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

Cerebral ischemia in the gerbil results in early hippocampal changes, which include transient activation and/or translocation of protein kinase C (PKC), increased enzymatic activity of ornithine decarboxylase (ODC), and elevated DNA binding ability of activator protein-1 (AP1). The time-course of all three of these postischemic responses was found to be almost parallel, peaking at 3 hr after the ischemic insult. The effectiveness of known modulators of postischemic morphological outcome (MK-801, L-NAME, and gingkolides BN 52020 and BN 52021) in counteracting the induction of PKC, ODC, and AP1 formation was tested. These drugs were administrated as followed: MK-801 (a noncompetitive inhibitor of NMDA channel), 0.8 mg/kg i.p., 30 min before ischemia, and 5 min after the insult; L-NAME (competitive inhibitor of NO synthase), 10 mg/kg i.p., 30 min before ischemia, and 5 mg/kg, 5 min after ischemia; BN52020 and BN52021 (inhibitors of platelet-activating factor: PAF receptors) were administered as a suspension in 5% ethanol in water by oral route, 10 mg/kg for 3 days before ischemia. Three of these drugs, MK-801, L-NAME, and BN52021, significantly reduced ischemia-elevated activity of PKC and ODC, whereas AP1 formation was only partially attenuated. Our observations implicate the existence of different mechanism(s) for postischemic PKC and ODC activation, which in turn is engaged in AP1 induction.
 ...
PMID:Modulation of ischemic signal by antagonists of N-methyl-D-aspartate, nitric oxide synthase, and platelet-activating factor in gerbil hippocampus. 774 16

1. Mediators of inflammation can increase vascular permeability in at least two different ways: by acting directly on endothelial cells or, indirectly, through an incompletely understood mechanism, dependent on circulating neutrophils. Neutrophil-dependent oedema formation has been described in the skin of rabbits, rats, hamsters, mice and man. In contrast, we presented evidence in a previous study that local oedema formation induced by i.d. injection of chemoattractants in guinea-pig skin was neutrophil-independent. In the present study, we sought evidence of neutrophil-dependent oedema formation in immune-complex-mediated vasculitis, the reversed passive Arthus (RPA) reaction, in guinea-pig skin. We also investigated whether haemorrhage in the RPA reaction was neutrophil-dependent (as it is in other species) and the role of endogenous mediators of inflammation (prostaglandins, nitric oxide, histamine, PAF and leukotrienes) in contributing to the local inflammatory response. 2. In the RPA reaction, most oedema formation occurred over the first 60 min whereas 111In-neutrophil accumulation was still increasing from 60 to 240 min. The different kinetics of these two events suggested that they may be dissociated. 3. Oedema formation was partially inhibited by a long-acting PAF antagonist (UK-74,505) and an H1 histamine receptor antagonist (mepyramine) but not by a 5-lipoxygenase inhibitor (ZM 230487). A nitric oxide synthesis inhibitor (NG-nitro-L-arginine methyl ester, L-NAME) suppressed oedema formation by 68% whereas a cyclo-oxygenase inhibitor suppressed oedema by 27%. 4. 111In-neutrophil accumulation in the RPA reaction was partially suppressed by UK-74,505. In contrast, ZM 230487 was without effect at doses which abrogated arachidonic acid-induced 111In-neutrophil accumulation. 5. The anti-CD18 monoclonal antibody, (mAb) 6.5E F(ab')2, effectively inhibited 111In-neutrophil accumulation induced by PAF, zymosan-activated plasma (ZAP) and in the RPA reaction. However, oedema formation measured in the same sites was not altered. In contrast, oedema formation in the RPA reaction was partially suppressed by 6.5E whole mAb which was 2.5 times more potent than 6.5EF(ab')2 at inhibiting guinea-pig neutrophil adhesion to protein-coated plastic. Haemorrhage induced by PAF and in the RPA reaction was significantly inhibited by 6.5E F(ab')2 pretreatment.6. We conclude that in the RPA reaction in guinea-pig skin, oedema formation is partially neutrophil dependent as assessed by using an anti-CD18 mAb, whereas ZAP-induced oedema formation is neutrophil-independent. Haemorrhage was also dependent on neutrophil accumulation. In addition, our studies support a role for PAF in mediating both oedema formation and "'In-neutrophil accumulation in the RPA reaction. Endogenous release of histamine also appears to be important in mediating oedema formation suggesting that mast cells play a critical role in increases of vascular permeability in inflammatory reactions in guinea-pig skin. Moreover, our results confirm previous findings which suggest a dominant role for nitric oxide in maintaining cutaneous blood flow in the guinea-pig.
 ...
PMID:Studies on the mechanisms involved in the inflammatory response in a reversed passive Arthus reaction in guinea-pig skin: contribution of neutrophils and endogenous mediators. 788 93

