Long-term lung preservation with the PAF antagonist BN 52021

Platelet activating factor (PAF, 1-alkyl-2(R)-acetyl-glycero-3- phosphorylcholine) is a phospholipid that is released by a variety of cells. The similarity between the pathophysiological effects of PAF and posttransplant pulmonary dysfunction led to an evaluation of a PAF antagonist as an adjunct to lung preservation. The ginkgolide B, BN 52021, was selected as the PAF antagonist to be studied because of the large data base available on this compound. BN 52021 was given to the donor and recipient (10 mg/kg i.v.) prior to harvest and transplantation and was included in 1 L of preservation solution (10 mg/kg) used for flushing the pulmonary artery and for storage. Left single-lung transplantation was performed following a 22-hr preservation period at 10 degrees C. Arterial oxygen tension (pO2), pulmonary vascular resistance (PVR), alveolar arterial oxygen difference (A-aDO2), and dynamic lung compliance (DLC) were recorded for 6 hours following ligation of the native pulmonary artery. At the end of 6 hr pO2 was 243.5 +/- 61.5 vs. 71.7 +/- 10.2 mmHg (P less than 0.02) for the controls. A-aDO2 was less in the BN 52021 groups: 431.8 +/- 58.3 vs. 606.0 +/- 9.8 mmHg in the control groups (P less than 0.001), and PVR was significantly less in the BN 52021 group: 346 +/- 70.8 vs. 663 +/- 64.3 dynes/sec/cm-5 (P less than 0.035). We conclude that PAF antagonists like BN 52021 may be useful adjuncts for lung preservation. The effects of BN 52021 are easily explained by PAF antagonist activity in ischemic and reperfusion-induced pulmonary dysfunction. However this study does not exclude that BN 52021 may have direct effects.     

血小板激活因子在急性重症胰腺炎发 病过程中作用的实验研究

作者为探讨血小板激活因子在狗急性重症胰腺炎发病过程中的作用，采用１７只比格（Ｂｅａ－ｇｌｅ）狗，随机分为三组：对照组（ｎ＝５）、胰腺炎组（ｎ＝６）、治疗组（ｎ＝６）。胰腺炎组及治疗组动物制成急性重症胰腺炎动物模型。治疗组动物在模型复制后５ｍｉｎ，３ｈ分别静脉注射血小板激活因子（ＰＡＦ）拮抗剂ＢＮ５２０２１（５ｍｇ／ｋｇ）。用温氏法测定血清淀粉酶活性，血小板聚集法测定血清及胰腺组织中ＰＡＦ的含量。结果显示：急性重症胰腺炎模型复制成功后３０ｍｉｎ，胰腺炎组血清淀粉酶活性即上升到基础值的２００±４４．７％，８ｈ高达４６６．７±１１１．６％。８ｈ时与对照组、治疗组差异均有显著性意义（Ｐ＜０．０５）。胰腺炎组血中ＰＡＦ含量在３０ｍｉｎ时即开始上升，８ｈ达最高１１．８１±０．７８ｎｇ／ｍｌ，在３０ｍｉｎ之后与对照组比较即差异有非常显著的意义（Ｐ＜０．０１），而１ｈ之后与治疗组差异有非常显著的意义（Ｐ＜０．０１）。胰腺组织中ＰＡＦ含量，胰腺炎组比治疗组及对照组明显增高（Ｐ＜０．０１）。作者认为ＰＡＦ在急性重症胰腺炎的发病过程中起重要作用，ＰＡＦ拮抗剂有希望成为治疗急性重症胰腺炎的有效药物。     

Platelet activating factor antagonist enhances lung preservation in a canine model of single lung allotransplantation.

