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

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Query: EC:1.6.99.1 (NADPH-diaphorase)
3,903 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:3-Acetylpyridine produces age-dependent excitotoxic lesions in rat striatum. 792 44

1. Electrical field stimulation (EFS) of intrinsic nerves in the rat proximal duodenum induces a frequency-dependent non-adrenergic-non-cholinergic (NANC) relaxation response. 2. The inhibitors of L-arginine-NO synthase L-NG-nitro arginine methyl-ester (L-NAME) and L-NOARG (L-NG-nitro arginine) reduced the NANC relaxations elicited by EFS in a dose- and time-dependent manner; L-NOARG was two times more potent than L-NAME (IC50 = 14.3 vs 25.2 microM) and these effects were partially reverted by the addition of 300-1000 microM L-arginine but not of 300-1000 microMD-arginine. Relaxation caused by vasoactive intestinal peptide (VIP; 0.1 microM) or ATP (20 microM) was not blocked by L-NAME or L-NOARG. 3. The magnitude of the blockade caused by L-NAME and L-NOARG was dependent on the frequency of stimulation. At low frequencies (below 1 Hz) both L-NAME and L-NOARG abolished the relaxations, while at 2 to 8 Hz only partial inhibition was observed (maximal inhibition: 44.6% +/- 5.2 and 63.4% +/- 3.4, respectively) 4. The basal tonus of the duodenum was increased by 10-300 microM L-NAME and 10-300 microM L-NOARG and this effect was blocked by 1 mM L-arginine. 5. Nitric oxide generated from acidified NaNO2 caused a dose-dependent (EC50 = 2.75 microM) relaxation of the duodenum which was not affected by 100 microM L-NAME, 100 microM L-NOARG or 1 microM tetrodotoxin (TTX). 6. NADPH-diaphorase positive neurons and fibers identified by histochemistry were present in the myenteric plexus and along both circular and longitudinal muscle fibers indicating that nitric oxide could be synthetized by these neural structures.
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PMID:Evidence for the participation of the L-arginine-nitric oxide pathway in neurally induced relaxation of the isolated rat duodenum. 813 34

Fe(II)- and Co(II)-Fenton systems (FS) inactivated the lipoamide reductase activity but not the diaphorase activity of pig-heart lipoamide dehydrogenase (LADH). The Co(II) system was the more effective as LADH inhibitor. Phosphate ions enhanced the Fe(II)-FS activity. EDTA, DETAPAC, DL-histidine, DL-cysteine, glutathione, DL-dithiothreitol, DL-lipoamide, DL-thioctic acid, bathophenthroline, trypanothione and ATP, but not ADP or AMP, prevented LADH inactivation. Reduced disulfide compounds were more effective protectors than the parent compounds. Mg ions counteracted ATP protective action. Glutathione and DL-dithiothreitol partially restored the lipoamide dehydrogenase activity of the Fe(II)-FS-inhibited LADH. DL-histidine exerted a similar action on the Co(II)-FS-inhibited enzyme. Ethanol, mannitol and benzoate did not prevent LADH inactivation by the assayed Fenton systems and, accordingly, it is postulated that site-specific generated HO. radicals were responsible for LADH inactivation. With the Co(II)-FS, oxygen reactive species other than HO., might contribute to LADH inactivation.
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PMID:Inactivation of lipoamide dehydrogenase by cobalt(II) and iron(II) Fenton systems: effect of metal chelators, thiol compounds and adenine nucleotides. 831 11

The NANC inhibitory innervation of the longitudinal muscle of the rabbit portal vein has been examined. Neurogenic relaxations were partially inhibited by the P2-purinoceptor antagonist, suramin. Addition of the NO-synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) also significantly reduced responses to electrical stimulation and the addition of L-arginine reversed this effect. A combination of both suramin and L-NAME abolished the neurogenic relaxation. A maximum relaxation of the vein was evoked by sodium nitroprusside which was not affected by L-NAME or suramin. Histochemical staining demonstrated the presence of NADPH-diaphorase containing nerves between the longitudinal and circular muscle coats of the media and also in the adventitia. It is concluded that both ATP and NO are inhibitory neurotransmitters in the NANC nerves of the rabbit portal vein.
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PMID:Evidence for the involvement of both ATP and nitric oxide in non-adrenergic, non-cholinergic inhibitory neurotransmission in the rabbit portal vein. 839 92

