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)

Inhibition of NO synthesis promotes P-selectin expression on endothelial cells; however, the precise mechanism is unclear. Because No has been shown to inhibit protein kinase C (PKC) activity, we examined the hypothesis that the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) stimulates P-selectin expression on platelets via PKC activation. Ten-minute incubation with either phorbol 12-myristate 13-acetate (PMA), thrombin, or L-NAME significantly increased P-selectin expression on platelets (as assessed by flow-cytometric analysis) and PKC activity of platelet membranes. Increased P-selectin expression induced by either PMA, thrombin, or L-NAME was significantly attenuated by the selective PKC inhibitor UCN-01 (7-hydroxystaurosporine). Furthermore, L-NAME-induced P-selectin expression was significantly attenuated by either L-arginine, 8-bromo-cGMP, or sodium nitroprusside (SNP). Interestingly, L-NAME further potentiated P-selectin upregulation by thrombin. L-NAME, thrombin, and PMA also significantly increased polymorphonuclear leukocyte adherence to the coronary artery endothelium, an effect that was significantly attenuated by the anti-P-selectin monoclonal antibody PB1.3 or by UCN-01, L-arginine, 8-bromo-cGMP or SNP but not by D-arginine or he nonblocking anti-P-selectin monoclonal antibody NBP1.6. These results indicate that inhibition of NO synthesis induces rapid P-selectin expression, which appears to be at least partially mediated by PKC activation in platelets. Similar effects and mechanisms of L-NAME on P-selectin function were also observed in endothelial cells, another site of P-selectin expression.
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PMID:Inhibition of nitric oxide biosynthesis promotes P-selectin expression in platelets. Role of protein kinase C. 758 91

Urocortin, an endogenous peptide structurally related to corticotropin-releasing factor (CRF), has potent cardiovascular effects, suggesting that it may be of significance in cardiovascular regulation. The objective of this study was to analyse the effects of urocortin and its action mechanisms on human blood vessels. To this, 3 mm long segments from human saphenous veins were prepared for isometric tension recording in an organ bath. In the segments at basal resting tone, urocortin did not produce any effect, but in the segments precontracted with endothelin-1 (1 - 10 nM), urocortin (1 pM - 10 nM) produced concentration-dependent relaxation. This relaxation was not modified by the inhibitor of nitric oxide synthase NG-nitro-L-arginine methyl ester (L-NAME, 100 microM), but it was potentiated by the cyclo-oxygenase inhibitor meclofenamate (10 microM) and it was reduced by the inhibitors of high-conductance Ca2+-dependent potassium channels tetraethylammonium (TEA, 10 mM) and charybdotoxin (100 nM). These results indicate that human saphenous veins are very sensitive to urocortin, which produces vascular relaxation by a mechanism independent of nitric oxide and dependent of high-conductance Ca2+-dependent potassium channels, and that it may be opposed by the release of vasoconstrictor prostanoids. Therefore, urocortin may be of significance for regulation of the venous circulation in humans.
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PMID:Relaxation by urocortin of human saphenous veins. 1197 72

Urocortin, a newly identified polypeptide, possesses cardiac effects. However, the underlying mechanism of its coronary action is still unclear. In the present study we investigated the possible role of endothelial nitric oxide and Ba2+-sensitive K+ channels in the endothelium-dependent relaxant response to urocortin in the isolated rat left anterior descending coronary arteries. Changes of vessel tone were measured in microvessel myographs. Urocortin produced both endothelium-dependent and -independent relaxation with IC50 of 2.52 nM and 16.5 nM, respectively. Denuation of endothelium decreased the relaxing potency of urocortin. In the endothelium-intact rings pretreated with 100 microM N(G)-nitro-L-arginine methyl ester (L-NAME) or 10 microM 1H-[1,2,4]oxadiazolo[4,2-alpha]quinoxalin-1-one (ODQ), the urocortin-induced relaxation was similar to that observed in endothelium-denuded rings. The relaxant response to urocortin was markedly reduced in endothelium-intact rings preconstricted by 35 mM K+. Pretreatment with 100 microM BaCl2 significantly reduced urocortin-induced relaxation without an effect on the maximum relaxation. Combined treatment with BaCl2 plus L-NAME did not produce additive inhibition. In contrast, BaCl2 did not alter urocortin-induced relaxation in the endothelium-denuded rings. In the endothelium-denuded rings, BaCl2 at 100 microM also inhibited nitric oxide donor-induced relaxation. In conclusion, our results suggest that urocortin-induced endothelium-dependent relaxation of rat coronary arteries is primarily mediated by endothelial nitric oxide and subsequent activation of Ba2+-sensitive K+ channels. The urocortin-induced endothelium-dependent relaxation appears to be cyclic GMP-dependent.
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PMID:Endothelium-dependent and -independent coronary relaxation induced by urocortin. 1254 85