Optimal techniques for lung preservation are yet to be defined. Platelet activating factor is a phospholipid released by a variety of cells and produces pulmonary abnormalities similar to posttransplantation pulmonary dysfunction. We investigated the strength of the effect of the platelet activating factor antagonist BN 52021 as compared with that of deferoxamine, an iron chelator previously shown to improve lung preservation. Differential lung function and pulmonary hemodynamics were used to assess preservation after a 6-hour period of cold ischemic storage in a modified canine model of left lung allotransplantation. Thirty size- and weight-matched mongrel male dogs were used for 15 transplant procedures randomized to one of three preservation techniques. The University of Wisconsin solution was used as the basic flush solution for all experimental animals. BN 52021 was added to the flush solution in one group (10 mg/kg, n = 5) and deferoxime in another group (10 mg/kg, n = 5). No additives were used for the control animals (n = 5). BN 52021 and deferoxime were administered to respective donor animals 30 minutes before organ harvesting (10 mg/kg) and to recipient animals 30 minutes before reperfusion (10 mg/kg). The pulmonary artery flush solution was administered (40 ml/kg) over 4 minutes. Recipient animals received double-lumen endotracheal tubes and were monitored with balloon-tipped, flow-directed catheters in both pulmonary arteries and dual-angle ultrasonic flow probes around each pulmonary artery. Solid-state high-fidelity micromanometers were used to measure pressures in the pulmonary artery, the left atrium, and the left ventricle. Systemic arterial, right and left pulmonary venous, and mixed venous blood samples were analyzed at 1, 2, 4, and 6 hours after transplantation. Pulmonary venous oxygen tension of the transplanted lung for the control group was 202 +/- 81 mm Hg versus 282 +/- 53 mm Hg for the BN 52021 group 6 hours after transplantation (p less than 0.05). Pulmonary vascular resistance of the transplanted lung for the control group was 319 +/- 54 dynes.sec.cm-5 versus 149 +/- 71 dynes.sec.cm-5 for the BN 52021 group (p less than 0.05). Proton magnetic resonance spectroscopy was performed on segments of upper and lower lobes of the native and transplanted lung from recipient animals to determine total lung water content. The BN 52021 group had a total lung water content of 57.3% as compared with 51.9% for the deferoxime group (p = not significant) and 88.6% for the control group (p less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)     

Actions of cyclosporin A on cultured rat mesangial cells

The effects of cyclosporin A (CsA) on planar surface area of cultured rat mesangial cells (PCSA) and cross-sectional area of isolated rat glomeruli (GCSA) were tested. The same experiments were performed after preincubation with platelet activating factor (PAF) antagonists (BN 52021, alprazolam) or calcium channel blockers (verapamil). Areas of cells or glomeruli were analyzed by a computer-assisted method. CsA reduced PCSA in a time-dependent (significant effects began at 15 min, about 12% of reduction with 10(-6) M CsA) and dose-dependent (no effect at 10(-9) M CsA, maximal reduction of about 30% at 60 min of incubation with 10(-7) M CsA) fashion. BN 52021 (5.10(-5) M) and alprazolam (10(-5) M) completely inhibited the reduction of mesangial cell area induced by CsA. Verapamil (10(-5) M) only partially inhibited this action. Glomerular cross-sectional area decreased after 30 minutes of incubation with 10(-6) M CsA (1.45 +/- 0.02 vs. 1.55 +/- 0.02 m2.10(-8), P less than 0.001), an effect that was inhibited by BN 52021 or verapamil. In addition, 10(-6) M CsA increased PAF production by isolated rat glomeruli (425 +/- 80 pg/mg vs. 198 +/- 13 pg/mg in control glomeruli, P less than 0.01), an effect which was not inhibited by verapamil. These results suggest that CsA could reduce GFR by decreasing the glomerular ultrafiltration coefficient, perhaps as a consequence of the contraction of mesangial cells. PAF seems to play a pivotal role in the genesis of this action.     

Protective effect of the PAF antagonist BN 52021 in an experimental renal warm ischemia model

Platelet activating factor is involved in warm ischemic damage. We studied the effect of the PAF receptor antagonist BN 52021 in an experimental model of 60 min of renal warm ischemia in which the left kidney was flushed with Euro-Collins solution and a right nephrectomy was performed. Eighty Wistar rats were divided into a sham-operated group, two control groups, and four study groups, according to the dosage and route of BN 52021 administration. BN 52021 was used in the flush solution at concentrations of 0.1 and 0.5 mg/ml, or intravenously prior to ischemia at 5 and 10 mg/kg body weight. Creatinine clearance per, 100g body weight, fractional sodium excretion, and conventional histology were studied. Rats that received BN 52021 intravenously showed a significantly higher creatinine clearance than controls. Intravenous BN 52021 produced a higher acceleration of renal function recovery at 10 mg/kg than at 5 mg/kg body weight. Conventional histology was better in animals that received BN 52021 at 10 mg/kg body weight than in controls. Addition of BN 52021 to Euro-Collins flushing solution showed no protective effect. We conclude that intravenous BN 52021 shows a renal protective effect against warm ischemia.     

