Effect Of PAF Antagonist Research Articles

Effect of PAF antagonist on NO content and expression of iNOS in gastric mucosal during endotoxemia in young rats

Effect of PAF antagonist on NO content and expression of iNOS in gastric mucosal during endotoxemia in young rats

Analysis of cardiac function during hyperacute rejection: effects of PAF antagonist, TXA 2 inhibitor/antagonists, and nitroglycerin

Analysis of cardiac function during hyperacute rejection: effects of PAF antagonist, TXA 2 inhibitor/antagonists, and nitroglycerin

Effect of SM-12502 on disseminated intravascular coagulation (DIC) in tumor-bearing rats.

To investigate the role of PAF in tumor-associated disseminated intravascular coagulation (DIC), we have established the tumor-induced DIC model in rats and examined the effect of PAF-antagonist as compared with commonly used anti-DIC drugs. Four days after the intraperitoneal inoculation of rat ascites hepatoma AH-130, DIC-like hematological parameter changes such as decrease in platelet count, prolongation of PTT and increase in FDP were observed. In addition, serum levels of GOT and GPT were increased, indicating that liver injury was provoked. PAF-antagonist SM-12502 inhibited the development of DIC (PT, PTT and FDP) and liver injury. These results indicate that PAF plays an important role in tumor-associated DIC as well as accompanying organ failure.

Paf antagonists block induction of nitric oxide synthase in cultured macrophages and vascular smooth muscle cells.

1. Nitric oxide (NO) synthase inhibitors and Paf antagonists abrogate hypotension in septic shock. The latter may act by blocking intracellular transduction mechanisms in vascular smooth muscle cells and inflammatory cells. We examined the effect of Paf antagonists on expression of inducible NO synthase. 2. A murine macrophage cell line (J774.2) and rat vascular smooth muscle cells (VSMC) were stimulated with lipopolysaccharide (LPS), either alone or in combination with Paf or Paf antagonists, BN 50739 or E-6123. 3. NO synthase activity in J774.2 was measured by the conversion of [3H]L-arginine to [3H]L-citrulline. Nitrite accumulation was measured in the culture medium of J774.2 and VSM. 4. BN 50739 (10 mumol/L and E-6123 (1 mumol#L) both reduced the expression of calcium-independent NO synthase activity and nitrite accumulation, while Paf alone had no effect. 5. Inhibition of NO synthase induction by Paf antagonists might afford therapeutic benefits in the management of septic shock and possibly other cardiovascular disorders.

Effect of PAF antagonists on cerulein-induced pancreatitis

The present study was undertaken to investigate the involvement of PAF in acute pancreatitis induced by cerulein in rats. Cerulein (two doses of 20 μ/rat, the first s.c. and the second i.v., 1 h apart) induced a significant increase in vascular permeability in the pancreas, evaluated by the Evans blue (EB) extravasation method. Plasma amylase levels were also significantly increased in this group. The PAY antagonists, BN-52021 (5 mg/kg) and WEB-2170 (1 and 10 mg/kg), both significantly reduced the extravasation of EB in the pancreas induced by i.v. injection of PAF (1 μg/kg). At these concentrations, BN-52021 was effective at inhibiting cerulein-induced pancreatitis (60–70% of inhibition) whereas WEB2170 had no significant effect. Although the inhibition induced by BN-52021 suggests the involvement of PAF in cerulein-pancreatitis, the lack of effect of WEB-2170 reported here does not allow a definite conclusion. Further studies are needed to elucidate the differential effect of the PAF antagonists.

The effect of topical application of the platelet-activating factor-antagonist, Ro 24-0238, in psoriasis vulgaris-a clinical and immunohistochemical study

Platelet-activating factor (PAF) is considered to be one of the most potent lipid mediators in allergic and inflammatory reactions. Suggestions that PAF is produced by cutaneous cells, and cells infiltrating the skin from the blood, have been reported. PAF has been identified in allergic cutaneous reactions and also in psoriatic lesions. The biological activity of PAF is thought to be mediated by cell membrane receptors. Studies revealed that PAF-antagonists can be active in animal models of cutaneous inflammation. In humans PAF-antagonists showed minimal therapeutic improvement in studies of antigen-induced cutaneous responses in atopic subjects. No data are available on the effects of PAF-antagonists in psoriasis. The objective of this study was to investigate the effect of a potent PAF-antagonist (Ro 24-0238, 10% solution in diethylene glycol monoethyl ether) in 10 patients with chronic plaque psoriasis, a placebo-controlled double-blind study. Clinical response was evaluated and markers of inflammation, differentiation and proliferation were studied immunohistochemically on punch biopsies taken from actively treated and placebo-treated lesions, before and after treatment. This study demonstrated that a 10% solution of the PAF-antagonist Ro 24-0238 was not effective at the clinical or cell biological level after a 4-week treatment period. The most likely explanation for these negative observations is that PAF is not a significant factor in the pathogenesis of psoriasis.

