Journal articles: 'Neuronal NOS'

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Lapointe, Jérome, Monica Roy, Isabelle St-Pierre, Sarah Kimmins, Danny Gauvreau, Leslie A. MacLaren, and Jean-François Bilodeau. "Hormonal and Spatial Regulation of Nitric Oxide Synthases (NOS) (Neuronal NOS, Inducible NOS, and Endothelial NOS) in the Oviducts." Endocrinology 147, no. 12 (December 1, 2006): 5600–5610. http://dx.doi.org/10.1210/en.2005-1548.

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Nitric oxide (NO) is a free radical produced by the action of NO synthases (NOS) and is known to be involved in the regulation of many reproductive events that occur in the oviducts. The oviducts are highly specialized organs that play crucial roles in reproduction by providing an optimal environment for the final maturation of gametes, fertilization, and early embryo development. In this study, we analyzed the expression, hormonal regulation, and cellular distribution of neuronal, inducible, and endothelial NOS in different bovine oviduct segments to better understand the roles played by these enzymes in oviductal functions in vivo. Quantitative RT-PCR analysis revealed that NOS isoforms are hormonally regulated and differentially expressed along the oviduct throughout the estrous cycle. All NOS were highly expressed around the time of estrus, and immunohistochemistry studies determined that neuronal NOS, inducible NOS (iNOS), and endothelial NOS are differentially distributed in cells along the oviduct. Interestingly, our results showed that estradiol selectively up-regulates iNOS expression in the oviduct during the periovulatory period corresponding to the window of ovulation, oocyte transport, and fertilization. The resulting NO production by this high-output NOS may be of crucial importance for reproductive events that occur in the oviduct. This study provided the first demonstration that NO production is hormonally regulated in the mammalian oviducts in vivo. Our results suggest that neuronal NOS, iNOS, and endothelial NOS contribute to oviductal functions in a timely and site-specific manner.

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KOHN, A. B., L. L. MOROZ, J. M. LEA, and R. M. GREENBERG. "Distribution of nitric oxide synthase immunoreactivity in the nervous system and peripheral tissues of Schistosoma mansoni." Parasitology 122, no. 1 (January 2001): 87–92. http://dx.doi.org/10.1017/s0031182000007022.

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The distribution of nitric oxide synthase (NOS) immunoreactivity and putative NOS activity in adult Schistosoma mansoni was analysed using 3 different types of NOS antibodies and NADPH-diaphorase histochemistry. Although potential involvement of the gaseous radical nitric oxide (NO) in host response to infection by schistosomes has been suggested, there is little or no information available regarding the role, or even the presence, of the NO pathway in schistosomes themselves. Here, we demonstrate that antibodies against neuronal NOS (nNOS) and inducible NOS (iNOS) isoforms stain adult worms with distinctive patterns; anti-endothelial NOS (eNOS) shows no selective labelling. nNOS-like immunoreactivity is found in the main nerve cords and the peripheral nervous system. Putative sensory neurons with apical neuronal processes leading to the tegument of male worms are also immunoreactive for nNOS. Anti-iNOS labels a variety of predominantly non-neuronal tissues, showing intense labelling at or near the surface of the worm and in components of the gastrointestinal tract. The distribution of NADPH-diaphorase reactivity (a histochemical marker of NOS), is generally similar to the pattern of NOS immunoreactivity, including labelling of neuronal-like cells as well as developing eggs. These results suggest that an NOS-like enzyme is present in S. mansoni, and indicate potential roles for the different NOS isoforms in neuronal signalling, reproduction and development.

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Premaratne, Shyamal, Chun Xue, John M. McCarty, Muhammad Zaki, Robert W. McCuen, Roger A. Johns, Wolfgang Schepp, et al. "Neuronal nitric oxide synthase: expression in rat parietal cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 280, no. 2 (February 1, 2001): G308—G313. http://dx.doi.org/10.1152/ajpgi.2001.280.2.g308.

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Nitric oxide synthases (NOS) are enzymes that catalyze the generation of nitric oxide (NO) from l-arginine and require nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor. At least three isoforms of NOS have been identified: neuronal NOS (nNOS or NOS I), inducible NOS (iNOS or NOS II), and endothelial NOS (eNOS or NOS II). Recent studies implicate NO in the regulation of gastric acid secretion. The aim of the present study was to localize the cellular distribution and characterize the isoform of NOS present in oxyntic mucosa. Oxyntic mucosal segments from rat stomach were stained by the NADPH-diaphorase reaction and with isoform-specific NOS antibodies. The expression of NOS in isolated, highly enriched (>98%) rat parietal cells was examined by immunohistochemistry, Western blot analysis, and RT-PCR. In oxyntic mucosa, histochemical staining revealed NADPH-diaphorase and nNOS immunoreactivity in cells in the midportion of the glands, which were identified as parietal cells in hematoxylin and eosin-stained step sections. In isolated parietal cells, decisive evidence for nNOS expression was obtained by specific immunohistochemistry, Western blotting, and RT-PCR. Cloning and sequence analysis of the PCR product confirmed it to be nNOS (100% identity). Expression of nNOS in parietal cells suggests that endogenous NO, acting as an intracellular signaling molecule, may participate in the regulation of gastric acid secretion.

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Pigott, B., K. Bartus, and J. Garthwaite. "On the selectivity of neuronal NOS inhibitors." British Journal of Pharmacology 168, no. 5 (February 20, 2013): 1255–65. http://dx.doi.org/10.1111/bph.12016.

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Jackson, Claire L., Jane S. Lucas, Woolf T. Walker, Holly Owen, Irnthu Premadeva, and Peter M. Lackie. "Neuronal NOS localises to human airway cilia." Nitric Oxide 44 (January 2015): 3–7. http://dx.doi.org/10.1016/j.niox.2014.11.003.

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O'Dell, T., P. Huang, T. Dawson, J. Dinerman, S. Snyder, E. Kandel, and M. Fishman. "Endothelial NOS and the blockade of LTP by NOS inhibitors in mice lacking neuronal NOS." Science 265, no. 5171 (July 22, 1994): 542–46. http://dx.doi.org/10.1126/science.7518615.

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Idigo, Winifred O., Svetlana Reilly, Mei Hua Zhang, Yin Hua Zhang, Raja Jayaram, Ricardo Carnicer, Mark J. Crabtree, Jean-Luc Balligand, and Barbara Casadei. "Regulation of Endothelial Nitric-oxide Synthase (NOS)S-Glutathionylation by Neuronal NOS." Journal of Biological Chemistry 287, no. 52 (October 22, 2012): 43665–73. http://dx.doi.org/10.1074/jbc.m112.412031.

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8

Kourosh-Arami, Masoumeh, Nasrin Hosseini, Monireh Mohsenzadegan, Alireza Komaki, and Mohammad Taghi Joghataei. "Neurophysiologic implications of neuronal nitric oxide synthase." Reviews in the Neurosciences 31, no. 6 (August 27, 2020): 617–36. http://dx.doi.org/10.1515/revneuro-2019-0111.

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AbstractThe molecular and chemical properties of neuronal nitric oxide synthase (nNOS) have made it a key mediator in many physiological functions and signaling transduction. The NOS monomer is inactive, but the dimer form is active. There are three forms of NOS, which are neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) nitric oxide synthase. nNOS regulates nitric oxide (NO) synthesis which is the mechanism used mostly by neurons to produce NO. nNOS expression and activation is regulated by some important signaling proteins, such as cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), calmodulin (CaM), heat shock protein 90 (HSP90)/HSP70. nNOS-derived NO has been implicated in modulating many physiological functions, such as synaptic plasticity, learning, memory, neurogenesis, etc. In this review, we have summarized recent studies that have characterized structural features, subcellular localization, and factors that regulate nNOS function. Finally, we have discussed the role of nNOS in the developing brain under a wide range of physiological conditions, especially long-term potentiation and depression.

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Fabricius, M., I. Rubin, M. Bundgaard, and M. Lauritzen. "NOS activity in brain and endothelium: relation to hypercapnic rise of cerebral blood flow in rats." American Journal of Physiology-Heart and Circulatory Physiology 271, no. 5 (November 1, 1996): H2035—H2044. http://dx.doi.org/10.1152/ajpheart.1996.271.5.h2035.

