Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nitric oxide (NO)-guanosine 3',5'-cyclic monophosphate (cGMP) signaling pathway plays an important role in the pulmonary vascular transition at birth. We studied pulmonary arteries and veins isolated from normal late-gestation fetal lambs and from fetal lambs with persistent pulmonary hypertension (PPHN) following prenatal ligation of the ductus arteriosus. We additionally used double immunolabeling and immunoblot analysis to determine relative vascular contents of endothelial nitric oxide synthase (NOS-III) and soluble guanylate cyclase (sGC). Cyclic GMP content and sGC activity were significantly lower in arteries from hypertensive lambs than controls. A rank order for contents of both soluble guanylate cyclase and NOS-III was observed by both immunolabeling and immunoblotting: Control vein = Hypertensive vein > Control artery > Hypertensive artery. Our data demonstrate that the relative expression of sGC correlates well with the relative expression of NOS-III, and indicate the potential importance of soluble guanylate cyclase in the regulation of the perinatal pulmonary circulation. These data may help us understand vascular mechanisms producing PPHN, as well as patterns of response to exogenous NO.
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PMID:Pulmonary hypertension alters soluble guanylate cyclase activity and expression in pulmonary arteries isolated from fetal lambs. 1118 Jun 84

Nitric oxide (NO) and cGMP may exert positive or negative effects on inducible NO synthase (iNOS) expression. We have explored the influence of the NO/cGMP pathway on iNOS levels in human mesangial cells. Inhibition of NOS activity during an 8-h stimulation with IL-1beta plus tumor necrosis factor (TNF)-alpha reduced iNOS levels, while NO donors amplified iNOS induction threefold. However, time-course studies revealed a subsequent inhibitory effect of NO donors on iNOS protein and mRNA levels. This suggests that NO may contribute both to iNOS induction and downregulation. Soluble guanylyl cyclase (sGC) activation may be involved in these effects. Inhibition of sGC attenuated IL-1beta/TNF-alpha-elicited iNOS induction and reduced NO-driven amplification. Interestingly, cGMP analogs also modulated iNOS protein and mRNA levels in a biphasic manner. Inhibition of transcription unveiled a negative posttranscriptional modulation of the iNOS transcript by NO and cGMP at late times of induction. Supplementation with 8-bromo-cGMP (8-BrcGMP) reduced iNOS mRNA stability by 50%. These observations evidence a complex feedback regulation of iNOS expression, in which posttranscriptional mechanisms may play an important role.
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PMID:Posttranscriptional regulation of human iNOS by the NO/cGMP pathway. 1118 8

In cerebellar slices conjunctive pairing of parallel fibre (PF) stimulation with depolarization of Purkinje cells (PCs) induces a long-term depression (LTD) of PF synaptic transmission that spreads to unpaired PF inputs to the same cell. Inhibitors of NO synthase (7-nitro-indazole), soluble guanylate cyclase (ODQ) and PKG (KT5823) all prevented depression at each of two independent PF pathways to a single PC. Inhibition of NOS also unmasked a platelet activating factor (PAF)-mediated synaptic potentiation of possible presynaptic origin. LTD was also prevented by the phospholipase A2 inhibitor OBAA but was rescued by co-perfusion with arachidonic acid. We conclude that NO and diffusible products of phospholipase A2 metabolism are potential mediators of the spread of cerebellar plasticity at the single cell level.
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PMID:Roles for nitric oxide and arachidonic acid in the induction of heterosynaptic cerebellar LTD. 1120 Oct 73