1. Administration of bovine thrombin (100 u kg-1) into the carotid artery of rabbits induces a sustained accumulation of 111 Indium-labelled platelets within the cranial vasculature over the subsequent 3 h. 2. Intracarotid (i.c.) administration of defibrotide (64 mg kg-1 bolus plus 64 mg kg-1 h-1 for 1 h) prior to i.c. thrombin (100 u kg-1) significantly reduces the ability of thrombin to induce cranial thromboembolism in rabbits. 3. Intravenous (i.v.) administration of thrombin (20 u kg-1) in rabbits induces a reversible accumulation of radiolabelled platelets into the thoracic circulation which is significantly reduced by i.v. administration of defibrotide (64 mg kg-1 bolus plus 64 mg kg-1 h-1 for 1 h) prior to i.v. thrombin. In contrast, platelet accumulation in response to adenosine diphosphate (ADP; 20 micrograms kg-1, i.v.) or platelet activating factor (PAF; 50 ng kg-1, i.v.) is not significantly affected by this treatment. 4. Intravenous administration of the nitric oxide (NO)-synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10 mg kg-1) potentiates platelet accumulation induced by low dose thrombin (10 u kg-1, i.v.) within the pulmonary vasculature of rabbits. The potentiated response is significantly abrogated following pretreatment with defibrotide (64 mg kg-1 bolus plus 64 mg kg-1 h-1 for 1 h, i.v.). 5. Intravenous injection of human thrombin (1250 u kg-1) to mice induces death within the majority of animals which is significantly reduced by pretreatment with defibrotide (150-175 mg kg-1, i.v.). In contrast, death induced by i.v. collagen (1.25 mg kg-1) plus adrenaline (75 microg kg-1) is not significantly affected by defibrotide pretreatment.6. The inhibitory effect of defibrotide in mice is abolished following concomitant treatment with the inhibitor of fribrinolysis, tranexamic acid (100 mg kg-1, i.v.), but is unaffected following treatment with the cyclo-oxygenase inhibitor, aspirin (300 mg kg-1, i.p.).7. The protective effect of defibrotide against thrombin-induced thromboembolism in the mouse is potentiated by recombinant tissue-plasminogen activator (rt-PA; 1 mg kg-1, i.v.) or unfractionated heparin (10 u kg-1, i.v.) administration.8. The results suggest that defibrotide may possess antithrombotic activity on thrombin-induced thromboembolism which, at least in the mouse, may be partially mediated via induction of the fibrinolytic pathway.
 ...
PMID:The effect of defibrotide on thromboembolism in the pulmonary vasculature of mice and rabbits and in the cerebral vasculature of rabbits. 830 2

1. The objective of the present study was to assess whether inhibition of nitric oxide (NO) production could modulate vascular permeability in the coronary circulation in conscious rats. 2. Intravenous injection of NG-nitro-L-arginine methyl ester (L-NAME, 2 mg kg-1) resulted in a slowly developing hypertension and evoked twofold increases in vascular permeability in the left ventricle and right atrium as measured by the extravasation of Evans blue dye. Maintenance of mean arterial blood pressure at the level observed following L-NAME injection by infusion of noradrenaline (620-820 ng kg-1 min-1) did not induce significant protein extravasation in the coronary circulation. 3. L-NAME treatment markedly enhanced (up to 490%) protein extravasation both in the left ventricle and right atrium in response to platelet-activating factor (PAF, 1.9 nmol kg-1, i.v.) and endothelin-1 (1 nmol kg-1, i.v.). Noradrenaline infusion potentiated (up to 69%) endothelin-1-induced protein extravasation. The permeability effect of PAF was only slightly enhanced by noradrenaline. 4. The present findings indicate that inhibition of endogenous NO synthesis leads to an increase in protein extravasation and to potentiation of the permeability effects of PAF and endothelin-1 in the coronary circulation. These results also suggest that NO may be an important regulator of vascular permeability under physiological and pathological conditions.
 ...
PMID:Nitric oxide modulates vascular permeability in the rat coronary circulation. 844 83

