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1.
The ability of three platelet activating factor (PAF) antagonists, BN52021, L652, 731 and 48740RP, and the leukotriene antagonist FPL55712 to block iv PAF-induced death was tested in mice. PAF-induced sudden death was been previously characterized as a model of systemic anaphylaxis and circulatory shock related its hypotensive actions. Of the drugs, BN52021 and L652, 731 provided dose-dependent protection against PAF toxicity, whereas the others had no effect. 48740RP was, however active against PAF-induced rabbit platelet aggregation. BN52021 was inactive in three other mouse sudden death models in which arachidonic acid, U46619 or collagen combined with epinephrine is injected iv to provoke a thrombotic/ischemic sudden death. In contrast, the TXA2 antagonist SQ29548 inhibited the acute toxicity of two of these latter challenges (arachidonic acid and thromboxane agonist U46619), but was inactive against PAF lethality.These results suggest that PAF toxicity in mice is a specific model for PAF agonism, and is not mediated by TXA2 or peptido-leukotrienes. Further, PAF-induced mortality should be a simple and useful technique for testing potential PAF antagonists for activity by various routes of administration.  相似文献   

2.
The aim of the present study was to investigate the possible effect of platelet-activating factor (PAF), by comparison with interleukin-1beta and polyriboinositic/polyribocytidylic (poly I-C) acid, on IL-6 production by L 929 mouse fibroblasts. At concentrations above 1 muM PAF, the production of IL-6 by mouse fibroblasts was enhanced in a dose dependent fashion. At 5 muM PAF, the peak increase (60.1 +/- 19.4 U/ml) was similar to that induced by 50 mug/ml poly I-C (60.0 +/- 35.0 U/ml) and higher than the one evoked by 100 U/ml IL-1beta (3.8 +/- 1.8 U/ml). The increase of 11-6 activity induced by 5 muM PAF was maximal after a 22 h incubation period with L 929 cells. Lyso-PAF (5 muM) also increased IL-6 activity from fibroblasts to a similar extent compared with 5 muM PAF. In addition, the IL-6 activity induced by 5 muM PAF was still observed when the specific PAF antagonist, BN 52021 (10 muM), was added to the incubation medium of L 929 cells. The result suggests that the production of IL-6 by L 929 cells evoked by PAF in vitro is not receptor mediated. The in vivo effect of PAF on IL-6 production was also investigated in the rat. Two hours after intravenous injection of PAF (2 to 4 mug/kg), a dramatic increase of IL-6 activity in rat serum was observed, this effect being dose dependent. The increase of IL-6 induced by 3 mug/kg PAF was not observed when the animals were treated with the PAF antagonist, BN 52021 (1 to 60 mg/kg0. These results demonstrate that PAF modulates IL-6 production and that the in vivo effect is receptor mediated.  相似文献   

3.
The inhibitory effect of BN 52021, a specific antagonist of platelet-activating factor (PAF) on PAF-induced activation of human polymorphonuclear granulocytes (PMNL) and on the binding of [3H]-PAF to neutrophils were examined. BN 52021 over the range of 10(-9)-10(-4) M inhibited PAF-induced degranulation and superoxide production of PMNLs in a dose-dependent manner with Kd values of 0.6 +/- 0.1 x 10(-6) M and 0.4 +/- 0.1 x 10(-6) M, respectively. BN 52021 (up to 1 mM) did not show any agonistic activity and it did not affect neutrophil responses to N-formyl-methionyl-leucyl-phenylalanine or leukotriene B4. The Ki value of BN 52021 for the specific binding of [3H]-PAF to neutrophils was 1.3 +/- 0.5 x 10(-6) M versus a Ki of 1.1 +/- 0.3 x 10(-7) M for PAF itself. BN 52021 did not affect metabolism of PAF by PMNL. These studies indicate that BN 52021 inhibits neutrophil responses to PAF by inhibiting binding of PAF to its specific PMNL receptor.  相似文献   