During infection, bacterial and viral products, such as bacterial lipopolysaccharide (LPS), cause the release of cytokines from immune cells. These cytokines can reach the brain by several routes. Furthermore, cytokines, such as interleukin-1 (IL-1), are induced in neurons within the brain by systemic injection of LPS. These cytokines determine the pattern of hypothalamic-pituitary secretion that characterizes infection. IL-2, by stimulation of cholinergic neurons, activates neural nitric oxide synthase (nNOS). The nitric oxide (NO) released diffuses into corticotropin-releasing hormone (CRH)-secreting neurons and releases CRH. IL-2 also acts in the pituitary to stimulate adrenocorticotropic hormone (ACTH) secretion. On the other hand, IL-1 alpha blocks the NO-induced release of luteinizing hormone-releasing hormone (LHRH) from LHRH neurons, thereby blocking pulsatile LH but not follicle-stimulating hormone (FSH) release and also inhibiting sex behavior that is induced by LHRH. IL-1 alpha and granulocyte macrophage colony-stimulating factor (GMCSF) block the response of the LHRH terminals to NO. The mechanism of action of GMCSF to inhibit LHRH release is as follows. It acts on its receptors on gamma-aminobutyric acid (GABA)ergic neurons to stimulate GABA release. GABA acts on GABAa receptors on the LHRH neuronal terminal to block NOergic stimulation of LHRH release. IL-1 alpha inhibits growth hormone (GH) release by inhibiting GH-releasing hormone (GHRH) release, which is mediated by NO, and stimulating somatostatin release, also mediated by NO. IL-1 alpha-induced stimulation of PRL release is also mediated by intrahypothlamic action of NO, which inhibits release of the PRL-inhibiting hormone dopamine. The actions of NO are brought about by its combined activation of guanylate cyclase-liberating cyclic guanosine monophosphate (cGMP) and activation of cyclooxygenase (COX) and lipoxygenase (LOX) with liberation of prostaglandin E2 and leukotrienes, respectively. Thus, NO plays a key role in inducing the changes in release of hypothalamic peptides induced in infection by cytokines. Cytokines, such as IL-1 beta, also act in the anterior pituitary gland, at least in part via induction of inducible NOS. The NO produced inhibits release of ACTH. The adipocyte hormone leptin, a member of the cytokine family, has largely opposite actions to those of the proinflammatory cytokines, stimulating the release of FSHRF and LHRH from the hypothalamus and FSH and LH from the pituitary directly by NO.
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PMID:The mechanism of action of cytokines to control the release of hypothalamic and pituitary hormones in infection. 1126 67

Hypochlorous acid/hypochlorite, generated by the myeloperoxidase/H(2)O(2)/halide system of activated phagocytes, has been shown to oxidize/modify low density lipoprotein (LDL) in vitro and may be involved in the formation of atherogenic lipoproteins in vivo. Accordingly, hypochlorite-modified (lipo)proteins have been detected in human atherosclerotic lesions where they colocalize with macrophages and endothelial cells. The present study investigates the influence of hypochlorite-modified LDL on endothelial synthesis of nitric oxide (NO) measured as formation of citrulline (coproduct of NO) and cGMP (product of the NO-activated soluble guanylate cyclase) upon cell stimulation with thrombin or ionomycin. Pretreatment of human umbilical vein endothelial cells with hypochlorite-modified LDL led to a time- and concentration-dependent inhibition of agonist-induced citrulline and cGMP synthesis compared with preincubation of cells with native LDL. This inhibition was neither due to a decreased expression of endothelial NO synthase (eNOS) nor to a deficiency of its cofactor tetrahydrobiopterin. Likewise, the uptake of l-arginine, the substrate of eNOS, into the cells was not affected. Hypochlorite-modified LDL caused remarkable changes of intracellular eNOS distribution including translocation from the plasma membrane and disintegration of the Golgi location without altering myristoylation or palmitoylation of the enzyme. In contrast, cyclodextrin known to deplete plasma membrane of cholesterol and to disrupt caveolae induced only a disappearance of eNOS from the plasma membrane that was not associated with decreased agonist-induced citrulline and cGMP formation. The present findings suggest that mislocalization of NOS accounts for the reduced NO formation in human umbilical vein endothelial cells treated with hypochlorite-modified LDL and point to an important role of Golgi-located NOS in these processes. We conclude that inhibition of NO synthesis by hypochlorite-modified LDL may be an important mechanism in the development of endothelial dysfunction and early pathogenesis of atherosclerosis.
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PMID:Hypochlorite-modified low density lipoprotein inhibits nitric oxide synthesis in endothelial cells via an intracellular dislocalization of endothelial nitric-oxide synthase. 1127 58