The purpose of the present study was to investigate the involvement of nitric oxide (NO) in the modulatory role of platelet-activating factor (PAF, 1-O-hexadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine), a vasoactive phospholipid mediator synthesized by endothelial cells, on the vascular tone and arterial blood pressure. In pentobarbitone-anaesthetized rabbits, unloading of the carotid sinus baroreceptors by a bilateral carotid artery occlusion elicited a reflex rise in systemic vascular resistance, which was markedly potentiated by pretreating the animals with the PAF receptor antagonist WEB 2086 ([3-4-(2-chlorphenyl-)-9-methyl-6H-thieno-3,2-f-1,2,4-triazolo-4,3 -alpha-1,4 -diazepin-2-yl-(4-morpholinyl)-1-propanone]; 5 mg/kg, i.v.). In contrast, the inhibition of the biosynthesis of NO via NO synthase using N omega-nitro-L-arginine methyl ester (L-NAME) neither affected the systemic vasoconstriction induced by carotid artery occlusion nor modified the potentiating effect of WEB 2086. The haemodynamic alterations induced by L-NAME administration were corrected by continuous infusions of the directly-acting vasodilators sodium nitroprusside or diazoxide. The results of the present study confirm previous studies from our group suggesting the involvement of PAF in a negative feedback mechanism effective in the local regulation of vasomotor tone in anaesthetized rabbits, but exclude the participation of NO in this process.
 ...
PMID:The acute increases in vasomotor tone and blood pressure induced by carotid artery occlusion are modulated by platelet-activating factor (PAF) independently of nitric oxide release. 952 24

We investigated the contribution of eicosanoids, platelet-activating factor, tumor necrosis factor and nitric oxide to the neutrophil influx and development of pulmonary haemorrhagic lesions following immune-complex-induced pneumonitis in rats and possible interactions between these mediators. Increased levels of leukotriene B4 and tumor necrosis factor, measured by enzyme immunoassay and L-929 cytotoxicity assay, were found in the bronchoalveolar lavage 1 and 4 h after induction of the reaction, respectively, and their release was dependent on the previous generation of platelet activating factor. Antagonism of leukotriene B4 receptors by RO-0254094 (2-[(5-carboxypentyl])oxy]-6-[6-[3,4-dihydro-4-oxo-8-propyl-2H-1-benzopy ran-7-yl)oxy]hexyl] benzenepropanoic acid), inhibition of nitric oxide synthesis by L-NAME (Nw-nitro-L-arginine methyl ester) and antagonism of PAF-receptors by WEB-2170 (5-(2-chlorphenyl)-3-4-dihydro-10-methyl-3-((4-morpholinyl)carbony l)-2 H,7H-cyclopenta (4,5)thieno(3,2-f)(1,2,4)-triazolo-4,3,a)91,4)diazepine), significantly inhibited the intensity of haemorrhage, evaluated by the increased levels of extravascular hemoglobin in homogenates of lung tissues. Little evidence support the role of tumor necrosis factor in these lesions. The infiltration of neutrophils, evaluated by measuring myeloperoxidase in homogenates of lungs, was reduced by compounds L-663,536 (3-[1-(4 chlorobenzyl)-3-t-butyl thio-5-isopropylindol-2-yl]-2-2-dimethylpropanoic acid), WEB-2170 and L-NAME. These results indicate that neutrophil infiltration and haemorrhagic lesions in immune-complex-induced lung inflammation are mediated by platelet activating factor, leukotriene B4 and nitric oxide and point out to interesting interactions between these mediators.
 ...
PMID:Lipid mediators, tumor necrosis factor and nitric oxide and their interactions in immune-complex-induced lung injury. 980 71

1. In anaesthetized rats, platelet activating factor (PAF; 1 microg kg(-1)) decreased mean arterial blood pressure by around 60 mmHg (n=18). This depressor response was completely blocked by the PAF antagonist, CV-6209 (1 mg kg(-1)), indicating the role of PAF-specific receptor in the response. 2. N(G)-nitro-L-arginine methyl ester (L-NAME; 50 mg kg(-1)), an NO synthase inhibitor, profoundly elevated systemic blood pressure (n=19), indicating an important role of NO in the basal blood pressure regulation. The depressor response to PAF (1 microg kg(-1)) normalized against that to sodium nitroprusside (SNP) (10 microg kg(-1)) was not substantially different between rats treated without and with L-NAME (n=4). In contrast, the depressor effect of acetylcholine (0.03 - 1.0 microg kg(-1)) normalized against that of SNP (10 microg kg(-1)) was significantly attenuated by L-NAME (n=5). 3. Charybdotoxin (0.4 mg kg(-1)) plus apamin (0.2 mg kg(-1)) significantly attenuated the depressor response to PAF (1 microg kg(-1)) (n=5) without affecting the blood pressure change due to SNP (1 mg kg(-1)) (n=3). Charybdotoxin (0.4 mg kg(-1)) (n=4) or apamin (0.2 mg kg(-1)) (n=4) alone did not affect the PAF-induced depressor response. 4. These findings suggest that EDHF may make a significant contribution to the depressor response to PAF in rats. Although NO plays the determinant role in the basal blood pressure regulation, its contribution to PAF-produced depressor response seems to be less as compared with that to the depressor response to acetylcholine.
 ...
PMID:Possible involvement of endothelium-derived hyperpolarizing factor (EDHF) in the depressor responses to platelet activating factor (PAF) in rats. 1108 18

