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Query: UNIPROT:P06889 (Mol)
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Nitric oxide (NO) is a recently discovered messenger for the activation of soluble guanylate cyclase in a wide variety of cell types. Although enzymes involved in NO synthesis have been discovered, the regulation of their action is not clear. The possibility of NO regulating the activity of a crude NO synthase (EC 1.14.23) preparation from bovine cerebellum was investigated. Authentic NO (50-400 microM) produced a marked attenuation of NO synthase activity, as measured by the stoichiometric conversion of L-[3H]arginine to L-[3H]citrulline. This inhibition was mimicked by the nitrovasodilators S-nitroso-N-acetylpenicillamine, sodium nitroprusside, and glyceryl trinitrate. NO was most potent in inhibiting the enzyme activity, followed by S-nitroso-N-acetylpenicillamine, sodium nitroprusside, and glyceryl trinitrate. The effects of NO and the nitrovasodilators were concentration dependent and reversible. Oxyhemoglobin (50 microM), a scavenger of NO, partially prevented the inhibition of NO synthase activity by NO. Inorganic nitrite (5 mM), the oxidation product of NO, did not produce any effect on the enzyme activity. The Km for L-arginine was not significantly changed by NO (200 microM) (from 6.4 +/- 0.8 microM to 10.6 +/- 1.6 microM), whereas the Vmax of the enzyme was markedly decreased (from 80 +/- 4 to 45 +/- 4 pmol/min/mg of protein). This study suggests that NO production may be regulated by a direct effect of NO on the activity of NO synthase.
Mol Pharmacol 1993 Jul
PMID:Regulation of nitric oxide synthase by nitric oxide. 768 67

Endogenously generated or exogenously applied nitric oxide (NO) redox species induce apoptotic cell death in murine RAW 264.7 macrophages. Activation of the inducible NO synthase by incubation of cells with a combination of lipopolysaccharide and interferon-gamma produced internucleosomal DNA fragmentation and morphological alterations, i.e., chromatin condensation, indicative of apoptotic cell death. These alterations, reflecting the production of NO, were prevented by an inhibitor of NO synthase, NG-monomethyl-L-arginine. Moreover, NO derived from endogenous or exogenous sources caused accumulation of the tumor suppressor gene p53. Proposing a link between NO generation and DNA fragmentation, we investigated interfering biochemical signaling pathways. Therefore, we tested the ability of four NO-releasing compounds [sodium nitroprusside (SNP), 3-morpholinosydnonimine (SIN-1), S-nitroso-N-acetylpenicillamine (SNAP), and S-nitrosoglutathione (GSNO)] to cause specific DNA fragmentation. All NO donors induced DNA fragmentation in a time- and concentration-dependent manner. However, substance-specific differences became obvious. After an 8-hr incubation period, GSNO proved to be the strongest apoptotic inducer, whereas SIN-1 was much less active. Apoptosis was rapid with GSNO and SNP, yielding specific DNA fragments after 4 hr and 5 hr, respectively. In contrast, SNAP and SIN-1 produced DNA fragmentation after considerable lag times of 9 hr and 14 hr, respectively. Furthermore, an inhibitory effect of protein kinase C (PKC) and cAMP-dependent protein kinase became apparent. 12-O-Tetradecanoylphorbol-13-acetate, an activator of PKC, inhibited DNA fragmentation by all four NO donors, whereas PKC inhibitors such as staurosporine and calphostin C sensitized macrophages to apoptosis induced by SNP and GSNO. Lipophilic cAMP analogues suppressed SNP-, SIN-1, and SNAP-induced DNA fragmentation. Thus, our study suggests the existence of specific down-modulatory mechanisms related to NO-induced apoptotic DNA fragmentation.
Mol Pharmacol 1995 Apr
PMID:Nitric oxide-induced apoptosis in RAW 264.7 macrophages is antagonized by protein kinase C- and protein kinase A-activating compounds. 772 36