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We examined whether attenuation of the hypercapnic increase of cerebral blood flow (CBF) associated with nitric oxide synthase (NOS) inhibition is related to local neuronal or aortic endothelial NOS activity or local endothelial/neuronal NOS-dependent vasodilation. Halothane-anesthetized rats were ventilated, and CBF was measured by laser-Doppler flowmetry over the parietal and cerebellar cortex. Intravenous N omega-nitro-L-arginine (L-NNA; 30 mg/kg) inhibited brain and aortic NOS activity by 67-70%. Topical L-NNA (1 mM) inhibited brain NOS activity by 91-94%, whereas aortic NOS activity remained constant. In contrast, intravenous L-NNA attenuated the hypercapnic CBF rise much more efficiently than topical L-NNA. 7-Nitroindazole, another NOS inhibitor, attenuated endothelial and neuronal NOS activity equally well and inhibited the hypercapnic CBF increase as effectively as L-NNA. Topical L-NNA and 7-nitroindazole abolished local endothelial NOS-dependent vasodilation after 15 min, whereas hypercapnic CBF was only slightly reduced. L-NNA injected into the tissue abolished neuronal NOS-dependent vasodilation, whereas hypercapnic CBF was unchanged. The findings suggest that local NOS activity, whether neuronal or endothelial, is unimportant for the hypercapnic rise of CBF.

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Li, Huiying, Joumana Jamal, Carla Plaza, Stephanie Hai Pineda, Georges Chreifi, Qing Jing, Maris A. Cinelli, Richard B. Silverman, and Thomas L. Poulos. "Structures of human constitutive nitric oxide synthases." Acta Crystallographica Section D Biological Crystallography 70, no. 10 (September 27, 2014): 2667–74. http://dx.doi.org/10.1107/s1399004714017064.

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Mammals produce three isoforms of nitric oxide synthase (NOS): neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS). The overproduction of NO by nNOS is associated with a number of neurodegenerative disorders; therefore, a desirable therapeutic goal is the design of drugs that target nNOS but not the other isoforms. Crystallography, coupled with computational approaches and medicinal chemistry, has played a critical role in developing highly selective nNOS inhibitors that exhibit exceptional neuroprotective properties. For historic reasons, crystallography has focused on rat nNOS and bovine eNOS because these were available in high quality; thus, their structures have been used in structure–activity–relationship studies. Although these constitutive NOSs share more than 90% sequence identity across mammalian species for each NOS isoform, inhibitor-binding studies revealed that subtle differences near the heme active site in the same NOS isoform across species still impact enzyme–inhibitor interactions. Therefore, structures of the human constitutive NOSs are indispensible. Here, the first structure of human neuronal NOS at 2.03 Å resolution is reported and a different crystal form of human endothelial NOS is reported at 1.73 Å resolution.

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11

Martin, Pierre-Yves, Mathieu Bianchi, Frank Roger, Laurent Niksic, and Eric Féraille. "Arginine vasopressin modulates expression of neuronal NOS in rat renal medulla." American Journal of Physiology-Renal Physiology 283, no. 3 (September 1, 2002): F559—F568. http://dx.doi.org/10.1152/ajprenal.00309.2001.

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Arginine vasopressin (AVP) plays a central role in water balance. In principal cells of the collecting duct system, AVP controls the expression of several genes, including aquaporin-2. Because nitric oxide (NO) participates in the regulation of water reabsorption by the collecting duct system, we analyzed the effect of AVP on the expression of NO synthase (NOS) isoforms in the kidney. Rats were either water restricted or water loaded to modify the circulating AVP levels, and expressions of NOS isoforms were assessed by Western blot analysis. In water-restricted rats, endothelial NOS (eNOS) expression increased in the outer medulla, and neuronal NOS (nNOS) expression rose in both the outer medulla and the papilla. Conversely, water loading induced a decrease in expression of nNOS in the outer medulla and papilla but did not alter eNOS expression. Oral administration of the specific V2-receptor antagonist SR-121463B decreased nNOS expression in the outer medulla and papilla but did not alter eNOS expression levels. Finally, the very low nNOS expression levels observed in AVP-deficient Brattleboro rats was restored by AVP infusion for 1 wk. Thus AVP specifically increases nNOS expression levels in the renal outer medulla and papilla. Because nNOS is specifically expressed in principal cells of the collecting duct system, the stimulation of nNOS expression by AVP may participate in the control of water reabsorption.

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12

Caggiano, Anthony O., and Richard P. Kraig. "Neuronal Nitric Oxide Synthase Expression is Induced in Neocortical Astrocytes after Spreading Depression." Journal of Cerebral Blood Flow & Metabolism 18, no. 1 (January 1998): 75–87. http://dx.doi.org/10.1097/00004647-199801000-00008.

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Spreading depression (SD) confers either increased susceptibility to ischemic injury or a delayed protection. Because nitric oxide modulates ischemic injury, we investigated if altered expression of nitric oxide synthase (NOS) by SD could account for the effect of SD on ischemia. Furthermore, the identity of cells expressing NOS after SD is important, since SD results in heterogeneous, cell type–specific changes in intracellular environment, which can control NOS activity. Immunohistochemical, computer-based image analyses and Western blotting show that the number of neuronal NOS (nNOS)–positive cells in the somatosensory cortex was significantly increased at 6 hours and 3 days after SD ( P < 0.05 and 0.01, respectively), whereas inducible NOS expression remained unchanged. Double-labeling of nNOS and glial fibrillary acidic protein identified these nNOS-positive cells as astrocytes. The effect of altered NO production on induced nNOS expression was examined by treating rats with sodium nitroprusside or NA-nitro-L-arginine methyl ester (LNAM) during SD. Increased nNOS expression was prevented by sodium nitroprusside and phenylephrine or phenylephrine alone, but not LNAM. Because SD increased astrocytic nNOS expression at time points correlating with both ischemic hypersensitivity and ischemic tolerance, the ability of SD to modulate ischemic injury must be complex, perhaps involving NOS but other factors as well.

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13

Wang, Yang, Derek C. Newton, and Philip A. Marsden. "Neuronal NOS: Gene Structure, mRNA Diversity, and Functional Relevance." Critical Reviews in Neurobiology 13, no. 1 (1999): 21–43. http://dx.doi.org/10.1615/critrevneurobiol.v13.i1.20.

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14

Sandt, A., R. Windler, A. Gödecke, J. Ohlig, S. Becher, T. Rassaf, J. Schrader, M. Kelm, and M. Merx. "Neuronal NOS-inhibition in the setting of septic cardiomyopathy." Critical Care 14, Suppl 1 (2010): P20. http://dx.doi.org/10.1186/cc8252.

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15

Yang, Rui-Fang, Jing-Xiang Yin, Yu-Long Li, Matthew C. Zimmerman, and Harold D. Schultz. "Angiotensin-(1–7) increases neuronal potassium current via a nitric oxide-dependent mechanism." American Journal of Physiology-Cell Physiology 300, no. 1 (January 2011): C58—C64. http://dx.doi.org/10.1152/ajpcell.00369.2010.

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Actions of angiotensin-(1–7) [Ang-(1–7)], a heptapeptide of the renin-angiotensin system, in the periphery are mediated, at least in part, by activation of nitric oxide (NO) synthase (NOS) and generation NO·. Studies of the central nervous system have shown that NO· acts as a sympathoinhibitory molecule and thus may play a protective role in neurocardiovascular diseases associated with sympathoexcitation, such as hypertension and heart failure. However, the contribution of NO in the intraneuronal signaling pathway of Ang-(1–7) and the subsequent modulation of neuronal activity remains unclear. Here, we tested the hypothesis that neuronal NOS (nNOS)-derived NO· mediates changes in neuronal activity following Ang-(1–7) stimulation. For these studies, we used differentiated catecholaminergic (CATH.a) neurons, which we show express the Ang-(1–7) receptor (Mas R) and nNOS. Stimulation of CATH.a neurons with Ang-(1–7) (100 nM) increased intracellular NO levels, as measured by 4-amino-5-methylamino-2′,7′-difluorofluorescein diacetate (DAF-FM) fluorescence and confocal microscopy. This response was significantly attenuated in neurons pretreated with the Mas R antagonist (A-779), a nonspecific NOS inhibitor (nitro-l-arginine methyl ester), or an nNOS inhibitor ( S-methyl-l-thiocitrulline, SMTC), but not by endothelial NOS (eNOS) or inhibitory NOS (iNOS) inhibition {l- N-5-(1-iminoethyl)ornithine (l-NIO) and 1400W, respectively}. To examine the effect of Ang-(1–7)-NO· signaling on neuronal activity, we recorded voltage-gated outward K+ current ( IKv) in CATH.a neurons using the whole cell configuration of the patch-clamp technique. Ang-(1–7) significantly increased IKv, and this response was inhibited by A-779 or S-methyl-l-thiocitrulline, but not l-NIO or 1400W. These findings indicate that Ang-(1–7) is capable of increasing nNOS-derived NO· levels, which in turn, activates hyperpolarizing IKv in catecholaminergic neurons.

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Vega Rasgado, Lourdes A., Guillermo Ceballos Reyes, and Fernando Vega Díaz. "Role of nitric oxide synthase on brain GABA transaminase activity and GABA levels." Acta Pharmaceutica 68, no. 3 (September 1, 2018): 349–59. http://dx.doi.org/10.2478/acph-2018-0022.

