Involvement Of Platelet-activating Factor Research Articles

Endothelin-induced sudden death and the possible involvement of platelet activating factor (PAF)

Endothelin (5 mol/kg, i.v.) caused a transient hypotension followed by a lasting hypertension in rats. However, an abrupt fall in the blood pressure was observed in most rats 6 to 30 min after the injection of endothelin and sudden death followed with lethality noted over 60 min. An abnormal electrocardiogram (EOG) (ventricular arrhythmias) was observed in rats injected with endothelin. Endothelin (i.v.) also caused sudden death in mice. Pretreatment (5 or 60 min) with specific PAF antagonists, CV-6209 (0.1 – 3 mg/kg, i.v.) and WEB 2086 (30 mg/kg, p.o.), and a calcium channel blocker, diltiazem (60 mg/kg, p.o.) prevented death and attenuated the EOG changes induced by endothelin, but CV-6209 did not prevent the blood pressure changes induced by endothelin. CV-6209 (0.5 – 3 mg/kg, i.v.), WEB 2086, diltiazem and dexamethasone (5 mg/kg, i.v.) protected mice against the death induced by endothelin. On the other hand, aspirin (cylcooxygenase inhibitor, 100 mg/kg, p.o.) did not protect mice from the death. Thus, endothelin is a highly toxic peptide with cardiotoxic effects, and PAF may be involved in the pathogenesis of the sudden death.

P-273 - Involvement of platelet activating factor in rat zymosan-induced pleurisy

P-273 - Involvement of platelet activating factor in rat zymosan-induced pleurisy

Involvement of platelet-activating factor (PAF) in endotoxin-induced intestinal motor disturbances in rats

Intestinal myoelectrical activity was investigated in conscious fasted rats chronically implanted with Nichrome electrodes in the duodeno-jejunum. Motility of the small intestine was characterized by the presence of migrating myoelectric complex (MMC) occuring regularly at 16.2 ± 5.8 minute intervals. Intravenous administration of endotoxin (E. coli S.O111:B4) at a dose of 50 μg/kg increased the interval between MMC to 112.6 ± 26.8 min, the duration of these effects being dose-related between 10 to 100 μg/kg. Such a typical myoelectrical alteration, corresponding to rapidly propagated groups of spike bursts, was mimicked by the IP administration of PAF at doses of 10 to 50 μg/kg. Previous administration of BN 52021, a specific PAF antagonist at a dose of 50 mg/kg abolished the motor alterations induced by IP injection of PAF (25 μg/kg) and significantly (p<0.01) reduced by 1.2% those induced by IV endotoxin (50 μg/kg). Indomethacin (10 mg/kg IP) as well as SC 19220 (5 mg/kg IV), a PGE 2 antagonist, injected prior to endotoxin (50μg/kg IV) or PAF (25 μg/kg IP) also reduced significantly (p<0.01) the duration of MMC inhibition. It is concluded that endogenous release of PAF is partly responsible for the intestinal motor alterations induced by endotoxin; these effects, strongly reduced after treatment with BN 52021, are also mediated through the release of prostaglandins.

Involvement of platelet-activating factor (PAF) in cerebral post-ischemic phase in mongolian gerbils

Involvement of platelet-activating factor (PAF) in cerebral post-ischemic phase in mongolian gerbils

Role of platelet-activating factor (PAF) in the ovoimplantation in the rat: Effect of the specific PAF-acether antagonist, BN 52021