Urocortin is a peptide recently identified, structurally related to corticotropin releasing factor (CRF). We have compared the effects of urocortin in different vascular beds, and have investigated whether there are gender differences in these effects or whether they are altered by diabetes. We have studied the response of isolated segments (2-mm long) from basilar, coronary and tail arteries to urocortin. The segments were obtained from male and female, normoglycaemic and streptozotocin-induced diabetic rats. In the arterial segments precontracted with endothelin-1, urocortin produced concentration-dependent relaxation, and the order of sensitivity was: tail > basilar > coronary. This relaxation was similar in arteries from male and female, diabetic and normoglycaemic rats. In tail arteries from normoglycaemic male rats, the cyclooxygenase inhibitor meclofenamate (10(-5) M) increased the relaxation to urocortin, and the inhibitor of nitric oxide synthesis N(omega)-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) or the potassium-channel-blocker charybdotoxin (10(-7) M) did not modify it. In tail arteries from normoglycaemic female rats meclofenamate, charybdotoxin or L-NAME did not modify the relaxation to urocortin. These results suggested that urocortin produced vasodilation which showed regional differences between basilar, coronary and tail arteries, but was not affected by diabetes. The mechanisms underlying this relaxation in tail arteries might differ between males and females.
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PMID:Relaxation of rat arteries by urocortin: effects of gender and diabetes. 1284 38

The aim was to examine if the depressor effect of urocortin involves activation of the nitric oxide (NO)/L-arginine pathway, production of prostanoids or opening of K(+)-channels. I. v. bolus urocortin (0.1-3 nmol/kg) dose-dependently decreased mean arterial pressure in thiobutabarbital-anesthetized rats. The depressor effect of urocortin was unaffected by pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME, inhibitor of NO synthase, i.v. bolus) or noradrenaline (i.v. infusion), which increased arterial pressure to a similar level as that produced by L-NAME. In addition, methylene blue (inhibitor of soluble guanylyl cyclase, i.v. infusion), indomethacin (cyclooxygenase inhibitor, i.v. bolus), glibenclamide (blocker of ATP-sensitive K(+)-channels, i.v. bolus) or tetraethylammonium (a non specific K(+)-channel blocker, i.v. bolus) did not affect the depressor effect of urocortin. In conclusion, the depressor effect of urocortin in anesthetized rats is not mediated via the NO/L-arginine pathway, activation of soluble guanylyl cyclase, production of prostanoids, opening of TEA sensitive K(+)-channels nor opening of ATP sensitive K(+)-channels.
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PMID:Analysis of the mechanism of the vasodepressor effect of urocortin in anesthetized rats. 1560 89

1 Urocortin is a vasodilator peptide related to corticotrophin-releasing factor, which may protect endothelial function during coronary ischemia-reperfusion (I-R). The aim of this study was to study the mechanisms of this protective effect. 2 Hearts from Sprague-Dawley rats were isolated and perfused at constant flow and then exposed to 15 min global zero-flow ischemia, followed by 15 min reperfusion. The relaxation to acetylcholine (10 nM-10 microM) was recorded after pre-constriction of the coronary vasculature with U46619 (100-300 nM) in ischemic-reperfused or time-control hearts. 3 After I-R, the coronary relaxation to acetylcholine was reduced and this reduction was attenuated by treatment with urocortin (10 pM), administered before ischemia and during reperfusion. 4 This urocortin-induced improvement of the relaxation to acetylcholine was not modified by tetraethylammonium (10 mM), blocker of Ca2+ dependent-potassium channels; glibenclamide (10 microM), blocker of K(ATP) channels; N(w)-nitro-L-arginine methyl ester (L-NAME, 100 microM), blocker of nitric oxide synthesis; or meclofenamate (10 microM), blocker of cyclooxygenase, but it was abolished by chelerythrine (3 microM), blocker of protein kinase C (PKC). 5 These results suggest that urocortin may protect coronary endothelial function during I-R by activation of PKC.
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PMID:Mechanisms of the protective effects of urocortin on coronary endothelial function during ischemia-reperfusion in rat isolated hearts. 1580 10

