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:1.5.1.19 (NOS)
7,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A subpopulation of interstitial cells (ICs) are interposed between nerve terminals and smooth muscle cells in the gastrointestinal tract and may participate in neuromuscular transmission. These cells appear to be targets for NO released from enteric inhibitory nerves and respond to exogenous NO with: (i) an elevation in cGMP levels; (ii) an increase in intracellular Ca2+; (iii) and release of a diffusible substance that has tentatively been identified as NO. For the latter to be possible, ICs must express a constitutive isoform of NOS. This study characterized the expression of NOS-like immunoreactivity (NOS-LI) in ICs of the canine colon using 3 antibodies raised against the 2 known constitutive forms of NOS (i.e., neural (nNOS) and endothelial (eNOS) isoforms). Antibodies raised against cNOS and an antibody raised against rat cerebellar nNOS labeled ICs along the submucosal surface of the circular muscle layer (IC-SM), along the surface of septa that separate the circular muscle into fiber bundles (IC-SM), and in the myenteric region between the circular and longitudinal muscle layers (IC-MY). Another antibody raised against rat cerebellar nNOS failed to label ICs. Cultured IC-SM also expressed NOS-LI, suggesting that this feature of the IC phenotype survives culture conditions. Arteriolar endothelial cells in the canine colon were labeled with the same 2 antibodies that labeled ICs, suggesting there are significant structural similarities between NO synthases in ICs and endothelial cells. The data suggest that IC-SM and IC-MY express a constitutive form of NOS. Synthesis of NO by ICs may influence electrical rhythmicity and may serve to amplify and even propagate enteric inhibitory neurotransmission.
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PMID:Expression of nitric oxide synthase immunoreactivity by interstitial cells of the canine proximal colon. 752 87

The ability of NG-nitro-L-arginine (NNA) and NG-methyl-L-arginine (NMMA) to inactivate native neuronal, endothelial cell, and macrophage nitric oxide synthases (nNOS, eNOS, and iNOS, respectively) was investigated. Each NOS isozyme (plus cofactors) was preincubated with either NNA or NMMA and then assayed for remaining activity by measuring the conversion of labeled L-arginine to labeled L-citrulline. Consistent with previous reports (Olken, N. M., et al., Biochem. Biophys. Res. Commun. 177, 828-833, 1991), NMMA was a mechanism-based irreversible inhibitor of iNOS, exhibiting time- and concentration-dependent inactivation of iNOS with a KI equal to 2.6 microM and a kinact equal to 0.042 min-1. When assayed without a preincubation period, NMMA exhibited typical reversible inhibition of iNOS (Ki = 3.9 microM). NMMA also reversibly inhibited nNOS and the eNOS with Ki equal to 0.65 and 0.7 microM, respectively. However, NMMA did not inactivate eNOS at concentrations up to 10 microM. In the presence, but not the absence, of 4 microM tetrahydrobiopterin, NMMA inactivated nNOS with a kinact equal to 0.022 min-1 and a KI equal to 2.0 microM. Since NNA did not inactivate iNOS at concentrations up to 25 microM, NNA is strictly a reversible inhibitor of iNOS (Ki = 8.1 microM). Neuronal NOS and eNOS, however, were rapidly inactivated by NNA with kintact equal to 0.083 and 0.047 min-1 and KI equal to 0.09 and 0.02 microM, respectively, when preincubated with NNA. Tetrahydrobiopterin did not affect the rate of inactivation of nNOS by NNA. In all cases, L-arginine protected against inactivation, suggesting that inactivation occurs at or near the active site. Thus, inactivation of the three NOS isozymes with NMMA and NNA reveals active-site differences between the isoforms.
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PMID:N-nitro-L-arginine and N-monomethyl-L-arginine exhibit a different pattern of inactivation toward the three nitric oxide synthases. 754 Aug 22

