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)

The contractile actions of the proteinase-activated receptor-2-activating peptides (PAR2APs), SLIGRL-NH2 (SL-NH2), SLIGKV-NH2 (KV-NH2), trans-cinnamoyl-LIGRLO-NH2 (tc-NH2), and the PAR1-AP. TFLLR-NH2 (TF-NH2) as well as trypsin and thrombin were studied in endothelium-denuded and intact human umbilical vein (HUV) ring preparations. In HUV rings with, but not without an intact endothelium, PAR2APs caused a concentration-dependent contractile response, whereas LSIGRL-NH2 trypsin and PAR1APs were inactive. The contractile response was not affected by the endothelin ETA receptor antagonist, BQ123, the cyclooxygenase inhibitor, indomethacin, the leukotriene synthesis inhibitor, MK886, or the epoxygenase/P450 inhibitor, SKF-525A. Other pharmacological antagonists (prazosin, Losartan") were similarly inactive. The order of potencies of the PAR2APs to cause a contraction in the endothelium-intact preparation was: SL-NH2 > > KV-NH2 > or = tc-NH2. Using an endothelium-free rat aorta ring as a reporter tissue, surrounded with endothelium-intact HUV as a donor tissue in a 'sandwich assay,' we also monitored the ability of SL-NH2, TF-NH2, trypsin and thrombin to release either contractile (EDCF) or relaxant (EDRF) factors. In the 'sandwich assay' done in the presence of L-NAME (0.1 mM), the endothelium-intact HUV tissue (but not endothelium-denuded HUV) released a contractile factor (EDCF) in response to SL-NH2 (50 microM) but not to trypsin or LSIGRL-NH2. The SL-NH2-mediated release/action of the EDCF was not affected by BQ123, indomethacin, MK886 or SKF-525A. In the 'sandwich assay', trypsin (4-10 nM), SL-NH2, KV-NH2 and tc-NH2 caused the release of a relaxant activity (EDRF) from the endothelium-intact (but not the denuded) HUV preparation. The release of EDRF was blocked by 0.1 mM (omega)nitro-L-arginine-methylester (L-NAME). Neither thrombin (10 u ml(-1), 100 nM) nor TF-NH2 (50 microM) were active in this EDRF-release assay. The relative potencies of the PAR2 agonists for causing the release of EDRF in the HUV sandwich assay were: trypsin> >SL-NH2> >tc-NH2>KV-NH2. This order of potencies differed from the one observed for the same agonists in the HUV contraction assay (above) and in an intracellular calcium signalling assay, conducted with cloned human PAR2 that was expressed in cultured rat kidney KNRK cells: trypsin > > SL-NH2 = tc-NH2 > KV-NH2. We conclude that PAR2APs (but not PAR1APs) via a receptor distinct from PAR2, can cause a contractile response in endothelium-intact HUV tissue via the release of a diffusable EDCF, that is different from previously recognized smooth muscle agonists (e.g. prostanoid metabolites, endothelin, noradrenaline, angiotensin-II, acetylcholine).
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PMID:Endothelium-dependent contractile actions of proteinase-activated receptor-2-activating peptides in human umbilical vein: release of a contracting factor via a novel receptor. 988 72

Primary cultures of human cerebral microvascular endothelial cells (HCMEC) were loaded with fura-2. The intracellular free Ca2+ concentration ([Ca2+]i) was measured by digital imaging microscopy. Agonists ATP (100 micro), thrombin (10 units/ml), and histamine (25 microM) induced a transient [Ca2+]i increase. Histamine (100 microM) induced a biphasic [Ca2+]i increase with an initial [Ca2+]i peak followed by a [Ca2+]i plateau. The [Ca2+]i plateau was blocked by the receptor-operated Ca2+ channel (ROC) blockers SK&F 96365 and NCDC, indicating a contribution by Ca2+ influx through ROC to the [Ca2+]i plateau. However, this [Ca2+]i plateau was not blocked by the voltage-gated Ca2+ channel (VGC) blocker diltiazem (DTZ). Depolarization with 80K+ or application of the VGC agonist BAY K 8644 did not alter the resting [Ca2+]i; but 80K+ reduced the histamine (100 microM) induced [Ca2+]i plateau. These results show that HCMEC are devoid of functional VGC. Thus the membrane potential (Em) regulates Ca2+ entry mainly by enhancing the electrochemical Ca2+ gradient, such that hyperpolarization increases while depolarization decreases [Ca2+]i. Blockade of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) by CPA increased [Ca2+]i. This effect was dependent on extracellular Ca2+ and reduced by iberiotoxin (IBTX) blockade of Ca2+-activated K+ channels (Kca), suggesting a role for Kca in regulating Ca2+ influx. Ca2+ is the principal activator of endothelial nitric oxide synthase (eNOS), which stimulates cyclic GMP production. The final result that the eNOS inhibitor L-NAME enhanced the histamine (100 microM) induced [Ca2+]i plateau suggests a negative feedback loop (via cGMP) of endothelial NO on its own synthesis in the regulation of endothelial [Ca2+]i signal.
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PMID:Agonist-stimulated calcium entry in primary cultures of human cerebral microvascular endothelial cells. 1032 49

