Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide production has been reported to be reduced in hypertensive patients. In this study, we investigated the effects of antihypertensive drugs such as calcium channel blocker, amlodipine, alpha 1-adrenoceptor blocker, doxazosin and angiotensin converting enzyme (ACE) inhibitor, imidapril on nitric oxide synthase (NOS) activity in the kidneys of L-NAME-induced hypertensive rats. An increased blood pressure in L-NAME-induced hypertensive rats was significantly decreased by these antihypertensives to the same extent at four weeks. Nitrite production from the kidney slices was significantly suppressed in L-NAME-induced hypertensive rats. This suppression of nitrite production was reversed to the control level in the rats treated with amlodipine, and significantly enhanced by doxazosin and imidapril. Immunoreactivity for both the brain-type NOS in the macula densa and endothelial cell-type NOS in renal vasculature was diminished in L-NAME rats, and antihypertensive therapies, especially doxazosin and imidapril, increased NOS immunostaining. The increased glomerulosclerosis score in the L-NAME group was significantly lowered by the treatment with doxazosin and imidapril. In conclusion, a decreased NOS activity in L-NAME-induced hypertensive rats was significantly increased by alpha 1-adrenoceptor blockers and ACE inhibitors in the kidney, and this increased NOS activity may have a role in the prevention of glomerulosclerosis.
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PMID:Effects of antihypertensive drugs on nitric oxide synthase activity in rat kidney. 874 36

1. It has been proposed that in inflammatory conditions, in which both the inducible isoforms of nitric oxide synthase (iNOS) and cyclo-oxygenase (COX-2) are induced, inhibition of NOS also results in inhibition of arachidonic acid metabolism. In the present study we have investigated whether mercaptoalkylguanidines, a novel class of selective iNOS inhibitors, may also influence the activity of cyclo-oxygenase (COX). Therefore, the effect of mercaptoethylguanidine (MEG) and related compounds on the activity of the constitutive (COX-1) and the inducible COX (COX-2) was investigated in cells and in purified enzymes. Aminoguanidine, NG-methyl-L-arginine (L-NMA) and NG-nitro-L-arginine methyl ester (L-NAME) were also studied for comparative purposes. 2. Western blot analysis demonstrated a significant COX-1 activity in unstimulated J774 macrophages and in unstimulated human umbilical vein endothelial cells (HUVEC). Immunostimulation of the J774 macrophages by endotoxin (lipopolysaccharide of E. coli, LPS 10 micrograms ml-1) and interferon gamma (IFN gamma, 100 u ml-1) for 6 h resulted in a significant induction of COX-2, and a down-regulation of COX-1. No COX-2 immunoreactivity was detected in unstimulated HUVEC or unstimulated J774 cells. Therefore, in subsequent studies, the effect of mercaptoalkylguanidines on COX-1 activity was studied in HUVEC stimulated with arachidonic acid for 6 h, and in J774 cells stimulated with arachidonic acid for 30 min. The effect of mercaptoalkylguanidines on COX-2 activity was studied in immunostimulated J774 macrophages, both on prostaglandin production by endogenous sources, and on prostaglandin production in response to exogenous arachidonic acid stimulation. In addition, the effect of mercaptoalkylguanidines on purified COX-1 and COX-2 activities was also studied. 3. In experiments designed to measure COX-1 activity in HUVEC, the cells were stimulated by arachidonic acid (15 microM) for 6 h. This treatment induced a significant production of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha, the stable metabolite of prostacyclin), while nitrite production was undetectable by the Griess reaction. MEG (1 microM to 3 mM) caused a dose-dependent inhibition of the accumulation of 6-keto-PGF1 alpha, with an IC50 of 20 microM. However, aminoguanidine, L-NAME or L-NMA (up to 3 mM) did not affect the production of 6-keto-PGF1 alpha in this experimental system. In experiments designed to measure COX-1 activity in J774.2 macrophages, the cells were stimulated by arachidonic acid (15 microM) for 30 min; this also induced a significant production of 6-keto-PGF1 alpha and MEG (1 microM to 3 mM), aminoguanidine (at 1 and 3 mM), but neither L-NAME nor L-NMA inhibited the production of prostaglandins. 4. In experiments designed to measure prostaglandin production by COX-2 with endogenous arachidonic acid, J774.2 cells were immunostimulated for 6 h in the absence or presence of various inhibitors. In experiments designed to measure prostaglandin production by COX-2 with exogenous arachidonic acid, J774.2 cells were immunostimulated for 6 h, followed by a replacement of the culture medium with fresh medium containing arachidonic acid and various inhibitors. Both of these treatments induced a significant production of 6-keto-PGF1 alpha. Nitrite production, an indicator of NOS activity, was moderately increased after immunostimulation. MEG (1 microM to 3 mM) caused a dose-dependent inhibition of the accumulation of COX metabolites. Similar inhibition of LPS-stimulated 6-keto PGF1 alpha production was shown by other mercaptoalkylguanidines (such as N-methyl-mercaptoethylguanidine, N,N'-dimethyl-mercaptoethylguanidine, S-methyl-mercaptoethylguanidine and guanidino-ethyldisulphide), with IC50 values ranging between 34-55 microM. However, aminoguanidine, L-NAME and L-NMA (up to 3 mM) did not affect the production of prostaglandins.5. In comparative experiments indomethacin, a non selective COX inhibitor, and NS-398, a selective COX-2 inhibitor, reduced (LPS) stimulated 6-keto-PGF1alpha production in J774 macrophages in a dose-dependent manner without affecting nitrite release. Indomethacin, but not NS-398, inhibited 6-keto-PGF1alpha production in the HUVECs. 6.The inhibitory effect of MEG was due to direct inhibition of the catalytic activity of COX as indicated in experiments with purified COX-1 and COX-2. MEG dose-dependently inhibited the purified COX-1 and COX-2 activity with IC50 values of 33microM and 36microM, respectively. Aminoguanidine (at the highest concentrations) inhibited the formation of COX-1 metabolites, without affecting COX-2 activity. High doses of L-NAME (3mM) decreased COX-1 activity only, while L-NMA (up to 3mM) had no effect on the activity of either enzyme. 7.These results suggest that MEG and related compounds are direct inhibitors of the constitutive and the inducible cyclo-oxygenases, in addition to their effects on the inducible NOS. The additional effect of mercaptoalkylguanidines on COX activity may contribute to the beneficial effects of these agents in inflammatory conditions where both iNOS and COX-2 are expressed.
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PMID:The inhibitory effects of mercaptoalkylguanidines on cyclo-oxygenase activity. 903 36

