UMLS:C0406810 - FACTA Search

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Query: UMLS:C0406810 (NAME)
13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelium-derived relaxing factor (EDRF) or nitric oxide (NO) biosynthesis from L-arginine occurs in the endothelium and platelets and may modulate platelet function and contribute to thromboresistance in the vessel wall. A rat model was used to evaluate selective accumulation of (III)In-labeled platelets in the pulmonary microcirculation following the administration of collagen, adenosine 5'-diphosphate (ADP) or thrombin. Platelet aggregation was monitored continuously over the thorax using a microcomputer-based system. Sodium nitroprusside, a stimulator of soluble guanylate cyclase and zaprinast, a phosphodiesterase V inhibitor, both known to cause accumulation of cyclic guanosine monophosphate, exhibited moderate inhibitory activity, which was shared by L-arginine. N(G)-monomethyl-L-arginine (L-NMMA; 1 mg/kg/min), an inhibitor of EDRF(NO), potentiated the aggregatory response to collagen at an intravenous dose of 100 &mgr;g/kg but not at one of 30 &mgr;g/kg. D-NMMA had no such effect. The augmenting effect of L-NMMA was abolished by L-arginine. N(G)-nitro-L-arginine methyl ester (L-NAME; 0.1 mg/kg/min) also markedly augmented the collagen-induced platelet response, and, at higher doses, all treated animals died upon collagen challenge. Both L-NMMA and L-NAME did not affect the responses to ADP and thrombin. The results suggest that in the intact vascular system, basal releae of EDRF(NO) is not critically involved in modulation of platelet function but becomes a significant factor when platelets are exposed to great amounts of collagen fibrils. Copyright 1994 S. Karger AG, Basel
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PMID:EDRF(NO)-Mediated Modulation of Collagen-Induced Platelet Accumulation in Rat Pulmonary Microcirculation. 1172 5

Long-term treatment in rats with l-NAME, an isoform-non-specific inhibitor of nitric oxide synthase (NOS), leads to fibrosis of the heart and kidney, suggesting that nitric oxide (NO) may play a role in preventing tissue fibrosis. In this process, a likely target of NO is the quenching of reactive oxygen species (ROS) through peroxynitrite formation, and one possible source for this NO is inducible NOS (iNOS). Using Peyronie's disease (PD) tissue from both human specimens and from a rat model of PD as the source of fibrotic tissue, we investigated if NO derived from iNOS could act as such an antifibrogenic defense mechanism by determining whether: (a) tunical ROS and iNOS are increased in PD; and (b) the long-term inhibition of iNOS activity decreases the NO/ROS balance in the tunica albuginea thereby promoting collagen deposition. It was determined that in the human PD plaque, iNOS mRNA and protein, ROS, collagen, and the peroxynitrite marker, nitrotyrosine, were all increased in comparison to the normal tunica. In the rat model of PD, the fibrotic plaque also showed significant increases in iNOS mRNA and protein, nitrotyrosine, ROS as measured by heme oxygenase-1, and collagen when compared with the normal control tunica. When a selective inhibitor of iNOS, L-NIL, was given to rats with the PD-like plaque, this resulted in a decrease in nitrotyrosine levels but intensified ROS levels and collagen deposition. These data demonstrate that: (a) iNOS induction occurs in both the human and rat PD fibrotic plaque; and (b) that the NO derived from iNOS appears to counteract ROS formation and collagen deposition. Because the inhibition of iNOS activity leads to a decrease in the NO/ROS ratio, thereby favoring the development of fibrosis, it is proposed that iNOS induction in this tissue may be a protective mechanism against fibrosis and abnormal wound healing.
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PMID:Antifibrotic role of inducible nitric oxide synthase. 1200 46

