Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pretreatment with monophosphoryl lipid A (MLA) can pharmacologically mimic the second window of ischemic preconditioning (SWOP) to protect the heart from prolonged ischemia and reperfusion injury. Based on the delayed time course for development of MLA associated cardioprotection, this study was designed to test if MLA's cardioprotective effect is mediated by signalling through production of inducible nitric oxide synthase (iNOS), a proposed effector of SWOP. Rabbits were assigned to one of four groups: (1) vehicle control; (2) MLA: (3) vehicle+aminoguanidine (AMG) control; or (4) MLA+AMG. Monophosphoryl lipid A (35 micrograms/kg) or vehicle was given intravenously 24 h before ischemia. The selective iNOS inhibitor AMG (300 mg/ kg) was injected subcutaneously 1 h before ischemia. All rabbits experienced 30 min coronary artery occlusion followed by 3 h of reperfusion. Infarct size was measured by triphenyltetrazolium chloride (TTC) staining. followed by 3 h of reperfusion. Infarct size was measured by triphenyltetrazolium chloride (TTC) staining. Myeloperoxidase activity, an index of neutrophil infiltration, was also quantified in heart tissue collected from the post-ischemic viable border zone surrounding the infarct area. MLA pretreatment significantly reduced infarct size and neutrophil infiltration in rabbit hearts compared to control (P < 0.05). Inhibition of iNOS activity by AMG abolished the infarct size reductive effect of MLA. Aminoguanidine also blocked the ability of MLA to significantly reduce neutrophil infiltration. Although measurement of iNOS activity did not show induction of the enzyme in normal myocardial tissue 24 h after MLA pretreatment, an increase in iNOS activity in ischemic tissue relative to non-ischemic tissue was found after either 15 or 30 min of coronary occlusion in MLA treated rabbits. These results suggest that MLA pretreatment may enhance iNOS enzyme activity by MLA during ischemia which may be responsible for the observed cardioprotection.
J Mol Cell Cardiol 1997 Jun
PMID:Role of inducible nitric oxide synthase in pharmacological "preconditioning" with monophosphoryl lipid A. 922 Mar 42

Transplanted hearts exhibit depressed contractile function during periods of acute rejection. Myocytes from rejecting hearts also express inducible nitric oxide synthase (iNOS). We hypothesized that an intrinsic defect, due to the increased nitric oxide production by myocytes, is responsible for much of the observed contractile dysfunction. To test our hypothesis, we recorded shortening of myocytes isolated from rejecting (allograft) and non-rejecting (isograft) transplanted rat hearts under control conditions and following exposure to aminoguanidine (an inhibitor of iNOS), or methylene blue (an inhibitor of nitric oxide stimulation of guanylate cyclase). Four days after transplantation, basal shortening was reduced in allograft myocytes compared to isograft myocytes (allografts: 7.0 +/- 0.8 microns; isografts; 10.7 +/- 0.9 microns; P < 0.05). Allograft myocytes also had higher cGMP levels than isograft myocytes (allografts: 0.58 +/- 0.16 pmol/mg protein; isografts: 0.13 +/- 0.08 pmol/mg protein; P < 0.05). Aminoguanidine (1 mM) had no effect on shortening or cGMP levels in isograft myocytes, whereas aminoguanidine significantly reduced cGMP levels and greatly enhanced shortening of allograft myocytes, such that shortening was now similar in allograft and isograft myocytes. Methylene blue (100 microM) also caused a more than three-fold greater increase in shortening of allograft myocytes (+80 +/- 15%) than isograft myocytes (+23 +/- 6%; P < 0.05 from allografts). These results suggest that myocytes isolated from rejecting hearts have a reversible intrinsic contractile depression which is mediated by overstimulation of the nitric oxide/cGMP pathway within the myocytes. This intrinsic contractile dysfunction may be a major factor responsible for the reversible cardiac depression associated with acute rejection of transplanted hearts.
J Mol Cell Cardiol 1998 May
PMID:Myocytes isolated from rejecting transplanted rat hearts exhibit reduced basal shortening which is reversible by aminoguanidine. 961 41