血管内皮細胞を介する好中球遊走における血小板活性化因子の役割解析

In an air pouch type allergic inflammation model in rats, PAF antagonists inhibit neutrophil migration into the pouch fluid although levels of PAF in the pouch fluid are less than the detectable amount. To clarify roles of PAF in neutrophil migration, effects of PAF antagonists (CV-6209, L-652, 731, Y-24180) on transendothelial migration of neutrophils were examined in vitro. Histamine and thrombin stimulated LTB4-induced transmigration of neutrophils through the confluent monolayer of human umbilical vein endothelial cells (HUVEC) . Treatment with PAF antagonists selectively inhibited the histamine- and thrombin-induced transendothelial migration, suggesting that PAF plays some significant roles in endothelial cell recognition by neutrophils.Treatment of HUVEC with TNF-α or IL-1/β induced neutrophil adherence to HUVEC monolayer and expression of adhesion molecules, such as ICAM-1, ELAM-1 or GMP-140. However, PAF antagonists showed no effect on the cytokine-induced neutrophil adherence to HUVEC nor the expression of these adhesion molecules. Furthermore, histamine- and thrombin-induced neutrophil adherence to HUVEC was inhibited by PAF antagonists without altering the expression of these adhesion molecules.Transendothelial migration of neutrophils was not inhibited by antibodies to GMP-140 and ELAM-1, but was completely inhibited by an antibody to LFA-1/β. An antibody to ICAM-1 partially inhibited the transendothelial migration of neutrophils.These results suggest that PAF produced by HUVEC plays important roles in signaling for neutrophil adherence to endothelial cells without affecting the expression of these adhesion molecules.

長期低酸素曝露による肺高血圧招来における血小板活性化因子の関与

Chronic hypoxic exposure causes pulmonary hypertension and right ventricular hypertrophy associated with pulmonary vascular remodeling in rats. Since platelet-activating factor (PAF) production has been shown to increase during hypoxia, and since PAF contributes to pulmonary hypertension, we hypothesized that increased PAF during hypoxia might play a role in the development of pulmonary hypertension induced by hypoxic exposure, and examined the effect of PAF-antagonists on hypoxia-induced pulmonary hypertension. Pulmonary hypertension and right ventricular hypertrophy developed at 3 weeks of hypoxic exposure. Treatment with WEB 2170 or BN 50739, specific PAF-antagonists significantly reduced hypoxia-induced pulmonary hypertension. Hypoxia-induced pulmonary hypertension was associated with an increase in the vessel wall thickness of the muscular arteries. In WEB 2170-treated rats, this change was significantly less severe than that observed in untreated chronically hypoxic rats. These results indicate that the PAF-antagonists inhibit the development of pulmonary hypertension induced by chronic hypoxic exposure and suggest a role for PAF in the remodeling process of pulmonary vessels induced by chronic hypoxia in rats.

PAF-induced death in NMRI mice — a suitable shock model for testing new PAF receptor antagonists. Correlation with eicosanoid related substances

The effects of PAF antagonists, of substances which influence the arachidonic acid metabolism, and of dexamethasone and ketotifen were evaluated in an acute PAF-induced mortality model in female NMRI mice. We established a dependence of sensitivity to PAF on strain (AB mice showed no dose dependence) and on sex of the animals as well as on the PAF charges used in our experiments. PAF produced resistance in surviving animals against the PAF-induced death on repeated application. The PAF antagonists, WEB 2170 and WEB 2086, provided the best dose-dependent protection against PAF toxicity, followed by dexamethasone, by the COX/LOX synthetase inhibitor X 86 (a BW 755 C-analogue) and by the PAF receptor antagonist BN 52021. Particularly remarkable was the excellent prevention by aspirin. Aspirin may not only inhibit the cyclooxygenase pathway but also endogenous PAF synthesis. Other drugs, i.e. indomethacin, the thromboxane receptor antagonist, BM 13177, the thromboxane synthetase inhibitor, HOE 944, as well as the lipoxygenase inhibitors (NDGA, esculetin, SHAM and phenidone) exerted a dose-dependent protection only at high doses.