Endothelial nitric oxide synthase (eNOS or NOS-III) is constitutively expressed. To elucidate the mechanism by which the basal expression of NOS-III gene is activated, we constructed in a luciferase vector, pXP1, serial 5'-deletion mutants of a 1.3-kb 5'-flanking fragment and transiently expressed them in cultured human endothelial cells. The promotor activity was detected in the -198/+22 region which contains several putative Sp1 binding sites. DNase I footprinting assays coupled with gel shift assays revealed the GC box(-104/-90) to be the Sp1 binding site. Site-directed mutation of 4 crucial bases in this site reduced the promotor activity by > 90%. These findings provide strong evidence that binding of Sp1 or closely related protein to this site is required for the activation of basal NOS-III transcription.
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PMID:Role of Sp1 in transcriptional activation of human nitric oxide synthase type III gene. 754 27

Nitric oxide (NO) and the dura mater are implicated in the pathogenesis of vascular headache. Many studies have demonstrated the participation of NO in headache; however, few studies have identified NO in the dura mater. In this study, nine Sprague-Dawley rats were examined with immunohistochemistry using two different endothelial nitric oxide synthase (eNOS) monoclonal antibodies, H32 and ECNOS. eNOS was successfully localized to the endothelium of the middle meningeal artery. To the best of our knowledge, this is the first study to report NOS immunopositive endothelial cells in the blood vessels of the rat dura mater. The authors propose that NO plays an active role in dural vasodilation, contributing to the pathogenesis of vascular headache; in the future, NO inhibitors could serve as pharmacological agents to treat vascular headache.
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PMID:Immunohistochemical localization of endothelial nitric oxide synthase in vessels of the dura mater of the Sprague-Dawley rat. 854 62

Diaminoguanidine (DAG) and NG-amino-L-arginine each produced a time- and concentration-dependent inactivation of the citrulline-forming activity of all three NOS isoforms. DAG inactivates both the NADPH-oxidase and the citrulline-forming activities of GH3 pituitary nNOS while NG-amino-L-arginine inactivates only its citrulline-forming activity. The inactivation by DAG of GH3 nNOS NADPH-oxidase and citrulline forming activities is stimulated by (6R)-5,6,7,8-tetrahydrobiopterin (BH4) cofactor, follows pseudo-first-order kinetics and is not substrate saturable. DAG-induced inactivation of the citrulline-forming activity for the iNOS and eNOS isoforms displayed maximal inactivation rates of 0.37 and 0.14 min-1 and Ki values of 385 and 670 microM, respectively. At 1 mM DAG and saturating BH4, half-times of inactivation of 0.7, 8, and 2 min were observed for the nNOS, eNOS, and iNOS isoforms, respectively. NG-Amino-L-arginine-induced inactivation of the citrulline-forming activity of the nNOS, iNOS, and eNOS isoforms displayed maximal inactivation rates of 0.35, 0.26, and 0.53 min-1 and Ki values of 0.3, 3, and 2.5 microM, respectively. The inactivation of the NOS activities by both DAG and NG-amino-L-arginine in preincubations required the presence of oxygen and Ca2+, consistent with an inactivation mechanism that requires active metabolism by NOS. Methylguanidine and 1,1-dimethylguanidine exhibited a reversible inhibition pattern in contrast to all three NOS isoforms. Neither agent exhibited significant isoform selectivity.
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PMID:Inactivation of nitric oxide synthase isoforms by diaminoguanidine and NG-amino-L-arginine. 856 1

