT (60%) and more episodes of VT (11.5 +/- 6.0 compared to 0.7 +/- 0.3 episodes in the preconditioned dogs not given L-NAME); none of the animals survived reperfusion (incidence of VF 100%). The improvement in the severity of the degree of inhomogeneity which resulted from preconditioning was abolished by L-NAME administration.5. L-NAME itself elevated blood pressure (from 96 +/- 5 mmHg diastolic to 119 +/- 7 mmHg), reduced heart rate (from 155 +/- 7 to 144 +/- 4 beats min-') but did not change LVEDP, LVdP/dt,,,,, coronary blood flow, ST-segment elevation or the degree of inhomogeneity of conduction. When given 10 min before the prolonged coronary artery occlusion in dogs not subjected to preconditioning, L-NAME had no significant effect on the severity of arrhythmias except for more periods of VT (a mean of 11.7 +/- 4.7 episodes per dog).6. It is concluded from these studies that the generation of nitric oxide contributes to the marked antiarrhythmic effects of preconditioning in the canine myocardium, probably through elevation of cyclic GMP.
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PMID:Central neuropeptide Y and the sigma ligand, JO 1784, reverse corticotropin-releasing factor-induced inhibition of gastric acid secretion in rats. 147 62

Nitric oxide (NO) synthase (NOS), the enzyme responsible for NO formation, is found in hypothalamic neurons containing oxytocin (OT), vasopressin (VP), and to a lesser extent corticotropin-releasing factor (CRF). Because NO is reported to modulate endocrine activity, we have investigated the hypothesis that endogenous NO participates in ACTH released by various secretagogues in the rat. In the adult male rat, the intravenous injection of interleukin-1 beta (IL-1 beta; 0.2-0.3 micrograms/kg), VP (0.3-0.9 micrograms/kg), and OT (30 micrograms/kg) significantly increased plasma ACTH and corticosterone levels. Pretreatment with the L-form, but not the D-form, of N omega nitro-L-arginine-methylester (L-NAME; a specific inhibitor of NOS) markedly augmented the effects of these secretagogues whether it was injected acutely or over a 4 d period. Blockade of NOS activity also caused significant (P < 0.01) extensions of the duration of action of IL-1 beta, VP, and OT. In contrast, L-NAME did not significantly alter the stimulatory action of peripherally injected CRF, or centrally administered IL-1 beta. Administration of L-arginine, but not D-arginine (100 mg/kg), used as a substrate for basal NO synthesis and which did not by itself alter the activity of the hypothalamic-pituitary-adrenal (HPA) axis, blunted IL-1-induced ACTH secretion, and reversed the interaction between L-NAME and IL-1 beta. The stimulatory action of endotoxin, a lipopolysaccharide that releases endogenous cytokines, was also augmented by inhibition of NO formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In the rat, endogenous nitric oxide modulates the response of the hypothalamic-pituitary-adrenal axis to interleukin-1 beta, vasopressin, and oxytocin. 815 53

We sought to determine whether nitric oxide (NO) influences the steady-state gene expression of corticotropin-releasing factor (CRF) in the paraventricular nucleus (PVN) of the rat hypothalamus and conversely, whether CRF alters the activity of PVN neurons containing NO synthase (NOS), the enzyme responsible for NO formation. Adult male rats exposed to a 30-min session of mild electrofootshocks displayed a significant (P<0.01) increase in mRNA levels of the immediate early gene NGFI-B in the parvocellular portion of the PVN, which contains neurons expressing CRF. This response was decreased (P<0.01) by pretreatment with l-NAME, an arginine derivative that blocks NOS activity. In contrast, the stimulatory effect of interleukin-1beta (IL-1beta), injected intracerebroventricularly (i.c.v.) 45 and 15 min earlier, on NGFI-B mRNA and CRF hnRNA levels, was not. The i.c.v. injection of CRF (1 microg) significantly upregulated transcription of the neuronal isoform of NOS in the PVN, while the ability of i.c.v. IL-1beta to stimulate this signal was not significantly altered by i.c.v. injection of CRF antagonists. These results indicate that even though CRF acts centrally to increase PVN NOS mRNA concentrations, this peptide is not required for the effect of i.c.v. IL-1beta on these transcripts. On the other hand, the ability of shocks to stimulate PVN neuronal activity depends on NO formation. It therefore appears that the functional interactions between NO and CRF-dependent pathways is a function of the type of homeostatic threat to which the organism is exposed.
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PMID:Interaction between corticotropin-releasing factor and nitric oxide in mediating the response of the rat hypothalamus to immune and non-immune stimuli. 963 May 12