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Abstract In an attempt to clarify the controversial role of nitric oxide (NO) in seizures, the effects of NO on brain GABA transaminase (GABA-T) activity and GABA levels were investigated. To this aim, the effects of the substrate (l-arginine) and inhibitors (Nω-nitro-l-arginine methyl ester, 7-nitroindazole) of NO synthase (NOS) on GABA-T activity and GABA levels in vitro and ex vivo were analyzed. In vitro NO diminished GABA-T activity and increased GABA. Ex vivo NO modified GABA-T activity and GABA levels biphasically. Inhibition of endothelial and neuronal NOS (eNOS and nNOS) had opposite effects on GABA-T activity and GABA levels, even during seizures induced by pentylenetetrazole. Different effects of NO on GABA-T activity and on GABA levels, depending on the NOS isoform involved, may explain its contradictory role in seizures, the endothelial NOS acting as an anticonvulsant and the neuronal NOS as a proconvulsant. nNOS inhibitors may represent a new generation of antiepileptics.

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YEN, Shih-Hui, and Jenn-Tser Pan. "Nitric Oxide Plays an Important Role in the Diurnal Change of Tuberoinfundibular Dopaminergic Neuronal Activity and Prolactin Secretion in Ovariectomized, Estrogen/Progesterone-Treated Rats**This study was supported, in part, by Grants NSC86–2314-B010-M10 and NSC87–2314-B010–016 (to J.-T.P) from the National Science Council of the Republic of China." Endocrinology 140, no. 1 (January 1, 1999): 286–91. http://dx.doi.org/10.1210/endo.140.1.6446.

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Abstract A significant diurnal change of tuberoinfundibular dopaminergic (TIDA) neuronal activity coincident with the estrogen (E2)-induced afternoon PRL surge has been reported in ovariectomized, E2-primed (OVX+E2) rats. Systemic injection of a nitric oxide (NO) synthase (NOS) inhibitor, NG-nitro-l-arginine (l-NA, 50 mg/kg, ip at 1000 and 1200 h), significantly blocked the diurnal changes of TIDA neuronal activity and PRL secretion at 1500 and 1700 h in OVX+E2 rats. Coadministration of l-arginine (300 mg/kg, ip) with l-NA completely prevented the effects of l-NA. Total nitrite/nitrate levels in the serum of l-NA- and l-NA+l-arginine-treated rats substantiated the effects of l-NA and l-arginine on NO production. Pretreatment of antisense oligodeoxynucleotide (ODN; 1μ g/3 μl; intracerebroventricularly at 48, 24, and 7 h before sacrifice) against the messenger RNA (mRNA) of constitutive NOS, i.e. neuronal NOS or endothelial NOS, was also effective in preventing the diurnal changes of TIDA neuronal activity and PRL surge at 1500 h. The same treatment of antisense ODN against the mRNA of inducible NOS, i.e. macrophage NOS, had no effect. Progesterone (P4) has been reported to advance and augment the diurnal changes of TIDA neuronal activity and the afternoon PRL surge, by 1 h, in both proestrous and OVX+E2 rats. We further showed that l-NA dose dependently (50 but not 5 mg/kg, ip at 1000 and 1200 h) blocked the effect of P4 on TIDA neurons and serum PRL at 1300 h, which effect could be negated by simultaneous administration of l-arginine (300 mg/kg, ip). Pretreatment with antisense ODNs against the mRNA of neuronal NOS or endothelial NOS, but not macrophage NOS, was also effective in preventing the P4’s effect on TIDA neuronal activity and PRL secretion at 1300 h. In summary, NO may play a physiological role in the E2- and P4-regulated diurnal changes of TIDA neuronal activity and PRL secretion.

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Daff, S., M. A. Noble, D. H. Craig, S. L. Rivers, S. K. Chapman, A. W. Munro, S. Fujiwara, E. Rozhkova, I. Sagami, and T. Shimizu. "Control of electron transfer in neuronal NO synthase." Biochemical Society Transactions 29, no. 2 (May 1, 2001): 147–52. http://dx.doi.org/10.1042/bst0290147.

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The nitric oxide synthases (NOSs) are dimeric flavocytochromes consisting of an oxygenase domain with cytochrome P450-like Cys-ligated haem, coupled to a diflavin reductase domain, which is related to cytochrome P450 reductase. The NOSs catalyse the sequential mono-oxygenation of arginine to N-hydroxyarginine and then to citrulline and NO. The constitutive NOS isoforms (cNOSs) are regulated by calmodulin (CaM), which binds at elevated concentrations of free Ca2+, whereas the inducible isoform binds CaM irreversibly. One of the main structural differences between the constitutive and inducible isoforms is an insert of 40–50 amino acids in the FMN-binding domain of the cNOSs. Deletion of the insert in rat neuronal NOS (nNOS) led to a mutant enzyme which binds CaM at lower Ca2+ concentrations and which retains activity in the absence of CaM. In order to resolve the mechanism of action of CaM activation we determined reduction potentials for the FMN and FAD cofactors of rat nNOS in the presence and absence of CaM using a recombinant form of the reductase domain. The results indicate that CaM binding does not modulate the reduction potentials of the flavins, but appears to control electron transfer primarily via a large structural rearrangement. We also report the creation of chimaeric enzymes in which the reductase domains of nNOS and flavo-cytochrome P450 BM3 (Bacillus megaterium III) have been exchanged. Despite its very different flavin redox potentials, the BM3 reductase domain was able to support low levels of CaM-dependent NO synthesis, whereas the NOS reductase domain did not effectively substitute for that of cytochrome P450 BM3.

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Poon, Chi H., Ka C. Tsui, Sze C. Chau, Pit S. Chong, Sylvia W. Y. Lui, Luca Aquili, Kah H. Wong, and Lee W. Lim. "Functional Roles of Neuronal Nitric Oxide Synthase in Neurodegenerative Diseases and Mood Disorders." Current Alzheimer Research 18, no. 10 (September 2021): 831–40. http://dx.doi.org/10.2174/1567205018666211022164025.

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Nitric oxide synthase (NOS) is well known for its involvement in the regulation of the nervous, cardiovascular, and immune systems. Neuronal NOS (nNOS) is the most characterized NOS among all the isoforms. It accounts for most of the production of nitric oxide (NO) in the nervous system required for synaptic transmission and neuroplasticity. Previous studies have described the localization of nNOS in specific brain regions of interest. There is substantial evidence in the literature suggesting that nNOS signaling has significant involvement in several disease pathologies. However, the association between brain nNOS expression profiles and disease remains largely unknown. In this review, we attempt to delineate the contribution of nNOS signaling in memory and mood disorders in order to achieve a better understanding of nNOS in disease modulation.

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Meng, Wei, Cenk Ayata, Christian Waeber, Paul L. Huang, and Michael A. Moskowitz. "Neuronal NOS-cGMP-dependent ACh-induced relaxation in pial arterioles of endothelial NOS knockout mice." American Journal of Physiology-Heart and Circulatory Physiology 274, no. 2 (February 1, 1998): H411—H415. http://dx.doi.org/10.1152/ajpheart.1998.274.2.h411.

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We evaluated the effects of superfusing 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), eNOS null ( B)an inhibitor of soluble guanylyl cyclase, and 7-nitroindazole sodium (7-NI), a selective neuronal nitric oxide synthase (nNOS) inhibitor, on the acetylcholine (ACh) response in endothelial NOS (eNOS) null mice. Pial arteriolar diameter was measured by intravital microscopy through a closed cranial window under α-chloralose anesthesia. NOS activity was measured by [3H]arginine-to-[3H]citrulline conversion in subjacent cortex in vitro. The density and distribution of muscarinic receptors in the brain were determined by quantitative [3H]quinuclidinyl benzilate autoradiography and did not differ between the eNOS mutants and wild-type mice. ACh superfusion (1 and 10 μM) dose dependently dilated pial arterioles in eNOS null and wild-type mice. ODQ (10 μM) attenuated ACh-induced dilation in both eNOS mutants (41% decrease at 10 μM ACh, P < 0.01, n = 6) and wild-type strains ( n = 5 per group). By contrast, topical superfusion of 7-NI (100 μM) attenuated the ACh response in eNOS mutants only (66%, P < 0.05, and 25% decrease, P < 0.05, at 1 and 10 μM ACh, respectively). Our findings suggest that nNOS-guanosine 3′,5′-cyclic monophosphate (cGMP)-dependent pathways dilate pial arterioles by compensatory mechanisms after eNOS gene disruption.

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Sanz, Maria-Jesus, Michael J. Hickey, Brent Johnston, Donna-Marie McCafferty, Eko Raharjo, Paul L. Huang, and Paul Kubes. "Neuronal nitric oxide synthase (NOS) regulates leukocyte-endothelial cell interactions in endothelial NOS deficient mice." British Journal of Pharmacology 134, no. 2 (September 2001): 305–12. http://dx.doi.org/10.1038/sj.bjp.0704234.