Vascular endothelial growth factor (VEGF) is an endothelium-specific secreted protein that induces vasodilation and increases endothelial release of nitric oxide (NO). NO is also reported to modulate leukocyte-endothelium interaction. Therefore, we hypothesized that VEGF might inhibit leukocyte-endothelium interaction via increased release of NO from the vascular endothelium. We used intravital microscopy of the rat mesenteric microcirculation to measure leukocyte-endothelium interactions 2, 4, and 24 h after systemic administration of VEGF to the rat (120 microg/kg, i.v., bolus). Superfusion of the rat mesentery with either 0.5 U/ml thrombin or 50 microM L-NAME consistently increased the number of rolling, adhering, and transmigrated leukocytes (P<0.01 vs. control mesenteries superfused with Krebs-Henseleit buffer). At 4 and 24 h posttreatment, VEGF significantly attenuated thrombin-induced and L-NAME-induced leukocyte rolling, adherence, and transmigration in rat mesenteric venules. In addition, adherence of isolated rat PMNs to thrombin-stimulated mesenteric artery segments in vitro was significantly reduced in mesenteric arteries isolated from VEGF-treated rats (P<0.001 vs. control rats). Direct measurement of NO demonstrated a threefold increase in basal NO release from aortic tissue of rats injected with VEGF, at 4 and 24 h posttreatment (P<0. 01 vs. aortic tissue from control rats). Finally, systemic administration of VEGF to ecNOS-deficient mice failed to inhibit leukocyte-endothelium interactions observed in peri-intestinal venules. We concluded that VEGF is a potent inhibitor of leukocyte-endothelium interaction, and this effect is specifically correlated to augmentation of NO release from the vascular endothelium.--Scalia, R., Booth, G., Lefer, D. J. Vascular endothelial growth factor attenuates leukocyte-endothelium interaction during acute endothelial dysfunction: essential role of endothelium-derived nitric oxide.
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PMID:Vascular endothelial growth factor attenuates leukocyte-endothelium interaction during acute endothelial dysfunction: essential role of endothelium-derived nitric oxide. 1033 86

Endothelial cell-derived nitric oxide (NO) has been suggested to inhibit smooth muscle cell proliferation, resulting in the reduction of intimal hyperplasia during atherogenesis. The present study investigates the role of NO from exogenous and endogenous sources on the proliferation of human umbilical vein endothelial cells (HUVEC) and human coronary artery endothelial cells (CAEC). Three different NO-generating compounds [sodium nitroprusside (SNP), S-nitroso-glutathione (GSNO) and S-nitroso-acetylpenicillamine (SNAP)] were found to inhibit endothelial cell proliferation measured with three independent methods (cell counting, [3H]thymidine incorporation, DNA histograms) with significant inhibition occurring at concentrations > or = 100 microM. Growth-inhibiting effects were observed after long-term treatment (18-96 h) as well as after short stimulation with NO donors (10 min with a subsequent NO donor-free culture period of 18 h) and were comparable in culture medium (20% serum, growth factor supplementation) and serum-deficient medium (1% serum). The NO donor effects were mediated by the release of NO as they were prevented by NO scavenging. Superoxide dismutase (SOD) was found not to interfere with these effects suggesting that peroxynitrite formation was unlikely to be involved. 1H-[l,2,4]Oxadiazolo[4,3,-alpha]quinoxalin-1-one (ODQ), a specific inhibitor of the soluble guanylate cyclase, was observed not to alter the antiproliferative effects of NO donors although it completely prevented NO-mediated increase of cyclic guanosine 3',5'-monophosphate (cGMP), suggesting that the NO-induced growth inhibition was not mediated by cGMP. Furthermore, inhibition of endogenous NO production by N-nitro-L-arginine methylester (L-NAME) did not affect endothelial cell growth regardless of using serum plus growth factor supplement, growth factor supplement alone, or thrombin to stimulate proliferation. We suggest that constitutively synthesized NO may not regulate endothelial cell proliferation whereas the growth-inhibiting NO effects may occur when an inducible NO synthase associated with a persistently high NO production is expressed in the atherosclerotic vessel wall.
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PMID:Nitric oxide inhibits proliferation of human endothelial cells via a mechanism independent of cGMP. 1038 Dec 77

Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been shown to lower serum cholesterol levels and normalize endothelial cell function. Moreover, HMG-CoA reductase inhibitors exert beneficial effects in coronary artery and cerebrovascular diseases. We examined the effects of simvastatin on leukocyte-endothelial cell interaction in vivo by intravital microscopy. Simvastatin (12.5 or 25 microg per rat) was given 18 hours before study. Superfusion with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 50 micromol/L) significantly increased leukocyte rolling from 12+/-2 to 60+/-8 leukocytes per minute, increased adherence to the mesenteric endothelium from 1.8+/-0.5 to 17+/-1.2 leukocytes per 100 microm of venular length, and raised leukocyte transmigration from 2.5+/-1.0 to 10+/-2 leukocytes per perivessel area (P<0.01). Similar results were obtained with thrombin (0.5 U/mL) superfusion of the mesentery. In contrast, pretreatment with simvastatin (25 microg per rat IP) significantly attenuated L-NAME-stimulated leukocyte rolling, to 12+/-2 (P<0.01); adherence, to 5+/-0.5 leukocytes per 100 microm (P<0.01); and leukocyte transmigration, to 3.5+/-1.5 leukocytes per perivessel area (P<0.01). Similar results were obtained in thrombin-superfused mesenteries. Moreover, immunohistochemical analysis demonstrated significantly increased P-selectin expression on the mesenteric venular endothelium after superfusion with either L-NAME (P<0.01) or thrombin (P<0.01), which was significantly attenuated by simvastatin. These results clearly demonstrate that simvastatin is a potent and effective endothelium-protective agent that reduces leukocyte-endothelial cell interactions independently of its well-known lipid-lowering effects. This effect was found to be at least partially mediated via downregulation of P-selectin expression on the microvascular endothelium. Thus, HMG-CoA reductase inhibitors like simvastatin have important anti-inflammatory effects besides their well-known lipid-lowering action.
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PMID:Simvastatin inhibits leukocyte-endothelial cell interactions and protects against inflammatory processes in normocholesterolemic rats. 1059 66

In this work we studied the influence of an acute exercise either on nitrite/nitrate plasma levels or on neutrophil and platelet adhesion in inactive and active subjects. Twelve healthy subjects (6 inactives and 6 actives) exercised on a racing cycle ergometer performing stepwise increases in intensity until reaching, within 5 min, a heart rate of 150 beats x min(-1) which represents an oxygen consumption of about 75 % of the individual maximum rate of oxygen uptake. From peripheral venous blood samples (drawn from all subjects before, immediately after the end of exercise, and 1 hour later) neutrophils and platelets were isolated to test plate adhesion, and nitrite/nitrate concentrations were measured in the plasma. Immediately after the acute exercise, in active subjects we observed a significant decrease in the percentage of neutrophil adhesion (7.96+/-2.38 vs. 14.10+/-3.14), associated with an increase in nitrite/nitrate plasma levels (81.38+/-10.76 vs. 41.08+/-8.13 micromol x l(-1)), restored by a 40 min pre-incubation with NG-nitro-L-arginine methyl ester (L-NAME). In unstimulated platelets we observed a significant lower percentage of platelet adhesion in active subjects compared to inactives after exercise. With thrombin or adenosine 5'-diphosphate as agonists platelet adhesion did not result significantly different in active subjects compared to inactives. In conclusion, our data show that physical exercise can induce changes in some cell activities, even if transient, and favour the generation of nitric oxide. The lower adhesion of neutrophils and platelets induced by regular exercise could be an important goal in the prevention of vascular and inflammatory diseases.
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PMID:Influence of an acute exercise on neutrophil and platelet adhesion, nitric oxide plasma metabolites in inactive and active subjects. 1085 1

Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes (PMNs) results in cardiac dysfunction. C-peptide, a cleavage product of proinsulin to insulin processing, induces nitric oxide (NO)-mediated vasodilation. NO is reported to attenuate cardiac dysfunction caused by PMNs after ischemia-reperfusion (I/R). Therefore, we hypothesized that C-peptide could attenuate PMN-induced cardiac dysfunction. We examined the effects of C-peptide in isolated ischemic (20 min) and reperfused (45 min) rat hearts perfused with PMNs. C-peptide (70 nmol/kg iv) given 4 or 24 h before I/R significantly improved coronary flow (P < 0.05), left ventricular developed pressure (LVDP) (P < 0.01), and the maximal rate of development of LVDP (+dP/dt(max)) compared with I/R hearts obtained from rats given 0.9% NaCl (P < 0.01). N(G)-nitro-L-arginine methyl ester (L-NAME) (50 micromol/l) blocked these cardioprotective effects. In addition, C-peptide significantly reduced cardiac PMN infiltration from 183 +/- 24 PMNs/mm(2) in untreated hearts to 44 +/- 10 and 58 +/- 25 PMNs/mm(2) in hearts from 4- and 24-h C-peptide-treated rats, respectively. Rat PMN adherence to rat superior mesenteric artery exposed to 2 U/ml thrombin was significantly reduced in rats given C-peptide compared with rats given 0.9% NaCl (P < 0.001). Moreover, C-peptide enhanced basal NO release from rat aortic segments. These results provide evidence that C-peptide can significantly attenuate PMN-induced cardiac contractile dysfunction in the isolated perfused rat heart subjected to I/R at least in part via enhanced NO release.
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PMID:C-peptide exerts cardioprotective effects in myocardial ischemia-reperfusion. 1100 29

We have investigated the ability of protease-activated receptor-1 (PAR-1), PAR-2, PAR-3 and PAR-4 agonists to induce contractile responses in isolated guinea-pig gallbladder. Thrombin, trypsin, mouse PAR-1 activating (SFLLRN-NH(2)) peptide, and mouse PAR-2 activating (SLIGRL-NH(2)) and human PAR-2 activating (SLIGKV-NH(2)) peptides produced a concentration-dependent contractile response. Mouse PAR-4 activating (GYPGKF-NH(2)) peptide, the mouse PAR-1 reverse (NRLLFS-NH(2)) peptide, the mouse PAR-2 reverse (LRGILS-NH(2)) and human PAR-2 reverse (VKGILS-NH(2)) peptides caused negligible contractile responses at the highest concentrations tested. An additive effect was observed following the contractile response induced by either trypsin or thrombin, with the addition of a different PAR agonist (SFLLRN-NH(2) and SLIGRL-NH(2), respectively). Desensitization to PAR-2 activating peptide attenuated the response to trypsin but failed to attenuate the response to PAR-1 agonists, and conversely desensitization to PAR-1 attenuated the response to thrombin but failed to alter contractile responses to PAR-2 agonists. The contractile responses produced by thrombin, trypsin, SFLLRN-NH(2) and SLIGRL-NH(2) were markedly reduced in the presence of the cyclo-oxygenase inhibitor, indomethacin, whilst the small contractile response produced by NRLLFS-NH(2) and LRGILS-NH(2) were insensitive to indomethacin. The contractile responses to thrombin, trypsin, SFLLRN-NH(2) and SLIGRL-NH(2) were unaffected by the presence of: the non-selective muscarinic antagonist, atropine; the nitric oxide synthase inhibitor, L-NAME; the sodium channel blocker, tetrodotoxin; the combination of selective tachykinin NK(1) and NK(2) receptor antagonists, (S)-1-[2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyphenylacetyl) piperidin-3-yl] ethyl]-4-phenyl-1 azaniabicyclo [2.2.2] octane chloride (SR140333) and (S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino-2-(3, 4-dichlorophenyl)-butyl] benzamide (SR48968), respectively. The results indicate that PAR-1 and PAR-2 activation causes contractile responses in the guinea-pig gallbladder, an effect that is mediated principally by prostanoid release, and is independent of neural mechanisms.
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PMID:Evidence that PAR-1 and PAR-2 mediate prostanoid-dependent contraction in isolated guinea-pig gallbladder. 1103 Jul 17