Effect of PAF antagonists in retinal diseases

Long-term potentiation (LTP), a model of activity-dependent synaptic plasticity and of certain forms of memory, comprises the persistent enhancement of excitatory neurotransmission that results from high-frequency activation. A presynaptic component of LTP is thought to be modulated by a retrograde messenger generated by the postsynaptic neuron. Arachidonic acid, nitrix oxide, carbon monoxide and PAF have each been proposed as retrograde messengers in LTP, but arachidonic acid, unlike PAF, requires NMDA receptor activation. A PAF antagonist (BN 52021) that provides neuroprotection in ischemia-reperfusion displaces [3H] PAF bound to presynaptic membranes, blocks PAF-induced glutamate exocytosis and inhibits LTP. An antagonist selective for the intracellular PAF binding site (BN 50730) did not affect LTP, nor did BN 52021 modify NMDA currents. LTP was induced with weak synaptic stimulation coupled with postsynaptically administered enzyme resistant mcPAF. Theta-burst stimulation (10 min) after bath applications of mcPAF (1 μM) induced APV-independent LTP that was blocked by 5 μM BN 52021. When this antagonist was infused into the hippocampus before or immediately after training, it impaired memory of inhibitory avoidance training in the rat. Memory was not altered if the antagonist is infused 30 or 60 min after training. Moreover, mcPAF enhances memory on retention test performance of step-down inhibitory avoidance habituation and learning in rats. Also, memory was studied using a caudate nucleus-dependent cued water maze task. Rats received an 8 trial (30 s intertrial interval) training session in which a visible cued escape platform was located in a different quadrant of the maze of each trial. Following trial 8, the rats received a unilateral post-training intra-caudate injection of mcPAF (1 μg/0.5 μl), BN 52021 (0.5 μg/0.5 μl) or vehicle. On a retention test session 24 h later, latency to mount the escape platform was used as a measure of memory. The retention test escape latencies of rats given mcPAF were significantly lower than those of the vehicle-injected controls, indicating a memory enhancing effect of mcPAF. Injection of mcPAF did not affect retention when administered 2 h post-training indicating a time-dependent effect of mcPAF on memory. The latencies for animals injected with BN 52021 were significantly higher than those of the controls, indicating that antagonism of endogenous PAF impairs memory. The findings show that PAF plays a role in memory formation in a caudate-mediated cued discrimination task. Administration of BN 52021 2 h post-training had no effect on retention, indicating a time-dependent effect of endogenous PAF on memory formation. PAF, the most potent bioactive lipid known, modulates excitatory synaptic transmission, neuronal plasticity and memory. When PAF production is overstimulated as in seizures or ischemia, it becomes neurotoxic.

The effects of PAF antagonist upon the ischemia-reperfusion injury

The effects of PAF antagonist upon the ischemia-reperfusion injury

Effects of PAF antagonists on renal vascular escape and tachyphylaxis in perfused rabbit kidney

Renal vascular escape is a physiological phenomenon of adaptation that occurs in vascular smooth muscle. It has been described in many preparations subjected to electrical stimulation or treated with vasoactive agents, such as noreprinephrine, angiotensin and vasopressin. We have recently demonstrated that a naturally occurring ginkgolide (BN 52021), which is a PAF antagonist, was able to block norepinephrine-induced escape in perfused rabbit kidney. In the present work other PAF antagonists, such as the ginkgolides BN 52022 and BN 52024, and the synthetic compounds 48740 RP and WEB 2086, were tested. Their effects on renal vascular escape, perfusion pressure and tachyphylaxis were evaluated. They all were shown to block the escape. Among the ginkgolides, BN 52024 is generally recognized as one of the weaker PAF antagonists. However, in spite of this, BN 52024 was able to significantly and simultaneously block renal vascular escape and tachyphylaxis in perfused rabbit kidney infused with norepinephrine.