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Bradman, Matthew J. G., Daleep K. Arora, Richard Morris, and Thimmasettappa Thippeswamy. "How do the satellite glia cells of the dorsal root ganglia respond to stressed neurons? – nitric oxide saga from embryonic development to axonal injury in adulthood." Neuron Glia Biology 6, no. 1 (February 2010): 11–17. http://dx.doi.org/10.1017/s1740925x09990494.

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Dorsal root ganglia (DRG) respond to peripheral nerve injury by up-regulating nitric oxide (NO) production by neurons and glia in addition to local fibroblasts, endothelium and macrophages. We hypothesise that NO produced from these cells has specific roles. We have shown that when neuronal NO synthase (nNOS) is blocked in axotomised DRG, neurons undergo degenerative changes (Thippeswamy et al., 2001, 2007a). Further, we demonstrated that increased neuronal NO production, in response to axotomy/growth factor-deprivation in vitro, signals glial cells to produce trophic factors to support neuronal survival (Thippeswamy et al., 2005a). Recently, we found that treating satellite glia–neuron co-cultures with nNOS inhibitor, 7-nitroindazole (7NI), decreases the number of nestin+ cells that show neuron-like morphology. Cultured/axotomised DRG also upregulate inducible NOS (iNOS) in non-neuronal cells. Therefore, it is plausible that degenerative changes following nNOS inhibition are also due to iNOS-mediated excessive NO production by non-neuronal cells, which indeed is cytotoxic. NG-nitro-l-arginine methylester (L-NAME), the pan NOS inhibitor did not significantly change nNOS+ neuron number in axotomised DRG compared to 7NI suggesting that iNOS-mediated NO contributes to the degenerative process. In this paper, these findings from our and others' past work on NO-mediated neuron–glia signalling in axotomised DRG are discussed.

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Okamoto, Hirotsugu, Wei Meng, Jinya Ma, Cenk Ayata, Richard J. Roman, Zeljko J. Bosnjak, John P. Kampine, Paul L. Huang, Michael A. Moskowitz, and Antal G. Hudetz. "Isoflurane-induced Cerebral Hyperemia in Neuronal Nitric Oxide Synthase Gene Deficient Mice." Anesthesiology 86, no. 4 (April 1, 1997): 875–84. http://dx.doi.org/10.1097/00000542-199704000-00018.

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Background Nitric oxide (NO) has been reported to play an important role in isoflurane-induced cerebral hyperemia in vivo. In the brain, there are two constitutive isoforms of NO synthase (NOS), endothelial NOS (eNOS), and neuronal NOS (nNOS). Recently, the mutant mouse deficient in nNOS gene expression (nNOS knockout) has been developed. The present study was designed to examine the role of the two constitutive NOS isoforms in cerebral blood flow (CBF) response to isoflurane using this nNOS knockout mouse. Methods Regional CBF (rCBF) in the cerebral cortex was measured with laser-Doppler flowmetry in wild-type mice (129/SV or C57BL/6) and nNOS knockout mice during stepwise increases in the inspired concentration of isoflurane from 0.6 vol% to 1.2, 1.8, and 2.4 vol%. Subsequently, a NOS inhibitor, N omega-nitro-L-arginine (L-NNA), was administered intravenously (20 mg/kg), and 45 min later, the rCBF response to isoflurane was tested again. In separate groups of wild-type mice and the knockout mice, the inactive enantiomer, N omega-nitro-D-arginine (D-NNA) was administered intravenously in place of L-NNA. Brain NOS activity was measured with radio-labeled L-arginine to L-citrulline conversion after treatment with L-NNA and D-NNA. Results Isoflurane produced dose-dependent increases in rCBF by 25 +/- 3%, 74 +/- 10%, and 108 +/- 14% (SEM) in 129/SV mice and by 32 +/- 2%, 71 +/- 3%, and 96 +/- 7% in C57BL/6 mice at 1.2, 1.8, and 2.4 vol%, respectively. These increases were attenuated at every anesthetic concentration by L-NNA but not by D-NNA. Brain NOS activity was decreased by 92 +/- 2% with L-NNA compared with D-NNA. In nNOS knockout mice, isoflurane increased rCBF by 67 +/- 8%, 88 +/- 12%, and 112 +/- 18% at 1.2, 1.8, and 2.4 vol%, respectively. The increase in rCBF at 1.2 vol% was significantly greater in the nNOS knockout mice than that in the wild-type mice. Administration of L-NNA in the knockout mice attenuated the rCBF response to isoflurane at 1.2 and 1.8 vol% but had no effect on the response at 2.4 vol%. Conclusions In nNOS knockout mice, the cerebral hyperemic response to isoflurane is preserved by compensatory mechanism(s) that is NO-independent at 2.4 vol%, although it may involve eNOS at 1.2 and 1.8 vol%. It is suggested that in wild-type mice, eNOS and nNOS contribute to isoflurane-induced increase in rCBF. At lower concentrations (1.2 and 1.8 vol%), eNOS may be involved, whereas at 2.4 vol%, nNOS may be involved.

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van’t Hof, Robert J., Jeny MacPhee, Helene Libouban, Miep H. Helfrich, and Stuart H. Ralston. "Regulation of Bone Mass and Bone Turnover by Neuronal Nitric Oxide Synthase." Endocrinology 145, no. 11 (November 1, 2004): 5068–74. http://dx.doi.org/10.1210/en.2004-0205.

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Abstract Nitric oxide (NO) is produced by NO synthase (NOS) and plays an important role in the regulation of bone cell function. The endothelial NOS isoform is essential for normal osteoblast function, whereas the inducible NOS isoform acts as a mediator of cytokine effects in bone. The role of the neuronal isoform of NOS (nNOS) in bone has been studied little thus far. Therefore, we investigated the role of nNOS in bone metabolism by studying mice with targeted inactivation of the nNOS gene. Bone mineral density (BMD) was significantly higher in nNOS knockout (KO) mice compared with wild-type controls, particularly the trabecular BMD (P < 0.01). The difference in BMD between nNOS KO and control mice was confirmed by histomorphometric analysis, which showed a 67% increase in trabecular bone volume in nNOS KO mice when compared with controls (P < 0.001). This was accompanied by reduced bone remodeling, with a significant reduction in osteoblast numbers and bone formation surfaces and a reduction in osteoclast numbers and bone resorption surfaces. Osteoblasts from nNOS KO mice, however, showed increased levels of alkaline phosphatase and no defects in proliferation or bone nodule formation in vitro, whereas osteoclastogenesis was increased in nNOS KO bone marrow cultures. These studies indicate that nNOS plays a hitherto unrecognized but important physiological role as a stimulator of bone turnover. The low level of nNOS expression in bone and the in vitro behavior of nNOS KO bone cells indicate that these actions are indirect and possibly mediated by a neurogenic relay.

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Kim, Chi Dae, Raj K. Goyal, and Hiroshi Mashimo. "Neuronal NOS provides nitrergic inhibitory neurotransmitter in mouse lower esophageal sphincter." American Journal of Physiology-Gastrointestinal and Liver Physiology 277, no. 2 (August 1, 1999): G280—G284. http://dx.doi.org/10.1152/ajpgi.1999.277.2.g280.

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To identify the enzymatic source of nitric oxide (NO) in the lower esophageal sphincter (LES), studies were performed in wild-type and genetically engineered endothelial nitric oxide synthase [eNOS(−)] and neuronal NOS [nNOS(−)] mice. Under nonadrenergic noncholinergic (NANC) conditions, LES ring preparations developed spontaneous tone in all animals. In the wild-type mice, electrical field stimulation produced frequency-dependent intrastimulus relaxation and a poststimulus rebound contraction. NOS inhibitor N ω-nitro-l-arginine methyl ester (100 μM) abolished intrastimulus relaxation and rebound contraction. In nNOS(−) mice, both the intrastimulus relaxation and rebound contraction were absent. However, in eNOS(−) mice there was no significant difference in either the relaxation or rebound contraction from the wild-type animal. Both nNOS(−) and eNOS(−) tissues showed concentration-dependent relaxation to NO donor diethylenetriamine-NO and there was no difference in the sensitivity to the NO donor in nNOS(−), eNOS(−), or wild-type animals. These results indicate that in mouse LES, nNOS rather than eNOS is the enzymatic source of the NO that mediates NANC relaxation and rebound contraction.

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Satake, Yohei, Kimio Satoh, Masamichi Nogi, Junichi Omura, Shigeo Godo, Satoshi Miyata, Hiroki Saito, et al. "Crucial roles of nitric oxide synthases in β-adrenoceptor-mediated bladder relaxation in mice." American Journal of Physiology-Renal Physiology 312, no. 1 (January 1, 2017): F33—F42. http://dx.doi.org/10.1152/ajprenal.00137.2016.

