共查询到20条相似文献,搜索用时 31 毫秒
1.
R.H. Bourgain L. Maes P. Braquet R. Andries L. Touqui M. Braquet 《Prostaglandins & other lipid mediators》1985,30(2):185-197
The effect of a topical paf-acether superfusion over an injured arterial segment was assessed in the guinea-pig, using an opto-electronic in vivo thrombosis model allowing on line quantification of small platelet thrombus dynamics.As compared to control, ADP-induced, thromboformation and behaviour, exogenous paf-acether causes a large, dense platelet thrombus, invaded and surrounded by numerous leukocytes, spreading widely over the adjoining, vacuolized, endothelium. Its embolization has to be forced with prostanoids, mepacrine, EDTA, or with a specific paf-acether antagonist3 (BN 52021). A few minutes after such forced embolization, a new thrombus starts growing at the same site, without renewal of the paf-acether superfusion. This phenomenon of spontaneous reappearance after forced embolization can be followed during several hours. Experiments with labelled paf-acether and the paf-acether antagonist indicate a possible endogenous paf-acether (or paf-acether-like) production triggered by superfusion with exogenous paf-acether. 相似文献
2.
The anti-thrombotic effects of specific paf-acether antagonist BN 52021 were compared to the effects of Ginkgo Biloba extracts A, B, (A+B), and C local superfusion of BN 52021 over an experimentally injured arterial segment embolizes an existent paf-acether induced platelet thrombus. When applied before paf-acether, BN 52021 prevents local thromboformation in this model. Applied intravenously, BN 52021 reduces local thromboformation in a significant way. As compared to this BN 52021 standard, only Ginkgo Biloba B and the (A+B)-mixture present major thromboreductive activity. 相似文献
3.
Thrombus induction by endogenic paf-acether and its inhibition by Ginkgo Biloba extracts in the guinea pig 总被引:1,自引:0,他引:1
The anti-thrombotic effects of specific paf-acether antagonist BN 52021 were compared to the effects of Ginkgo Biloba extracts A, B, (A + B), and C. Local superfusion of BN 52021 over an experimentally injured arterial segment embolizes an existent paf-acether induced platelet thrombus. When applied before paf-acether, BN 52021 prevents local thromboformation in this model. Applied intravenously, BN 52021 reduces local thromboformation in a significant way. As compared to this BN 52021 standard, only Ginkgo Biloba B and the (A + B)-mixture present major thromboreductive activity. 相似文献
4.
Occlusive thrombosis accounts for many heart attacks and strokes. These acute events are difficult to catch in patients and animal test methods may be misleading because anti-thrombotic therapeutics often do not cross-react with different species. This paper presents a new flow-through system that leads to rapid occlusive thrombosis in arterial flow conditions. Whole porcine blood is perfused through a tubular test section. The growing thrombus is visualized in real time from early platelet attachment, through accumulation, to occlusion. The progression of flow rate reduction provides a clear distinguishing parameter between thrombus formation and embolization. Thrombus growth rate is a linear function of very high shear rate beyond 40,000 s(-1). The histology of the thrombus reveals predominantly platelet accumulation and growth as a rough surface with tendrils. This flow-through system may be useful for the economic testing of new anti-thrombosis therapies. 相似文献
5.
S Philipose V Konya M Lazarevic LM Pasterk G Marsche S Frank BA Peskar A Heinemann R Schuligoi 《PloS one》2012,7(8):e40222
The use of the lipid lowering agent niacin is hampered by a frequent flush response which is largely mediated by prostaglandin (PG) D(2). Therefore, concomitant administration of the D-type prostanoid (DP) receptor antagonist laropiprant has been proposed to be a useful approach in preventing niacin-induced flush. However, antagonizing PGD(2), which is a potent inhibitor of platelet aggregation, might pose the risk of atherothrombotic events in cardiovascular disease. In fact, we found that in vitro treatment of platelets with laropiprant prevented the inhibitory effects of PGD(2) on platelet function, i.e. platelet aggregation, Ca(2+) flux, P-selectin expression, activation of glycoprotein IIb/IIIa and thrombus formation. In contrast, laropiprant did not prevent the inhibitory effects of acetylsalicylic acid or niacin on thrombus formation. At higher concentrations, laropiprant by itself attenuated platelet activation induced by thromboxane (TP) and E-type prostanoid (EP)-3 receptor stimulation, as demonstrated in assays of platelet aggregation, Ca(2+) flux, P-selectin expression, and activation of glycoprotein IIb/IIIa. Inhibition of platelet function exerted by EP4 or I-type prostanoid (IP) receptors was not affected by laropiprant. These in vitro data suggest that niacin/laropiprant for the treatment of dyslipidemias might have a beneficial profile with respect to platelet function and thrombotic events in vascular disease. 相似文献
6.