The myxomycete Physarum polycephalum expresses a calcium-independent nitric oxide (NO) synthase (NOS) resembling the inducible NOS isoenzyme in mammals. We have now cloned and sequenced this, the first nonanimal NOS to be identified, showing that it shares < 39% amino acid identity with known NOSs but contains conserved binding motifs for all NOS cofactors. It lacks the sequence insert responsible for calcium dependence in the calcium-dependent NOS isoenzymes. NOS expression was strongly up-regulated in Physarum macroplasmodia during the 5-day starvation period needed to induce sporulation competence. Induction of both NOS and sporulation competence were inhibited by glucose, a growth signal and known repressor of sporulation, and by L-N6-(1-iminoethyl)-lysine (NIL), an inhibitor of inducible NOS. Sporulation, which is triggered after the starvation period by light exposure, was also prevented by 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of NO-sensitive guanylate cyclase. In addition, also expression of lig1, a sporulation-specific gene, was strongly attenuated by NIL or ODQ. 8-Bromo-cGMP, added 2 h before the light exposure, restored the capacity of NIL-treated macroplasmodia to express lig1 and to sporulate. This indicates that the second messenger used for NO signaling in sporulation of Physarum is cGMP and links this signaling pathway to expression of lig1.
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PMID:Nitric oxide synthase is induced in sporulation of Physarum polycephalum. 1135 72

Haloperidol persists in brain tissue long after discontinuation while haloperidol-induced tardive dyskinesia often worsens after withdrawal of the drug. The mechanism of haloperidol-associated tardive dyskinesia is unknown, although neurotoxic pathways are suspected. Nitric oxide (NO) synthase (NOS) inhibitors exacerbate haloperidol-induced catalepsy, while haloperidol itself is a potent neuronal NOS inhibitor in vitro. Since NO and cGMP are involved in striatal neural plasticity, this study investigates a possible relation between cGMP and extrapyramidal symptoms as early predictors of haloperidol-associated tardive dyskinesia. Sprague-Dawley rats were administered either water or oral haloperidol (0.25 mg/kg/d p.o.) for 17 weeks, followed by 3 weeks withdrawal. Saline (i.p.) or the nNOS/guanylate cyclase inhibitor, methylene blue (5 mg/kg/d i.p.), were co-administered with haloperidol for the first three weeks of treatment. Vacous chewing movements (VCM's) were continuously monitored, followed by the determination of striatal cGMP and peripheral serum nitrogen oxide (NOx) levels. Chronic haloperidol engendered significant VCM's, with acute withdrawal associated with significantly reduced striatal cGMP levels as well as reduced serum NOx. Furthermore, suppressed cGMP levels were maintained and VCM's were significantly worse after early administration of methylene blue to the chronic haloperidol group. However, serum NOx was unchanged from control. We conclude that the central effects of chronic haloperidol on striatal NO-cGMP function persist for up to 3 weeks post-withdrawal. Moreover, suppression of striatal cGMP constitutes an early neuronal insult that determines the presence and intensity of haloperidol-associated motor dysfunction.
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PMID:Early suppression of striatal cyclic GMP may predetermine the induction and severity of chronic haloperidol-induced vacous chewing movements. 1138 52

Activated hepatic stellate cells play a major role in the pathophysiology of chronic liver disease. They can influence the metabolism of hepatocytes by producing a variety of cytokines and growth factors. Upon stimulation with endotoxin, stellate cells also synthesize nitric oxide (NO), a potent mediator of growth of several cell types including hepatocytes. We investigated the effect of serum-free medium conditioned by activated stellate cells in the absence and presence of endotoxin on NO and DNA synthesis in hepatocytes. Stellate cells and hepatocytes were isolated by enzymatic digestion of the liver. Stellate cells were cultured for 10 days after which the majority exhibited alpha-smooth muscle actin (a marker for activated cells); hepatocytes were used after overnight culture. While the medium conditioned by stellate cells in the absence of endotoxin stimulated DNA synthesis in hepatocytes, medium conditioned in its presence inhibited this process in an endotoxin concentration-dependent manner (10 - 1000 ng ml(-1)). Endotoxin-conditioned stellate cell medium also stimulated NO synthesis in hepatocytes; the effect was consistent with increased protein and mRNA expression of inducible NO synthase (iNOS). However, inhibition of DNA synthesis in hepatocytes caused by endotoxin-conditioned stellate cell medium was unaffected by the NOS inhibitor, L-N(G)-monomethylarginine (L-NMMA), guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), and neutralizing antibodies for TGF-beta, IL-1beta, IL-6 and TNF-alpha. These results indicate that factors other than these cytokines produced by activated stellate cells upon stimulation with endotoxin or by hepatocytes challenged with endotoxin-conditioned stellate cell medium inhibit DNA synthesis in hepatocytes.
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PMID:Inhibition of DNA synthesis in cultured hepatocytes by endotoxin-conditioned medium of activated stellate cells is transforming growth factor-beta and nitric oxide-independent. 1148 24