Platelet-activating factor antagonists do not attenuate delayed posttraumatic cerebral edema in rats

Platelet-activating factor (PAF) receptor antagonists reportedly improve early postischemic neurological recovery and cerebral blood flow in selected experimental models. Their effects on posttraumatic cerebral edema have, however, not been examined. In a rat model of right hemispheric percussive cerebral trauma, we examined the effects of two PAF receptor antagonists on posttraumatic edema formation. Two groups of rats received either BN 52021 (n = 14) or WEB 2086 (n = 11), 10 mg/kg i.v. at 15 min posttrauma. Two other groups treated with the BN 52021 (n = 17) and WEB 2086 (n = 10) vehicles served as controls. Hemispheric percent brain water was determined at 24 h. Edema occurred in all groups. Neither PAF receptor antagonist significantly reduced right hemispheric percent brain water (81.08 +/- 0.25 and 81.04 +/- 0.15 in Bn 52021 and WEB 2086-treated rats, respectively, versus 81.31 +/- 0.23 and 81.14 +/- 0.17% brain water in BN 52021 vehicle and WEB 2086 vehicle-treated rats). Mortality was not statistically different between groups. These data do not support a major role for PAF in the development of posttraumatic cerebral edema.     

Platelet-activating factor antagonist, BN-52021 protects against cis-diamminedichloroplatinum nephrotoxicity in the rat

The protective effect of the platelet-activating factor (PAF) antagonist, BN 52021, was assessed on cis-diammine-dichloroplatinum (CDDP)-induced nephrotoxicity. Wistar male rats were treated with either a single dose of CDDP (10 mg/kg b.w. ip) alone or in association with 7 daily doses of BN 52021 (10 mg/kg b.w. ip). At the end of the experiment, the CDDP-treated rats lost 25% of body weight and serum creatinine and urea increased from 0.041 +/- 0.006 mmol/l and 0.165 +/- 0.007 g/l for the control group to 0.202 +/- 0.019 mmol/l and 1.51 +/- 0.131 g/l versus CDDP respectively. Body weight, serum creatinine, serum urea and creatinine clearances were similar to the control group in animals treated with CDDP and BN 52021. CDDP caused proximal tubular necrosis and dilatation of cortical collecting tubes, changes that were markedly less in the BN 52021-protected animals. The concomitant administration of BN 52021 with CDDP did not modify the plasma pharmacokinetic of CDDP. In addition, BN 52021 did not interfere with the antiproliferative and antitumoral actions of CDDP in cultured human tumor cells. BN 52021 therefore could prevent the nephrotoxicity of CDDP.     

Platelet-Activating Factor Antagonist,BN-52021 Protects Against Cis-Diamminedichl or Oplatinum Nephrotoxicity in the Rat

The protective effect of the platelet-activating factor (PAF) antagonist, BN 52021, was assessed on cis-diammine-dichloroplatinum (CDDP)-induced nephrotoxicity. Wistar male rats were treated with either a single dose of CDDP (10 mg/kg b.w. ip) alone or in association with 7 daily doses of BN 52021 (10 mg/kg b.w. ip). At the end of the experiment, the CDDP-treated rats lost 25% of body weight and serum creatinine and urea increased from 0.041±0.006 mmol/1 and 0.165±0.007 g/1 for the control group to 0.202±0.019 mmol/1 and 1.51±0.131 g/1 versus CDDP respectively. Body weight, serum creatinine, serum urea and creatinine clearances were similar to the control group in animals treated with CDDP and BN 52021. CDDP caused proximal tubular necrosis and dilatation of cortical collecting tubes, changes that were markedly less in the BN 52021-protected animals. The concomitant administration of BN 52021 with CDDP did not modify the plasma pharmacokinetic of CDDP. In addition, BN 52021 did not interfere with the antiproliferative and antitumoral actions of CDDP in cultured human tumor cells. BN 52021 therefore could prevent the nephrotoxicity of CDDP.     