The purposes of this study were 1) to identify the nitric oxide (NO) synthase (NOS) isoform responsible for NO-mediated radiation-induced lung injury, 2) to examine the formation of nitrotyrosine, and 3) to see whether nitrotyrosine formation and lung injury are reduced by an inducible NOS (iNOS) inhibitor, aminoguanidine. The left hemithorax of rats was irradiated (20 Gy), and the degree of lung injury, the expression of NOS isoforms, and the formation of nitrotyrosine and superoxide were examined after 2 wk. iNOS mRNA was induced, and endothelial NOS mRNA was markedly increased in the irradiated lung. Nitrotyrosine was detected biochemically and immunohistochemically. Aminoguanidine prevented acute lung injury as indicated by decreased protein concentration and lactate dehydrogenase activity in bronchoalveolar lavage fluid and improved NMR parameters and histology. Furthermore, the formation of nitrotyrosine was significantly reduced in the aminoguanidine group. We conclude that iNOS induction is a major factor in radiation-induced lung injury and that nitrotyrosine formation may participate in the NO-induced pathogenesis.
Am J Physiol Lung Cell Mol Physiol 2000 Apr
PMID:Increased production of nitrotyrosine in lung tissue of rats with radiation-induced acute lung injury. 1074 49

The cardiotoxicity-induced by chronic treatment of doxorubicin have recently be attributed to free radical formation and/or release of nitric oxide. In the present study, an already established rat model of doxorubicin -induced cardiotoxicity was used. Doxorubicin in a total cumulative dose of 15 mgkg(-1) I.P. given in six equal injections over two week period was administered. After three weeks of doxorubicin administration, the blood pressure, serum lactate dehydrogenase, lipid peroxides, asites fluid and mortality rate were significantly increased. Doxorubicin-induced cardiotoxicity was further confirmed by examining the histopathology of heart sections. Myocardial fibres necrosis with prominent acute inflammatory cells were observed in rats hearts treated with doxorubicin. Aminoguanidine, an inhibitor of nitric oxide synthase, 100 mgkg(-1) injected every other day for two week was given concurrently with doxorubicin. Aminoguanidine given concurrently with doxorubicin return blood pressure, lactate dehydrogenase and lipid peroxides to normal control values. Furthermore, aminoguanidine reduces the mortality rate, ascites fluid formation- induced by doxorubicin and improved the histopathology of rats hearts treated with doxorubicin. In conclusion, inhibition of nitric oxide formation may be beneficial in protecting rat hearts against doxorubicin- induced cardiotoxicity.
Res Commun Mol Pathol Pharmacol 1999
PMID:Protective effect of aminoguanidine against cardiovascular toxicity of chronic doxorubicin treatment in rats. 1148 49

During periods of acute rejection, transplanted hearts have increased nitric oxide (NO) production and depressed contractile function. Myocytes isolated from rejecting hearts exhibit parallel increases in NO production and reduced shortening, indicating that the contractile dysfunction of the transplanted heart is intrinsic to the myocytes. We tested the hypothesis that the contractile dysfunction of the rejecting heart is due to an NO-mediated inhibition of the L-type calcium current. Ventricular myocytes isolated from rejecting rat hearts (allografts) expressed inducible nitric oxide synthase (iNOS) and produced substantially more NO than did myocytes isolated from non-rejecting rat hearts (isografts). Aminoguanidine, an inhibitor of iNOS, reduced NO production by allograft myocytes, but was without effect on NO production by isograft myocytes. In the absence of exogenous l -arginine (the precursor of NO), the calcium current was identical in allograft and isograft myocytes. In the presence of l -arginine, the calcium current was reduced in allograft myocytes compared to isograft myocytes. Superfusion of the myocytes with either aminoguanidine or KT5823 (an inhibitor of the cyclic GMP-dependent protein kinase) reversed the depression of the calcium current in allograft myocytes, but neither inhibitor had an effect on calcium current in isograft myocytes. These results indicate that increased production of NO by myocytes isolated from rejecting hearts leads to a reduction in the calcium current. This mechanism may contribute substantially to the contractile dysfunction of rejecting transplanted hearts.
J Mol Cell Cardiol 2001 Sep
PMID:Myocytes isolated from rejecting transplanted rat hearts exhibit a nitric oxide-mediated reduction in the calcium current. 1154 47