These observations clearly indicate that NO inhibits NOS activity and that nNOS and eNOS are more sensitive than iNOS to the inhibitory action of NO. Not only exogenously added NO but also enzymatically generated NO inhibits the activity of nNOS and eNOS. The mechanism by which NO inhibits NOS appears to involve the heme iron prosthetic group of NOS. Moreover, the oxidation state of the heme iron is critical in determining the magnitude of inhibition of NOS by NO. Conditions that favor the higher oxidation state of FeIII markedly increase the inhibitory action of NO, whereas conditions that favor the lower oxidation state of FeII markedly decrease the inhibitory action of NO. One of the cofactor roles of tetrahydrobiopterin may be to reduce the negative-feedback effect of NO on NOS by favoring the formation of the ferrous heme state in NOS. The inhibitory influence of NO on eNOS, albeit indirectly, was also observed in vascular endothelial cells, arterial rings, and in vivo in the perfused rabbit hindquarters vascular bed. Excess NO in the form of NO donor compounds inhibited the endothelium-dependent formation of EDRF/NO in response to endothelium-dependent vasorelaxants such as acetylcholine and bradykinin without influencing the relaxant effect of NO itself. These studies are consistent with the view that enzymatically generated NO may play an important negative-feedback regulatory role on eNOS, and therefore on vascular endothelial cell function. Several biological implications of a negative-feedback modulatory effect by NO on constitutive isoforms of NOS are evident. In nonadrenergic-noncholinergic transmission, in which NO is believed to be the principal inhibitory neurotransmitter (Sanders and Ward, 1992; Rand, 1992; Rajfer et al., 1992), NO may regulate its own synthesis, and therefore the neurotransmission process. Excess NO production may be undesirable because of the potential of NO or a reaction product of NO to elicit cytotoxic effects. Many extraneuronal factors could also contribute to decreasing the potentially cytotoxic actions of NO. For example, reduced hemoproteins such as hemoglobin, myoglobin, and/or their oxygen adducts could inactivate NO, as could superoxide anion generated in the vicinity of NO. In vascular endothelial cells either enzymatically generated NO or the presence of exogenously added NO in the form of nitrovasodilator drugs could diminish the vasodilator responses to endothelium-dependent relaxants and flow or shear stress. Although iNOS is less sensitive than either eNOS or nNOS to inhibition by NO, the generation of relatively large quantities of NO by iNOS within the confines of a cell may lead to a negative-feedback effect. The concomitant generation of superoxide anion by the same or adjacent cells could result in a diminished negative-feedback effect because of the rapid reaction between NO and superoxide anion to form peroxynitrite. Thus, NO production would increase and there would be increased peroxynitrite formation as well, which would result in enhanced cytotoxicity, provided that peroxynitrite is a cytotoxic species. Alternatively, iNOS may be conveniently insensitive to NO in order to allow for the generation of large quantities of NO for the purpose of producing cytotoxic effects.
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PMID:Negative modulation of nitric oxide synthase by nitric oxide and nitroso compounds. 856 36

NADPH-diaphorase (NADPH-D) activity and immunoreactivity for neural and endothelial nitric oxide synthase (nNOS and eNOS, respectively) were used to investigate nitric oxide (NO) regulation of penile vasculature. Both the histochemical and immunohistochemical techniques for NOS showed that all smooth muscles regions of the penis (dorsal penile artery and vein, deep penile vessels, and cavernosal muscles) were richly innervated. The endothelium of penile arteries, deep dorsal penile vein, and select veins in the crura and shaft were also stained for NADPH-D and eNOS. However, the endothelium of cavernous sinuses was unstained by both techniques. Fewer fibers were seen in the glans penis, those present being associated with small blood vessels and large nerve bundles near the trabecular walls. All penile neurons in the pelvic plexus, located by retrograde transport of a dye placed in the corpora cavernosa penis, were stained by the NADPH-D method. Essentially similar results were obtained with an antibody to nNOS. These data suggest that penile parasympathetic neurons comprise a uniform population, as all seem capable of forming nitric oxide. However, in contrast to the endothelium of penile vessels, the endothelium lining the cavernosal spaces may not be capable of nitric oxide synthesis.
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PMID:Neural and endothelial nitric oxide synthase activity in rat penile erectile tissue. 858 13