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The specific roles of nitric oxide (NO) synthases (NOSs) in bladder smooth muscle remain to be elucidated. We examined the roles of NOSs in β-adrenoceptor (AR)-mediated bladder relaxation. Male mice (C57BL6) deficient of neuronal NOS [nNOS-knockout (KO)], endothelial NOS (eNOS-KO), neuronal/endothelial NOS (n/eNOS-KO), neuronal/endothelial/inducible NOS (n/e/iNOS-KO), and their controls [wild-type (WT)] were used. Immunohistochemical analysis was performed in the bladder. Then the responses to relaxing agents and the effects of several inhibitors on the relaxing responses were examined in bladder strips precontracted with carbachol. Immunofluorescence staining showed expressions of nNOS and eNOS in the urothelium and smooth muscle of the bladder. Isoproterenol-induced relaxations were significantly reduced in nNOS-KO mice and were further reduced in n/eNOS-KO and n/e/iNOS-KO mice compared with WT mice. The relaxation in n/e/iNOS-KO mice was almost the same as in n/eNOS-KO mice. Inhibition of Ca2+-activated K+ (KCa) channel with charybdotoxin and apamin abolished isoproterenol-induced bladder relaxation in WT mice. Moreover, direct activation of KCa channel with NS1619 caused comparable extent of relaxations among WT, nNOS-KO, and n/eNOS-KO mice. In contrast, NONOate (a NO donor) or hydrogen peroxide (H2O2) (another possible relaxing factor from eNOS) caused minimal relaxations, and catalase (H2O2 scavenger) had no inhibitory effects on isoproterenol-induced relaxations. These results indicate that both nNOS and eNOS are substantially involved in β-AR-mediated bladder relaxations in a NO- or H2O2-independent manner through activation of KCa channels.

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Scala, G., M. Sammarco, V. Esposito, and E. Langella. "Neuronal nitric oxide synthase (NOS I) in the buffalo epididymis." Italian Journal of Animal Science 6, sup2 (January 2007): 603–6. http://dx.doi.org/10.4081/ijas.2007.s2.603.

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Yoshimitsu, Tokunaga, Matsumura Hitoshi, and Maeda Toshihiro. "258 Subcellular localization of neuronal NOS in the rat caudoputamen." Neuroscience Research 28 (January 1997): S50. http://dx.doi.org/10.1016/s0168-0102(97)90126-7.

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Liu, Guo-Long, Li Liu, and Luciano Barajas. "Development of NOS-containing neuronal somata in the rat kidney." Journal of the Autonomic Nervous System 58, no. 1-2 (April 1996): 81–88. http://dx.doi.org/10.1016/0165-1838(95)00120-4.

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Hare, Gregory M. T., C. David Mazer, William Mak, Reginald M. Gorczynski, Kathryn M. Hum, Steve Y. Kim, Leslie Wyard, Aiala Barr, Rong Qu, and Andrew J. Baker. "Hemodilutional anemia is associated with increased cerebral neuronal nitric oxide synthase gene expression." Journal of Applied Physiology 94, no. 5 (May 1, 2003): 2058–67. http://dx.doi.org/10.1152/japplphysiol.00931.2002.

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Severe hemodilutional anemia may reduce cerebral oxygen delivery, resulting in cerebral tissue hypoxia. Increased nitric oxide synthase (NOS) expression has been identified following cerebral hypoxia and may contribute to the compensatory increase in cerebral blood flow (CBF) observed after hypoxia and anemia. However, changes in cerebral NOS gene expression have not been reported after acute anemia. This study tests the hypothesis that acute hemodilutional anemia causes cerebral tissue hypoxia, triggering changes in cerebral NOS gene expression. Anesthetized rats underwent hemodilution when 30 ml/kg of blood were exchanged with pentastarch, resulting in a final hemoglobin concentration of 51.0 ± 1.2 g/l ( n = 7 rats). Caudate tissue oxygen tension (PbrO2 ) decreased transiently from 17.3 ± 4.1 to 14.4 ± 4.1 Torr ( P < 0.05), before returning to baseline after ∼20 min. An increase in CBF may have contributed to restoring PbrO2 by improving cerebral tissue oxygen delivery. An increase in neuronal NOS (nNOS) mRNA was detected by RT-PCR in the cerebral cortex of anemic rats after 3 h ( P < 0.05, n = 5). A similar response was observed after exposure to hypoxia. By contrast, no increases in mRNA for endothelial NOS or interleukin-1β were observed after anemia or hypoxia. Hemodilutional anemia caused an acute reduction in PbrO2 and an increase in cerebral cortical nNOS mRNA, supporting a role for nNOS in the physiological response to acute anemia.

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Dreyer, J. "Nitric Oxide Synthase (NOS)-Interacting Protein Interacts with Neuronal NOS and Regulates Its Distribution and Activity." Journal of Neuroscience 24, no. 46 (November 17, 2004): 10454–65. http://dx.doi.org/10.1523/jneurosci.2265-04.2004.

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Gonzalez-Hernandez, T., M. A. Perez de la Cruz, and B. Mantolan-Sarmiento. "Histochemical and immunohistochemical detection of neurons that produce nitric oxide: effect of different fixative parameters and immunoreactivity against non-neuronal NOS antisera." Journal of Histochemistry & Cytochemistry 44, no. 12 (December 1996): 1399–413. http://dx.doi.org/10.1177/44.12.8985132.

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This study focused on two points concerning the histochemical and immunohistochemical detection of neurons that produce nitric oxide (NO): (a) the effect of fixation and other methodological parameters on the staining pattern of both NADPH-diaphorase (NADPH-d) histochemistry and nitric oxide synthase (NOS) immunohistochemistry, and (b) the possibility that neurons display immunoreactivity against NOS antisera obtained from non-neuronal sources. Frontal sections of rat brains, fixed with 4% paraformaldehyde according to different protocols, were processed for single and double labeling using NADPH-d histochemistry and neuronal (nNOS), macrophagic (macNOS), and endothelial (eNOS) NOS immunohistochemistry. Our results show that variations in the fixative schedule, even within standard parameters, produce qualitative and quantitative changes in NADPH-d labeling. The effect of fixative on weakly stained neurons is different from that on heavily stained neurons. In subfixed brains, a large number of NOS-positive neurons lose their NADPH-d activity, whereas NOS immunolabeling remains unaltered. This finding may be particularly interesting in morphological studies that compare NADPH-d activity under experimental conditions that can affect brain perfusion. On the other hand, many cortical and subcortical neurons show macNOS immunoreactivity, most of it colocalized with nNOS.

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Ye, Shaohua, Pantea Mozayeni, Michael Gamburd, Huiqin Zhong, and Vito M. Campese. "Interleukin-1β and neurogenic control of blood pressure in normal rats and rats with chronic renal failure." American Journal of Physiology-Heart and Circulatory Physiology 279, no. 6 (December 1, 2000): H2786—H2796. http://dx.doi.org/10.1152/ajpheart.2000.279.6.h2786.

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Increased sympathetic nervous system (SNS) activity plays a role in the genesis of hypertension in rats with chronic renal failure (CRF). The rise in central SNS activity is mitigated by increased local expression of neuronal nitric oxide synthase (NOS) mRNA and NO2/NO3 production. Because interleukin (IL)-1β may activate nitric oxide in the brain, we have tested the hypothesis that IL-1β may modulate the activity of the SNS via regulation of the local expression of neuronal NOS (nNOS) in the brain of CRF and control rats. To this end, we first found that administration of IL-1β in the lateral ventricle of control and CRF rats decreased blood pressure and norepinephrine (NE) secretion from the posterior hypothalamus (PH) and increased NOS mRNA expression. Second, we observed that an acute or chronic injection of an IL-1β-specific antibody in the lateral ventricle raised blood pressure and NE secretion from the PH and decreased NOS mRNA abundance in the PH of control and CRF rats. Finally, we measured the IL-1β mRNA abundance in the PH, locus coeruleus, and paraventricular nuclei of CRF and control rats by RT-PCR and found it to be greater in CRF rats than in control rats. In conclusion, these studies have shown that IL-1β modulates the activity of the SNS in the central nervous system and that this modulation is mediated by increased local expression of nNOS mRNA.

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Spessert, R., C. Wohlgemuth, S. Reuss, and E. Layes. "NADPH-diaphorase activity of nitric oxide synthase in the olfactory bulb: co-factor specificity and characterization regarding the interrelation to NO formation." Journal of Histochemistry & Cytochemistry 42, no. 5 (May 1994): 569–75. http://dx.doi.org/10.1177/42.5.7512584.