It has been postulated that nitric oxide (NO) can react with superoxide anion (.O2-) to generate hydroxyl (.OH) radical. If this is correct, inhibition of NO synthesis could attenuate .OH radical mediated ischemia/reperfusion injury. Therefore we studied the effects of NG-nitro-L-arginine (L-NNA), a competitive inhibitor of the NO synthase enzyme on ischemia/reperfusion injury injury in isolated perfused rat hearts. Three groups of rats (n = 12-15) were studied. Group I: Untreated ischemia/reperfusion control (37.5 min of global ischemia followed by 20 min reperfusion); Group II: ischemia/reperfusion with 25 microM NG-nitro-L-arginine; and Group III: ischemia/reperfusion in the presence of L-NNA and 2 mM L-arginine, the substrate for NO synthase. Coronary flow (in ml/min) and ventricular developed pressure, +dP/dt and -dP/dt were measured 5 min prior to ischemia and at the end of reperfusion. Baseline preischemic developed pressure was significantly lower in L-NNA perfused hearts than controls (76.8 +/- 5.9 v 97.6 +/- 2.9 mmHg, P < 0.05). However, the developed pressure following reperfusion was significantly greater in L-NNA perfused hearts (57.4 +/- 7.4 v 20.8 +/- 6.4 mmHg in control). This protective effect was reversed by the addition of L-arginine. Preischemic coronary flow was decreased significantly in the L-NNA group (6.4 +/- 0.5 ml/min) compared to controls (11.6 +/- 0.7 ml/min). The duration of sinus rhythm was significantly improved from 3.8 +/- 1.2 min in controls to 15.1 +/- 0.8 min in L-NNA perfused hearts. A corresponding significantly lower incidence of arrhythmias was observed (10.2 +/- 1.5 in ischemia/reperfusion group v 1.7 +/- 0.8 min with L-NNA).(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1995 Jan
PMID:Sustained inhibition of nitric oxide by NG-nitro-L-arginine improves myocardial function following ischemia/reperfusion in isolated perfused rat heart. 776 Mar 62

Retinal neurons that express the immediate early gene c-fos after light exposure were characterized by neurotransmitter content using histochemical and immunocytochemical staining. In Northern blots the amount of c-fos mRNA peaked at 30 min, but remained detectable 60 min following light stimulation. Fos proteins were seen in the inner nuclear and ganglion cell layers, and the staining was most intense two and three hours after beginning the light exposure. In the ganglion cell layer 30-40% of Fos-immunoreactive cells were cholinergic displaced amacrine cells and 3-5% were ganglion cells. In the inner nuclear layer 24% of Fos-immunoreactive cells were Type I and 7% Type II NADPH-diaphorase-reactive (nitric oxide synthase) amacrine cells, 11% were tyrosine hydroxylase-containing cells, and 10-15% cholinergic amacrine cells. No Fos immunoreactivity was seen in serotoninergic, somatostatin- or VIP-immunoreactive cells, bipolar, horizontal or photoreceptor cells. Nicotine, kainic acid, NMDA and SCH 38393, a dopamine D1 receptor agonist, induced Fos immunostaining in the inner nuclear and ganglion cell layers, but administration of the corresponding receptor blockers mecamylamine, kynuretic acid, MK-801, haloperidol and SCH 23990 did not prevent light-induced Fos expression.
Brain Res Mol Brain Res 1995 Mar
PMID:Light-induced c-fos expression in amacrine cells in the rabbit retina. 777 1

Calmodulin, the ubiquitous and multifunctional Ca(2+)-binding protein, mediates many of the regulatory effects of Ca2+, including the contractile state of smooth muscle. The principal function of calmodulin in smooth muscle is to activate crossbridge cycling and the development of force in response to a [Ca2+]i transient via the activation of myosin light-chain kinase and phosphorylation of myosin. A distinct calmodulin-dependent kinase, Ca2+/calmodulin-dependent protein kinase II, has been implicated in modulation of smooth-muscle contraction. This kinase phosphorylates myosin light-chain kinase, resulting in an increase in the calmodulin concentration required for half-maximal activation of myosin light-chain kinase, and may account for desensitization of the contractile response to Ca2+. In addition, the thin filament-associated proteins, caldesmon and calponin, which inhibit the actin-activated MgATPase activity of smooth-muscle myosin (the cross-bridge cycling rate), appear to be regulated by calmodulin, either by the direct binding of Ca2+/calmodulin or indirectly by phosphorylation catalysed by Ca2+/calmodulin-dependent protein kinase II. Another level at which calmodulin can regulate smooth-muscle contraction involves proteins which control the movement of Ca2+ across the sarcolemmal and sarcoplasmic reticulum membranes and which are regulated by Ca2+/calmodulin, e.g. the sarcolemmal Ca2+ pump and the ryanodine receptor/Ca2+ release channel, and other proteins which indirectly regulate [Ca2+]i via cyclic nucleotide synthesis and breakdown, e.g. NO synthase and cyclic nucleotide phosphodiesterase. The interplay of such regulatory mechanisms provides the flexibility and adaptability required for the normal functioning of smooth-muscle tissues.
Mol Cell Biochem 1994 Jun 15
PMID:Calmodulin and the regulation of smooth muscle contraction. 781 54