The present study was designed to define the role of nitric oxide (NO) in tumor microcirculation, through the direct intravital microcirculatory observations after administration of NO synthase (NOS) inhibitor and NO donor both regionally and systemically. More specifically, we tested the following hypotheses: 1) endogenous NO derived from tumor vascular endothelium and/or tumor cells increases and/or maintains tumor blood flow, decreases leukocyte-endothelial interactions, and increases vascular permeability, 2) exogenous NO can increase tumor blood flow via vessel dilatation and decrease leukocyte-endothelial interactions, and 3) NO production and tissue responses to NO are tumor dependent. To this end, a murine mammary adenocarcinoma (MCaIV) and a human colon adenocarcinoma (LS174T) were implanted in the dorsal skinfold chamber in C3H and severe combined immunodeficient mice, respectively, and observed by means of intravital fluorescence microscopy. Both regional and systemic inhibition of endogenous NO by N omega-nitro-L-arginine methyl ester (L-NAME; 100 mumol/L superfusion or 10 mg/kg intravenously) significantly decreased vessel diameter and local blood flow rate. The diameter change was dominant on the arteriolar side. Superfusion of NO donor (spermine NO, 100 mumol/L) increased tumor vessel diameter and flow rate, whereas systemic injection of spermine NO (2.62 mg/kg) had no significant effect on these parameters. Rolling and stable adhesion of leukocytes were significantly increased by intravenous injection of L-NAME. In untreated animals, both MCaIV and LS174T tumor vessels were leaky to albumin. Systemic NO inhibition significantly attenuated tumor vascular permeability of MCaIV but not of LS174T tumor. Immunohistochemical studies, using polyclonal antibodies to endothelial NOS and inducible NOS, revealed a diffuse pattern of positive labeling in both MCaIV and LS174T tumors. Nitrite and nitrate levels in tumor interstitial fluid of MCaIV but not of LS174T were significantly higher than that in normal subcutaneous interstitial fluid. These results support our hypotheses regarding the microcirculatory response to NO in tumors. Modulation of NO level in tumors is a potential strategy for altering tumor hemodynamics and thus improving oxygen, drug, gene vector, and effector cell delivery to solid tumors.
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PMID:Role of nitric oxide in tumor microcirculation. Blood flow, vascular permeability, and leukocyte-endothelial interactions. 903 84