Mathematical analysis of mural thrombogenesis. Concentration profiles of platelet-activating agents and effects of viscous shear flow. 总被引:4,自引:2,他引:2
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The concentration profiles of adenosine diphosphate (ADP), thromboxane A2 (TxA2), thrombin, and von Willebrand factor (vWF) released extracellularly from the platelet granules or produced metabolically on the platelet membrane during thrombus growth, were estimated using finite element simulation of blood flow over model thrombi of various shapes and dimensions. The wall fluxes of these platelet-activating agents were estimated for each model thrombus at three different wall shear rates (100 s-1, 800 s-1, and 1,500 s-1), employing experimental data on thrombus growth rates and sizes. For that purpose, whole human blood was perfused in a parallel-plate flow chamber coated with type l fibrillar human collagen, and the kinetic data collected and analyzed by an EPl-fluorescence video microscopy system and a digital image processor. It was found that thrombin concentrations were large enough to cause irreversible platelet aggregation. Although heparin significantly accelerated thrombin inhibition by antithrombin lll, the remaining thrombin levels were still significantly above the minimum threshold required for irreversible platelet aggregation. While ADP concentrations were large enough to cause irreversible platelet aggregation at low shear rates and for small aggregate sizes, TxA2 concentrations were only sufficient to induce platelet shape change over the entire range of wall shear rates and thrombi dimensions studied. Our results also indicated that the local concentration of vWF multimers released from the platelet alpha-granules could be sufficient to modulate platelet aggregation at low and intermediate wall shear rates (less than 1,000 s-1). The sizes of standing vortices formed adjacent to a growing aggregate and the embolizing stresses and the torque, acting at the aggregate surface, were also estimated in this simulation. It was found that standing vortices developed on both sides of the thrombus even at low wall shear rates. Their sizes increased with thrombus size and wall shear rate, and were largely dependent upon thrombus geometry. The experimental observation that platelet aggregation occurred predominantly in the spaces between adjacent thrombi, confirmed the numerical prediction that those standing vortices are regions of reduced fluid velocities and high concentrations of platelet-activating substances, capable of trapping and stimulating platelets for aggregation. The average shear stress and normal stress, as well as the torque, acting to detach the thrombus, increased with increasing wall shear rate. Both stresses were found to be nearly independent of thrombus size and only weekly dependent upon thrombus geometry. Although both stresses had similar values at low wall shear rates, the average shear stress became the predominant embolizing stress at high wall shear rates. 相似文献
7.
Thrombus formation over a ruptured atherosclerotic plaque cap can occlude an artery with fatal consequences. We describe a computational model of platelet transport and binding to interpret rate-limiting steps seen in experimental thrombus formation over a collagen-coated stenosis. The model is used to compute shear rates in stenoses with growing boundaries. In the model, moving erythrocytes influence platelet transport based on shear-dependent enhanced diffusivity and a nonuniform platelet distribution. Adhesion is modeled as platelet-platelet binding kinetics. The results indicate that observed thrombus growth rates are limited by platelet transport to the wall for shear rates up to 6000 s−1. Above 7000 s−1, the thrombus growth rate is likely limited by binding kinetics (10−4 m/s). Thrombus growth computed from these rate-limiting steps match the thrombus location and occlusion times for experimental conditions if a lag time for platelet activation is included. Using fitted parameters, the model is then used to predict thrombus size and shape at a higher Reynolds number flow consistent with coronary artery disease. 相似文献
8.