The present investigation was undertaken to verify if the two nitric oxide synthase isoforms, eNOS and iNOS, are present in swine granulosa cells and whether the enzyme soluble guanylate cyclase is functionally active in the same cells and can account for NO effects. Using western blotting, the presence of endothelial NO synthase was demonstrated in freshly collected cells; on the contrary, iNOS expression was not observed in the same cells either before or after culture with the inflammatory cytokine hTNF-alpha. The treatment with a strong NO donor (S-Nitroso-L-acetyl penicillamine, SNAP) determined an increase of cGMP levels in culture media, which was attenuated by the combined treatment with an inhibitor of NO-sensitive soluble guanylate cyclase, 1H-[1,2,3]oxadiaziolo [4,3a]quinoxaline -1-one (ODQ). The cGMP analog, 8 bromo-cGMP, mimicked the strong inhibitory effect exerted by SNAP on estradiol 17 beta and progesterone production, while ODQ did not modify steroids concentrations in culture media. These observations demonstrate the presence of a follicular NO-generating system, which in swine granulosa cells seems to include only the endothelial NOS isoform. Furthermore, the nitric oxide/cyclic GMP system seems to be functionally active in these cells, since cGMP appears to mediate NO action, even if it cannot account completely for NO inhibitory effect on steroidogenesis.
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PMID:Nitric oxide synthase expression and nitric oxide/cyclic GMP pathway in swine granulosa cells. 1151 18

Stimulation of alpha(2)-adrenergic receptors inhibits transport in various nephron segments, and the thick ascending limb of the loop of Henle (THAL) expresses alpha(2)-receptors. We hypothesized that selective alpha(2)-receptor activation decreases NaCl absorption by cortical THALs through activation of NOS and increased production of NO. We found that the alpha(2)-receptor agonist clonidine (10 nM) decreased chloride flux (J(Cl)) from 119.5 +/- 15.9 to 67.4 +/- 13.8 pmol. mm(-1). min(-1) (43% reduction; P < 0.02), whereas removal of clonidine from the bath increased J(Cl) by 20%. When NOS activity was inhibited by pretreatment with 5 mM N(G)-nitro-L-arginine methyl ester, the inhibitory effects of clonidine on THAL J(Cl) were prevented (81.7 +/- 10.8 vs. 71.6 +/- 6.9 pmol. mm(-1). min(-1)). Similarly, when the NOS substrate L-arginine was deleted from the bath, addition of clonidine did not decrease THAL J(Cl) from control (106.9 +/- 11.6 vs. 132.2 +/- 21.3 pmol. mm(-1). min(-1)). When we blocked the alpha(2)-receptors with rauwolscine (1 microM), we found that the inhibitory effect of 10 nM clonidine on THAL J(Cl) was abolished, verifying that alpha(2), rather than I(1), receptors mediate the effects of clonidine in the THAL. We investigated the mechanism of NOS activation and found that intracellular calcium concentration did not increase in response to clonidine, whereas pretreatment with 150 nM wortmannin abolished the clonidine-mediated inhibition of THAL J(Cl), indicating activation of phosphatidylinositol 3-kinase and the Akt pathway. We found that pretreatment of THALs with 10 microM LY-83583, an inhibitor of soluble guanylate cyclase, blocked clonidine-mediated inhibition of THAL J(Cl). In conclusion, alpha(2)-receptor stimulation decreases THAL J(Cl) by increasing NO release and stimulating guanylate cyclase. These data suggest that alpha(2)-receptors act as physiological regulators of THAL NO synthesis, thus inhibiting chloride transport and participating in the natriuretic and diuretic effects of clonidine in vivo.
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PMID:Alpha(2)-adrenergic-mediated tubular NO production inhibits thick ascending limb chloride absorption. 1155 15


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