The aim of this study was to determine the effects of endothelin-1 (ET-1) on proteoglycan (PG) and collagen synthesis by rat articular chondrocytes (RAC). PG and collagen synthesis was measured by [(35)S]-sulphate and [(3)H]-glycine incorporation, respectively into monolayers of confluent RAC exposed to ET-1 (10(-11) M-10(-7) M). ET-1 stimulated PG and collagen synthesis in these cells in a concentration-dependent manner during the first 24 h of incubation. Prolonged contact of the cells with ET-1 resulted in a gradual decrease, and finally, inhibition of ET-1 effects. This inhibition is mediated by nitric oxide (NO) released in response to ET-1 since: (1) nitric oxide synthase inhibitor, nitro-L-arginine-methyl ester (L-NAME), enhanced both basal and ET-1-induced [(35)S]-sulphate and [(3)H]-glycine incorporations; (2) sodium nitroprusside (SNP), which spontaneously releases NO, inhibited both basal and ET-1-induced incorporations, and was also able to suppress the effects of L-NAME; (3) NO levels in the culture media were also correlated with the inhibition of [(35)S]-sulphate and [(3)H]-glycine incorporation; and (4) SNP also inhibited aggrecan and collagen II transcriptions, probably via cGMP. This effect was mimicked with 8-bromo-cGMP. Interestingly, the LY83583, which blocks the NO-dependent production and release of cGMP, inhibited PG-collagen synthesis but had no effect on their mRNA expressions. Thus, normal levels of cGMP appeared to be necessary for PG-collagen synthesis, whereas decreased levels are detrimental. In conclusion, NO, produced by rat AC in response to ET-1, counteracts the stimulation and finally induces inhibition of PG-collagen synthesis by ET-1 in these cells but NO-induced cGMP is only partially responsible for this inhibition.
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PMID:Mechanism of inhibition of endothelin-1-stimulated proteoglycan and collagen synthesis in rat articular chondrocytes. 1202 6

Recent studies have indicated that a number of factors contribute to the pathophysiology in response to nitric oxide synthase (NOS) inhibition. We previously demonstrated that plasminogen activator inhibitor-1 deficient (PAI-1-/-) mice are protected against hypertension and perivascular fibrosis induced by relatively short-term NOS inhibition. In this study, we compared the temporal changes in systolic blood pressure and coronary perivascular fibrosis induced by long-term treatment with N(omega)-nitro- L -arginine methyl ester (L -NAME) in wild type (WT), PAI-1(-/-) and tissue-type plasminogen activator deficient (t-PA-/-) mice. After initiating L -NAME, systolic blood pressure increased in all groups at 2 weeks. Over a 16 week study period, systolic blood pressure increased to 143+/-3 mmHg (mean+/-SEM) in WT animals, 139+/-2 in t-PA-/- mice vs 129+/-2 in PAI-1-/- mice (P < 0.01). Coronary perivascular fibrosis increased in L -NAME-treated WT and t-PA(-/-) mice compared to each control group (P<0.01 in WT, P<0.05 in t-PA-/-), while PAI-1-/- mice were protected against fibrosis induced by L -NAME. t-PA deficiency did not accentuate the vascular pathology or the changes in blood pressure. In situ zymography demonstrated augmented gelatinolytic activity in PAI-1-/- mice at baseline, suggesting that PAI-1 deficiency prevents the increase of collagen deposition by promoting matrix degradation. Plasma TGF-beta1 levels increased in L -NAME-treated WT and PAI-1-/- mice (P < 0.01), but not in L -NAME-treated t-PA-/- mice. These findings support the hypothesis that the plasminogen activator system protects against the structural vascular changes induced by long-term NOS inhibition. While PAI-1 deficiency protects against L -NAME-induced hypertension and perivascular fibrosis, t-PA deficiency does not exacerbate the vascular pathology or hypertension.
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PMID:Potential roles of plasminogen activator system in coronary vascular remodeling induced by long-term nitric oxide synthase inhibition. 1205 49

It was previously demonstrated that administration of the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME) aggravated viral myocarditis in mice. In the current study, the effects of l-arginine, a precursor of nitric oxide, on congestive heart failure (CHF) in myocarditis were evaluated. Dietary l-arginine and l-arginine plus l-NAME (l-arginine + l-NAME group) were administered to encephalomyocarditis virus-infected BALB/c mice over 4 weeks (experiment I) and to encephalomyocarditis virus-infected DBA/2 mice from the 4th through 12th weeks after the virus inoculation (experiment II). An infected control was prepared in each experiment. In experiment I, survival was higher in the l-arginine group compared with the other two groups, and cardiac damage was less, as was incidence of CHF. In addition, extravasated fibrin was less prominent in the l-arginine group. Plasma concentrations of l-arginine and nitric oxide were elevated in the l-arginine group. In experiment II, plasma cardiomyopathic lesions in the l-arginine group were less prominent and were associated with lower plasma catecholamine and lower myocardial collagen concentrations compared with the other two groups. l-arginine treatment may be effective in preventing the development of CHF in viral myocarditis by modifying postmyocarditic architectural remodeling.
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PMID:Oral administration of L-arginine prevents congestive heart failure in murine viral myocarditis. 1207 71