The study has been designed to investigate downstream mechanisms in the PTPase inhibition mediated attenuation of diabetes mellitus and hypercholesterolemia-induced vascular endothelial dysfunction. Diabetes mellitus was induced in rats using streptozotocin (55 mg/kg, i.v. once), while hypercholesterolemia was produced by feeding high cholesterol diet. After 4 weeks of streptozotocin and Cholesterol rich diet administration, vascular endothelium dysfunction was assessed, in terms of attenuation of acetylcholine-induced, endothelium-dependent relaxation (Isolated Aortic Ring Preparation), a decrease in serum nitrate/nitrite level, as well as mRNA expression of eNOS (rtPCR) and disruption of integrity of vascular endothelium (Electron microscopy). After 14 days of daily administration, sodium orthovanadate (8 mg/kg, p.o., 16 mg/kg, p.o and 24 mg/kg, p.o) and atorvastatin (30 mg/kg, p.o) (positive control) significantly improved acetylcholine-induced endothelium-dependent relaxation, serum nitrate/nitrite level, mRNA expression of eNOS and maintained integrity of vascular endothelium. However, this ameliorative effect of SOV was significantly blocked by UCN-01, (PDK inhibitor) and L-NAME (Inhibitor of eNOS). Therefore, it may be concluded that sodium orthovanadate, a specific inhibitor of PTPase, may stimulate PDK and eNOS and consequently improve vascular endothelium dysfunction. Thus, inhibition of PTPase might be a useful approach in the therapeutics of vascular endothelium dysfunction.
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PMID:Mechanism of attenuation of diabetes mellitus and hypercholesterolemia induced vascular endothelial dysfunction by protein tyrosine phosphatase inhibition. 2123 89

Imbalance of l-arginine/endothelial nitric oxide synthatase (eNOS) activity is the hallmark of vascular endothelium dysfunction. Hyperhomocysteinemia (Hhy) has been identified as a potential risk factor for vascular endothelium dysfunction that leads to cardiovascular disorders. Phosphatidylinositol-3 kinase (PI3K) is a ubiquitous enzyme involved in plethora of cell signaling including the endothelial cells and it has been reported that signaling through this enzyme and its downstream pathway viz phosphoinositide-dependent kinase (PDK)/protein kinase B (Akt) and eNOS is impaired in diseased conditions. Thus present study was designed to investigate the role of PI3K and PDK/Akt in vascular endothelium dysfunction produced by Hhy. Hhy was produced by administering l-methionine (1.7%w/w, p.o). After four weeks of l-methionine administration, vascular endothelium dysfunction was assessed in terms of attenuation of acetylcholine-induced endothelium dependent relaxation (Isolated aortic ring preparation), a decrease in serum nitrite level, mRNA expression of eNOS (rtPCR) and disruption of integrity of vascular endothelium (Electron microscopy). Administration of insulin (0.6 IU/kg/day, s.c), YS-49 (1.6 mg/kg/day, i.p), DAQB1 (5mg/kg/day, i.p) and atorvastatin (30 mg/kg/day, p.o) significantly improved acetylcholine-induced endothelium-dependent relaxation, serum nitrate/nitrite level, mRNA expression of eNOS and integrity of vascular endothelium. This ameliorative effect of insulin was blocked by wortmannin (inhibitor of PI3K), UCN-01(PDK inhibitor), API-2 (Akt inhibitor) and l-NAME (eNOS inhibitor). Thus, it may be concluded that activation of PI3K and its downstream pathways viz. PDK/Akt and eNOS improve Hhy-induced vascular endothelium dysfunction and that therapeutic interventions designed for these pathways may provide potential therapeutic strategies to combat vascular complications.
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PMID:Mechanism of hyperhomocysteinemia-induced vascular endothelium dysfunction - possible dysregulation of phosphatidylinositol-3-kinase and its downstream phosphoinositide dependent kinase and protein kinase B. 2402 35