4.
The cardiac effects of PAF and its antagonist BN 52021 have been investigated on the isolated perfused guinea-pig heart maintained at a constant hydrostatic perfusion pressure of 80 cm water. In this model, PAF (1 x 10(-11) to 1 x 10(-7) moles) induced a dose-dependent coronary vasoconstriction, a decrease in heart rate and a fall in contractile force. BN 52021 (1 x 10(-6) to 2 x 10(-4) M) dose-dependently inhibited the vasospasm induced by PAF (1 x 10(-10) moles). BN 52021 also antagonized the decrease in coronary flow and heart rate, but not that of contractile force induced by a high dose of PAF (1 x 10(-7) moles). This dose of PAF also significantly (p less than 0.001) provoked a marked release of TxB2 but did not alter the generation of 6 Keto PGF1 alpha, PGE2 or LTC4. The PAF-induced increase in TxB2 release was completely abolished by BN 52021.  相似文献   

5.
The involvement of platelet activating factor (PAF) in anaphylaxis was examined by recording the pulmonary responses of anesthetized passively sensitized guinea-pigs to the aerosolization of ovalbumin. Animals were tested with and without BN 52021 (a ginkgolide B, PAF receptor antagonist) pretreatment. Aerosolization of ovalbumin produced a bronchoconstriction (BC) which could be made refractory to additional challenges with the antigen. In animals desensitized to ovalbumin, aerosolization of PAF produced an unattenuated BC. Guinea pigs desensitized by repeated aerosolizations of PAF subsequently showed reduced responses to aerosolized antigen suggesting that PAF may be involved in the BC. Animals pretreated with BN 52021, were protected against the effects of systemically administered PAF and also showed reduced responses to aerosolized antigen. Aerosolization of the leukotriene antagonist, FPL 55712, was ineffective against anaphylactic BC under conditions where catecholamine and histamine release were blocked.  相似文献   

6.
The involvement of platelet activating factor (PAF) in anaphylaxis was examined by recording the pulmonary responses of anesthetized passively sensitized guinea-pigs to the aerosolization of ovalbumin. Animals were tested with and without BN 52021 (a ginkgolide B, PAF receptor antagonist) pretreatment. Aerosolization of ovalbumin produced a bronchoconstriction (BC) which could be made refractory to additional challenges with the antigen. In animals desensitized to ovalbumin, aerosolization of PAF produced an unattenuated BC. Guinea pigs desensitized by repeated aerosolizations of PAF subsequently showed reduced responses to aerosolized antigen suggesting that PAF may be involved in the BC. Animals pretreated with BN 52021, were protected against the effects of systematically administered PAF and also showed reduced responses to aerosolized antigen. Aerosolization of the leukotriene antagonist, FPL 55712, was ineffective against anaphylactic BC under conditions where catecholamine and histamine release were blocked.  相似文献   

7.
In order to investigate the effects of varying the rate of flow on endothelial integrity the rat isolated small intestinal vasculature was perfused at 1, 5, 10 or 20 ml/min with a gelatin-containing physiological salt solution (GPSS), followed by an injection of colloidal carbon suspension (CC). Significantly greater microvascular CC leakage occurred at 1 or 5 ml/min than at 10 or 20 ml/ mitt. CC leakage at the two slower rates of flow was reduced by adding red blood cells to the GPSS, suggesting that the microvascular endothelium became hypoxic when perfused with GPSS at 1 or 5 ml/min. After perfusion at 20 ml/min with GPSS containing resiniferatoxin (1 muM) or 5-hydroxytryptamine (100 muM), CC leakage was significantly lower than after similar perfusion at 10 ml/min. Two nitric oxide (NO) synthesis blockers, N-nitro-L-arginine methyl ester (L-NAME, 100 muM) and methylene blue (20 muM), and an NO scavenger CPTIO (100 muM) each increased CC leakage. This suggests that NO was being produced at perfusion rates of 10 or 20 ml/min. Sodium nitroprusside (10 muM), 8-bromo-cGMP (100 muM) and BN52021 (10 muM) each significantly reduced CC leakage in the presence of L-NAME.  相似文献   