The role of PAF (platelet-activating factor) in early pregnancy has been recently postulated. Indeed, platelet count is markedly reduced immediately prior to and returns to normal following ovoimplantation. Using a pharmacological approach, we therefore further investigated the possible involvement of PAF in ovoimplantation. BN 52021 (10 nmol), a PAF antagonist, was administered after fecondation in the lumen of the left uterine horn. A group of animals was injected with the vehicle alone. The animals were sacrificed 1 week latter and the number of implanted embryos in the treated horn and in the untreated contralateral one was assessed. When injected on day 4 of pregnancy, the PAF antagonist, BN 52021, inhibited in a dose-dependent fashion ovoimplantation suggesting a role for this lipid mediator in this process. Total inhibition of ovoimplantation was observed in the horns treated with indomethacin, NDGA or BW 755 C. In addition, a significant inhibition of ovoimplantation was also produced by the lipoxygenase inhibitor, EP 10045 (10nmol). Since both PAF and leukotrienes trigger the generation of prostaglandins in various tissues, our results indicate that these two lipid mediators may be implicated in early stages of the inflammatory reaction accompanying ovoimplantation and may contribute to the local generation of cyclooxygenase metabolites.

The involvement of platelet activating factor in endotoxin‐induced pulmonary platelet recruitment in the guinea‐pig

1 Exposure of conscious guinea-pigs to an aerosol of endotoxin (25-100 micrograms ml-1) resulted in a dose-related, progressive accumulation of platelets in the thoracic region. Accumulation of 111indium oxine labelled erythrocytes was not observed following exposure to an aerosol of endotoxin (50 micrograms ml-1). 2 Pretreatment of guinea-pigs with the selective platelet activating factor (Paf)-antagonists. CV-3988 or brotizolam resulted in a dose-related inhibition of endotoxin-induced pulmonary platelet recruitment. Pretreatment of guinea-pigs with the selective Paf-antagonist BN 52021 resulted in significant inhibition of endotoxin-induced pulmonary platelet recruitment, although the effects of BN 52021 were not dose-related. 3 Pretreatment of guinea-pigs with indomethacin at doses known to inhibit cyclo-oxygenase did not inhibit endotoxin-induced pulmonary platelet recruitment, whereas higher doses of indomethacin produced a reduction in platelet recruitment in the lung. 4 Pretreatment of guinea-pigs with the anticoagulant heparin and the prostacyclin analogue ZK 36374 inhibited endotoxin-induced platelet recruitment. 5 These observations suggest that endotoxin-induced pulmonary platelet recruitment in the guinea-pig is secondary to the release of platelet activating factor, but not to cyclo-oxygenase products of arachidonic acid and may also involve activation of the coagulation cascade.

Involvement of platelet-activating factor (PAF) in cerebral post-ischemic phase in Mongolian gerbils

Platelet-activating factor (PAF) is a potent mediator of anaphylaxis and shock. In addition, evidence for PAF participation in gastric, intestinal and heart psot-ischemic phase has been recently demonstrated. Ginkgo biloba extracts improve cerebral metabolism and protect brain against hypoxic damage in various models of cerebral ischemia. Potent and specific antagonists of PAF have been found in Ginkgo biloba and termed Ginkgolides: BN 52020, BN 52022, BN 52024. We therfore undertook the investigation of the role of Ginkgolides in cerebral ischemia obtained by bilateral ligature of the common carotid for 10 min and 6 h of recirculation in male Mongolian adult gerbils. Given preventively (one week treatment 10 mg/kg/day orally) or at the time of clamping BN 52021 and relted Ginkgolides dose-dependently antagonize morbidity assessed by the stroke-index. Similarly the mitochondrial respiration evaluated by the respiratory control ratio is significantly improved. In both determinations, the range of activity: BN 52021 >, BN 52020>BN 52022>BN 52024 shows that the effect of Ginkgolides in cerebral ischemia are correlated with their PAF antagonistic properties. Given curatively, 1 h after declamping, BN 52021 is able to reverse the cerebral impairment trend. Kadsureno and brotizolam, two other chemically unrelated PAF antagonists led to similar recovery. Therefore PAF appears to play an important role in the post-ischemic phase after bilateral carotid ligation in Mongolian gerbils.

Increased aortic PGI2 and plasma lyso-PAF in the unclipped one-kidney hypertensive rat.