The antithrombotic activity of pelrinone, a phosphodiesterase III inhibitor was examined in a canine model of coronary thrombosis that uses electrical current to injure the coronary endothelium. Ninety percent of vehicle treated animals developed complete coronary occlusion and thrombus mass was 32.0 +/- 5.8 mg. In a group of animals treated with zomepirac, 10 mg/kg i.v., included as a positive control, thrombus mass was decreased to 10.3 +/- 3.3 mg and incidence of occlusion was reduced to 37.5%. Pelrinone, 5.0 mg/kg i.v. decreased the incidence of occlusion to 50%, thrombus mass to 21.3 +/- 8.3 mg and inhibited platelet aggregation to collagen, ADP and arachidonic acid by 80%, 54% and 87% of baseline, respectively. When yohimbine, an alpha 2-adrenergic antagonist, was co-administered (2.0 mg/kg at the beginning of the experiment +0.5 mg/kg halfway through the experiment) with the same dose of pelrinone, thrombus mass was decreased to 1.0 +/- 0.5 mg and none of the animals developed coronary occlusion. Yohimbine administration by itself at 2.0-3.0 mg/kg showed no evidence of antithrombotic activity (thrombus mass = 32.8 +/- 8.0 mg, incidence of occlusion = 100%). This dose of yohimbine inhibited significantly ADP-induced aggregation in the presence of epinephrine. These results demonstrate that, even though this dose of pelrinone elicited near maximal inhibition of platelet aggregation, the concurrent administration of an alpha 2-adrenergic antagonist was able to potentiate markedly the phosphodiesterase inhibitor antithrombotic activity. 相似文献
9.
Most antithrombotic approaches target prevention rather than the more clinically relevant issue of resolution of an existing thrombus. In this study, we describe a novel and effective therapeutic strategy for ex vivo clearance of pre-existing platelet thrombus by the combination of two bifunctional platelet GPIIIa49-66 ligands that target different parts of the arterial thrombus. We produced an additional GPIIIa49-66 agent (named APAC), which homes to activated platelets. Like our previously described SLK (which targets newly deposited fibrin strands surrounding the platelet thrombus), APAC destroys platelet aggregates ex vivo in an identical fashion with 85% destruction of platelet aggregates at 2 hours. The combined application of APAC and SLK demonstrated a ~2 fold greater platelet thrombus dissolution than either agent alone at a low concentration (0.025 μM). Platelet-rich clot lysis experiments demonstrated the time required for 50% platelet-rich fibrin clot lysis (T(50%)) by APAC (95 ± 6.1 min) or SLK (145 ± 7.1 min) was much longer than that by combined APAC + SLK (65 ± 7.6 min) at the final concentration of 0.025 μM (APAC + SLK vs APAC, p<0.05; APAC + SLK vs SLK, p<0.01). Thus these low concentrations of a combination of both agents are likely to be more effective and less toxic when used therapeutically in vivo. 相似文献
10.
R H Bourgain 《Archives internationales de physiologie et de biochimie》1978,86(1):165-168
White platelet thrombi induced after electrical current application followed by ADP superfusion can be inhibited by indomethacin. These findings suggest that the synthesis of PGG2 and PGH2 is inhibited, which results in less local platelet aggregating activity. 相似文献
11.
Y Thomas Y Denizot E Dassa C Boullet J Benveniste 《Comptes rendus de l'Académie des sciences. Série III, Sciences de la vie》1986,303(17):699-702
Paf-acether (platelet-activating factor) is one of the most potent mediator of inflammation released from and acting on most cells that participate in inflammatory diseases. Its molecular structure is 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine. Two metabolic steps are involved in its biosynthesis: the action of a phospholipase A2 on choline-containing membrane alkyl-ether lipids results in the production of lyso paf-acether and acetylation of the lyso compound by an acetyltransferase yields the biologically active molecule. Membrane alkyl-ether lipids can therefore be considered as potential precursors of paf-acether and their composition has been studied in various cell types. In this work, we investigated the presence of paf-acether in E. coli. Our results showed that paf-acether can be obtained from E. coli K12 under a variety of bacterial growth conditions. Paf-acether from E. coli exhibited the same physicochemical and biological characteristics as synthetic paf-acether and that from eucaryotic cells. Therefore, it appears that E. coli itself has the ability of producing paf-acether, a result that could be of some importance with respect to the pathogenesis of Enterobacteria and the use of E. coli in the recombinant DNA technology. 相似文献
12.