C-peptide is a cleavage product that comes from processing proinsulin to insulin that induces nitric oxide (NO) -mediated vasodilation. NO modulates leukocyte-endothelium interaction. We hypothesized that C-peptide might inhibit leukocyte-endothelium interaction via increased release of endothelial NO. Using intravital microscopy of the rat mesentery, we measured leukocyte-endothelium interactions after administration of C-peptide to the rat. Superfusion of the rat mesentery with either thrombin or L-NAME consistently and significantly increased the number of rolling, adhering, and transmigrated leukocytes. C-peptide significantly attenuated either thrombin- or L-NAME-induced leukocyte-endothelium interactions in rat mesenteric venules. A control scrambled sequence of C-peptide characterized by the same amino acid composition in a randomized sequence failed to inhibit leukocyte-endothelium interactions. These effects of C-peptide were associated with decreased surface expression of the cell adhesion molecules P-selectin and ICAM-1 on the microvascular endothelium. Endothelial nitric oxide synthase (eNOS) mRNA levels were increased in rats injected with C-peptide. This enhanced eNOS expression was associated with a marked increase in basal NO release from the aorta of C-peptide-treated rats. We conclude that C-peptide is a potent inhibitor of leukocyte-endothelium interaction and that this effect is specifically related to inhibition of endothelial cell adhesion molecules via maintenance of NO release from the vascular endothelium.
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PMID:C-peptide inhibits leukocyte-endothelium interaction in the microcirculation during acute endothelial dysfunction. 1105 58

Using a method employing front-surface fura-2 fluorometry to measure the cytosolic Ca(2+) concentration, [Ca(2+)](i), the mechanism of endothelium-dependent regulation of vascular tone by thrombin was studied in porcine renal interlobar arterial strips. At concentrations lower than 3 u ml(-1), thrombin evoked only early transient relaxation, while at 3 u ml(-1) and higher concentrations, thrombin caused an early relaxation and a subsequent transient contraction. Both thrombin-induced relaxation and contraction were abolished by removing the endothelium. Similar biphasic responses were observed with a protease-activated receptor-1-activating peptide. Early relaxation was associated with a decrease in [Ca(2+)](i), while the transient contraction was not associated with a change in [Ca(2+)](i) of smooth muscle cells. A thromboxane A(2) (TXA(2))/prostaglandin H(2) (PGH(2)) receptor antagonist (10(-5) M ONO-3708) completely inhibited the thrombin-induced contraction, whereas a thromboxane A(2) synthase inhibitor (10(-5) M OKY-046) only partly inhibited it. When the thrombin-induced contraction was inhibited by ONO-3708, either pretreatment with N(omega)-nitro-L-arginine methylester (L-NAME) or an increase in the amount of external K(+) to 40 mM did not abolish thrombin-induced relaxation during phenylephrine-induced sustained contraction. However, the combination of pretreatment with L-NAME and an elevation of external K(+) to 40 mM completely abolished the relaxation. There was no significant difference in the concentration-dependent effects of thrombin on the initial early relaxation between conditions in which the contractile components either were or were not inhibited. Thrombin is thus considered to mainly activate protease-activated receptor-1 and cause a biphasic response, early relaxation and a transient contraction, in the porcine renal interlobar artery in an endothelium-dependent manner. The thrombin-induced endothelium-dependent relaxation was mediated by nitric oxide and hyperpolarizing factors, while the contraction was mediated by TXA(2) and PGH(2).
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PMID:Thrombin causes endothelium-dependent biphasic regulation of vascular tone in the porcine renal interlobar artery. 1113 41

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