Nitric oxide (NO) is an unstable gas that participates in the response of the hypothalamic-pituitary-adrenal (HPA) axis to a variety of immune signals, including turpentine-induced tissue damage and the systemic injection of the pro-inflammatory cytokine interleukin 1-beta (IL-1beta). Studies that have investigated the role of this gas in the intact rat have relied on blockade of NO formation with the NO synthase (NOS) inhibitor N(omega)nitro-L-arginine-methylester (L-NAME). They have suggested that endogenous NO blunts the ACTH response to intravenous (i.v.) IL-1beta in part by exerting an inhibitory influence on the release of hypothalamic peptides such as corticotropin-releasing factor (CRF) from nerve terminals in the median eminence. It must nevertheless be noted that, at present, evidence for this mode of action remains circumstantial. Significant controversy remains regarding the specificity of the compounds used to block NO formation, the characteristics of their effect in terms of dose and timing of administration, the possibility that their effect is restricted to IL-1beta or can be expanded to other pro-inflammatory cytokines, and the question of whether the possibility that they might also influence ACTH release by altering circulating levels of tumor necrosis factor-alpha (TNF-alpha) and IL-6. The purpose of the present study was to elucidate these points. In the first series of experiments, we determined the i.v. IL-1beta-induced ACTH response to various doses of systematically injected L-NAME (1-100 mg/kg). At 10-100, but not 1 mg/kg, L-NAME significantly (P<0.01) augmented the ACTH response to IL-1beta, with a maximum effect observed at 30 and 100 mg/kg. At the 30 mg/kg dose, L-NAME was equally effective in augmenting the ACTH response when administered between 5 and 240 min prior to the cytokine. The effect of L-NAME was fully mimicked by equivalent doses of other arginine derivatives such as N(omega)-monomethyl-L-arginine (L-NMMA) or N(omega)-nitro-L-arginine (L-NNA), indicating that controversy in the published literature concerning the influence of NO on CRF secretion does not appear to be due to the use of different arginine derivatives. The ability of other cytokines such as TNF-alpha and IL-6 to release ACTH and corticosterone was significantly (P<0.01) augmented by blockade of NO formation in a manner similar to that found with IL-1beta. To test the hypothesis that L-NAME might alter ACTH secretion at least in part by modifying the secretion of pro-inflammatory cytokines, we measured plasma concentrations of TNF-alpha and IL-6 following endotoxin injection in the presence or absence of L-NAME. Blockade of NO formation reduced TNF-alpha but increased IL-6 levels in rats administered the lipopolysaccharide (25 microg/kg i.v.). As L-NAME augments the ACTH response to TNF-alpha as well as IL-6, it is improbable that changes in TNF-alpha and IL-6 secretion during immune stimulation represents an important mechanism mediating the inhibitory influence of endogenous NO on the HPA axis activity. Collectively, these results indicate that the systemic injection of L-NAME very quickly augments the stimulatory effect of pro-inflammatory cytokines on ACTH secretion, and does so for at least 4 h. Other arginine derivatives known to block the activity of constitutive NO syntheses, such as L-NMMA and L-NNA, exert an effect that is virtually identical to that of L-NAME. The ability of L-NAME to increase the ACTH response to i.v. IL-1beta is also observed in rats injected with TNF-alpha and IL-6. Because of the opposite effects of L-NAME on the levels of these two cytokines, the influence of arginine derivatives on ACTH release is probably not due to changes in cytokines produced during immune stimulation such as endotoxemia.
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PMID:Influence of nitric oxide synthase inhibitors on the ACTH and cytokine responses to peripheral immune signals. 966 49