Liu X Li C Gebremedhin D Hwang SH Hammock BD Falck JR Roman RJ Harder DR Koehler RC 《American journal of physiology. Heart and circulatory physiology》2011,301(2):H373-H381
Group I metabotropic glutamate receptors (mGluR) on astrocytes have been shown to participate in cerebral vasodilation to neuronal activation in brain slices. Pharmacological stimulation of mGluR in brain slices can produce arteriolar constriction or dilation depending on the initial degree of vascular tone. Here, we examined whether pharmacological stimulation of mGluR in vivo increases cerebral blood flow. A 1-mM solution of the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) superfused at 5 μl/min over the cortical surface of anesthetized rats produced a 30 ± 2% (±SE) increase in blood flow measured by laser-Doppler flowmetry after 15-20 min. The response was completely blocked by superfusion of group I mGluR antagonists and attenuated by superfusion of an epoxyeicosatrienoic acid (EET) antagonist (5 ± 4%), an EET synthesis inhibitor (11 ± 3%), and a cyclooxygenase-2 inhibitor (15 ± 3%). The peak blood flow response was not significantly affected by administration of inhibitors of cyclooxygenase-1, neuronal nitric oxide synthase, heme oxygenase, adenosine A(2B) receptors, or an inhibitor of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE). The blood flow response gradually waned following 30-60 min of DHPG superfusion. This loss of the flow response was attenuated by a 20-HETE synthesis inhibitor and was prevented by superfusion of an inhibitor of epoxide hydrolase, which hydrolyzes EETs. These results indicate that pharmacological stimulation of mGluR in vivo increases cerebral blood flow and that the response depends on the release of EETs and a metabolite of cyclooxygenase-2. Epoxide hydrolase activity and 20-HETE synthesis limit the duration of the response to prolonged mGluR activation. 相似文献
13.
Immunoregulatory functions of paf-acether. I. Effect of paf-acether on CD4+ cell proliferation 总被引:3,自引:0,他引:3
A Dulioust E Vivier P Salem J Benveniste Y Thomas 《Journal of immunology (Baltimore, Md. : 1950)》1988,140(1):240-245
Paf-acether or platelet-activating factor (1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a phospholipid mediator of inflammation initially described as a potent platelet-aggregating compound. It is newly formed by a variety of cells including monocytes and is now recognized as a major mediator of cell-cell interactions. The present studies were undertaken to determine whether paf-acether could modulate T cell function. We found that addition of paf-acether to CD4+ cells cultured with phytohemagglutinin markedly inhibited the proliferative response in a dose-dependent manner. Maximal inhibition occurred when paf-acether was present during the first 24 hr of cell culture and the presence of paf-acether did not alter the kinetics of CD4+ cell proliferation. Importantly, the mechanism by which paf-acether inhibited the proliferative response was not related to inhibition of interleukin 2 (IL-2) secretion since the amount of IL-2 in cultures was not altered and addition of exogenous IL-2 failed to restore the CD4+ cell proliferative response. Further, as judged by indirect immunofluorescence, paf-acether did not inhibit IL-2 receptor expression. Taken together, these data indicate that paf-acether interferes with some processes leading to CD4+ cell proliferation. This new role for the chemically defined monokine paf-acether emphasizes the potential role of inflammatory lipid mediators in the regulation of T cell response. 相似文献
14.
In this study, we report BF066, a novel adenine derivative, inhibits platelet activation and thrombosis via the adenosine receptor (A(2A)) activation and phosphodiesterase (PDE) inhibition. BF066 inhibits platelet aggregation and ATP releasing induced by multiple platelet agonists in a dose-dependent manner. The inhibition of BF066 on ADP-induced aggregation is potentiated by adenosine and can be dramatically antagonized by the A(2A) antagonist SCH58261. BF066 also inhibits the PDE activity and platelet spreading on fibrinogen. In FeCl(3)-injured mouse mesenteric arterial thrombosis model, BF066 prevents thrombus formation effectively, similar to clopidogrel. Intriguingly, at dose achieving similar antithrombotic effect compared to clopidogrel, BF066 does not increase bleeding significantly. Taken together, these results suggest that BF066 may be an effective and safe antiplatelet agent targeting both PDE and A(2A). Considering the successful use of combined antiplatelet therapy, BF066 may be further developed as a novel dual target antiplatelet agent. 相似文献
15.