1. Neurogenic responses to transmural electrical stimulation were examined in endothelium-denuded extrameningeal (vertebral and carotid) and intrameningeal (spinal, basilar and middle cerebral) arteries isolated from dogs. 2. In the extrameningeal arteries, transmural electrical stimulation produced a phasic contraction. This contraction was abolished by tetrodotoxin, prazosin and guanethidine. However, alpha,beta-methylene ATP and NG-nitro-L-arginine (L-NOARG) had no significant effect on the contractile responses. 3. In the intrameningeal arteries, the neurogenic responses to electrical stimulation were composed of a transient contraction and relaxation. The transient contraction was selectively inhibited by guanethidine L-NOARG abolished the relaxation but not the contraction induced by electrical stimulation. Prazosin had no effect on either neurogenic response. 4. Noradrenaline produced a large contraction in the extrameningeal arteries which was selectively inhibited by prazosin. alpha,beta-Methylene ATP produced neither contraction nor inhibition of the response to noradrenaline in the extrameningeal arteries. 5. In the intrameningeal arteries, alpha,beta-methylene ATP produced a greater contraction than noradrenaline. The response to alpha,beta-methylene ATP was selectively abolished by desensitization of P2x-purinoceptors with alpha,beta-methylene ATP itself. The contractile response to noradrenaline was inhibited by rauwolscine but not by prazosin. 6. ATP produced endothelium-dependent relaxations in the extrameningeal and intrameningeal arteries, which were attenuated by endothelium removal. 7. NADPH diaphorase-positive fibres were dense in the middle cerebral and basilar arteries but rare or absent in the spinal artery. In the extrameningeal arteries diaphorase-positive traces were observed in the vasa vasorum. 8. The present findings indicate that the neurogenic responses of intrameningeal arteries of dogs are composed of NO-ergic and sympathetic purinergic components, while the extrameningeal arteries tested produced only sympathetic adrenergic responses, suggesting that regional heterogeneity may be associated with a sudden transition in innervation and receptor expression at the meninx.
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PMID:Heterogeneity of neurogenic responses in intra- and extrameningeal arteries of dogs. 859 Sep 70

1. The involvement of nitric oxide (NO) and the signal transduction mechanisms mediating neurogenic relaxations were investigated in deep intracavernous penile arteries with an internal lumen diameter of 600-900 microns, isolated from the corpus cavernosum of young horses. 2. The presence of nitric oxide synthase (NOS)-positive nerves was examined in cross and longitudinal sections of isolated penile arteries processed for NADPH-diaphorase (NADPH-d) histochemistry. NADPH-d-positive nerve fibres were observed in the adventitia-media junction of deep penile arteries and in relation to the trabecular smooth muscle. 3. Electrical field stimulation (EFS) evoked frequency-dependent relaxations of both endothelium-intact and denuded arterial preparations treated with guanethidine (10(-5) M) and atropine (10(-7) M), and contracted with 10(-6) M phenylephrine. These EFS-induced relaxations were tetrodotoxin-sensitive indicating their non-adrenergic non-cholinergic (NANC) neurogenic origin. 4. EFS-evoked relaxations were abolished at the lowest frequency (0.5-2 Hz) and attenuated at higher frequencies (4-32 Hz) by the NOS inhibitor, NG-nitro-L-arginine (L-NOARG, 3 x 10(-3) M). This inhibitory effect was antagonized by the NO precursor, L-arginine (3 x 10(-3) M). NG-nitro-D-arginine (10(-4) M) did not affect the relaxations to EFS. 5. Incubation with either the NO scavenger, oxyhaemoglobin (10(-5) M), or methylene blue (10(-5) M), an inhibitor of guanylate cyclase activation by NO, caused significant inhibitions of the EFS-evoked relaxations, and while oxyhaemoglobin abolished the relaxations to exogenously added NO (acidified sodium nitrite, 10(-6) - 10(-3) M), there still persisted a relaxation to NO of 24.4 +/- 5.1% (n = 6) in the presence of methylene blue. 6. Glibenclamide (3 x 10(-6) M), an inhibitor of ATP-activated K(+)-channels, did not alter the relaxations to either EFS-stimulation or NO, while the blocker of Ca(2+)-activated K(+)-channels, charybdotoxin (3 x 10(-8) M), caused a significant inhibition of both the electrically-induced relaxations and the relaxations to exogenously added NO. Furthermore, charybdotoxin blocked relaxations induced by the cell permeable analogue of cyclic GMP, 8-bromo cyclic GMP (8 Br-cyclic GMP). 7. These results suggest that relaxations of horse deep penile arteries induced by NANC nerve stimulation involve mainly NO or a NO-like substance from nitrergic nerves. NO would stimulate the accumulation of cyclic GMP followed by increases in the open probability of Ca(2+)-activated K(+)-channels and hyperpolarization leading to relaxation of horse penile arteries.
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PMID:Involvement of nitric oxide in the non-adrenergic non-cholinergic neurotransmission of horse deep penile arteries: role of charybdotoxin-sensitive K(+)-channels. 859 Sep 74

Nitric oxide (NO) plays an important role in the regulation of Ca2+ -dependent airway epithelial function such as ciliary motility. In this experiment, the effect of NO on intracellular Ca2+ ([Ca2+]1) was studied in cultured cow tracheal epithelium by the fura-2 method. L-NG-nitroarginine methyl ester, an NO synthase inhibitor, per se did not significantly alter baseline [Ca2-]i, but bradykinin- and ATP-induced increases in [Ca2+]i were significantly reduced in the presence of L-NG-nitroarginine methyl ester. This inhibitory effect disappeared by a simultaneous addition of L-arginine. Sodium nitroprusside or dibutyryl cyclic GMP potentiated bradykinin- and ATP-induced increases in [Ca2+]i. Cytochemistry for NADPH diaphorase activity revealed the presence of NO synthase in the cultured epithelium. These results suggest that NO produced by NO synthase in airway epithelium modulates bradykinin- and ATP-induced [Ca2+]i responses, which may be dependent on cyclic GMP.
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PMID:Nitric oxide modulation of Ca2+ responses in cow tracheal epithelium. 871 23