This study examined the production of nitric oxide (NO) in the renal cortex and medulla through the use of an in vivo microdialysis technique. Oxyhemoglobin (OxyHb) at a concentration of 3 mumol/L was perfused through the dialysis system to trap tissue NO. Methemoglobin (MetHb), which was formed by NO oxidation of OxyHb in the dialysate, was spectrophotometrically assayed at 401 nm. Because the oxidation of OxyHb to produce MetHb is stoichiometric with NO, the production of NO can be determined by the rate of MetHb formation. We found that NO concentration was significantly higher (P < .05) in the medulla (57.1 +/- 5.57 nmol/L, n = 10) than in the cortex (31.2 +/- 5.7 nmol/L, n = 9). The minimal detectable NO level of this assay is approximately 10 nmol/L. Intravenous infusion of L-arginine (3 mg/kg per minute) for 30 minutes produced a twofold to three fold increase in cortical and medullary NO; NG-nitro-L-arginine methyl ester (L-NAME) (10 micrograms/kg per minute) decreased NO by 33% in the renal cortex and by 46.5% in the renal medulla. We have also compared under the same conditions the degradation products of NO, nitrite, and nitrate in the renal cortex and medulla using in vivo microdialysis combined with microtiter plate colorimetry. Nitrite/nitrate concentration was significantly higher (P < .05) in the medulla (2.7 +/- 0.6 mumol/L, n = 4) than in the cortex (2.1 +/- 0.2 mumol/L, n = 4). Infusion of L-arginine increased cortical and medullary nitrite/nitrate by 65% and 39%, respectively. L-NAME reduced cortical and medullary nitrite/nitrate by 18% and 23%, respectively. The results indicate that the OxyHb-NO microdialysis trapping technique is a highly sensitive in situ method for detecting regional tissue NO concentration and changes in the NO synthase activity in the kidney. These studies have shown that NO concentration is higher in medullary tissue than in the cortex.
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PMID:Nitric oxide in renal cortex and medulla. An in vivo microdialysis study. 903 1

Nitric oxide (NO) synthase inhibitors, such as NG-nitro-L-arginine methyl ester (L-NAME), have been shown to attenuate endotoxin-induced uveitis (EIU) but they could increase leukocyte adhesion to the vascular endothelium. We hypothesize that a concomitant treatment with the 5-lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) in 50% dimethylsulfoxide (DMSO, a hydroxyl radical scavenger) could improve the anti-inflammatory activity of L-NAME. EIU was induced in albino rabbits by intravitreal injection of 100 ng lipopolysaccharide. Animals were treated with multiple intraperitoneal injections of 50% DMSO in phosphate-buffered saline (PBS), NDGA (10 mg/kg) in 50% DMSO, L-NAME (50 mg/ kg) in PBS, or the combination NDGA+L-NAME. Uveitis was assessed by slit lamp examination, protein levels in aqueous humor, and myeloperoxidase (MPO) activity in the iris/ciliary body 6 h after induction. Nitrite, leukotriene B4 (LTB4), prostaglandin E2 (PGE2), platelet-activating factor (PAF) and interleukin-1 beta (IL-1 beta) levels in aqueous humor were also determined. NDGA or L-NAME alone did not show a significant reduction of uveitis intensity, although a significant decrease in MPO or in proteins was found, respectively. The combination NDGA+L-NAME significantly reduced the uveitis intensity, MPO in the iris/ciliary body, and the levels of nitrites, LTB4, PGE2, and PAF in aqueous humor. IL-1 beta levels were lower than the detection limit of the radioimmunoassay in all treatment groups. We conclude that concomitant treatment with NDGA in DMSO improves the anti-inflammatory activity of L-NAME during the early phase of EIU, suggesting that the inhibition of NO synthesis could enhance leukocyte infiltration and the release of oxygen free radicals.
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PMID:Concomitant treatment with a 5-lipoxygenase inhibitor improves the anti-inflammatory effect of the inhibition of nitric oxide synthase during the early phase of endotoxin-induced uveitis in the rabbit. 926 46