Beneficial effects of recombinant platelet-activating factor acetylhydrolase and BN 52021 on bacterial translocation in cerulein-induced pancreatitis

BACKGROUND: Bacterial translocation (BT) has been suggested to be responsible for the high incidence of infections occurring after acute pancreatitis (AP). The aim of this study was to investigate the effects of the platelet-activating factor (PAF) inactivator, recombinant PAF-acetylhydrolase (rPAF-AH), and the PAF receptor antagonist, BN 52021, in AP. METHODS: Forty-eight male Wistar rats were divided into 4 groups: the sham group received saline intraperitoneally every hour for 6 h; the control group received cerulein 50 g/kg i.p. every hour for 6 h; the rPAF-AH group received AP plus rPAF-AH (5 mg/kg i.v. bolus), and the BN52021 group received AP plus BN 52021 (5 mg/kg i.v. bolus). The animals were sacrificed 12 h after the first cerulein injection. RESULTS: Supramaximal cerulein stimulation induced an increase in serum pancreatic enzymes, interleukin (IL)-6, pancreatic edema, and produced histologic evidence of AP. Compared with the control group, the addition of PAF receptor antagonists had a significant effect on serum pancreatic enzymes, pancreatic edema, and the histologic score of the pancreatitis. AP caused significant increases in BT in mesenteric lymph nodes (MLNs), pancreas, liver, spleen and blood. Compared with the control group, both rPAF-AH and BN 52021 decreased BT in the pancreas and blood. In addition, rPAF-AH decreased BT in the MLNs. We also found that PAF receptor antagonists suppressed the elevation in IL-6 levels. CONCLUSION: PAF antagonists attenuated the severity of experimental AP and reduced pancreatitis-induced BT to distant sites.     

Prevention of cyclosporin nephrotoxicity with a platelet-activating factor (PAF) antagonist

BACKGROUND.: Cyclosporin (CsA) is a potent immunosuppressive drug whose mainside-effect is nephrotoxicity. In the kidney, CsA induces vasoconstrictionwith a decrease in renal blood flow (RBF) and glomerular filtrationrate (GFR) and a significant increase in renal vascular resistance(RVR). CsA enhances platelet-activating factor (PAF) synthesisin mesangial cells in vitro. PAF, a secondary mediator of anaphylaxisand inflammation, exhibits vasoactive properties in the kidneysimilar to those of CsA. METHODS.: The in situ autoperfused rat kidney model was used to investigatewhether PAF plays a role in the haemodynamic injury inducedby CsA. RESULTS.: In this model, CsA (40 mg/kg and 20 mg/kg i.v.) induced a significantdecrease in RBF and in GFR and an increase in RVR. BN 52021,a potent and specific PAF antagonist (20 mg/kg i.v. bolus dose)induced a significant increase in GFR (137±32% of initialvalue, P<0.05). BN 52021 (20 and 10 mg/kg) also significantlyprevented the decline in RBF and GFR induced by CsA. CONCLUSIONS.: We have demonstrated that the PAF antagonist BN 52021 can minimizethe alteration of renal function induced by CsA.     

Role of platelet-activating factor in leukocyte-independent plasma extravasation and mast cell activation during endotoxemia