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The neuronal form of the enzyme nitric oxide synthase (nNOS) synthesizes the messenger molecule nitric oxide (NO). In addition to NO formation, nNOS exhibits a so-called NADPH-diaphorase (NADPH-d) activity. This study focused on the characterization of NADPH-d activity with regard to NO formation in the rat olfactory bulb. In this area of the brain pronounced staining is localized in discrete populations of neuronal somata and in olfactory glomeruli. Diaphorase staining combined with demonstration of nNOS by polyclonal antibodies revealed that NADPH-d activity of neuron somata is associated with nNOS immunoreactivity. It is concluded that neuron somata exhibit NADPH-d activity of nNOS. NADPH-d activity of nNOS did not utilize beta-NADH or alpha-NADPH. Moreover, NADPH-d activity was inhibited in the presence of alpha-NADPH. Dichlorophenolindophenol (DPIP), an artificial electron acceptor and an inhibitor of NO formation, totally suppressed NADPH-d staining of neurons, supporting the concept that the NADPH-d of neuron somata is due to nNOS. Cytochrome C, miconazole, EGTA, and trifluoperazine, which have been reported to inhibit cytochrome P450 reductase activity of NOS, did not affect NADPH-d staining. Hence, NADPH-d activity of NOS does not involve cytochrome P450 reductase activity as required for NO formation. Contrary to NADPH-d activity of neuron somata, staining of olfactory glomeruli was not co-localized with nNOS immunoreactivity. Glomerular staining was also observed in the presence of beta-NADH and alpha-NADPH. Further, it was unchanged in the presence of the NO formation inhibitor DPIP. Hence, the glomerular staining in the presence of NADPH is not due to the NADPH-d activity of NOS. We conclude that staining of neuronal structures in the presence of NADPH does not necessarily represent NADPH-d activity of NOS.

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Chakder, Sushanta, Alok Bandyopadhyay, and Satish Rattan. "Neuronal NOS gene expression in gastrointestinal myenteric neurons and smooth muscle cells." American Journal of Physiology-Cell Physiology 273, no. 6 (December 1, 1997): C1868—C1875. http://dx.doi.org/10.1152/ajpcell.1997.273.6.c1868.

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Nitric oxide synthase (NOS) has been characterized in different tissues, and its localization has been suggested in different neuronal tissues, including the myenteric neurons and other nonneuronal cells. The present study examined the distribution of the neuronal NOS (nNOS) mRNA in different tissues of the opossum gastrointestinal tract, internal anal sphincter (IAS) smooth muscle cells, and myenteric neurons using slot-blot and Northern blot hybridization techniques with a specific rat brain nNOS cDNA probe. Significant levels of nNOS gene expression were found in both smooth muscle cells and myenteric neurons of the opossum IAS. This finding was confirmed by reverse transcriptase-polymerase chain reaction analysis of the RNA obtained from cultured opossum IAS smooth muscle cells and myenteric neurons and also from human intestinal smooth muscle and neuroblastoma cell lines. Pyloric sphincter had the highest level of nNOS gene expression compared with other gastrointestinal tissues. There was no significant difference in the nNOS gene expression between other sphincteric and nonsphincteric tissues examined. The present study shows the presence of nNOS gene expression in both neurons and smooth muscle cells. The higher levels of nNOS gene expression in the pyloric sphincter compared with other tissues may have pathophysiological significance in some disease conditions.

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Roberts, Christian K., R. James Barnard, Arnie Jasman, and Thomas W. Balon. "Acute exercise increases nitric oxide synthase activity in skeletal muscle." American Journal of Physiology-Endocrinology and Metabolism 277, no. 2 (August 1, 1999): E390—E394. http://dx.doi.org/10.1152/ajpendo.1999.277.2.e390.

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This study examined the effects of acute exercise on skeletal muscle nitric oxide synthase (NOS) activity. Female Sprague-Dawley rats were divided into three groups: control, exercise, and exercise + N G-nitro-l-arginine methyl ester (l-NAME). In the exercise + l-NAME group, l-NAME was administered in the drinking water (1 mg/ml) for 2 days and subsequently the exercise and exercise + l-NAME groups underwent a 45-min bout of exhaustive treadmill running after which NOS activity and muscle glycogen were measured. In the control and exercise groups, 1-amino- S-methylisothiourea (AMITU), a selective neuronal NOS inhibitor, with and without additional nonselective NOS blockade [with N G-monomethyl-l-arginine (l-NMMA)], was used in vitro to assess the contribution of nNOS to total NOS activity. The exercise bout increased NOS activity by 37% in exercise compared with control groups, and both groups had significantly greater NOS activity compared with exercise + l-NAME. AMITU decreased total NOS activity in the control and exercise groups by 31.8 and 30.2%, respectively, and these activities were significantly greater than AMITU +l-NMMA in both control and exercise groups. We conclude that 1) there is basal neuronal NOS and endothelial NOS activity in skeletal muscle, 2) an acute exercise bout increases NOS activity in skeletal muscle, and 3) glycogen depletion during exercise occurs irrespective of NOS activity.

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Kamii, Hideyuki, Shigeki Mikawa, Kensuke Murakami, Hiroyuki Kinouchi, Takashi Yoshimoto, Liza Reola, Elaine Carlson, Charles J. Epstein, and Pak H. Chan. "Effects of Nitric Oxide Synthase Inhibition on Brain Infarction in SOD-1-Transgenic Mice following Transient Focal Cerebral Ischemia." Journal of Cerebral Blood Flow & Metabolism 16, no. 6 (November 1996): 1153–57. http://dx.doi.org/10.1097/00004647-199611000-00009.

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To investigate the role of superoxide in the toxicity of nitric oxide (NO), we examined the effect of nitric oxide synthase (NOS) inhibition on brain infarction in transgenic mice overexpressing CuZn-superoxide dismutase (SOD-1). Male SOD-transgenic mice and nontransgenic littermates (30–35 g) were subjected to 60 min of middle cerebral artery occlusion followed by 24 h of reperfusion. Either N G-nitro-l-arginine methyl ester (l-NAME; 3 mg/kg), a mixed neuronal and endothelial NOS inhibitor, or 7-nitroindazole (7-NI; 25 mg/kg), a selective neuronal NOS inhibitor, was administered intraperitoneally 5 min after the onset of ischemia. At 24 h of reperfusion, the mice were decapitated and the infarct volume was evaluated in each group. In the nontransgenic mice, l-NAME significantly increased the infarct volume as compared with the vehicle, while 7-NI significantly decreased it. In the SOD-transgenic mice, l-NAME-treated animals showed a significantly larger infarct volume than vehicle-treated ones, whereas there were no significant differences between 7-NI- and vehicle-treated mice. Our findings suggest that selective inhibition of neuronal NOS ameliorates ischemic brain injury and that both neuronal and endothelial NOS inhibition may result in the deterioration of ischemic injury due to vasoconstriction of the brain. Since l-NAME increased infarct volume even in SOD-transgenic mice, the protective effect of SOD could result from the vasodilation by increased endothelial NO as well as the reduction of neuronal injury due to less production of peroxynitrite compared to wild-type mice. Moreover, the neurotoxic role of NO might not be dependent on NO itself, but the reaction with superoxide to form peroxynitrite, because of no additive effects of SOD and a neuronal NOS inhibitor.

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Sears, Claire E., Euan A. Ashley, and Barbara Casadei. "Nitric oxide control of cardiac function: is neuronal nitric oxide synthase a key component?" Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 359, no. 1446 (June 29, 2004): 1021–44. http://dx.doi.org/10.1098/rstb.2004.1477.

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Nitric oxide (NO) has been shown to regulate cardiac function, both in physiological conditions and in disease states. However, several aspects of NO signalling in the myocardium remain poorly understood. It is becoming increasingly apparent that the disparate functions ascribed to NO result from its generation by different isoforms of the NO synthase (NOS) enzyme, the varying subcellular localization and regulation of NOS isoforms and their effector proteins. Some apparently contrasting findings may have arisen from the use of non–isoform–specific inhibitors of NOS, and from the assumption that NO donors may be able to mimic the actions of endogenously produced NO. In recent years an at least partial explanation for some of the disagreements, although by no means all, may be found from studies that have focused on the role of the neuronal NOS (nNOS) isoform. These data have shown a key role for nNOS in the control of basal and adrenergically stimulated cardiac contractility and in the autonomic control of heart rate. Whether or not the role of nNOS carries implications for cardiovascular disease remains an intriguing possibility requiring future study.

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Capettini, L. S. A., S. F. Cortes, M. A. Gomes, G. A. B. Silva, J. L. Pesquero, M. J. Lopes, M. M. Teixeira, and V. S. Lemos. "Neuronal nitric oxide synthase-derived hydrogen peroxide is a major endothelium-dependent relaxing factor." American Journal of Physiology-Heart and Circulatory Physiology 295, no. 6 (December 2008): H2503—H2511. http://dx.doi.org/10.1152/ajpheart.00731.2008.