Inhibition of Ehrlich ascites tumor in vivo by PAF-antagonists

Several lines of evidence support that PAF modulates the inflammatory and immune responses, and that tumors may inhibit both these processes. In the present study we analysed the effect of PAF antagonists on the growth of Ehrlich Ascites Tumor (EAT) in vivo. Mice were inoculated intraperitoneally with 1 × 10 3 EAT cells and the tumor growth evaluated by counting the number of peritoneal cells, 1, 6 and 10 days after tumor implantation. BN 52021 was administered intraperitoneally, intravenously or subcutaneously once or twice a day, at 1.0, 2.5, 5.0 and 20.0 mg/kg. Control animals received 0.1 ml of the vehicle in the same schedule. It was found that i.p. and i.v. administration of BN 52021 (5 mg/kg, twice a day) significantly inhibited EAT growth (80.8% and 56.0% respectively). Other routes and doses were less effective. Another PAF antagonist, SRI 63441 (5 mg/kg, i.p., twice a day) also inhibited EAT growth (80.4%). The BN 52021 added to EAT cells in culture, at concentration of 10 −3 and 10 −4 M, did not affect the viability and proliferation of tumors cells. In an attempt to understand the mechanism of this inhibition, we analyzed the peritoneal macrophages for spreading ability and H 2O 2 release. It was found that 24 h after tumor implantation there was an increase in the spreading ability of peritoneal macrophages (75%) and that, as the tumor grew, the spreading index fell to control levels (<10%). In the groups treated with BN 52021 (5 mg/kg/twice a day) the spreading remained elevated (50–60%) at all the times examined. Release of H 2O 2, measured by horseradish peroxidase-phenol red oxidation, was below detectable levels throughout tumor growth. Treatment with BN 52021 as above, significantly stimulated the release of H 2O 2, 6 and 10 days after tumor implantation (0.4 to 0.6 nmol/10 5 cells). The data presented show that PAF antagonists inhibit EAT growth in vivo and that this inhibition is concomitant with activation of peritoneal macrophages. These results suggest that macrophages can critically influence tumor growth and that PAF or PAF-like substances may modulate macrophages-tumor interactions.

The effect of Paf antagonists on bronchial hyperresponsiveness induced by Paf, propranolol or indomethacin.

1. Intravenous administration of platelet activating factor, Paf (600 ng kg-1 h-1) to ventilated anaesthetised guinea-pigs induced bronchial hyperresponsiveness to i.v. acetylcholine. 2. Pretreatment of ventilated, anaesthetised guinea-pigs with the beta-adrenoceptor antagonist, propranolol, or the non-steroidal anti-inflammatory drug, indomethacin, induced bronchial hyperresponsiveness to i.v. histamine. 3. Paf-induced bronchial hyperresponsiveness was significantly attenuated by pretreatment with three different Paf antagonists, CV-3988, BN 52021 and WEB 2086. 4. Pretreatment of guinea-pigs with CV-3988, BN 52021 or WEB 2086 at doses inhibiting Paf-induced bronchial hyperresponsiveness, had no significant effect on propranolol or indomethacin-induced bronchial hyperresponsiveness. 5. It is suggested that bronchial hyperresponsiveness induced by propranolol or indomethacin is not secondary to Paf release in the guinea-pig.

Interstitial Mononuclear Cell Infiltrates in Experimental Nephrosis: Effect of PAF Antagonist

Rats receiving a single injection of either aminonucleoside of puromycin (PAN, 10 mg/100 g) or Adriamycin (ADR, 7.5 mg/kg) develop heavy proteinuria and tubulointerstitial nephritis. Interstitial mononuclear cells were markedly more intense in PAN- than in ADR-treated rats. The composition of cell infiltrates was characterised in frozen kidney sections using an immunoperoxidase staining method and a panel of specific monoclonal antibodies. The severe mixed cellular lesions observed in the PAN model on day 14 were dominated by ED1+ macrophages, OX6+ Ia-interstitial and OX8+ T-cytotoxic/suppressor cell surface markers. A similar but more discrete ADR-interstitial cell accumulation was observed on day 11 of the experiment. A correlation existed in the PAN model between the severity of interstitial nephritis and the degree of proteinuria. In contrast, there was no such correlation in ADR nephrosis. Administration of PAF antagonist (BN 52021), started on the first day and continued throughout the 4 weeks of the experiment, induced in both ADR and PAN-treated rats a partial reduction in the number of interstitial cell infiltrates. Glomeruli from normal control rats incubated with 3H acetate, substrate for lyso-PAF: acetyl-CoA acetyltransferase and ADR stimulated PAF generation. Although the precise mechanism of interstitial cell accumulation in these two models of nephrosis are still unknown, our results suggest that PAF could be an important factor involved in interstitial cell recruitment.

