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)

We studied the effect of cultured endothelial cells on the secretion of catecholamines by cultured bovine chromaffin cells. Chromaffin cell catecholamine secretion was stimulated by either boluses of potassium (K+) or the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP). Endothelial cells inhibited the catecholamine release and stimulatory effects of K+ and DMPP. This inhibition increased with time, and in 25 min the initial stimulated secretory response (100%) to 30 mM K+ or 25 microM DMPP dropped to 45 +/- 3% and 53.5 +/- 2.3%, respectively. This endothelial cells-induced inhibition was blocked by the nitric oxide synthase inhibitors N-nitro-L-arginine methyl ester (L-NAME) and N-monoethyl-L-arginine (L-NMMA), and by the guanylate cyclase inhibitor methylene blue, indicating that the L-arginine/nitric oxide/cyclic GMP pathway is involved in this endothelial cell-chromaffin cell interaction. In the absence of endothelial cells, incubation of chromaffin cells with L-NAME, L-NMMA, or methylene blue also augmented the secretagogue-induced catecholamine secretion, indicating that nitric oxide from chromaffin cells could be implicated in an autoinhibitory process of catecholamine release. These results provide indirect evidence for the presence of nitric oxide synthase in bovine adrenomedullary chromaffin cells. Our results show that there is an autoinhibitory mechanism of catecholamine release in chromaffin cells and that an additional level of inhibition is observed when cultured vascular endothelial cells are present. These two inhibitory processes may have different origins, but they appear to converge into a common pathway, the L-arginine/nitric oxide synthase/guanylate cyclase pathway.
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PMID:Possible role of nitric oxide in catecholamine secretion by chromaffin cells in the presence and absence of cultured endothelial cells. 751 69

Rat neurotensin (NT) receptor (NTR) cDNA was subcloned into the pRC-CMV expression vector and transfected into 293 cells, and cellular clones that stably expressed the NTR were isolated and characterized. [3H]NT binding to membranes prepared from the NTR cDNA-transfected cells displayed specificity and saturability, with an apparent Kd of 1.25 nM and a Bmax of 43.4 pmol/mg of protein (approximately 3.5 x 10(6) binding sites/cell). NT stimulated an increase in [3H]inositol phosphate levels in the NTR-expressing cells up to 2500% of basal levels. The response was time and dose dependent, with an EC50 of 10.4 nM. NT also stimulated cAMP formation in these cells, with an EC50 of 27.0 nM. In addition, NT evoked an increase in the level of intracellular calcium. Approximately 60% of the calcium rise was attributable to the release of intracellular stores and 40% was attributable to calcium influx. Although NTR occupancy has been shown to stimulate cGMP formation in several brain preparations and cell lines, NT was unable to mediate cGMP synthesis in the NTR-expressing 293 cells. We found that 293 cells have guanylate cyclase activity but have undetectable levels of nitric oxide synthase (NOS) activity. Because it was possible that the production of nitric oxide is required as the mediator of NT-induced cGMP synthesis, we subcloned NOS cDNA into the pCEP4 expression vector and transiently expressed it in the NTR cells. We report that NT increased cGMP levels up to 375% of basal levels when NOS cDNA was coexpressed and that the increase was completely inhibited by the NOS inhibitor N omega-nitro-L-arginine. NT-induced cGMP accumulation was time and dose dependent, with an EC50 of 1.7 nM. To our knowledge, this is the first report of NT mediating cGMP formation with a cloned receptor and the first evidence that NT-induced cGMP accumulation requires the production of nitric oxide.
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PMID:The cloned neurotensin receptor mediates cyclic GMP formation when coexpressed with nitric oxide synthase cDNA. 752 Jan 23