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Endothelium-dependent vasorelaxation in large vessels is mainly attributed to Nω-nitro-l-arginine methyl ester (l-NAME)-sensitive endothelial nitric oxide (NO) synthase (eNOS)-derived NO production. Endothelium-derived hyperpolarizing factor (EDHF) is the component of endothelium-dependent relaxations that resists full blockade of NO synthases (NOS) and cyclooxygenases. H2O2 has been proposed as an EDHF in resistance vessels. In this work we propose that in mice aorta neuronal (n)NOS-derived H2O2 accounts for a large proportion of endothelium-dependent ACh-induced relaxation. In mice aorta rings, ACh-induced relaxation was inhibited by l-NAME and Nω-nitro-l-arginine (l-NNA), two nonselective inhibitors of NOS, and attenuated by selective inhibition of nNOS with l-ArgNO2-L-Dbu-NH2 2TFA (L-ArgNO2-L-Dbu) and 1-(2-trifluoromethylphehyl)imidazole (TRIM). The relaxation induced by ACh was associated with enhanced H2O2 production in endothelial cells that was prevented by the addition of l-NAME, l-NNA, L-ArgNO2-L-Dbu, TRIM, and removal of the endothelium. The addition of catalase, an enzyme that degrades H2O2, reduced ACh-dependent relaxation and abolished ACh-induced H2O2 production. RT-PCR experiments showed the presence of mRNA for eNOS and nNOS but not inducible NOS in mice aorta. The constitutive expression of nNOS was confirmed by Western blot analysis in endothelium-containing vessels but not in endothelium-denuded vessels. Immunohistochemistry data confirmed the localization of nNOS in the vascular endothelium. Antisense knockdown of nNOS decreased both ACh-dependent relaxation and ACh-induced H2O2 production. Antisense knockdown of eNOS decreased ACh-induced relaxation but not H2O2 production. Residual relaxation in eNOS knockdown mouse aorta was further inhibited by the selective inhibition of nNOS with L-ArgNO2-L-Dbu. In conclusion, these results show that nNOS is constitutively expressed in the endothelium of mouse aorta and that nNOS-derived H2O2 is a major endothelium-dependent relaxing factor. Hence, in the mouse aorta, the effects of nonselective NOS inhibitors cannot be solely ascribed to NO release and action without considering the coparticipation of H2O2 in mediating vasodilatation.

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Park, Shin-Young, Min-Jeong Kang, and Joong-Soo Han. "Neuronal NOS Induces Neuronal Differentiation Through a PKCα-Dependent GSK3β Inactivation Pathway in Hippocampal Neural Progenitor Cells." Molecular Neurobiology 54, no. 7 (September 13, 2016): 5646–56. http://dx.doi.org/10.1007/s12035-016-0110-1.

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Xia, Yun, and Teresa L. Krukoff. "Estrogen Induces Nitric Oxide Production via Activation of Constitutive Nitric Oxide Synthases in Human Neuroblastoma Cells." Endocrinology 145, no. 10 (October 1, 2004): 4550–57. http://dx.doi.org/10.1210/en.2004-0327.

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Abstract Although it is becoming increasingly evident that nitric oxide (NO) mediates some of estrogen’s actions in the brain, the effects of estrogen on NO production through NO synthases (NOS) in neuronal cells have not yet been identified. Here we assessed changes in NO production induced by 17β-estradiol (E2) in cells of neuronal origin using human SK-N-SH neuroblastoma cells, which we show express all three isoforms of NOS. Involvement of NOS isoforms in E2-induced NO production was examined using isoform-specific NOS inhibitors. E2 (10−10–10−6m) induced rapid increases in NO release and changes in endothelial NOS (eNOS) expression, which were blocked by ICI 182,780, an antagonist of estrogen receptors. Increased levels of NO release and NOS activity induced by E2 were blocked by N5-(1-Imino-3-butenyl)-l-ornithine, a neuronal NOS inhibitor, and N5-(1-Iminoethyl)-l-ornithine, an eNOS inhibitor, but not by 1400W, an inducible NOS inhibitor. These results demonstrate that E2-stimulated NO production occurs via estrogen receptor-mediated activation of the constitutive NOSs, neuronal NOS and eNOS. The E2-induced NO increase was abolished when extracellular Ca2+ was removed from the medium or after the addition of nifedipine, an L-type channel blocker, and was partially inhibited using 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid acetoxymethyl ester, an intracellular Ca2+ chelator. However, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid acetoxymethyl ester itself also caused an increase in NO release that was blocked by 1400W, suggesting that inducible NOS mediates this response. Together these data reveal that constitutive NOS activities are responsible for E2- induced NO production in neuroblastoma cells and that differential activation of NOS isoforms in these cells occurs in response to different treatments.

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Xu, Lieming, Ethan P. Carter, Mamiko Ohara, Pierre-Yves Martin, Boris Rogachev, Kenneth Morris, Melissa Cadnapaphornchai, Mladen Knotek, and Robert W. Schrier. "Neuronal nitric oxide synthase and systemic vasodilation in rats with cirrhosis." American Journal of Physiology-Renal Physiology 279, no. 6 (December 1, 2000): F1110—F1115. http://dx.doi.org/10.1152/ajprenal.2000.279.6.f1110.

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Cirrhosis is typically associated with a hyperdynamic circulation consisting of low blood pressure, low systemic vascular resistance (SVR), and high cardiac output. We have recently reported that nonspecific inhibition of nitric oxide synthase (NOS) with nitro-l-arginine methyl ester reverses the hyperdynamic circulation in rats with advanced liver cirrhosis induced by carbon tetrachloride (CCl4). Although an important role for endothelial NOS (eNOS) is documented in cirrhosis, the role of neuronal NOS (nNOS) has not been investigated. The present study was carried out to specifically investigate the role of nNOS during liver cirrhosis. Specifically, physiological, biochemical, and molecular approaches were employed to evaluate the contribution of nNOS to the cirrhosis-related hyperdynamic circulation in CCl4-induced cirrhotic rats with ascites. Cirrhotic animals had a significant increase in water and sodium retention. In the aorta from cirrhotic animals, both nNOS protein expression and cGMP concentration were significantly elevated compared with control. Treatment of cirrhotic rats for 7 days with the specific nNOS inhibitor 7-nitroindazole (7-NI) normalized the low SVR and mean arterial pressure, elevated cardiac index, and reversed the positive sodium balance. Increased plasma arginine vasopressin concentrations in the cirrhotic animals were also repressed with 7-NI in association with diminished water retention. The circulatory changes were associated with a reduction in aortic nNOS expression and cGMP. However, 7-NI treatment did not restore renal function in cirrhotic rats (creatinine clearance: 0.76 ± 0.03 ml · min−1· 100 g body wt−1in cirrhotic rats vs. 0.79 ± 0.05 ml · min−1· 100 g body wt−1in cirrhotic rats+7-NI; P NS.). Taken together, these results indicate that nNOS-derived NO contributes to the development of the hyperdynamic circulation and fluid retention in cirrhosis.

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Liu, Qing Shan, Zi Qian Zhang, Xiao Yu Chen, Duo Ming Zhao, Yun Xia Duan, Liang Fang, and Xiao Ying Yin. "Recombinant Human Ciliary Neurotrophic Factor Protects MCAO/R Rat Brain against Neuronal Degeneration and Apoptosis by Regulating NOS Expression." Advanced Materials Research 699 (May 2013): 354–59. http://dx.doi.org/10.4028/www.scientific.net/amr.699.354.

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To research the effects and mechanisms of recombinant human ciliary neurotrophic factor (rhCNTF) on ischemia/reperfusion in vivo and in vitro, rhCNTF was biosynthesized, and ischemia/reperfusion-like models were used. Protection by rhCNTF was studied at the in vivo level using a model of middle cerebral artery occlusion and reperfusion (MCAO/R) in rats. RhCNTF was administrated just before reperfusion. RhCNTF markedly increased animal viability, decreased infarct volumes and neurological deficit scores. Primary cortical neuronal cultures were subjected to oxygen-glucose deprivation/reoxygenation, and treated with rhCNTF prophylactically. Results indicated that neuronal survival rates were increased, LDH release was decreased and lose of neurite length were alleviated in rhCNTF group, and this protection was associated with nerotrophic effect, nitric oxide and neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS). The data suggest that rhCNTF may be a good therapeutic reagent to reduce cerebral ischemia/reperfusion injury, and may act by NOS regulation.

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Buskila, Yossi, and Yael Amitai. "Astrocytic iNOS-Dependent Enhancement of Synaptic Release in Mouse Neocortex." Journal of Neurophysiology 103, no. 3 (March 2010): 1322–28. http://dx.doi.org/10.1152/jn.00676.2009.