Tumor responses to radioimmunotherapy combined with peptide agonists of human C5a anaphylatoxin such as GCGYSFKPMPLaR (C5aAP) are two- to four-fold better, depending on the dose of C5aAP, than responses to radioimmunotherapy alone. The enhanced tumor vascular permeability (VP) is the key factor responsible for this improvement. These studies were designed to identify the sequence of events leading to the improved extravasation of immunoglobulin in response to C5aAP. The VP changes were measured in mice after administration of C5aAP alongside of various mediators. The depletion of circulating polymorphonuclear neutrophils (PMN) in mice abolished the C5aAP-induced VP increase. Blocking of P-selectin also returned VP to its basal levels after the C5aAP treatment, indicating that C5aAP-induced VP changes are initiated by interactions of C5aAP with PMNs. Aminoguanidine, an inducible nitric oxide synthase (NOS) inhibitor, given before C5aAP returned VP to control levels. N(omega)-nitro-L-arginine methyl ester, a nonselective NOS inhibitor, had a marginal effect on the activity of C5aAP. Indomethacin, a nonselective cyclooxygenase inhibitor, suppressed C5aAP-induced increases in VP, whereas N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide, a selective cyclooxygenase-2 inhibitor, was active only at high doses. While C5aAP given i.p. did not alter tumor uptake of (125)I-B72.3, the i.v. administration resulted in approximately 40% increase, confirming the prerequisite interaction of C5aAP with PMNs. The sequence leading to the increased VP appears to be initiated by the interaction of C5aAP with C5a receptor expressed on PMNs followed by binding to endothelial cells of blood vessels. The interaction with P-selectin is responsible for the initiation of the nitric oxide cascade as evidenced by inducible NOS activation. Additionally, prostaglandins are required for expression of the full magnitude of the C5aAP activities.
Mol Cancer Ther 2004 Jan
PMID:Role of polymorphonuclear leukocytes, nitric oxide synthase, and cyclooxygenase in vascular permeability changes induced by C5a agonist peptides. 1474 78

The mechanism responsible for cardiac depression in septic shock remains unknown. The present study examined whether nitric oxide (NO) overproduced by inducible NO synthase (iNOS) can inhibit aerobic energy metabolism and impair the myocardial function in endotoxin-treated rat hearts. Lipopolysaccharide (LPS) significantly decreased systolic blood pressure (BP) to 44% of control during the 48 h treatment. Hearts from control and LPS-treated rats were perfused in a Langendorff apparatus. After LPS injection, left ventricular (LV) developed pressure (LVDP) was significantly depressed, plasma NO2-/NO3- (NO(x)) concentration was markedly increased, and myocardial adenosine 5'-triphosphate (ATP), creatine phosphate (CrP), and the ratio of ATP/adenosine 5'-diphosphate were progressively decreased with time. Immunological examination showed a significant expression of iNOS protein in the LPS-treated myocytes. Aminoguanidine, an inhibitor of iNOS, significantly attenuated these LPS-induced functional and metabolic changes. Myocardial cyclic guanosine 3',5'-monophosphate (cGMP) content was significantly increased after LPS injection. Methylene blue, an inhibitor of soluble guanylate cyclase, blunted this increase in cGMP and significantly restored the LPS-induced contractile dysfunction 6 h after LPS injection. In addition, there was a significant negative correlation between LVDP and myocardial cGMP levels as well as a significant negative correlation between LVDP and plasma NO(x) levels. In contrast, 48 h after LPS injection, methylene blue no longer affected cardiac performance, and there was a significant positive correlation between LVDP and myocardial ATP content. Furthermore, the normalized activities (as a ratio of the citrate synthase activity) of mitochondrial NADH-CoQ reductase, succinate-CoQ reductase, and ATPase, were significantly inhibited, and the swelling or disruption of mitochondria cristae was seen in the 48 h LPS treatment. These LPS-induced functional and morphological disorders in the mitochondria were significantly improved by aminoguanidine. The findings suggest that sustained production of NO by iNOS leads to contractile dysfunction via cGMP in the early stage, but that it can directly impair the mitochondrial function, lower myocardial energy production, and contribute significantly to the myocardial dysfunction in the later stage of septic shock.
J Mol Cell Cardiol 2004 Sep
PMID:Cytokine-induced nitric oxide inhibits mitochondrial energy production and induces myocardial dysfunction in endotoxin-treated rat hearts. 1535 Aug 50

