Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.99.1 (NADPH-diaphorase)
 3,903 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The distribution of nitric oxide synthase was investigated in human cerebral blood vessels and brain tissues. NADPH-diaphorase histochemistry, which is a marker for nitric oxide synthase in neurons and endothelial cells, revealed periadventitial nerve fibers in the arteries of the circle of Willis and their cortical branches, as well as the common carotid and subclavian arteries. The fibers were mostly nonvaricose in the periadventitial nerve trunk and were varicose within the adventitia. Patchy reaction products were distributed in the perinuclear region of each endothelial cell. Smooth muscle cells in the tunica media were weakly stained. Staining was particularly intense in regions with atherosclerotic changes, which consist of macrophage infiltration and proliferation of fibroblasts. In the neural parenchyma, two types of NADPH-diaphorase reactive neurons were differentiated. Type I neurons were intensely stained, medium-sized, and bipolar or multipolar. They were distributed in the cerebral cortex and white matter, mostly in the subcortical white matter. Type II neurons were lightly stained, small oval neurons with fine processes and were distributed in the cerebral cortex. Endothelial cells were intensely reactive for NADPH-diaphorase in the arteries, arterioles, and capillaries but weakly in veins. Immunohistochemistry for neural nitric oxide synthase labeled perivascular nerves in the larger arteries and those in the neural parenchyma. Both type I and type II neurons were labeled. Nitric oxide synthase in endothelial cells and the nerve encircling blood vessels further suggests a dual control of cerebral circulation by nitric oxide in human brain.
J Cereb Blood Flow Metab 1994 Nov
PMID:Distribution of nitric oxide synthase in the human cerebral blood vessels and brain tissues. 752 31

We studied the effect of focal cerebral ischemia on inducible (iNOS) and constitutive (cNOS) nitric oxide synthase enzymatic activities in the affected brain. The middle cerebral artery (MCA) was occluded in spontaneously hypertensive rats. Animals were killed 1, 2, 4, and 7 days later. cNOS and iNOS enzymatic activities were determined in the infarcted cortex using the assay of Bredt and Snyder. cNOS was assayed in the presence of calcium, whereas iNOS was assayed in the absence of calcium and in the presence of tetrahydrobiopterin. The validity of the iNOS assay was verified in rats treated with bacterial lipopolysaccharide. In these animals, the magnitude of the induction of iNOS enzymatic activity in lung, spleen, and brain paralleled the expression of iNOS mRNA, assessed by reverse-transcription polymerase chain reaction. After MCA occlusion, calcium-dependent (cNOS) activity was markedly reduced only in lesioned cerebral cortex at days 1-7 (p < 0.001; analysis of variance and Tukey's test). In contrast to cNOS, calcium-independent (iNOS) activity was induced substantially in the infarct (p < 0.005) but not in the contralateral intact cortex (p > 0.05). iNOS activity peaked at day 2 and was not different from baseline at day 7 (p > 0.05). No NADPH diaphorase-positive neurons were observed in the area of the lesion at days 1-7. Macrophages appeared at day 2 and invaded the infarcted tissue by day 7. At this time, numerous glial fibrillary acidic protein-positive astrocytes were observed within the lesion. The results suggest that the decline in calcium-dependent (cNOS) activity reflects loss of NOS neurons within the lesion.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cereb Blood Flow Metab 1995 Jan
PMID:Marked induction of calcium-independent nitric oxide synthase activity after focal cerebral ischemia. 752 24