8.
The haemodynamic effects of adenosine are thought to result in part from a release of mast cell amines via A3 receptor stimulation. To investigate the nature of the receptors involved in adenosine-induced mast cell degranulation in the rat isolated omentum we have used adenosine analogues with varying specificities as activators of the A(1), A(2) and A(3) receptors, and antagonists with differing specificities for A(1) and A(2) receptors. Analogues which act predominantly as A(1) (e.g. N(6)-cyclopentyladenosine) or as mixed A(1)/A(2) receptor agonists (e.g. adenosine, inosine, 5'-(Nethylcarboxamido) adenosine) caused mast cell degranulation, whereas a predominantly A3 receptor agonist (IB-MECA) was inactive. Pre-treatment of the omentum with the A(1)/A(2) receptor antagonist 8-phenyltheophylline or with the more specific A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine significantly reduced agonist-induced degranulation. Pre-treatment with disodium cromoglycate or with BN52021 also reduced degranulation of mast cells in response to N(6)-cyclopentyladenosine. In the rat isolated omental mast cell we conclude that degranulation is an indirect result of A(1) receptor stimulation. Platelet-activating factor release appears to mediate at least part of the degranulation.  相似文献   

9.
The rabbit cornea accumulates platelet activating factor (PAF) three hrs after alkali burn. PAF was isolated by HPLC and assayed by platelet aggregation. This bioactivity was blocked by the PAF receptor antagonists BN 52021 and alprazolam. Added PAF increases the chemiluminescence response of the cornea in vitro and BN 52021 inhibits this effect. In vivo experiments show that the synthesis of 5-HETE and 12-HETE is inhibited by the PAF antagonist BN 52021. It is concluded that a metabolic interrelationship may exist between the PAF cycle and the lipoxygenation of arachidonic acid, and that drugs that affect these lipid mediators may modulate the inflammatory response of the anterior segment of the eye.  相似文献   

10.
To study the effect of the in vivo administration of platelet-activating factor (PAF) on cytokine production, alzet minipumps loaded with the mediator or solvent alone were connected to the jugular vein and placed under the skin of Sprague-Dawley rats. Over 7 days the animals received total doses of 0.5, 1, 4.5, 9, or 28 micrograms PAF or the solvent alone. The spleen mononuclear cells isolated from Ficoll gradients and the adherent cell fraction were separated before determination of basal and mitogen-stimulated IL-1 and IL-2 production, respectively. Adherent splenocytes from rats having received 28 micrograms PAF exhibited a decreased capability to produce IL-1, as compared to those from vehicle-treated animals. In contrast, adherent splenocytes from rats having received 9 and 4.5 micrograms PAF yielded higher amounts of released and cell-associated IL-1 activity upon LPS stimulation, as compared to those from solvent-treated animals. The PAF antagonist, BN 52021, given orally (5 mg/kg, twice a day throughout the experiments) inhibited the in vivo effect of 28 micrograms PAF. Statistically significant 144 +/- 43% (p less than 0.001, n = 5) and 73 +/- 33%, (p less than 0.01, n = 3) increases in IL-2 production were observed when whole spleen mononuclear cells from rats administered with 1 and 4.5 micrograms PAF, respectively, were stimulated with Con A. BN 52021 markedly inhibited the in vivo effect of 1 microgram PAF on the IL-2 release. Our study demonstrates that PAF can modulate immune functions in vivo and suggests that the specific PAF antagonist, BN 52021, may be used as an immunomodulatory agent.  相似文献   

11.
The effect of a new PAF antagonist BN 50739 was studied on PAF-induced [3H]-serotonin release from washed rabbit platelets in vitro and on PAF-induced hypotension in vivo. BN 50739 competitively inhibited PAF-induced [3H]-serotonin release from the platelets in a dose-dependent manner. In the presence of 4, 10 and 50 nM of BN 50739, the concentration of PAF inducing 50% maximal [3H]-serotonin release from the platelets (EC50) increased from 2.15 nM to 5.10, 45.10 and 900 nM, respectively. The IC50 of BN 50739 for PAF (10 nM) induced [3H]-serotonin release was 3.67 nM. Under the same experimental condition, the IC50s of BN 50726, BN 50730, BN 50741, WEB 2086, SRI 63-441 and BN 52021 were 5.40, 4.61, 6.88, 5.98, 40.90 nM and 14.90 microM, respectively. PAF-induced hypotension in conscious rats was also inhibited dose-dependently by i.p. pretreatment of BN 50739 (3 and 10 mg/kg). PAF-induced hypotension was diminished both in magnitude and duration in rats pretreated with BN 50739. These data taken together indicate that BN 50739 is a most potent PAF antagonist in vitro and in vivo.  相似文献   