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Nitric oxide (NO) has been recognized as an atypical neuronal messenger affecting synaptic transmission, but its cellular source has remained unresolved as the neuronal NO synthase isoform (nNOS) in brain areas such as the neocortex is expressed only by a small subset of inhibitory neurons. The involvement of the glial NOS isoform (iNOS) in modulating neuronal activity has been largely ignored because it has been accepted that this enzyme is regulated by gene induction following detrimental stimuli. Using acute brain slices from mouse neocortex and electrophysiology, we found that selective inhibition of iNOS reduced both spontaneous and evoked synaptic release. Moreover, iNOS inhibition partially prevented and reversed the potentiation of excitatory synapses in layer 2/3 pyramidal neurons. NOS enzymatic assay confirmed a small but reliable Ca2+-independent activity fraction, consistent with the existence of functioning iNOS in the tissue. Together these data point to astrocytes as a source for the nitrosative regulation of synaptic release in the neocortex.

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Gibson, Claire L., Philip MW Bath, and Sean P. Murphy. "G-CSF Administration is Neuroprotective following Transient Cerebral Ischemia Even in the Absence of a Functional NOS-2 Gene." Journal of Cerebral Blood Flow & Metabolism 30, no. 4 (February 10, 2010): 739–43. http://dx.doi.org/10.1038/jcbfm.2010.12.

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Granulocyte colony-stimulating factor (G-CSF) is a candidate neuroprotective factor following cerebral ischemia. To determine whether G-CSF acts partly through the inhibition of nitric oxide synthase (NOS)-2 expression, we administered G-CSF to male NOS-2−/− mice after cerebral ischemia. Although male NOS-2−/− mice exhibit resistance to the gross effects of cerebral ischemia, they display neuronal loss and skilled motor deficits following cerebral ischemia. Administration of G-CSF during reperfusion reduced motor deficit and neuronal loss. Thus, G-CSF is still effective in NOS-2 gene-deficient mice, suggesting that part of the mechanism of action is independent of NOS-2.

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Lekontseva, Olga, Yanyan Jiang, Caitlyn Schleppe, and Sandra T. Davidge. "Altered Neuronal Nitric Oxide Synthase in the Aging Vascular System: Implications for Estrogens Therapy." Endocrinology 153, no. 8 (June 14, 2012): 3940–48. http://dx.doi.org/10.1210/en.2012-1071.

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Ovarian dysfunction at any age is associated with increased cardiovascular risk in women; however, therapeutic effects of exogenous estrogens are age dependent. Estradiol (E2) activates neuronal nitric oxide synthase (nNOS) in vascular cells. Because nNOS is prone to uncoupling under unfavorable biochemical conditions (as seen in aging), E2 stimulation of nNOS may lack vascular benefits in aging. Small mesenteric arteries were isolated from female Sprague Dawley rats, 3 or 12 months old, who were ovariectomized (Ovx) and treated with placebo or E2 for 4 wk. Vascular relaxation to exogenous E2 (0.001–100 μmol/liter) ± selective nNOS inhibitor (N-propyl-l-arginine, 2 μmol/liter) or pan-NOS inhibitor [Nω-nitro-l-arginine methyl ester (l-NAME), 100 μmol/liter] was examined on wire myograph. NOS expression was measured by Western blotting in thoracic aortas, in which superoxide generation was detected as dihydroethidium (DHE) fluorescence. E2 relaxations were impaired in Ovx conditions. E2 treatment (4 wk) normalized vascular function in young rats only. Both l-N-propyl-l-arginine and l-NAME blunted E2 relaxation in young controls, but only l-NAME did so in aging controls. NOS inhibition had no effect on acute E2 relaxation in Ovx rats, regardless of age or treatment. nNOS expression was similar in all animal groups. However, nNOS inhibition increased DHE fluorescence in young controls, whereas it reduced it in aging or Ovx animals. In E2-treated animals of either age, superoxide production was NOS independent. In conclusion, nNOS contributed to vascular relaxation in young, but not aging rats, where its enzymatic function shifted toward superoxide production. Thus, nNOS dysfunction may explain a mechanism of impaired E2 signaling in aging conditions.

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Meng, W., J. Ma, C. Ayata, H. Hara, P. L. Huang, M. C. Fishman, and M. A. Moskowitz. "ACh dilates pial arterioles in endothelial and neuronal NOS knockout mice by NO-dependent mechanisms." American Journal of Physiology-Heart and Circulatory Physiology 271, no. 3 (September 1, 1996): H1145—H1150. http://dx.doi.org/10.1152/ajpheart.1996.271.3.h1145.

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We used mice with deletions in either the endothelial nitric oxide synthase (eNOS) or neuronal NOS (nNOS) gene to investigate the role of eNOS and nNOS in acetylcholine (ACh)-induced relaxation of pial arterioles (20-30 microns). Pial arteriolar diameter was measured by intravital microscopy through a closed cranial window, and NOS activity was determined by the conversion of [3H]arginine to [3H]citrulline in subjacent cortex. ACh superfusion (1, 10 microM) caused atropine-sensitive dose-dependent arteriolar dilation in all three mouse strains. At 10 microM, increases of 20 +/- 2, 31 +/- 3, and 23 +/- 3% were recorded in wild-type (n = 25), nNOS mutant (n = 15), and eNOS mutant (n = 20) mice, respectively. NG-nitro-L-arginine (L-NNA, 1 mM) superfusion inhibited cortical NOS activity by > 70% and abrogated the response in wild-type mice while blocking the dilation by approximately 50% in eNOS mutant and nNOS mutant mice. Only in the eNOS mutant did tetrodotoxin (TTX) superfusion (1 microM) attenuate ACh-induced dilation (n = 6). The residual dilation after L-NNA in eNOS mutant mice could be blocked completely by TTX-plus L-NNA. Our findings indicate that 1) ACh dilates pial arterioles of wild-type mice by NOS-dependent mechanisms as reported in other species, 2) the response in nNOS mutant mice resembles the wild-type response except for enhanced dilation to ACh and reduced L-NNA sensitivity, and 3) surprisingly, the response in eNOS mutant mice is partially NOS dependent and attenuated by both TTX and L-NNA. Because nNOS is constitutively expressed in eNOS mutants, these findings coupled with the TTX results suggest that an nNOS-dependent mechanism may compensate for the chronic loss of eNOS activity after targeted gene disruption.

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Kandratavicius, Ludmyla, Mariana Raquel Monteiro, Raquel Araujo do Val-da Silva, and João Pereira Leite. "Neurotrofinas na epilepsia do lobo temporal." Journal of Epilepsy and Clinical Neurophysiology 16, no. 1 (2010): 7–12. http://dx.doi.org/10.1590/s1676-26492010000100002.

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INTRODUÇÃO: A neurotrofinas NGF, BDNF, NT-3 e NT-4 são os principais representantes da família das neurotrofinas no sistema nervoso central de mamíferos. Estão presentes em estágios específicos do crescimento e sobrevivência neuronal como a divisão celular, diferenciação e axogênese e também nos processos naturais de morte celular neuronal. A atividade biológica das neurotrofinas é mediada pelos receptores de tropomiosina quinase Trk. NGF ativa principalmente os receptores TrkA, BDNF e NT-4 interagem com os receptores TrkB e NT-3 com TrkC. Todas as NTs também podem se ligar, com menor afinidade, ao receptor p75NTR. Nesta breve revisão serão levantadas as principais evidências sobre o papel e expressão das principais neurotrofinas no hipocampo, com ênfase nas alterações que ocorrem em modelos animais de epilepsia. RESULTADOS: As neurotrofinas parecem ter um papel chave na plasticidade sináptica relacionada à epilepsia, onde elas poderiam agir tanto como fatores promotores da epileptogênese quanto como substâncias anti-epiléptogênicas endógenas. Além disso a expressão dos genes que codificam os fatores neurotróficos e seus receptores pode ser alterada pela atividade de crises em diversos modelos de epilepsia. CONCLUSÃO: Vários estudos têm demonstrado a relação entre a expressão das neurotrofinas e as alterações na plasticidade dos circuitos neuronais que ocorrem após danos cerebrais, tais como a epilepsia. O conhecimento das alterações na expressão das neurotrofinas na plasticidade neuronal pode nos auxiliar a entender como estas moléculas participam dos mecanismos epileptogênicos e dessa forma, dar início ao estudo de novas terapias e ao desenvolvimento de novas drogas que auxiliem no tratamento da epilepsia.

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Talukder, Hassan M. A., Hiroaki Shimokawa, Takako Fujiki, Keiko Morikawa, Hiroshi Kubota, Tetsuya Matoba, and Akira Takeshita. "P-33 Neuronal nos contributes to bradykinin-induced coronary flow in endothelial NOS knockout (eNOS-KO) mice." Journal of Molecular and Cellular Cardiology 34, no. 10 (October 2002): A33. http://dx.doi.org/10.1016/s0022-2828(02)90356-1.

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Moore, P. K., and R. L. C. Handy. "Selective inhibitors of neuronal nitric oxide synthase – is no NOS really good NOS for the nervous system?" Trends in Pharmacological Sciences 18, no. 6 (June 1997): 204–11. http://dx.doi.org/10.1016/s0165-6147(97)01064-x.

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Journal articles on the topic 'Neuronal NOS'

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