We have previously shown that nitric oxide (NO) release by the coronary circulation in the failing and nonfailing human heart is, in part, regulated by local kinin production in coronary microvessels. Angiotensin-converting enzyme (ACE) also known as kininase II, inactivates kinins. ACE inhibitors prevent kinin breakdown by ACE, thereby increasing the concentration of bradykinin (BK) and related kinins. The goal of this study was to determine if kinins contribute to the therapeutic action of ACE inhibitors. Six hearts from end-stage heart failure patients were harvested at the time of orthotopic cardiac transplantation. Microvessels were prepared as previously described, and nitrite production, a metabolic product of NO in vitro, was determined by the Griess reaction. Microvessels were incubated in the presence of kininogen and bradykinin, and with the ACE inhibitors ramiprilat, enalaprilat, or captopril. All caused dose-dependent increases in nitrite. For instance, ramiprilat increased nitrite from 76 +/- 5.6 to 155 +/- 15 pmol/min per mg wet weight. Nitrite production in response to ACE inhibition was blocked by N-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, and icatibant (HOE 140), a B2-kinin receptor-specific antagonist. Furthermore, NO production was prevented by 3 different serine protease inhibitors, which block kallikrein, the enzyme responsible for conversion of kininogen to kinins. Our results indicate that ACE/kininase inhibitors increase NO production by the coronary microvasculature in the failing human heart, through increased available active kinins. The therapeutic action of ACE inhibition in the failing human heart may result in part from increased NO production by coronary microvessels.
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PMID:Angiotensin-converting enzyme inhibitors promote nitric oxide production in coronary microvessels from failing explanted human hearts. 929 67

The purpose of the present study was to determine whether interventions that promote kinin production or decrease kinin inactivation affect nitric oxide production in isolated canine coronary microvessels. Accordingly, bradykinin (10[-8] to 10[-5] mol/L), ramiprilat (10[-10] to 10[-8] mol/L), A23187 (10[-8] to 10[-6] mol/L), kallikrein (1 to 20 U/mL), and kininogen (0.5 to 10 microg/mL) were used to stimulate endothelium-dependent nitric oxide production. Receptor antagonists, serine protease inhibitors, and a kinin antibody were used to inactivate local kallikrein-kinin activity. Nitrite, the metabolite of nitric oxide in aqueous solution, was measured using the Griess reaction. All the agonists significantly increased nitrite release. For instance, the highest dose of bradykinin, ramiprilat, A23187, kallikrein, and kininogen markedly increased nitrite production, from 60+/-10 to 156+/-12, 153+/-11, 161+/-15, 176+/-15, and 168+/-16 pmol/mg (all P<.05), respectively. The increased nitrite production caused by these agents was not only blocked by N omega-nitro-L-arginine methyl ester (L-NAME) and HOE 140 (which blocks B2 kinin receptor) but by the kinin antibody also. For instance, nitrite production elicited by bradykinin, ramiprilat, A23187, and kininogen was reduced to 95+/-8, 87+/-8, 94+/-11, and 85+/-11 pmol/mg (all P<.05), respectively, by the kinin antibody. Carbachol-induced nitrite production (from 66+/-8 to 144+/-13) was blocked by L-NAME but not by HOE 140 or the kinin antibody. These results suggest that either increasing kininogen to promote endogenous kinin formation or inhibiting angiotensin-converting enzyme to decrease kinin breakdown, increases nitric oxide production in isolated coronary microvessels. These data indicate that a microvessel kallikrein-kinin system has an important role in the control of nitric oxide production in coronary microvessels.
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PMID:Role of endothelial kinins in control of coronary nitric oxide production. 936 63