The study demonstrates a strong enzyme histochemical and immunohistochemical reaction staining for NADPH-diaphorase/NO-synthase in the secretory cells of the apocrine glands in the hairy skin, and the eccrine glands in the foot pads of domesticated mammals. The results obtained are discussed in view of a regulatory action of the NO generated by these enzyme activities, implying a direct influence of NO on the contractile properties of glandular myoepithelial cells. In this way, a basic and simple mechanism to couple secretion production and secretion extrusion can be proposed.
Cell Mol Biol (Noisy-le-grand) 1994 Mar
PMID:Demonstration of NADPH-diaphorase (NO-synthase) in the apocrine and eccrine skin glands of domesticated mammals. 800 48

Nitric oxide (NO) is an intercellular mediator produced within the cerebellum and other central nervous system sites. Results from the present study suggest a novel role for this gaseous second messenger in mediating the stimulatory actions of the excitatory amino acid agonist N-methyl-D-aspartate (NMDA) on turnover of phosphatidylinositol (PI) in the neonatal cerebellum. Activation of the NMDA receptor stimulates PI turnover in developing cerebellum when these neurons are in a depolarized state, but the mechanism underlying this effect is unknown. We measured changes in PI hydrolysis induced by NMDA in the presence of baclofen, which is known to depolarize neurons by activating presynaptic inhibitory gamma-aminobutyric acidB autoreceptors. NMDA increased PI hydrolysis by 80% in the presence of 1 microM baclofen. This modulatory action of NMDA was prevented by two competitive inhibitors of NO synthase, L-NG-monomethylarginine and L-N omega-nitroarginine, as well as by hemoglobin, which binds NO. Inhibition of NMDA-induced PI hydrolysis by L-NG-monomethylarginine was reversed by prior administration of L-arginine (200 microM), the physiological substrate of NO synthase. Arginine (500 microM) alone was also able to increase PI hydrolysis significantly. Superoxide dismutase, which prolongs the half-life of NO, also significantly increased the ability of NMDA to stimulate PI hydrolysis. However, NO-induced activation of the cGMP pathway did not appear to be responsible for the NMDA-induced increase in PI hydrolysis, because addition of 8-bromo-cGMP decreased this parameter, and methylene blue, which blocks guanylate cyclase activity, did not inhibit the PI hydrolysis evoked by NMDA receptor activation. These results suggest that NMDA receptor activation acts to release NO, which then acts through a novel pathway to enhance the hydrolysis of PI in the developing rat cerebellum. This novel role for NO in mediating the stimulatory actions of NMDA on PI hydrolysis may be important for developmental processes in the central nervous system.
Mol Pharmacol 1993 Jan
PMID:Novel action of nitric oxide as mediator of N-methyl-D-aspartate-induced phosphatidylinositol hydrolysis in neonatal rat cerebellum. 838 Aug 82