The role of the L-arginine-NO pathway on the formation of PGE2 by cultured astroglial cells incubated with the HIV coating glycoprotein gp120 was investigated. Preincubation of human cultured T 67 astrocytoma cells with gp 120 (100-500 nM) produced a significant increase of nitrite (the breakdown product of NO) and PGE2 in cell supernatants. The effect of gp 120 on both nitrite and PGE2 production was antagonized by inhibition of NO synthase by L-NAME (20-300 microM). The inhibition of gp120-induced PGE2 production by L-NAME was reverted by addition of arachidonic acid (30 microM), an effect antagonized by the cyclo-oxygenase inhibitor indomethacin (10 microM). Methylen bleu, an inhibitor of the biological activity of NO acting at the guanylate cyclase level failed to affect gp 120-mediated PGE2 release showing that the increase of cGMP subsequent to NO production was not involved in the modulatory activity of NO on arachidonic acid cascade. On the basis of present experiments we conclude that gp-120-induced release of PGE2 by astroglial cells is driven by NO, thereby contributing in the involvement of glial cells in HIV-related cerebral disorders.
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PMID:HIV coating gp 120 glycoprotein-dependent prostaglandin E2 release by human cultured astrocytoma cells is regulated by nitric oxide formation. 752 Nov 67

Acute hypoxia causes pulmonary hypertension in the fetus and newborn that is contrasted by systemic hypotension or normotension. To better understand the role of nitric oxide (NO) in this specific pulmonary vascular response, we determined the acute effects of decreased oxygenation on NO production in ovine fetal pulmonary and systemic (mesenteric) endothelial cells. NO was assessed by measuring cGMP accumulation in fetal vascular smooth muscle (VSM) cells during co-culture incubations of endothelium and VSM (40 s) in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine. Changes in cGMP were dependent on the endothelium and on NO synthase and guanylate cyclase activity. At high O2 (680 mm Hg), basal NO was detectable and NO increased 6- to 10-fold with bradykinin or A23187. In pulmonary endothelium, basal NO fell 58% at pO2 = 150 mm Hg and 51% at 40 mm Hg versus 680 mm Hg, while NO with bradykinin fell 56% and 63%, respectively. NO with A23187, however, was unchanged at 150 mm Hg, but it fell 56% at 40 mm Hg. In contrast, in systemic endothelium basal and stimulated NO production were not altered at lower O2. Findings were similar using pulmonary or systemic detector VSM cells, and exogenous L-arginine had no effect. Thus, decreased O2 acutely attenuates NO production specifically in fetal pulmonary endothelial cells. This process is not related to changes in O2 or L-arginine availability as substrates for NO synthase; alternatively, it may be partially mediated by specific effects of O2 on pulmonary endothelial cell calcium homeostasis.
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PMID:Oxygen modulates nitric oxide production selectively in fetal pulmonary endothelial cells. 752 86

Available studies indicate that the adrenergic stimulation of pineal cyclic GMP production involves stimulation of guanylyl cyclase activity by nitric oxide (NO) derived from arginine. This line of investigation was extended in the present study. Using a highly sensitive microassay, it was found that pineal NO synthase activity is present at levels approximately 30% of those in the cerebellum, that approximately 95% of enzyme activity is cytoplasmic, that the enzyme is Ca2+/calmodulin-dependent and that enzyme activity is inhibited by the arginine analog NG-nitro-L-arginine methyl ester (L-NAME). Norepinephrine treatment of intact glands in culture increased [3H]citrulline formation from [3H]arginine. This treatment also increased the formation of an NO-like compound, indicating that NO synthase activity in the intact gland is elevated by adrenergic stimulation. Studies on the effects of inhibition of NO synthase activity indicated that treatments known to inhibit NO synthase activity and the adrenergic stimulation of cyclic GMP accumulation did not inhibit adrenergic stimulation of pineal cyclic AMP, N-acetyltransferase activity or melatonin production. These observations support the hypothesis that NE stimulation of pineal cyclic GMP accumulation involves stimulation of a Ca2+/calmodulin-sensitive form of NO synthase, resulting in enhanced accumulation of NO; and, that although NO appears to play a role in the adrenergic stimulation of pineal cyclic GMP accumulation, it does not appear to play a critical role in the adrenergic stimulation of cyclic AMP, N-acetyltransferase activity or melatonin production.
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PMID:Pineal nitric oxide synthase: characteristics, adrenergic regulation and function. 752 30