The effects of tumor necrosis factor-alpha (TNF-alpha) on the production of the vasoactive substances nitric oxide (NO) and endothelin-1 (ET-1) were investigated in cerebrovascular cells in culture. Bovine cerebral endothelial cells (BCEC) stained positively for NADPH-diaphorase/NO synthase activity and spontaneously produced nitrite, a stable NO oxidation product, which accumulated in the culture medium in a linear way for 48 h. Low concentrations of TNF-alpha (0.5-2 ng/ml) significantly enhanced nitrite production after a 24-h incubation. Higher concentrations or longer exposure times resulted in a cytotoxic effect that altered cell morphology, released lactate dehydrogenase (LDH) to the culture medium, and reduced the protein content. Dexamethasone, but not the NO synthase inhibitor N-iminoethyl-L-ornithine (L-NIO), prevented the cytotoxic effect of TNF-alpha in BCEC. TNF-alpha also significantly enhanced nitrite production in bovine cerebral smooth muscle cells (BCSMC). The enhancement was detected at all times between 8 and 72 h and at all concentrations tested (2-100 ng/ml). Signs of cytotoxicity were not observed in BCSMC after incubation with TNF-alpha. ET-1 was constitutively secreted by BCEC. The production of ET-1 was stimulated by thrombin. TNF-alpha enhanced the release of ET-1 in BCEC, and this enhancement was not modified by the simultaneous addition of interferon-gamma (IFN-gamma). BCSMC did not produce ET-1, either spontaneously or in the presence of TNF-alpha, IFN-gamma, or of both together.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cereb Blood Flow Metab 1995 Nov
PMID:Effects of TNF-alpha on the production of vasoactive substances by cerebral endothelial and smooth muscle cells in culture. 759 52

The effects of 3-acetylpyridine (3-AP) were studied in rat striatum. Striatal injections of 3-AP produced dose-dependent lesions. The lesion size was significantly increased in 4- and 12-month-old rats compared to 1-month-old rats. Coinjection of the competitive N-methyl-D-aspartate (NMDA) antagonist 2-amino-5-phosphonovaleric acid (APV) or systemic administration of the noncompetitive NMDA antagonist MK-801, the competitive NMDA antagonist LY274614, or the glutamate release inhibitor lamotrigine partially but significantly attenuated striatal lesion volume. Consistent with an NMDA receptor-mediated excitotoxic effect, histologic studies showed that 3-AP lesions result in relative sparing of NADPH-diaphorase neurons. Using freeze clamp, 3-AP resulted in a marked depletion of ATP. Two-dimensional water-suppressed proton chemical shift magnetic resonance imaging showed a striatal depletion of the neuronal marker N-acetylaspartate but no focal increase in lactate during the first 3 h after intrastriatal 3-AP injections. Pretreatment with fructose-1,6-biphosphate attenuated the lesion volume significantly, which may be due to its ability to serve as a substrate for glycolytic metabolism, with resulting ATP production. The results of the present studies support the hypothesis that 3-AP produces an impairment of energy metabolism due to its substitution for niacinamide in the formation of NAD(P). Furthermore, 3-AP toxicity may involve a secondary excitotoxic mechanism mediated by NMDA receptors.
J Cereb Blood Flow Metab 1994 Nov
PMID:3-Acetylpyridine produces age-dependent excitotoxic lesions in rat striatum. 792 44

Electrical stimulation of perivascular nerves induced a relaxation of endothelium-denuded cat pial arteries that was significantly reduced by nitric oxide (NO) synthase inhibition, indicating that NO was involved in the neurogenic relaxation of these vessels. Histochemical staining of the pial arteries for NADPH-diaphorase (NADPH-d), used as a marker for NO synthase, showed positive nerve fibers in the adventitial layer. Interestingly, in some restricted areas stained neuronal cell bodies were also observed. These neurons were scattered or distributed in small groups in a ganglion-like manner, and they sent fibers to the vessel wall. No NADPH-d-positive nerve fibers or cell bodies were detected in forelimb, pulmonary, or coronary arteries. Within the brain parenchyma, blood vessels also showed positive fibers around their walls. These fibers were organized in a branching pattern and presented varicosities. NADPH-d-positive neurons were found in the proximity of the intracerebral vascular profiles, sending processes to the vessels and/or being directly apposed to their wall. The neurovascular contacts were preferentially located close to the interface between the cerebral cortex and white matter. The anatomical relationship between NADPH-d-positive neurons and fibers and the cerebral blood vessels, together with the participation of NO in the neurogenic relaxation of pial arteries, suggests that NO is involved in the regulation of cerebral blood flow.
J Cereb Blood Flow Metab 1993 Nov
PMID:Local NADPH-diaphorase neurons innervate pial arteries and lie close or project to intracerebral blood vessels: a possible role for nitric oxide in the regulation of cerebral blood flow. 840 22