12.
Platelet-activating factor (PAF) and sulphidopeptide leukotrienes, such as leukotriene D4 (LTD4), are potent constrictors that are probably released simultaneously in a variety of inflammatory respiratory events. The purpose of the present study was to determine whether LTD4-induced contractions of guinea pig parenchymal lung strips (GPPS) are modified in the presence of PAF. The contractile responses of isolated GPPS to cumulative doses of LTD4, acetylcholine, histamine, and potassium chloride in the presence of PAF (0.1 nM, 0.1 microM) were compared with parallel controls. There was no significant alteration of the response to acetylcholine and potassium chloride and the PAF-induced inhibition of the response to histamine, although significant, was not concentration dependent. In contrast, PAF in a concentration range from 0.1 nM to 1.0 microM caused a marked, concentration-dependent reduction of LTD4-induced contractions. Pretreatment with the PAF receptor antagonist, BN52021, prevented the attenuation of LTD4-induced contraction by PAF. The attenuation of LTD4-induced contraction by PAF was also prevented by pretreatment with indomethacin or with the thromboxane synthase inhibitor U63,557A, but not by pretreatment with the lipoxygenase inhibitors BW755c or nordihydroguaiaretic acid. Thus inhibition of LTD4-induced GPPS contraction by PAF is receptor dependent and probably secondary to thromboxane generation. The respiratory smooth muscle response to leukotrienes may be modified significantly by concomitant PAF release.  相似文献   

13.
Here we explored the mechanisms of secretory phospholipase A2 (sPLA2) and glutamate (glu) in neuronal signalling and cell damage. Rats or primary neuronal cultures were treated with MK‐801 and injected with/exposed to sPLA2 or glu. MK‐801 partially inhibited sPLA2‐ and glu‐induced neuronal death as well as [3H]arachidonic acid release. The involvement of cytosolic PLA2 (cPLA2) and plateletactivating factor (PAF) in sPLA2 or glu signalling was explored by treating cells with the selective cPLA2 inhibitor, AACOCF3, PAF‐acetyl hydrolase (PAF‐AH) or the presynaptic PAF‐receptor antagonist, BN52021. AACOCF3 blocked sPLA2‐ and glu‐induced neuronal death by 26 and 77%, respectively. PAF‐AH ameliorated sPLA2 as well as glu neurotoxicity by 31 and 47%, whereas BN52021 inhibited sPLA2 induced neurotoxicity by 11% but did not significantly protect against glu‐induced neurotoxicity. Expression in neurons of early response genes in response to sPLA2 or glu was further examined. An up‐regulation of COX‐2, c‐fos, and c‐jun, but not COX‐1, was observed at earlier time points after rat striatal injection of glu as compared to sPLA2 injection. Moreover we treated neuronal cells with COX‐2 inhibitors and found that neuronal cell death after sPLA2 and glu exposure was inhibited by 35 and 33%, respectively. Thus sPLA2 activates a neuronal signalling cascade that includes activation of cPLA2, AA‐release, production of PAF and induction of COX‐2. Hence sPLA2 and glu signalling are overlapping, but not identical. Cytosolic PLA2 may primarily drive glutamatergic neurotransmission, whereas PAF plays a more crucial role in sPLA2 neuronal signalling. Acknowledgements: Supported by EPSCoR grant NSF/LEQSF(2001‐04)‐RII‐01 from the National Science Foundation.  相似文献   