We have previously demonstrated that administration of nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), aggravated murine coxsackievirus B3 myocarditis. In the present study, we evaluated the effects of L-arginine, a precursor of NO, upon acute and chronic myocarditis. Dietary L-arginine and L-arginine plus L-NAME (L-arginine+L-NAME group) were administered to coxsackievirus B3 (CB3)-infected C(3)H/He mice for 2 weeks (experiment I), and to CB3-infected mice from the second week until the fourth week after virus inoculation (experiment II). Infected control was prepared in each experiment. In experiment I, survival was higher in the L-arginine group compared with the other two groups, and cardiac damage was less. In addition, plasma concentrations of L-arginine and NO were elevated in the L-arginine group. In experiment II, cardiomyopathic lesion in the L-arginine group was less prominent associated with lower plasma catecholamine and lower myocardial collagen concentrations compared with the other two groups. Thus, L-arginine treatment may be effective not only in preventing the development of acute CB3 myocarditis but in ameliorating cardiac dysfunction in chronic myocarditis.
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PMID:Oral L-arginine prevents murine coxsackievirus B3 myocarditis. 1241 66

Our in vivo assay for thrombolysis consisted of recording the weight of platelet-rich thrombi adhering to a collagen strip that was superfused with arterial blood in extracorporal circulation of anaesthetised Wistar rats. Immediate thrombolysis occurred in response to intravenously administrated angiotensin-converting enzyme inhibitor (ACE-I) at non-hypotensive doses of 3-30 microg kg(-1) (captopril<perindopril<quinapril). The thrombolytic response lasted up to 3 h with maximum reduction of the weight of thrombus by 75%. Pretreatment with COX-1 and COX-3 inhibitors (aspirin at a low dose of 1 mg kg(-1), SC 560 and acetaminophen, 0.3-3 mg kg(-1)) slightly augmented thrombolysis by ACE-I, while COX-2 inhibitors (nimesulide and coxibs at doses <1 mg kg(-1) and aspirin at a high dose of 50 mg kg(-1)) or a kinin B2 receptor antagonist (icatibant) abolished it. NOS inhibition by L-NAME blunted and delayed thrombolysis by ACE-I. In parallel to maximum thrombolysis by quinapril (30 microg kg(-1)), plasma levels of 6-keto-PGF1alpha rose significantly from 40 +/- 7 to 554 +/- 91 pg ml(-1) (n=5, mean +/- S.D.), while basal levels of PGE2 (12 +/- 3 pg ml(-1)) and TXB2 (47 +/- 11 pg ml(-1)) remained essentially unchanged. Pretreatment with celecoxib (0.1-1.0 mg kg(-1)) abolished not only thrombolysis by quinapril but also the quinapril-induced rise in plasma 6-keto-PGF1alpha. In cultured bovine aortic endothelial cells, perindoprilate (30 microM) increased cytosolic free calcium [Ca2+]i, but this effect was by three to four orders of magnitude weaker than that of bradykinin (Bk). In aortas of Wistar rats, the transcripts of COX-2 and PGI-S were overexpressed as compared to COX-1. Thus, in blood vessels of Wistar rats, the preferable route of the PGI2 generation might lead through the COX-2 pathway. We conclude that in Wistar rats, ACE-I induces thrombolysis via accumulation of endogenous kinins over the endothelium and a subsequent activation of B2 receptors followed by the release of prostacyclin and nitric oxide. Thrombolysis by ACE-I seems to be mediated mainly through prostacyclin that is made by COX-2. It may well be that an increase in endothelial [Ca2+]i by ACE-I activates phospholipase A2, which supplies COX-2 with the substrate for making thrombolytic prostacyclin.
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PMID:Mechanisms of angiotensin-converting enzyme inhibitor induced thrombolysis in Wistar rats. 1459 56