血小板表面的整合蛋白aⅡbb3对血栓的形成具有很重要的调控作用, aⅡbb3与纤维蛋白原上的RGD特征序列结合, 促进血小板凝集进而形成血栓。这样可以在理论上设计一个环形RGD小分子(RGD-c)与aⅡbb3蛋白结合, 阻断其与纤维蛋白原的结合位点, 进而阻断血栓形成。以糖蛋白avb3(pdb 代码 1jv2)作为模板, 利用modeller8v2软件进行同源模拟得到aⅡbb3三维模型。而小分子则以RGD序列为主, 两边各加一个氨基酸X、Y, X和Y之间用一个二硫键相连, 通过改变X和Y, 重复优化过程则可得到不同的小分子模型, 将其与aⅡbb3进行分子对接, 可以找出比较理想的XY组合, 对治疗血栓的药物设计具有重要的理论指导作用 相似文献
16.
Y Denizot J Benveniste 《Comptes rendus de l'Académie des sciences. Série III, Sciences de la vie》1989,309(14):593-597
Paf-acether (platelet-activating factor) is one of the most potent inflammatory mediators synthesized by and acting on most inflammatory cells. It also displays potent immunoregulatory properties. Two metabolic steps are involved in its biosynthesis: the action of a phospholipase A2 on membrane alkyl-acyl (long chain) phospholipids with choline polar head results in the production of lyso paf-acether, and acetylation of the lyso compound by an acetyltransferase yields the biologically active molecule. Recently we showed that E. coli and other bacteria are able to produce paf-acether using exogenous lyso paf-acether. This finding prompted us to search for the presence of paf-acether in fermented milk products. The fraction corresponding to paf-acether isolated from milk exhibited the same physicochemical and biological characteristics as synthetic paf-acether and that from eukaryotic cells. The presence of a biologically active phospholipid in fermented products may bring new perspectives with respect to the study of gastrointestinal diseases as well as the putative immunostimulating effect of yogurt. 相似文献
17.
Rumbaut RE Bellera RV Randhawa JK Shrimpton CN Dasgupta SK Dong JF Burns AR 《American journal of physiology. Heart and circulatory physiology》2006,290(4):H1671-H1679
Endotoxemia promotes adhesive interactions between platelets and microvascular endothelium in vivo. We sought to determine whether endotoxin (lipopolysaccharide, LPS) modified platelet thrombus formation in mouse cremaster venules and whether Toll-like receptor 4 (TLR4) and neutrophils were involved in the response. Intravital videomicroscopy was performed in the cremaster microcirculation of pentobarbital-anesthetized mice; venular platelet thrombi were induced with a light/dye endothelial injury model. C57BL/6 mice treated with Escherichia coli endotoxin had enhanced rates of venular platelet thrombus formation: the time to microvessel occlusion was reduced by approximately 50% (P < 0.005) compared with saline-treated animals. Enhanced microvascular thrombosis was evident as early as 2 h after LPS administration. LPS had no effect on thrombosis in either of two mouse strains with altered TLR4 signaling (C57BL/10ScNJ or C3H/HeJ), whereas it enhanced thrombosis in the control strains (C57BL/10J and C3H/HeN). LPS also enhanced platelet adhesion to endothelium in the absence of light/dye injury. Platelet adhesion, but not enhanced thrombosis, was inhibited by depletion of circulating neutrophils. LPS failed to enhance platelet aggregation ex vivo and did not influence platelet P-selectin expression, a marker of platelet activation. These findings support the notion that endotoxemia promotes platelet thrombus formation independent of neutrophils and without enhancement of platelet aggregation, via a TLR4-dependent mechanism. 相似文献
18.