Two populations of scattered neurons containing nitric oxide synthase activity were detected in the wall of the third and lateral cerebral ventricles of rat brain, using histochemistry for NADPH-diaphorase activity. One type was multipolar and lay supraependymally, with dendrites oriented in the plane of the ependymal layer. The second type was bipolar and was situated subependymally, with dendrites extending in opposite directions, either into the surrounding brain tissue or to the ventricular surface. Moreover, multipolar neurons, situated in the corpus callosum and in the subcortical white matter, had long varicose dendrites extending toward the roof of the lateral ventricles. As a result, numerous NADPH-diaphorase neurites spread out on the free surface of the ependymal layer in contact with the CSF. These observations raise the possibility that periventricular nitrergic neurons play an essential role in registering the composition of the CSF and in modulating subcortical cerebral blood flow. A further possibility is that supraependymal nitrergic neuronal processes are effectors regulating activity of ependymal cells.
J Cereb Blood Flow Metab 1996 May
PMID:NADPH-diaphorase neurons contacting the cerebrospinal fluid in the ventricles of rat brain. 862 57

Neurons in the monkey cerebral cortex containing nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) can be divided into two distinct types, both nonpyramidal. Type I neurons have a large soma (diameter 20-50 microm), a dense NADPH-d histochemical reaction, and are distributed throughout the cortex, but mainly in the subcortical white matter, and are mostly aspiny. Type II cells have a small soma ( Together with previous observations that almost all cortical NADPH-d cells in various subprimates are like type I cells, we suggest that type II cells may form a group of NADPH-d-rich neurons differentiated in higher mammalian cortex from a subpopulation of calbindin-containing GABAergic interneurons, and these nitric oxide-synthesizing cells may play a role in control of intracortical neuronal activity characteristic of higher cerebral functions in advanced mammals.
Cereb Cortex
PMID:NADPH-diaphorase-positive neurons in primate cerebral cortex colocalize with GABA and calcium-binding proteins. 867 Jun 78

Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry was used to study the morphology and development of neurons that metabolize nitric oxide (NO) in the frontal cortex of human fetuses aged from 13 weeks of gestation (13W) to term, to investigate whether the two distinct types of NO neuron described in the adult develop differently. Large, heavily stained, sparsely spiny, non-pyramidal neurons (Type I) develop by 15W mainly in the subplate (SP) of the cortical Anlage. They achieve an adult-like pattern by 32W, distributed thoughout the cortex and subcortical white matter, but with the highest concentration in the white matter. Small, lightly stained cells (Type II) develop later (32W) thoughout the cortex, but especially in layers II-IV, and increase in number to term. NADPH-d-positive dendrites and axons appear in the cortex and white matter by 15W. They include thick, radially oriented, dendritic processes from Type I neurons in SP and CP. Their arbors expand and mature between 17 and 28W. Fine horizontal axons are visible in layer I by 17W. Others develop in layers II-IV from 28W, and have reached a high degree of development by term. NADPH-d-positive axons in the cortex seem to have both intrinsic and extrinsic origins. Thus the two types of NADPH-d neurons found in adult primate, including human, cortex are reflected by different developmental forms prenatally. It is concluded that NO-metabolizing neurons in the human cortex may be involved in various aspects of development, including morphological and functional maturation, and that the late-developing Type II neurons may represent a cell line specific to primates, perhaps related to the development of their higher cortical activity and of potential importance in the pathophysiology of diseases of cognitive function.
Cereb Cortex
PMID:Prenatal development of NADPH-diaphorase-reactive neurons in human frontal cortex. 892 Dec 8