Previous studies have implicated vasodilatory prostaglandins (PGs) in the reversal of hypertension following unclipping in the one-kidney, one-clip (1K,1C) hypertensive rat. The capacity of the aorta to synthesize prostacyclin (PGI2) was compared in clipped (group A, n = 9), unclipped (group B, n = 8 and group D, n = 9), and sham-unclipped (group C, n = 9) 1K,1C hypertensive rats. The involvement of platelet-activating factor (PAF), a potent renal antihypertensive phospholipid, in the reversal of renal clip hypertension was also examined. Hypertensive rats [systolic blood pressure (BP) greater than 180 mmHg] were fed a synthetic diet for 4 wk, after which group A was killed immediately, group C was sham-unclipped, and groups B and D unclipped and killed 24 h later. Blood was drawn for the measurement of plasma lyso-PAF (the precursor of PAF) and the aorta removed for determination of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha, the stable hydrolysis product of PGI2). BP fell substantially in the unclipped rats (groups B and D) but did not change in the sham-unclipped rats (group C). Mean aortic 6-keto-PGF1 alpha was increased in the unclipped groups [group B, 15.4 +/- 2.4 (SE) ng/mg; group D, 10.8 +/- 2 ng/mg] compared with group A (7.7 +/- 1 ng/mg) and group C (7.1 +/- 1 ng/mg) (H = 13.74, P less than 0.01). Plasma lyso-PAF was also significantly increased in the unclipped (group D, 261 +/- 26 ng/ml) vs. the sham-unclipped group (group C, 211 +/- 23 ng/ml, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Relative roles of leukotrienes and platelet activating factor in experimentally-induced gastric ulceration

1. 1 Leukotrienes (LT's) are produced in a number of hypersensitivity and in inflammatory conditions in the gastro-intestinal (GI) tract and may contribute to the pathogenesis of GI mucosal injury in their states. LT's do not appear to be produced by the GI mucosa in appreciable quantities under basal “physiological” conditions. 2. 2 Another important leucocyte derived mediator, platelet activating factor (PAF), which is produced in large quantities in hyper-sensitivity and inflammatory conditions, when given i.v. induces hyperaemia, vascular status and accompanying lesions of the gastric mucosa in rats. This might be related to its hypotensive effects or other actions on the microvasculature of the stomach. Thus PAF may have particular significance in those conditions where there is a profound leucocyte response. It might be an important link between the leucocyte activation that occurs in burn injury and the GI ulceration and haemorrhage that is observed in such patients. 3. 3 There does not appear to be any involvement of PAF in non-inflammatory gastric ulceration induced by aspirin or ethanol+HCl, since the PAF antagonist kadsurenone fails to exert any protective effects when coadministered with either of these drugs.

A study with BN 52021 demonstrates the involvement of PAF-acether in IgE-dependent anaphylactic bronchoconstriction

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.

Proof of the involvement of platelet activating factor (Paf-acether) in pulmonary complex immune systems using a specific Paf-acether receptor antagonist: BN 52021

Proof of the involvement of platelet activating factor (Paf-acether) in pulmonary complex immune systems using a specific Paf-acether receptor antagonist: BN 52021

Involvement of platelet activating factor in physiological stress in the lizard, Anolis carolinensis

1. Platelet activating factor (PAF) and 1- O-alkyl-linked choline-containing phosphoglycerides have been identified in the blood of the lizard, Anolis carolinensis. 2. The level of PAF in the blood of chronically stressed lizards is 250% higher than in that of controls; the blood contains sufficient 1- O-alkyl-linked choline-containing phosphoglycerides to support the synthesis of PAF. 3. Incorporation of PAF is higher in the liver than in the blood; control animals incorporate more PAF than chronically stressed animals. 4. “Lyso”-PAF is the major metabolite in the blood; whereas, in the liver both “lyso”-PAF and “acyl”-PAF are predominant products. 5. 1-Alkyl-2-acetyl- sn-glycero-3-phosphocholine:acetylhydrolase activity in the chronically stressed or corticosterone-implanted lizards is increased 2- to 3-fold over the control. 6. Involvement of PAF in the physiological response to psychological stress is indicated.