The aim of this study was to determine whether AT1-receptor antagonists could inhibit platelet activation-dependent pulmonary thromboembolism in mice and to investigate the involvement of nitric oxide in this action. Losartan, its active metabolite EXP3174, and valsartan given intraperitoneally 1 hour before the thrombotic challenge (in doses of 3, 10, or 30 mg/kg) protected mice from death or hind-limb paralysis in response to intravenous injection of a mixture of collagen and epinephrine; losartan was effective in all doses used, whereas EXP3174 and valsartan reduced mortality only in the two higher doses. The protective action of EXP3174 and valsartan was abolished when nitric oxide synthase was inhibited with l-NAME, whereas that of losartan was only partially reduced. Moreover, only losartan protected mice from death caused by intravenous injection of the thromboxane A2 mimetic U46619 and this action was preserved in l-NAME-pretreated animals. Our results demonstrate the ability of AT1-receptor antagonists to inhibit platelet activation in vivo in a nitric oxide-dependent mechanism. Stronger antiplatelet activity of losartan, most likely due to its blockade of thromboxane A2/prostaglandin H2 receptor, could be of potential clinical relevance, particularly in conditions in which synthesis of endogenous nitric oxide is impaired.
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PMID:Nitric oxide-dependent antiplatelet action of AT1-receptor antagonists in a pulmonary thromboembolism in mice. 1463 91

A number of epidemiological studies have demonstrated that moderate red wine consumption significantly decreases the risk of ischemic heart disease. Our earlier studies provide evidence that Italian red wine modulates primary hemostasis and prevents experimental venous thrombosis in rats, independently of its alcohol content, by a nitric oxide (NO)-mediated mechanism. In the present study, we have tested whether Bulgarian red and white wines can influence thrombotic process and primary hemostasis in rats. NO and PGI2 were evaluated as possible mediators of these effects. We have found that red wine treatment (for 10 days) induced a marked prolongation of bleeding time, decrease in platelet adhesion to fibrillar collagen, reduction in venous thrombus weight and shortening of occlusion time in arterial thrombosis model. The fall in venous thrombus weight was also observed after white wine supplementation. Red wine affects hemostasis and venous thrombosis after its iv injection 15 min before experiment. These effects were prevented by NO inhibitor (L-NAME) and PGI2 inhibitor (indomethacin). Our results demonstrate the ability of Bulgarian wines to modulate primary hemostasis and prevent venous and arterial thrombosis in rat.
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PMID:Effects of Bulgarian red and white wines on primary hemostasis and experimental thrombosis in rats. 1473 Jan 5

Hypertension is frequently associated with the development of renal vascular and glomerular fibrosis. The purpose of the present study was to investigate whether epidermal growth factor receptor (EGFR) activation participates in the development of renal fibrosis and to test if blockade of EGFR activation would have therapeutic effects. Experiments were performed during nitric oxide (NO) deficiency-induced hypertension in rats (L-NAME model). After 4 weeks of L-NAME treatment, animals developed hypertension associated to deterioration of renal structure and function. Over the same period, EGFR was activated twofold within glomeruli. This activation was accompanied by increased activity of the mitogen-activated protein kinase (MAPK) p42/p44 pathway and exaggerated collagen I expression. Gefitinib, an EGFR-tyrosine kinase inhibitor, given concomitantly with L-NAME, normalized MAPK activation and collagen I expression and prevented the decline of renal function and the development of fibrosis. Since endothelin mediates the L-NAME-induced fibrogenesis, the endothelin-EGFR interaction was tested in transgenic mice expressing luciferase under the control of collagen I-alpha2 promoter: In renal cortex of these animals, the endothelin-induced collagen I gene activity was inhibited by an EGFR-phosphorylation inhibitor. These results provide the first evidence that EGFR activation plays an important role in the progression of renal vascular and glomerular fibrosis.
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PMID:Prevention of renal vascular and glomerular fibrosis by epidermal growth factor receptor inhibition. 1503 24

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