Nitric oxide is known to function as a neurotransmitter in the central nervous system. It is also known to be involved in the central nervous system excitatory amino acid neurotransmission cascade. Activation of excitatory amino acid receptors causes an influx of calcium, which activates nitric oxide synthase. The resulting increase in intracellular nitric oxide activates soluble guanylate cyclase, leading to a rise in cyclic guanosine monophosphate. The excitatory amino acids glutamate and aspartate are found in the vestibular system and have been postulated to function as vestibular system neurotransmitters. Although nitric oxide has been investigated as a neurotransmitter in other tissues, no published studies have examined the role of nitric oxide in the vestibular system. Neuronal NADPH-diaphorase has been characterized as a nitric oxide synthase. This enzyme catalyzes the conversion of L-arginine to L-citrulline, producing nitric oxide during the reaction. We used a histochemical stain characterized by Hope et al. (Proc Natl Acad Sci 1991;88:2811) as specific for neuronal nitric oxide synthase to localize the enzyme in the rat vestibular system. An immunocytochemical stain was used to examine rat inner ear tissue for the presence of the enzyme's end product, L-citrulline, thereby demonstrating nitric oxide synthase activity. Staining of vestibular ganglion sections showed nitric oxide synthase presence and activity in ganglion cells and nerve fibers. These results indicate the presence of active nitric oxide synthase in these tissues and suggest modulation of vestibular neurotransmission by nitric oxide.
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PMID:Nitric oxide in the rat vestibular system. 752 6

Nitric oxide (NO) is a messenger molecule that is produced from L-arginine by NO synthase (NOS). Some NOS isoforms are present in cells constitutively, whereas others can be induced by cytokines. Recent evidence suggests that NO inhibits intracellular pH regulation by the vacuolar H(+)-adenosinetriphosphatase (ATPase) in macrophages, which contain an inducible form of NOS. The vacuolar H(+)-ATPase is involved in proton secretion in intercalated cells in the collecting duct. We have therefore examined the effect of NO on bafilomycin-sensitive H(+)-ATPase activity in individual cortical collecting ducts (CCD) microdissected from collagenase-treated kidneys of normal rats using a fluorometric microassay. Incubation of CCD with the NO donors, sodium nitroprusside (0.1 and 1 mM) or 3-morpholino-sydnonimine hydrochloride (SIN-1, 30 microM), caused a dose-dependent decrease in H(+)-ATPase activity. Incubation of CCD with lipopolysaccharide (LPS) and interferon-gamma, which induces NOS in macrophages, decreased H(+)-ATPase activity by 85%. This effect was prevented by simultaneous incubation with N omega-nitro-L-arginine, a competitive inhibitor of NOS, indicating that the decrease in H(+)-ATPase activity was caused by NO production. Incubation with 8-bromo-guanosine 3',5'-cyclic monophosphate (cGMP) also inhibited H(+)-ATPase activity, suggesting that NO may exert its effect in the CCD via activation of guanylyl cyclase and production of cGMP. Immunohistochemistry using antibodies to the macrophage-type NOS revealed strong labeling of intercalated cells in the CCD, confirming the presence of NOS in these cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nitric oxide inhibits bafilomycin-sensitive H(+)-ATPase activity in rat cortical collecting duct. 752 55

A genetically engineered recombinant human hemoglobin (rHb1.1) was recently developed for use as a blood substitute (Nature 1992;356:258-60). Like other mammalian hemoglobin (Hb) molecules, it might bind and antagonize the actions of nitric oxide (NO). We used an isolated rabbit aortic ring preparation to examine the ability of rHb1.1 to inhibit acetylcholine (ACh)- and interleukin-1 beta (IL-1 beta)-induced reductions of vasoconstrictor responses to the alpha-adrenoceptor agonist phenylephrine (PE). rHb1.1 (0.04-4.4 microM) rapidly and reversibly inhibited, in a concentration-dependent manner, both ACh- and IL-1 beta-induced decreases in PE contractile responses. These inhibitory effects of rHb1.1 were non-competitive and were equipotent to those of purified, cell-free human Hb (p.hHb). These two forms of soluble Hb were at least 10 times more potent than Hb in erythrocytes (red blood cells: RBC-Hb). Both NG-nitro-L-arginine (10 microM) a NO synthase inhibitor, and LY-83583 (10 microM), a guanylyl cyclase inhibitor, mimicked the effects of rHb1.1. The inhibitory effects of rHb1.1 were not shared by either human serum albumin (HSA 44 microM), which combines with but does not deactivate NO, or cytochrome C (44 microM), a heme-containing protein that does not bind NO; neither were they reversed by L-arginine (L-ARG) (1 mM), the presumed NO precursor. These and other results suggest that the chemical antagonism of NO is likely to be the mechanism by which rHb1.1 and other Hbs inhibit ACh- and IL-1 beta-induced decreases in the response to PE in rabbit aortic rings.
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PMID:Recombinant human hemoglobin inhibits both constitutive and cytokine-induced nitric oxide-mediated relaxation of rabbit isolated aortic rings. 752 54