We investigated the cytotoxic effects of various cytokines secreted by macrophages or T lymphocytes on luteal cells, and the role of nitric oxide (NO) produced by luteal cells in cytotoxic actions of cytokines. Mouse luteal cells were cultured in serum-free medium with interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) or interleukin-1 beta (IL-1 beta) alone, or with various combinations of these cytokines for 6 days. Cytotoxic actions of cytokines and NO production by luteal cells were evaluated by number of viable cells and the amount of nitrite and nitrate (stable metabolites of NO) in medium, respectively. IFN-gamma (1000 U/ml), TNF-alpha (3000 U/ml), or IL-1 beta (30 U/ml) alone, and the combination of TFN-alpha and IL-1 beta (10 U/ml) did not decrease number of viable cells and was without effects on NO production. The combination of IFN-gamma and IL-1 beta (10 U/ml) also did not decrease the number of viable cells, while it increased NO production a little but significantly. Combinations of INF-gamma and TNF-alpha, and IFN-gamma, TNF-alpha and IL-1 beta (10 U/ml) markedly decreased number of viable cells. The combination of IFN-gamma and TNF-alpha increased NO production a little but significantly, and the combination of three cytokines (IFN-gamma, TNF-alpha, and IL-1 beta) caused a greater increase in NO production. An NO synthase inhibitor, L-NG-monomethy-L-arginine (0.5 mM) or aminoguanidine (0.5 mM) abolished increases in NO production induced by combinations of IFN-gamma and TNF-alpha, and IFN-gamma, TNF-alpha and IL-1 beta completely without effects on number of viable cells. The present results indicate that combinations of cytokines including IFN-gamma and TNF-alpha induce death of cultured mouse luteal cells, and that the cytotoxic actions of these cytokines are independent of NO production by luteal cells.
J Steroid Biochem Mol Biol 1995 Dec
PMID:Cytotoxic actions of cytokines on cultured mouse luteal cells are independent of nitric oxide. 854 Dec 25

Prior administration of endotoxin to rats is known to aggravate the hepatotoxicity of galactosamine. It has been proposed that this exacerbation occurs as a result of the release of cytokines and other humoral factors by resident macrophages (Kupffer cells). In order to study this phenomenon we have utilized a co-culture system consisting of rat activated peritoneal macrophages and rat hepatocytes. Peritoneal macrophages were isolated and cultured; LPS was added as a macrophage activator 16 hours later. Rat hepatocytes were isolated and plated in Transwell COL inserts, which were placed in wells with and without activated macrophages. Cytotoxicity was determined 24 hours later by measuring lactate dehydrogenase (LDH) leakage into the culture medium. In the presence of activated macrophages an approximate 3-fold increase in galactosamine-induced hepatocyte toxicity was observed, as compared to the toxicity in hepatocytes cultured alone. Using this co-culture system, we examined the role of leukotriene D4 (LTD4) and nitric oxide (NO) as mediators of this enhancement. Addition of either LTD4 or NO to hepatocytes cultured alone did not exacerbate galactosamine toxicity. Furthermore, addition of the LTD4 receptor antagonist SK & F 104353 (50 microM) or the NO synthase inhibitor N-monomethyl-L-arginine (1.0 mM) to macrophage/hepatocyte co-cultures did not attenuate the enhanced galactosamine hepatocyte toxicity in the co-cultures. Collectively, these data indicate that this co-culture system will be useful in examining the mechanism of macrophage enhancement of chemical-induced hepatoxicity and, further, suggest that LTD4 and NO may not be involved in the exacerbation of galactosamine toxicity to hepatocyte cultures.
Res Commun Mol Pathol Pharmacol 1995 Jun
PMID:Macrophage enhancement of galactosamine hepatotoxicity using a rat hepatocyte culture system. 856 88

The broad objective of these studies was to understand the nature of cyclic GMP system and the mechanism(s) whereby hormone, autacoids and drugs alter this signal in various physiological systems. Studies were undertaken on the modulation of guanylate cyclase activity by oxygen-radicals/nitric oxide and the mechanism(s) of generation of nitric oxide by receptor-selective hormones. We observed that cytosolic guanylate cyclase undergoes significant stimulation in the presence of oxygen-radicals/nitric oxide. This activation by nitric oxide can be reversed by hemeproteins, thus, enabling guanylate cyclase system to cycle between activated and deactivated state. The evidence is presented that oxygen-radicals are required for the synthesis of nitric oxide by NO synthase as demonstrated by inhibition of NO formation by oxygen-radical scavengers. And finally, the data is presented that acetylcholine-induced elevations of intracellular levels of cyclic GMP can be attenuated by muscarinic antagonist, atropine and superoxide anion scavenger, nitroblue tetrazolium. These observations establish a novel concept that activation of hormone receptors on the cell surface, triggers generation of oxygen radicals and hydrogen peroxide which participates in the catalytic conversion of L-arginine to nitric oxide by nitric oxide synthase in the presence of calcium ion. The oxygen-radicals/NO, thus formed, oxidatively activate guanylate cyclase and transduce the message of calcium-dependent hormones.
Mol Cell Biochem
PMID:Oxygen-radical/nitric oxide mediate calcium-dependent hormone action on cyclic GMP system: a novel concept in signal transduction mechanisms. 856 37


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