Bradykinin is a substrate for both neutral endopeptidase 24.11 (NEP) and angiotensin-converting enzyme (ACE). Our previous studies showed that ACE inhibitors can stimulate nitric oxide production in coronary microvessels, which is mediated by local kinins. Whether inhibition of NEP also can affect local vascular NO production has not been established. To determine the role of NEP in the control of NO production, coronary microvessels were isolated from seven mongrel dogs. Two NEP inhibitors, phosphoramidon and thiorphan, and an ACE inhibitor, ramiprilat, were used. Nitrite, the metabolite of NO in aqueous solution, was measured by using the Griess reaction. Phosphoramidon and thiorphan (10(-6) M) increased nitrite production from 80 +/- 6 to 136 +/- 6 and 144 +/- 7 pmol/mg, respectively. Ramiprilat (10(-8) M) increased nitrite production from 78 +/- 6 to 155 +/- 7 pmol/mg wet weight. The effect of these agents on nitrite release was blocked by L-NAME, which inhibits NO synthase, HOE-140, which blocks bradykinin B2-receptor, and dichloroisocoumarin, which blocks kinin-forming enzymes. These results clearly indicate that inhibition of kinin metabolism by using neutral endopeptidase inhibitors increases NO production from coronary microvessels. Thus neutral endopeptidase plays an important role in local kinin-modulated NO production in the coronary microcirculation and NEP inhibitors may be useful clinical tools in treatment of cardiovascular disease.
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PMID:Neutral endopeptidase and angiotensin-converting enzyme inhibitors increase nitric oxide production in isolated canine coronary microvessels by a kinin-dependent mechanism. 955 14

Nitrite (NO2-), an end product of nitrogen radical metabolism, has recently been shown to increase tyrosine nitration by activated leukocytes indicating that nitrite modulates the immune response. We investigated the hypothesis that nitrite may increase nitration of molecular targets within activated cells leading to altered cell cycle progression. Intracellular nitrite was increased by transfection of murine macrophage-like RAW 264.7 cells with the nitrate reductase gene obtained from barley. Nitrate reductase facilitates the conversion of nitrate to nitrite; thus when extracellular nitrate is present, intracellular nitrite will be increased. Results show that addition of KNO3 increases NO2- production and intracellular nitrotyrosine accumulation in the transfectant but not the parent. Inhibition of nitric oxide synthesis with L-NAME during activation with IFN-gamma + LPS reduced NO2- production to the same extent in both cell lines; however, cellular accumulation of nitrotyrosine was reduced by only 25% in the transfectant (P = 0.21) and 49% in the parent cell line (P = 0.007), suggesting that intracellular nitrite increased nitrotyrosine accumulation through a pathway not requiring NO synthesis, i.e., myeloperoxidase system. Approximately 15% of the transfected cells had 4n DNA content 24 h postactivation compared to < 1% of the parent cells. Increased DNA copy number was correlated to nitrotyrosine accumulation. These findings show that intracellular nitrite can increase accumulation of nitrotyrosine and that nitration is linked to cell cycle perturbation.
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PMID:Nitrate reductase alters 3-nitrotyrosine accumulation and cell cycle progression in LPS + IFN-gamma-stimulated RAW 264.7 cells. 1010 Apr 92

Since nitric oxide (NO) was recognized as a potent microbicidal agent, its role in host defence against intracellular parasites has been widely demonstrated. Recent evidence suggests a role for NO in combating extracellular and multicellular pathogens. This defence activity has been demonstrated toward the larvae of Schistosoma mansoni, microfilariae of Onchocerca linealis, several stages of Brugia malayi and protoscoleces of Echinococcus multilocularis. Many parasites suppress Th1 lymphocytes and directly inhibit NO production by inducing cytokines, such as IL-4, IL-10 and TGF-beta. In this study, we have investigated the effects of Anisakis simplex, an enhancer of Th2-dominant responses, on NO production. We studied the effect of crude extracts (CE) and excretory-secretory (ES) products on the induction of inducible nitric oxide synthase (iNOS) in bacterial lipopolysaccharide (LPS)-treated J774 macrophages. Stimulation of macrophages by LPS (1 microg/ml) increased nitrite concentrations in the culture medium at 24 h. Co-administration of A. simplex products with LPS, dose-dependently reduced the accumulation of nitrite. Nitrite production is due to induction of iNOS, and both L-NAME (N(G)-nitro-L-arginine methyl ester) (50 microM) and dexamethasone (10 microM) inhibited nitrite accumulation (54.2 and 92.1% inhibition, respectively). The inhibition of nitrite production by A. simplex was 42.1-97.8% in the range 4.75-76 microg/well (CE products) and 37.2-61.5% in the range 5-20 microg/well (ES products). Cell viability assayed by the mitochondrial-dependent reduction of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) verified that the inhibition was not due to general cellular toxicity. However, the effects of A. simplex, were reduced when NOS had been induced by prior exposure to LPS and any possible further induction was blocked by cycloheximide, an inhibitor of protein synthesis.
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PMID:Effects of Anisakis simplex on nitric oxide production in J774 macrophages. 1022 90


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