Although nitric oxide (NO) appears to be one of the oxidation products of L-arginine catalyzed by NO synthase (NOS; EC 1.14.13.39), past studies on the measurement of NO in cell-free enzymatic assays have not been based on the direct detection of the free NO molecule. Instead, assays have relied on indirect measurements of the stable NO oxidation products nitrite and nitrate and on indirect actions of NO such as guanylate cyclase activation and oxyhemoglobin oxidation. Utilizing a specific chemiluminescence assay, we report here that the gaseous product of L-arginine oxidation, catalyzed by both inducible macrophage and constitutive neuronal NOS, is indistinguishable from authentic NO on the basis of their physicochemical properties. NO gas formation by NOS was dependent on L-arginine, NADPH, and oxygen and inhibited by NG-methyl-L-arginine and cyanide anion. Superoxide dismutase (SOD) caused a marked, concentration-dependent increase in the production of free NO by mechanisms that were unrelated to the dismutation of superoxide anion or activation of NOS. These observations indicate that free NO is formed as a result of NOS-catalyzed L-arginine oxidation and that SOD enhances the generation of NO without directly affecting NO itself. SOD appears to elicit a novel biological action, perhaps accelerating the conversion of an intermediate in the L-arginine-NO pathway such as nitroxyl (HNO) to NO.
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PMID:Formation of free nitric oxide from l-arginine by nitric oxide synthase: direct enhancement of generation by superoxide dismutase. 752 87

General anesthetics, including halothane, isoflurane, and barbiturates, suppress endothelium-dependent formation of 3',5'-cyclic guanosine monophosphate (cGMP) in the systemic and cerebral vasculature. The present study was conducted to determine whether these anesthetics have similar effects on the nitric oxide (NO)-cGMP system in the brain, and to elucidate the mechanism responsible. In rat cerebellar slices, formation of cGMP was suppressed by halothane after stimulation by N-methyl-D-aspartate (NMDA, 0.1 mM) and D-aspartate (1.0 mM) but not after stimulation by sodium nitroprusside (SNP, 0.3 mM). Isoflurane (2%) suppressed NMDA (0.1 mM)-stimulated, but not D-aspartate (1.0 mM)- and nitroprusside (0.3 mM)-stimulated formation of cGMP. In contrast, thiopental (0.1-1.0 mM) suppressed NMDA (0.1 mM)-, D-aspartate (1.0 mM)-, and nitroprusside (0.3 mM)-stimulated formation of cGMP. Treatment with aminophylline (0.1 mM), a phosphodiesterase inhibitor, did not influence the effect of thiopental, suggesting that the effect of thiopental was not mediated by activation of phosphodiesterase. D-Aspartate increases intracellular calcium, which in turn activates NO synthase, and nitroprusside generates NO without activation of NO synthase. Therefore, the present findings strongly suggest that halothane inactivates NO synthase (or related cofactors) without marked interaction with the NMDA receptor, that isoflurane may interact with the NMDA receptor, receptor-coupled G-protein, or calcium channels, and that thiopental suppresses guanylate cyclase activity.
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PMID:Inhibitory effects of anesthetics on cyclic guanosine monophosphate (cGMP) accumulation in rat cerebellar slices. 752 47


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