The development of treatments for AD is being pursued along many diverse lines. While the ACh hypothesis has generated abundant development efforts, little clinical progress has been achieved to date. Recent efforts aimed at developing more potent, more specific, and safer ChE inhibitors appear to offer greater potential for therapeutic success than achieved to date. Treatments aimed at the NMDA Glu system lag much further behind in their development. Progress in this area must be tempered by the potential for glutamate excitotoxicity mediated through this neurotransmitter system. Development of indirect agonists operating at the glycine and polyamine modulatory sites on the NMDA receptor might offer the safest alternative to applying more direct agonists. While a great degree of interest had been generated by the reports of NO involvement in signal transduction through the NMDA system, this area of research has been complicated by conflicting reports regarding NO involvement in learning and LTP. Moreover, the interaction of drugs acting on NOS with the vascular effects mediated by eNOS has also complicated development of drugs that act specifically on the neural actions of NO. This area will continue to receive extensive research attention; but similar to the development of Glu agonists, attention must be given to the potential neurotoxic effects of overstimulating this system. Perhaps targeting other presynaptic mechanisms that effect glutamate release might be a safer strategy to pursue. Considerable progress has been made over the last two decades in identifying the genetic and neural mechanisms involved in AD. Progress in developing treatments will remain highly correlated with this effort, and with basic research geared to comprehending how memories are formed and why neurons degenerate and regenerate.
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PMID:Cognitive enhancement. New strategies for stimulating cholinergic, glutamatergic, and nitric oxide systems. 868 34

Other workers have identified two constitutive forms of NOS in endothelial cells: endothelial or eNOS and neuronal or nNOS. The present study tests the functional significance of these NOS in brain surface arterioles of mice. Antisense oligodeoxynucleotides (ODN) were injected into the cerebral ventricles. Anti eNOS and anti nNOS were tested separately and in combination. Each antisense reduced the dilation produced by topical acetylcholine (ACh) or by tetrahydrobiopterin (THBP). These are endothelium dependent, NOS dependent dilators, with the THBP being a cofactor for NOS. The endothelium derived mediator actually causing the dilation is EDRF(ACh). When both antisenses were given together there was an additive effect which approached 100% inhibition. Neither sense nor mismatched (scrambled) ODN inhibited either ACh or THBP. Moreover, anti eNOS did not inhibit dilation by bradykinin (endothelium dependent but not NOS dependent) or by sodium nitroprusside (endothelium independent). The data strongly support the conclusion that both eNOS and nNOS are functionally important in the endothelium of mouse pial arterioles. Each isoform of NOS appears to contribute significantly to the synthesis of basally released (THBP triggered) and agonist (ACh) released EDRFACh.
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PMID:Antisense evidence for two functionally active forms of nitric oxide synthase in brain microvascular endothelium. 870 23

The kidney vasculature is under tonic control by nitric oxide (NO) and in cortex, NO controls RA and Kf. Systemic NO inhibition leads to systemic hypertension, increases in RE, mediated by Ang II and ET, and direct effects on RA and Kf. The relationship between NO and other vasoconstrictor systems is variable. In the conscious relaxed animal, vasoconstrictor activity is low, yet acute NO inhibition leads to pressor and renal vasoconstrictor responses. At physiologic levels, ET unexpectedly is a renal vasodilator, possibly via NO generation at RA. When vasoconstrictor activity is high, NO is very important in maintenance of renal perfusion. Chronic L-NAME produces dose dependent systemic and glomerular capillary hypertension and eventual proteinuria and glomerular damage. NO deficiency is key in this process, although the hypertension becomes refractory to L-arginine administration and dependent on Ang II and the SNS, by mechanisms not yet defined. In contrast, the renal vasculature remains fully responsive to L-arginine, suggesting that pressor and renal vascular responses to chronic NO inhibition are separately regulated. NO generated from iNOS does not normally control BP or renal hemodynamics. The relative contributions of NO from bNOS and eNOS, and importance of NOS in different locations in the kidney, remain to be determined.
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PMID:Importance of nitric oxide in the control of renal hemodynamics. 874 86


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