Results from biochemical and pharmacologic studies suggest that Lcitrulline is taken up by cerebral perivascular nerves and is converted to Larginine for synthesizing nitric oxide (NO). The current study was designed using morphologic techniques to determine whether Lcitrulline is taken up into axoplasm of perivascular nerves and to explore the possibility that conversion of Lcitrulline to Larginine in these nerves is through the argininosuccinate pathway in porcine cerebral arteries. Results from light and electron microscopic autoradiographic studies indicated that dense silver grains representing L-[3H] citrulline uptake were found in cytoplasm of perivascular nerves, smooth muscle cells, and endothelial cells. The neuronal silver grains were significantly decreased in arteries pretreated with glutamine, which has been shown biochemically to block neuronal uptake of Lcitrulline. Results from light and electron microscopic immunohistochemical and histochemical studies indicate that dense nitric oxide synthase-immunoreactive (NOS-I), argininosuccinate synthetase-immunoreactive (ASS-I), and argininosuccinate lyase-immunoreactive (ASL-I) fibers were found in the adventitia of cerebral arteries. NOS-, ASS-, and ASL-immunoreactivities fibers were found in the axoplasm and in the endothelium. In whole-mount preparations, the NOS-I, ASS-I, and ASL-I fibers were completely coincident with NADPH diaphorase fibers, suggesting that axoplasmic ASS, ASL, and NOS were co-localized in the same neurons. These studies provide the first morphologic evidence indicating that Lcitrulline is taken up into cytoplasm of cerebral perivascular nerves and that the axoplasmic enzymes catalyzing the conversion of Lcitrulline to Larginine (for synthesizing NO) by argininosuccinate pathway always are co-localized in same neurons. These results support the hypothesis that Lcitrulline, the by-product of NO synthesis, is recycled to form Larginine for synthesizing NO in perivascular nerves to mediate cerebral neurogenic vasodilation. Results of the current morphologic studies also support the presence of Lcitrulline-Larginine cycle in cerebral vascular endothelium.
J Cereb Blood Flow Metab 1997 Aug
PMID:Morphologic evidence for L-citrulline conversion to L-arginine via the argininosuccinate pathway in porcine cerebral perivascular nerves. 929 May 86

The participation of nitric oxide and vasoactive intestinal peptide (VIP) in the neurogenic regulation of bovine cerebral arteries was investigated. Nitrergic nerve fibers and ganglion-like groups of neurons were revealed by NADPH-diaphorase staining in the adventitial layer of bovine cerebral arteries. NADPH diaphorase also was present in endothelial cells but not in the smooth muscle layer. Double immunolabeling for neuronal nitric oxide synthase and VIP indicated that both molecules co-localized in the same nerve fibers in these vessels. Transmural nerve stimulation (200 mA, 0.2 milliseconds, 1 to 8 Hz) of endothelium-denuded bovine cerebral artery rings precontracted with prostaglandin F2 alpha, produced tetrodotoxin-sensitive relaxations that were completely suppressed by NG-nitro-L-arginine methyl ester (L-NAME) and by the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline (ODQ), but were not affected by the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22,536), nor by VIP tachyphylaxis induced by pretreatment with 1 mumol/L VIP. Transmural nerve stimulation also elicited increases in intracellular cyclic GMP concentration, which were prevented by L-NAME, and small decreases in intracellular cyclic AMP concentration. Addition of VIP to bovine cerebral artery rings without endothelium produced a concentration-dependent relaxation that was partially inhibited by L-NAME, ODQ, and SQ 22,536. The effects of L-NAME and SQ 22,536 were additive. VIP induced a transient increase in intracellular cyclic GMP concentration, which was maximal 1 minute after VIP addition, when the highest relaxation rate was observed, and which was blocked by L-NAME. It is concluded that nitric oxide produced by perivascular neurons and nerve fibers fully accounts for the experimental neurogenic relaxation of bovine cerebral arteries and that VIP, which also is present in the same perivascular fibers, acts as a neuromodulator by activating neuronal nitric oxide synthase.
J Cereb Blood Flow Metab 1997 Sep
PMID:Neuronal nitric oxide synthase activation by vasoactive intestinal peptide in bovine cerebral arteries. 930 11


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