The role played by nitric oxide (NO) and carbon monoxide (CO) was explored in the adult male rat by determining whether antagonizing the activity of the enzymes responsible for the formation of these gases altered the response of the hypothalamic-pituitary-adrenal (HPA) axis to immune (cytokines) or nonimmune (mild electroshocks) signals. The arginine derivative Nomeganitro-L-arginine-methylester (L-NAME), which inhibits all three NO synthase (NOS) isoforms [inducible (i), endothelial (e) and neuronal (n)] significantly augments the ACTH response to blood-borne cytokines, but decreases it in rats exposed to shocks or other physico-emotional stresses. The effect of L-NAME in both models is mimicked by L-nitroarginine (L-NNA) and L-nitromethylarginine (L-NMMA), which block constitutive (e and n) forms of NOS, but not by aminoguanidine (which blocks iNOS) or 7-nitroindazole (which specifically blocks nNOS). Despite the ability of L-NAME to markedly augment the stimulatory effect of vasopressin on ACTH secretion, removal of this peptide does not interfere with the interaction between L-NAME and systemically administered interleukin-1beta (IL-1beta). In contrast, blockade of prostaglandin formation prevents both the stimulatory effect of IL-1beta on ACTH release, and its potentiation by L-NAME. In contrast to the investigation of the importance of endogenous NO, studies focused on the role of CO remain scarce. Our preliminary results suggest that while blockade of the formation of this gas decreases the ACTH response to various stimuli, it also significantly interferes with the effect of L-NAME in rats systemically administered cytokines, and further decreases the ACTH response to shocks in animals also injected with arginine analogs. These results indicate the possible presence of functional interactions between NO and CO in regulating the activity of the HPA axis. Our present working hypothesis is that in the presence of elevated circulating cytokine levels, endogenous NO acts presynaptically to inhibit the release of ACTH secretagogues from nerve terminals in the infundibulum. As the acute ACTH response to these immune proteins is believed to primarily depend on events taking place within the median eminence, blockade of NO formation results in exaggerated ACTH release. During exposure to shocks and other nonimmune stresses, on the other hand, increased ACTH secretion is primarily due to activation of hypothalamic neurons. In this case, because of the stimulatory influence of endogenous NO on hypothalamic perikarya that manufacture corticotropin-releasing factor (CRF) and/or of the afferents to these neurons, blockade of NOS activity blunts CRF production, and consequently ACTH release. What remains undetermined is the net effect of the opposite influences of NO during long-term exposure to immune or nonimmune stress. Finally, it is possible that the conflicting results reported by investigators who study the role of NO and CO in isolated cell preparations may reflect, at least in part, these opposite effects of NO on different elements of the HPA axis.
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PMID:Role of nitric oxide and carbon monoxide in modulating the ACTH response to immune and nonimmune signals. 973 Jun 87

In the present study, we examined whether the human immunodeficiency virus type I (HIV-I) gp120 coat protein can modulate corticotropin releasing factor (CRF) secretion by using the incubation of rat hypothalamic explants as an in vitro model. Treatment of the hypothalamic fragments with recombinant gp120 resulted in a time- and concentration-dependent increase in CRF release. The maximal dose of 10 nM gp120 increased CRF release by 56.4% after 1 h, and 78.4% after 3 h, as compared with their respective controls. The intra-hypothalamic amount of CRF was also increased by 54.7% and 77.3% vs. controls after 1 and 3 h, respectively. Moreover, the action of gp120 was blocked by pretreatment with cycloheximide, suggesting that the viral protein modulates CRF secretion via an increase in its synthesis. We also investigated the effects of gp120 on CRF gene expression. RNase protection analyses of total RNA isolated from the explants indicated that 10 nM gp120 significantly increases CRF mRNA in a time-dependent manner. Furthermore, gp120 did not modify CRF mRNA stability, suggesting that the viral protein modulates CRF gene expression at the transcriptional level. Analysis of the mechanisms that mediate gp120-induced CRF synthesis was conducted. The incubation of the explants with recombinant interleukin-1 (IL-1) type I receptor antagonist (hrIL-1 ra) did not antagonize the actions of gp120 at 1 and 3 h, indicating that the effect of the latter is independent of IL-1 mediated mechanisms. The involvement of some second messenger pathways was also investigated. Specific inhibitors of cAMP-PKA, cyclo-oxygenase or heme oxygenase pathways failed to antagonize the gp120-induced increase in CRF production. By contrast, incubation with nonselective inhibitors of nitric oxide synthase (NOS), L-NAME and L-NNA, or aminoguanidine (AG), a selective inhibitor of inducible NOS (iNOS), blocked CRF release and, AG, its mRNA accumulation, stimulated by gp120, whereas selective inhibitors of endothelial and neuronal NOS had no effect. In addition, only L-NAME, L-NNA and AG were able to inhibit the gp120-stimulated production of nitrites. These results indicate that gp120 directly stimulates CRF gene expression and peptide synthesis from the rat hypothalamus in vitro via the activation of iNOS. Therefore, the actions of this viral protein on the HPA axis may, in part, reflect its ability to modulate CRF synthesis.
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PMID:HIV-1 Gp120 protein modulates corticotropin releasing factor synthesis and release via the stimulation of its mRNA from the rat hypothalamus in vitro: involvement of inducible nitric oxide synthase. 1149 61