ラット実験潰瘍とPAF(platelet-activating factor,血小板活性化因子)

Platelet-activating factor (PAF,1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a ether-linked phospholipid that exhibits a wide range of biological activities, that include stimulation of platelet and neutrophile, vasodilation, increase in vascular permeability, bronchoconstriction and pulmonary hypertension. Such actions have implicated PAF as a potent chemical mediator in anaphylactic or inflammatory processes. Furthermore, in recent studies, it has been elucidated that PAF was not only produced in response to pathological stimulation but also generated in normal animal tissues. But, it remains to be unclear what is the biological role of the endogenous PAF in normal tissues.On the other hand, there have also been many reports on gastric mucosal damage induced by exogenous PAF or protective effect of PAF antagonist in experimental ulcer model. However, these observations suggested that stomach was the target organ for PAF which contributed to pathological state (e. g. inflammation).This study focussed the relation between endogenou s PAF in stomach and the alteration of gastric microenvironment and suggested the following matters.1) It was elucidated that the endogenous PAF was indeed present in stomach of normal rat. The significantly high level of PAF was detected in the antrum.2) The endogenous PAF level dynamically altered in quick resp onse to stimuli which affected the gastric microenvironment (e. g. water-immersion stress).3) It was suggested that PAF might play some role in the formation or deterioration of gastric mucosal lesion induced by water-immersion stress and ethanol, because the specific PAF antagonists prevented such experimental ulcer.4) It was also suggested that the endogen ous PAF level in stomach was changed in association with physiological alteration, aging.Stomach maintains its homeostasis by many kinds of factors. PAF may play some biological role as one of such factors. Hence, the alteration of endogenous PAF level may cause the imbalance of gastric microenvironment which contributed to the etiopathogenesis in gastric mucosal lesion (especially in the early phase of ulceration), or may be expression of senescence.

IL-1-induced adhesion of polymorphonuclear leukocytes to cultured human endothelial cells. Role of platelet-activating factor.

In early studies we found that IL-1 stimulated endothelial cells (EC) to produce platelet-activating factor (PAF, 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine). Inasmuch as this phospholipid has a wide range of biologic activities, including polymorphonuclear leukocytes (PMN) aggregation and chemotaxis, we investigated whether EC-associated PAF could contribute to IL-1-induced PMN adhesion to EC. When four selective PAF antagonists were added to IL-1-stimulated EC during the PMN adhesion assay, adhesion was reduced in a concentration-related way. Similarly, pre-treatment of PMN with PAF before the adhesion assay to induce desensitization to this phospholipid reduced PMN adhesion to IL-1-treated EC. However, comparing the time course and the concentration response curve of IL-1-induced EC adhesivity and PAF synthesis, we found that increased EC adhesivity to PMN required a shorter incubation time and lower concentration of IL-1 to become apparent than PAF production. When acetyl-coenzyme A was added to EC cultures at a concentration that raised PAF synthesis by 60%, no significant increase in PMN adhesion was observed. In addition, after 9 to 10 doublings, the EC ability to synthesize PAF decreased by 85 to 90%, whereas IL-1-induced EC adhesivity to PMN was only slightly diminished. When IL-1-alpha and -beta were tested on EC, we observed that both were equally active in promoting PMN adhesion to EC but only the alpha-form was able to stimulate PAF production. When PMN were seeded on IL-1-treated EC, increased amounts of PAF were detected even when EC were fixed; in addition, the inhibitory effect of a PAF antagonist was evident also in these conditions. Overall these results indicate that IL-1-induced PAF production by EC does not significantly contribute to PMN adhesion to them. We hypothesize that the observed inhibitory effect of PAF antagonists and PAF desensitization of PMN might be directed at PAF produced by PMN themselves during adhesion to IL-1-treated EC.

Effects of PAF antagonists on platelet behaviour and arrhythmias during myocardial ischaemia

Effects of PAF antagonists on platelet behaviour and arrhythmias during myocardial ischaemia

The effect of PAF antagonists on the hepatic glycogenolysis and diabetes induced by alloxan

The effect of PAF antagonists on the hepatic glycogenolysis and diabetes induced by alloxan

Effects of PAF antagonists on renal vascular escape and tachyphylaxis in the isolated prefused rabbit kidney

Effects of PAF antagonists on renal vascular escape and tachyphylaxis in the isolated prefused rabbit kidney