14.
Injection of PAF into the left uterine horn induced a dose-dependent decidua-like reaction in the pseudopregnant rat. This reaction was maximal when PAF was injected at Day 5 of pseudopregnancy and was blocked by the specific PAF antagonist, BN 52021. BN 52021 did not interfere with the decidual reaction induced by prostaglandin E-2 or insertion of a cotton thread in the uterine horn. In contrast, a decidua-like reaction was not evoked by the inactive lyso-PAF, demonstrating the specificity of the action of PAF. The decidua-like reaction induced by PAF involves the generation of cyclooxygenase metabolites of arachidonic acid since it was inhibited by indomethacin. The histological alterations induced by PAF were similar to those observed after embryo implantation, strengthening the postulate for a role of the autacoid in the early stages of pregnancy.  相似文献   

15.
The effect produced by the injection of platelet activation factor (PAF) and its antagonist BN 52021 on the intensity of humoral immune response in (CBA x C57BL)F1 mice was studied. PAF was found to stimulate the formation of antibodies to sheep red blood cells. In addition PAF stimulated the phagocytic activity of mouse peritoneal macrophages. The stimulation of immune response under the action of PAF may be attributed to an increase in the phagocytic activity of macrophages. The stimulating effect of PAF on immune response in vivo was abolished by the injection of BN 52021, the antagonist of PAF. At the same time the dose-dependent decrease of immune response was observed after the injection of BN 52021. Indomethacin, an inhibitor of prostaglandin synthesis, when administered to mice treated with BN 52021, abolished the BN 52021-induced suppression of humoral immune response. Mouse peritoneal macrophages, treated in vitro with BN 52021, were found to produce significantly more prostaglandin E than control macrophages. Thus, BN 52021 induced the suppression of humoral immune response in vivo; this suppression was probably due to the action of prostaglandin E2, a messenger of the second order. Besides, the PAF antagonist BN 52021 significantly decreased leukotriene B4 production by macrophages in vitro. BN 52021 may be supposed to switch over the synthesis and/or secretion of arachidonic acid from the lipoxygenase pathway to the cycloxygenase one.  相似文献   

16.
PAF-acether may be involved in anaphylaxis and asthma. We tested the new PAF-acether antagonist BN 52021 against the effects of antigen in passively sensitized guinea-pigs. Bronchoconstriction by ovalbumin administered i.v. (1 mg/kg) or by aerosol (1 or 10 mg/ml for a period of 1 min) was significantly reduced by BN 52021 (1-10 mg/kg), which did not inhibit drop of leukocyte counts after the i.v. challenge. In both cases, when the guinea-pigs were pretreated by propranolol, high amounts of BN 52021 became ineffective against shock. The reduction of the anaphylactic bronchoconstriction, induced by the combination of mepyramine, aspirin and FPL 55712 was not improved by BN 52021. Tested on isolated lung strips from passively sensitized guinea-pig, BN 52021, at a concentration which inhibits PAF-induced contraction (0.1 mM), did not inhibit the anaphylactic contraction triggered by the administration of ovalbumin (10 micrograms/ml) nor the accompanying release of histamine and thromboxane. In contrast, BN 52021 (30 microM) significantly reduced the anaphylactic release of histamine and of thromboxane from perfused lungs of passively sensitized guinea-pigs. The results with the isolated lung strips and the propranolol-treated guinea-pigs in vivo suggest a dissociation between the anti-anaphylactic and the anti-PAF-acether properties of BN 52021.  相似文献   

17.
The effect of a thrombin receptor agonist peptide (TRAP-6) on the release of nitric oxide (NO) and platelet activating factor (PAF) from resting and calcium-ionophore (A23187)-activated rat peritoneal mast cells (RPMC) was studied using a platelet aggregation bioassay. RPMC spontaneously released NO, which inhibited TRAP-6-, ADP-, and PAF-stimulated platelet aggregation. This effect of NO was abolished by the addition of an NO binding agent, oxyhemoglobin (oxyHb), to the platelet suspension. The RPMC-induced suppression of platelet aggregation was completely inhibited by the NO-synthase inhibitor L-NAME. TRAP-6 and its high affinity analog haTRAP stimulated the rapid release of NO from RPMC. The effect of TRAP-6 was inhibited by pretreatment of the RPMC with L-NAME or with the inhibitor of the constitutive NO-synthase isoform (cNOS) calmidazolium. TRAP-6 inhibited PAF release from A23187-activated RPMC via an NO-dependent mechanism. Platelet aggregation induced by PAF release from activated RPMC was also confirmed in experiments using the PAF receptor antagonist ginkgolide B. Thus, TRAP-6 is a rapidly acting modulator of mast cell reactivity; it stimulates NO release and inhibits PAF secretion.  相似文献   