Doxorubicin (DOX) is a broad-spectrum anthracycline antibiotic that has cardiotoxicity as a major side effect. One mechanism of this toxicity is believed to involve the reactive oxygen radical species (ROS); these agents likely account for the pathophysiology of DOX-induced cardiomyopathy. Aminoguanidine (AG) is an effective antioxidant and free radical scavenger which has long been known to protect against ROS formation. We investigated the effects of AG on DOX-induced changes in thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) content. The rats were divided into four groups:1) Control; 2) DOX group; injected intraperitoneally (i.p.) with DOX 20 mg/kg in a single dose 3) AG-treated group; injected i.p. in single dose of 20 mg/kg DOX plus 100 mg/kg AG 1 h before the DOX for 3 days, 4) AG group; injected i.p. with AG 100 mg/kg for 3 days. DOX administration to control rats increased TBARS and decreased GSH levels. AG administration before DOX injection caused significant decrease in TBARS and increase in GSH levels in the heart tissue when compared with DOX only. Morphological changes, including severe myocardial fibrosis and inflammatory cell infiltration were clearly observed in the DOX-treated heart. AG reversed the DOX-induced heart damage. Therefore AG could protect the heart tissue against free radical injury. The application of AG during cancer chemotherapy may attenuate tissue damage and improve the therapeutic index of DOX.
Mol Cell Biochem 2006 Apr
PMID:Beneficial role of aminoguanidine on acute cardiomyopathy related to doxorubicin-treatment. 1661 75

Inflammatory and infectious conditions were simulated in cultures of ras/myc-transformed serum-free mouse embryo (ras/myc SFME) cells, using interferon-gamma (IFN-gamma, 100 units/ml) and lipopolysaccharide (LPS, 0.5 microg/ml) co-treatment for 24 h, to investigate their effects on the expression of inducible nitric oxide synthase (iNOS) mRNA and the production of NO. Aminoguanidine (AG, 1 mM; an NOS inhibitor) along with IFN-gamma and LPS, S-nitroso-N-acetyl-DL-penicillamine (SNAP, 100 microM; an NO donor) and/or (+/-)-N-[(E)-4-Ethyl-2-[(Z)-hydroxyimino]-5-nitro-3-hexene-1-yl]-3-pyridine carboxamide (NOR4, 100 microM; an NO donor), were also added to analyze the possible association of NO with matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1). Co-treatment of cells with IFN-gamma and LPS increased iNOS mRNA expression, NO production, MMP-9 mRNA expression, and 105 kDa MMP-9 production. Additional treatment with the NOS inhibitor AG inhibited NO production, but did not down-regulate the expression of MMP-9 mRNA or 105 kDa MMP-9. The NO donors SNAP and NOR4 did not affect the expression of MMP-9 mRNA, 105 kDa MMP-9 or TIMP-1 mRNA. These results suggest that ras/myc SFME cells respond to infectious and inflammatory conditions and can enhance malignancy as cancer cells due to their increased levels of NO and MMP-9 production, but that NO is not directly associated with MMP-9 in these cells.
Mol Cell Biochem 2007 Dec
PMID:Ras/myc-transformed serum-free mouse embryo cells under simulated inflammatory and infectious conditions increase levels of nitric oxide and matrix metalloproteinase-9 without a direct association between them. 1766 Sep 54

Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by visceral hypersensitivity and altered bowel function. There are increasing evidences suggested that VSL#3 probiotics therapy has been recognized as an effective method to relieve IBS-induced symptoms. The aim of this study was to examine the effects of VSL#3 probiotics on visceral hypersensitivity (VH), nitric oxide (NO), fecal character, colonic epithelium permeability, and tight junction protein expression. IBS model was induced by intracolonic instillation of 4% acetic acid and restraint stress in rats. After subsidence of inflammation on the seventh experimental day, the rats were subjected to rectal distension, and then the abdominal withdrawal reflex and the number of fecal output were measured, respectively. Also, colonic permeability to Evans blue was measured in vivo, and tight junction protein expression was studied by immunohistochemistry and immunoblotting method. Rats had been pretreated with VSL#3 or aminoguanidine (NOS inhibitor) or VSL#3+ aminoguanidine before measurements. The rats at placebo group showed hypersensitive response to rectal distension (P < 0.05) and defecated more stools than control rats (P < 0.05), whereas VSL#3 treatment significantly attenuated VH and effectively reduced defecation. Aminoguanidine reduced the protective effects of VSL#3 on VH. A pronounced increase in epithelial permeability and decreased expression of tight junction proteins (occludin, ZO-1) in placebo group were prevented by VSL#3, but not aminoguanidine. VSL#3 treatment reduce the hypersensitivity, defecation, colonic permeability and increase the expression of tight junction proteins (occludin, ZO-1). As the part of this effect was lowered by NOS inhibitor, NO might play a role in the protective effect of VSL#3 to some extent.
Mol Cell Biochem 2012 Mar
PMID:Antinociceptive effect of VSL#3 on visceral hypersensitivity in a rat model of irritable bowel syndrome: a possible action through nitric oxide pathway and enhance barrier function. 2202 Jul 49


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