Ewelina M. Golebiewska Matthew T. Harper Christopher M. Williams Joshua S. Savage Robert Goggs Gabriele Fischer von Mollard Alastair W. Poole 《The Journal of biological chemistry》2015,290(3):1536-1545
Platelet secretion not only drives thrombosis and hemostasis, but also mediates a variety of other physiological and pathological processes. The ubiquitous SNARE machinery and a number of accessory proteins have been implicated in regulating secretion in platelet. Although several platelet SNAREs have been identified, further members of the SNARE family may be needed to fine-tune platelet secretion. In this study we identified expression of the t-SNARE syntaxin 8 (STX8) (Qc SNARE) in mouse and human platelets. In mouse studies, whereas STX8 was not essential for α-granule or lysosome secretion, Stx8−/− platelets showed a significant defect in dense granule secretion in response to thrombin and CRP. This was most pronounced at intermediate concentrations of agonists. They also showed an aggregation defect that could be rescued with exogenous ADP and increased embolization in Stx8−/− mice in vivo consistent with an important autocrine and paracrine role for ADP in aggregation and thrombus stabilization. STX8 therefore specifically contributes to dense granule secretion and represents another member of a growing family of genes that play distinct roles in regulating granule release from platelets and thus platelet function in thrombosis and hemostasis. 相似文献
19.
It has been postulated that metabolites of the arachidonic acid pathway exert an important influence on hemostasis and thrombosis. This notion is based on in vitro experiments. We have utilized two experimental models to elucidate the physiologic roles of thromboxane A2 (TxA2) and prostacyclin (PGI2) in the modulation of thrombus formation. The role of TxA2 in promoting thrombus formation was evaluated in a rabbit model where the aorta was deendothelialized by a balloon catheter technique and indium-111-labeled platelets were used as a marker for quantifying platelet deposition. Both 1-benzylimidazole, a thromboxane synthase inhibitor, and 13-azaprostanoic acid, an antagonist of thromboxane/endoperoxide receptors significantly reduced the platelet deposition onto the damaged vessel wall. The data indicate the TxA2 plays an important role in thrombosis and hemostasis. The influence of PGI2 insufficiency due to accelerated PGI2 degradation on microvascular thrombosis was evaluated in a unique clinical disease, i.e. thrombotic thrombocytopenic purpura (TTP). Accelerated PGI2 degradation was observed in several patients with chronic TTP. The degradation abnormalities were corrected by plasma infusion in vivo or serum supplement in vitro. To test the hypothesis that PGI2 must be bound to serum macromolecules to prevent rapid hydrolysis, serum binding capacity for PGI2 was measured by Sephadex G-25 gel filtration. The binding capacity was significantly reduced in the patients and was corrected by serum supplement. Abnormalities of PGI2 binding were also noted in a group of patients with ischemic stroke. Our findings suggest that there exist in the serum certain constituents which bind and stabilize PGI2.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
20.
Our aim was to investigate whether guinea pig urothelium-derived bioactivities compatible with the existence of urothelium-derived inhibitory factor could be demonstrated by in vitro serial bioassay and whether purinergic P1 receptor agonists, nitric oxide, nitrite or prostaglandins might explain observed activities. In a cascade superfusion system, urothelium-denuded guinea pig ureters were used as bioassay tissues, recording their spontaneous rhythmic contractions in presence of scopolamine. Urothelium-intact or -denuded guinea pig urinary bladders were used as donor tissues, stimulated by intermittent application of carbachol before or during the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), the adenosine/P1 nucleoside receptor antagonist 8-(p-sulfophenyl)theophylline (8-PST) or the cyclo-oxygenase inhibitor diclofenac infused to bath donor and bioassay tissues. The spontaneous contractions of bioassay ureters were unaltered by application of carbachol 1–5 µM in the presence of scopolamine 5–30 µM. When carbachol was applied over the urothelium-denuded bladder, the assay ureter contraction rate was unaltered. Introducing carbachol over the everted urothelium-intact bladder significantly inhibited the contraction frequency of the assay ureter, suggesting the transfer of an inhibitory activity from the bladder to the assay ureter. The transmissible inhibitory activity was not markedly antagonized by L-NAME, 8-PST or diclofenac, while L-NAME nearly abolished nitrite release from the urothelium-intact bladder preparations. We suggest that urothelium-derived inhibitory factor is a transmissible entity over a significant distance as demonstrated in this novel cascade superfusion assay and seems less likely to be nitric oxide, nitrite, an adenosine receptor agonist or subject to inhibition by administration of a cyclo-oxygenase inhibitor. 相似文献