Urocortin, an endogenous peptide structurally related to corticotropin-releasing factor (CRF), has potent cardiovascular effects, suggesting that it may be of significance in cardiovascular regulation. The objective of this study was to analyse the effects of urocortin and its action mechanisms on human blood vessels. To this, 3 mm long segments from human saphenous veins were prepared for isometric tension recording in an organ bath. In the segments at basal resting tone, urocortin did not produce any effect, but in the segments precontracted with endothelin-1 (1 - 10 nM), urocortin (1 pM - 10 nM) produced concentration-dependent relaxation. This relaxation was not modified by the inhibitor of nitric oxide synthase NG-nitro-L-arginine methyl ester (L-NAME, 100 microM), but it was potentiated by the cyclo-oxygenase inhibitor meclofenamate (10 microM) and it was reduced by the inhibitors of high-conductance Ca2+-dependent potassium channels tetraethylammonium (TEA, 10 mM) and charybdotoxin (100 nM). These results indicate that human saphenous veins are very sensitive to urocortin, which produces vascular relaxation by a mechanism independent of nitric oxide and dependent of high-conductance Ca2+-dependent potassium channels, and that it may be opposed by the release of vasoconstrictor prostanoids. Therefore, urocortin may be of significance for regulation of the venous circulation in humans.
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PMID:Relaxation by urocortin of human saphenous veins. 1197 72

This work examines the role of nitric oxide (NO) in the periphery (i.e., on the pituitary) and the brain (particularly on corticotropin-releasing factor [CRF] and vasopressin [VP] neurons in the paraventricular nucleus [PVN] of the hypothalamus) as a modulator of the ACTH response to lipopolysaccharide. We previously showed that NO restricted the pituitary response to VP while it facilitated the synthesis of PVN CRF and VP. In our experience, only relatively high doses of lipopolysaccharide (>50 microg/kg, injected intravenously [i.v.]) cause detectable increases in PVN neuronal activation. Our hypothesis, therefore, was that pituitary NO-VP interactions would predominate in rats injected with a low dose of lipopolysaccharide (0.5 microg/kg, i.v.) while the stimulatory influence of the gas on PVN neuronal activity would play an important role following i.v. injection of a large dose of lipopolysaccharide (50 microg/kg, i.v.). We observed that the ability of 0.5 microg/kg lipopolysaccharide to release ACTH was significantly enhanced by the subcutaneous (s.c.), but not the intracerebroventricular (i.c.v.) injection of L-NAME, an arginine derivative that blocks NO synthesis. The effect of s.c. L-NAME was reversed by immunoneutralization of endogenous VP, which indicated that in this model, the ability of lipopolysaccharide to release ACTH depended, at least in part, on the influence exerted by NO on the pituitary response to VP. In rats injected with the high lipopolysaccharide dose, the s.c. injection of L-NAME decreased plasma ACTH levels compared to those in rats pretreated with the vehicle. The effect of s.c. L-NAME was not significantly altered by VP antibodies. These results indicate that in this model, the primary influence of NO was exerted in the PVN and/or its afferents and that it did not depend on a peripheral, VP-mediated effect of the gas. On the one hand, these data are at odds with our finding that the i.c.v. injection of L-NAME only marginally altered the ACTH response to the large dose of lipopolysaccharide. As i.c.v. injected L-NAME should have primarily decreased hypothalamic, but not pituitary NOS, its only modest influence on ACTH release may have been due to a balance between stimulating and inhibiting effects of NO within the brain. As high doses of lipopolysaccharide increase brain levels of prostaglandin, monoamine, and proinflammatory cytokines, it will be important to investigate the influence exerted by NO on these secretagogues and on their interactions with PVN CRF and VP neurons, which may help us resolve the issues raised by our results. Collectively, these data support our hypothesis that the mechanisms mediating the ACTH response to a low lipopolysaccharide concentration involve the inhibitory VP-mediated influence of NO on pituitary activity. By contrast, the stimulatory effect of high doses of lipopolysaccharide on ACTH release depends, at least in part, on the ability of NO to upregulate PVN neuronal activity.
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PMID:Role of nitric oxide in regulating the rat hypothalamic-pituitary-adrenal axis response to endotoxemia. 1279 48