18.
Phorbol-12-myristate-13-acetate (PMA), calcium ionophore A23187 and platelet activating factor (PAF) stimulated the generation of oxygen free radicals (nitro-blue tetrazolium reduction) in Ehrlich ascites tumour (EAT) cells. PAF was effective at an optimal concentration of 4 muM, but was inhibited by BN 52021, a specific PAF antagonist. Lyso-PAF was ineffective. Inclusion of different lipids during incubation prior to the addition of PAF, resulted in the activation/inhibition of free radical generation. Among the phospholipids at a concentration of 50 mug/ml, the order of activation was phosphatidylserine > phosphatidylglycerol > phosphoinositides > phosphatidylinositol > phosphatidylethanolamine. Phosphatidylcholine was not effective, while sphingolipids were inhibitory. In addition, Ehrlich ascites tumour cells grown in mice under marginal vitamin A deficiency, showed an augmented production of free radicals compared to control cells. This was suppressed by exogenous addition of vitamin A or superoxide dismutase. These results suggest that membrane lipids and dietary factors like vitamin A probably function as physiological modulators in regulating the free radical generation.  相似文献   

19.
《Free radical research》2013,47(1):725-735
Oxygenated free-radicals appear to play a prominent role in mediating damage associated with gastrointestinal diseases. Production of reactive oxygen metabolites in ischemia-reperfusion involves oxidases found in resident phagocytic cells and microvascularand mucosal epithelial cells. Platelet activating factor (PAF), a phospholipid associated with inflammatory disorders, has been shown to both prime and amplify the release of superoxide anion and hydrogen peroxide from polymorphonuclear neutrophils and macrophages stimulated by FMLP or PMA. To further elucidate the involvement of free radicals in intestinal damage and the potential role of PAF in their production, we examined the effect of superoxide dismutase (SOD) and BN 52021 (ginkgolide B) on ischemia-reperfusion induced damage in the small intestine.

The study involved 32 Sprague-Dawley rats (100–200 g) divided into four groups. Three of these groups were subjected to occlusion of the mesenteric artery 30 mins followed by 24 h reperfusion. On 2 groups SOD (15,000 U/kg/iv) and BN 52021 (20 mg/kg/po) were administered 45 mins before arterial occlusion. Following the 24 h reperfusion, the rats were sacrificed after overnight fasting. The jejunum and ileon were removed and fixed for morphological examination. Lesions in the small intestine were quantified.

The results showed extensive necrosis, hemorrhage, oedema and neutrophil invasion in the jejunal and ileal mucosa. This injury was significantly reduced by SOD (15.000 U/kg/iv) and BN 52021 (20 mg/kg/po) pretreatment. In conclusion, free-oxygenated radicals appear to mediate reperfusion damage in the small intestine and PAF appears to be involved in the genesis of these toxic products. Thus, SOD and BN 52021 may be considered as protectors against ischemic disorders.  相似文献   

20.
The intraplantar injection of PAF-acether (PAF), induced acute oedema in the rat paw, and desensitized it to subsequent challenges with the same agonist, but not to serotonin. The desensitization was maximal (up to 80% of initial response) after seven consecutive daily injections. In this condition, PAF-induced oedema of the contralateral paw was maintained. The analogue 2-methyl carbamate-PAF (2MC-PAF) was more effective than PAF as a desensitizing agent. Furthermore, the PAF-desensitized paw was refractory to challenges with 2-MC and vice-versa. PAF-acether, but not serotonin-induced rat paw oedema was inhibited by previous intravenous injection of PAF. Intravenous injections of serotonin were also effective in inhibiting selectively serotonin-induced paw oedema, but it was not possible to induce desensitization by repeated intraplantar injections of serotonin. Desensitization to PAF or the pre-treatment with the PAF antagonist BN 52021 did not block the edematogenic response induced by carrageenan.  相似文献   

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