Intravenous injection of NG-nitro-L-arginine (L-NA), a nitric oxide synthase inhibitor, elevated mean blood pressure by 29.0 +/- 4.9 mm Hg and decreased heart rate by 40.7 +/- 5.6 beats per minute in anesthetized Japanese monkeys (n = 6), whereas NG-nitro-D-arginine was without effect. After pretreatment with pentolinium, the magnitude of the pressure elevation by L-NA was significantly less than that after pretreatment with phentol-amine. The reduced blood pressure by either of the pretreatment drugs was compensated to control levels by a continuous infusion of angiotensin II before L-NA administration. Isolated monkey distal mesenteric arteries (150 to 200 microns OD) without endothelium responded to nerve stimulation by nicotine with a contraction, which was abolished by prazosin alone or in combination with alpha, beta-methylene ATP. In the strips thus treated and contracted with prostaglandin F2 alpha, nicotine caused a relaxation that L-NA abolished. L-NA but not NG-nitro-D-arginine reversed the inhibition. Histochemical staining of NADPH diaphorase, considered to be identical to nitric oxide synthase in neuronal tissues, demonstrated that positively stained nerve fibers were consistently present in the adventitia of monkey distal mesenteric arteries and arterioles. These results strongly suggest that nitroxidergic vasodilator nerves innervate peripheral small arteries and arterioles in the monkey and that these nerves participate in the regulation of systemic blood pressure. High blood pressure caused by nitric oxide synthase inhibitors is associated with an elimination of nitroxidergic nerve function together with an impairment of the basal release of nitric oxide from the endothelium.
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PMID:Neural mechanism of pressor action of nitric oxide synthase inhibitor in anesthetized monkeys. 879 14

The potential role of nitrergic nerves in the regulation of the South American (SA) opossum ileocolonic junction (ICJ) function was investigated. In vitro, the effects of nitric oxide (NO) synthase inhibitors and NO inactivators on the non-adrenergic non-cholinergic (NANC) nerve-mediated relaxations of the circular muscle of the SA opossum ICJ were determined by employing isolated strips. Electrical field stimulation (0.2-8.0 Hz) caused frequency-dependent NANC relaxations. Nicotine and ATP also induced concentration dependent NANC relaxations that were abolished by tetrodotoxin (TTX). The relaxation response induced by NANC nerve activation was reduced in a dose dependent manner by NO synthase inhibitors while vasoactive intestinal peptide (VIP) and sodium nitroprusside (SNP) induced relaxations were uninfluenced by these drugs. In vivo, the NO synthase inhibitor, L-NAME, administered into the local artery caused a raise in intraluminal pressure of the ICJ in anaesthetized SA opossums in a L-arginine-preventable manner. Hydroquinone and pyrogallol, while being able to reduce, in a superoxide dimutase (SOD) reversible manner, the relaxations induced by exogenous NO failed to affect the NANC nerve-induced relaxations. Finally, neurones and nerve fibres in the myenteric plexus as well as varicose nerve fibres on the circular smooth layer were positive for NADPH-diaphorase activity. These findings indicate that nitrergic nerves inhibit ICJ circular smooth muscle in vitro and in vivo but cast doubts on the neuromediator being the NO radical.
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PMID:In vitro and in vivo effects of nitric oxide synthase inhibitors and nitric oxide inactivators on the South American opossum ileocolonic junction. 965 68

The involvement of nitric oxide (NO) and the mechanisms mediating neurogenic relaxation were investigated in the horse corpus cavernosum. NADPH-diaphorase activity was expressed in nerve fibres around arteries and muscular bundles in the horse trabecular tissue. Relaxations in response to electrical field stimulation were tetrodotoxin (10(-6) M)-sensitive, indicating their neurogenic origin. The NO synthase inhibitor, L-NO-arginine (L-NO-Arg, 3 x 10(-5) M), abolished the electrically induced relaxations, which were significantly reversed by L-arginine (3 x 10(-3) M). Exogenous NO (10(-6)-10(-3) M) evoked relaxations which were unaffected by L-NO-Arg. 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 5 x 10(-6) M), an inhibitor of guanylate cyclase activation by NO, reduced the relaxations in response to electrical stimulation and exogenous NO. Iberiotoxin (3 x 10(-8) M) or apamin (5 x 10(-7) M), inhibitors of large and small conductance Ca2+-activated K+ channels, respectively, and glibenclamide (3 x 10(-6) M), a blocker of ATP-sensitive K+ channels, failed to modify the relaxations with NO. It is suggested that NO is present in nerve fibres of the horse corpus cavernosum and relaxes smooth muscle through a guanylate cyclase-dependent mechanism. Neither Ca2+-activated nor ATP-sensitive K+ channels seem to be involved in these relaxations.
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PMID:Nitrergic relaxation of the horse corpus cavernosum. Role of cGMP. 969 9


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