Urocortin is a peptide recently identified, structurally related to corticotropin releasing factor (CRF). We have compared the effects of urocortin in different vascular beds, and have investigated whether there are gender differences in these effects or whether they are altered by diabetes. We have studied the response of isolated segments (2-mm long) from basilar, coronary and tail arteries to urocortin. The segments were obtained from male and female, normoglycaemic and streptozotocin-induced diabetic rats. In the arterial segments precontracted with endothelin-1, urocortin produced concentration-dependent relaxation, and the order of sensitivity was: tail > basilar > coronary. This relaxation was similar in arteries from male and female, diabetic and normoglycaemic rats. In tail arteries from normoglycaemic male rats, the cyclooxygenase inhibitor meclofenamate (10(-5) M) increased the relaxation to urocortin, and the inhibitor of nitric oxide synthesis N(omega)-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) or the potassium-channel-blocker charybdotoxin (10(-7) M) did not modify it. In tail arteries from normoglycaemic female rats meclofenamate, charybdotoxin or L-NAME did not modify the relaxation to urocortin. These results suggested that urocortin produced vasodilation which showed regional differences between basilar, coronary and tail arteries, but was not affected by diabetes. The mechanisms underlying this relaxation in tail arteries might differ between males and females.
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PMID:Relaxation of rat arteries by urocortin: effects of gender and diabetes. 1284 38

It has been shown that glucagon like peptide-1 (GLP-1) acts on the central nervous system (CNS), in addition to its peripheral actions. Central administration of glucagon like peptide-1 (GLP-1) delays liquid gastric emptying via non-adrenergic, non-cholinergic neurons in rats. However, it remains unclear how central GLP-1 delays solid gastric emptying in rats. GLP-1 receptors at the CNS mediates the endocrine and anxiety responses to psychogenic and interoceptive stress. Corticotropin-releasing factor (CRF) is also known as a stress-related peptide, which delays gastric emptying of liquid and solid food via the autonomic nervous system. We have recently showed that central CRF delays solid gastric emptying via sympathetic pathways in rats. However, it remains unknown how central GLP-1 and CRF interact in mediating the inhibitory effect on solid gastric emptying. After a 24 h-fasting, GLP-1 was administered by intracisternal (ic)-injection immediately after the solid meal ingestion. Ninety minutes after the peptide injection, gastric contents were measured. Ic-injection of GLP-1 (30-3000 pmol) dose-dependently inhibited solid gastric emptying. Ic-injection of GLP-1 (3000 pmol)-induced delay of gastric emptying was partially antagonized by celiac ganglionectomy but not by atropine or N(G)-nitro-l-arginine methyl ester (L-NAME). Ic-injection of a CRF antagonist, astressin (2.8 nmol), partially antagonized GLP-1-induced delay of solid gastric emptying. These results indicate that central CRF and peripheral sympathetic pathway are, at least in part, involved in mediating central GLP-1-induced delay of solid gastric emptying in rats.
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PMID:Central glucagon like peptide-1 delays solid gastric emptying via central CRF and peripheral sympathetic pathway in rats. 1688


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