The participation of endothelins (ETs) in a model of neutrophil-dependent lung injury induced by intrabronchial instillation of rabbit antibodies to ovalbumin followed by i.v. injection of the antigens (Arthus reaction) was investigated. Hemorrhagic lesions were evaluated by measuring the extravasations of hemoglobin in lung parenchyma. From 5 min to 24 h after the Arthus reaction (AR), endothelin (ir-ET) levels in bronchoalveolar lavage fluid (BALF) and in plasma were measured by radioimmunoassay. BALF levels of ir-ET were not different between control and AR animals for the first 90 min after the antigen challenge but increased from 2 to 24 h after induction of AR. ET levels in the plasma did not change from the respective controls over the same 24 h period. Increased ir-ET in BALF was not affected by pretreatment with L-NAME (30 mg/kg, i.v.). A PAF antagonist (BN52021; 5 and 10 mg/kg, i.v.) increased ET content in BALF and decreased the intensity of the AR. Thiorphan (2 mg/kg, i.v.) inhibited the AR-induced hemorrhagic lesions in lungs. An ET(A) receptor antagonist, BQ-123 (1 mg/kg, i.v.) potentiated, whereas the ET(B) antagonist, BQ-788 (1 mg/kg, i.v.) inhibited the lung hemorrhage. It is concluded that ETs are released during and play a role in the lung AR.
 ...
PMID:Association of endothelin with lung hemorrhage induced by immune complexes in rats. 1613 98

The role of endogenous nitric oxide (NO) on vascular and respiratory smooth muscle basal tone was evaluated in six anaesthetized, paralysed, mechanically ventilated pigs. The involvement of endogenous NO in PAF-induced shock and airway hyperresponsiveness was also studied. PAF (50 ng/kg, i.v.) was administered before and after pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, i.v.), an NO synthesis inhibitor. PAF was also administered to three of these pigs after indomethacin infusion (3 mg/kg, i.v.). In normal pigs, L-NAME increased systemic and pulmonary vascular resistances, caused pulmonary hypertension and reduced cardiac output and stroke volume. The pulmonary vascular responses were correlated with the increase in static and dynamic lung elastances, without changing lung resistance. Inhibition of NO synthesis enhanced the PAF-dependent increase in total, intrinsic and viscoelastic lung resistances, without affecting lung elastances or cardiac activity. The systemic hypotensive effect of PAF was not abolished by pretreatment with L-NAME or indomethacin. This indicates that systemic hypotension is not correlated with the release of endogenous NO or prostacyclines. Indomethacin completely abolished the PAF-dependent respiratory effects.
 ...
PMID:Role of endogenous nitric oxide on PAF-induced vascular and respiratory effects. 1847 28

DMTI-II is a Kunitz-type inhibitor isolated from Dimorphandra mollis seeds that causes rat inflammatory edema by mechanisms involving activation of mast cells and sensory C-fibers. The present study aimed to further explore the inflammatory mechanisms involved in DMTI-II-induced inflammation, focusing to the leukocyte migration in vivo. Male Wistar rats (250-280 g) were injected with DMTI-II (1-100microg/cavity), and at 4-24h thereafter the leukocyte counts in peritoneal lavage were evaluated. DMTI-II caused dose- and time-dependent accumulation of neutrophils and eosinophils. The peritoneal neutrophil influx initiated at 4h, achieving maximal responses at 16 h after DMTI-II injection (16- and 22-fold increase, respectively). The DMTI-II-induced eosinophil recruitment was observed as early as 4h achieving the maximal responses at 16 h (12- and 17-fold increase, respectively). The mononuclear cell number increased at 4h and 16 h (1.5-fold and 1.6-increase, respectively). Prior treatments with dexamethasone, the cyclooxygenase (COX) inhibitors indomethacin and celecoxib, as well as the PAF receptor antagonist PCA4248 largely reduced the neutrophil and eosinophil accumulation. The selective lypoxygenase inhibitor AA861, the tachykinin NK(1) antagonist SR-140333 and the nitric oxide inhibitor L-NAME reduced only the eosinophil number. The eotaxin levels were significantly higher in DMTI-II-injected rats compared with control animals. In conclusion, DMTI-II causes an early migration of eosinophils and neutrophils by mechanisms involving COX-2- and lipoxygenase-derived metabolites, PAF, substance P and NO. The capacity of DMTI-II to recruit eosinophils at early times is likely to reflect the allergen properties of proteinase inhibitors belonging to Kunitz family.
 ...
PMID:Mechanisms involved in the rat peritoneal leukocyte migration induced by a Kunitz-type inhibitor isolated from Dimorphandra mollis seeds. 1910 16


1 2 Next >>