BACKGROUND: Independently from leukocyte adherence, endothelial factors and mast cell activation seems to promote microvascular permeability. Platelet-activating factor (PAF) has been shown to play a significant role in endotoxin-induced leukocyte adherence. The aim of our study was to investigate if there is also a role for PAF in mediating leukocyte-independent microvascular permeability changes and activation of mast cells during endotoxemia. Therefore, during endotoxemia microvascular permeability and mast cell activation were determined after inhibition of L-selectin-mediated leukocyte adherence by fucoidin and after inhibition of PAF effects by the PAF receptor antagonist BN52021. MATERIALS AND METHODS: In male Wistar rats, red cell velocity (V(RBC)), venular wall shear rate, microvascular permeability, leukocyte adherence, and mast cell activation were determined in mesenteric postcapillary venules using intravital microscopy at baseline and 60 and 120 min after start of a continuous infusion of endotoxin (ETX; 2 mg/kg/h, Escherichia coli O26:B6) (ETX group). Animals in the FUCO/ETX group received fucoidin (25 mg/kg body wt) in addition to the procedure described above. Animals in the FUCO/ETX/PAF-ANT group received fucoidin and the PAF receptor antagonist BN52021 (5 mg/kg body wt) prior to the continuous endotoxin infusion. Control animals (control group) received only equivalent volumes of NaCl 0.9%. RESULTS: There were no microhemodynamic and macrohemodynamic differences between groups. In all endotoxin-challenged groups macromolecular leakage and mast cell activity increased significantly, starting at 60 min. Both macromolecular leakage and mast cell activity were significantly higher in the FUCO/ETX group than in the FUCO/ETX/PAF-ANT group and control group. Differences in macromolecular leakage between groups were significant at 120 min. Differences in mast cell activity between groups were significant at 60 and 120 min. CONCLUSIONS: The results of our study demonstrate a leukocyte-independent plasma extravasation that can be inhibited by the PAF receptor antagonist BN52021, indicating the involvement of PAF in the pathophysiology of leukocyte-independent microvascular damage during early endotoxemia. Mast cell activity seems to precede leukocyte-independent macromolecular leakage.     

The effects of aprotinin and steroids on generation of cytokines during coronary artery surgery.

OBJECTIVE: To compare the efficacy of aprotinin and methylprednisolone in reducing cardiopulmonary bypass (CPB)-induced cytokine release, to evaluate the effect of myocardial cytokine release on systemic cytokine levels, and to determine the influence of cytokine release on perioperative and postoperative hemodynamics. DESIGN: Prospective, randomized clinical trial. SETTING: University teaching hospital and clinics. PARTICIPANTS: Thirty patients undergoing elective coronary artery bypass graft surgery. INTERVENTION: Patients were randomly allocated into groups treated with aprotinin (n = 10) or methylprednisolone (n = 10) or into an untreated control group (n = 10). Aprotinin-treated patients received aprotinin as a high-dose regimen (6 x 10(6) KIU), and methylprednisolone-treated patients received methylprednisolone (30 mg/kg intravenously) before CPB. MEASUREMENTS AND MAIN RESULTS: Patients were analyzed for hemodynamic changes and alveolar-arterial PO2 difference (AaDO2) until the first postoperative day. Plasma levels of proinflammatory cytokines (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta, IL-6, and IL-8) were measured in peripheral arterial blood immediately before the induction of anesthesia, 5 minutes before CPB, 3 minutes after the start of CPB, 2 minutes after the release of the aortic cross-clamp, 1 hour after CPB, 6 hours after CPB, and 24 hours after CPB; and in coronary sinus blood immediately before CPB and 2 minutes after the release of the aortic cross-clamp. The hemodynamic parameters did not differ among the groups throughout the study. After CPB, AaDO2 significantly increased (p < 0.05) in all groups. A significant decrease in AaDO2 was observed in aprotinin-treated patients at 24 hours after CPB compared with the other groups (p < 0.05). TNF-alpha level from peripheral arterial blood significantly increased in control patients 1 hour after CPB (p < 0.01) and did not significantly increase in methylprednisolone-treated patients throughout the study. In all groups, IL-6 levels increased after the release of the aortic cross-clamp and reached peak values 6 hours after CPB. At 6 hours after CPB, the increase in IL-6 levels in methylprednisolone-treated patients was significantly less compared with levels measured in control patients and aprotinin-treated patients (p < 0.001). In control patients, IL-8 levels significantly increased 2 minutes after the release of the aortic cross-clamp (p < 0.05), and peak values were observed 1 hour after CPB (p < 0.01). IL-8 levels in control patients were significantly higher compared with patients treated with aprotinin and patients treated with methylprednisolone 1 hour after CPB (p < 0.05). CONCLUSION: This study showed that methylprednisolone suppresses TNF-alpha, IL-6, and IL-8 release; however, aprotinin attenuates IL-8 release alone. Methylprednisolone does not produce any additional positive hemodynamic and pulmonary effects. An improved postoperative AaDO2 was observed with the use of aprotinin.     

Role of platelet activating factor in gentamicin and cisplatin nephrotoxicity.

The present study was undertaken to evaluate the effects of platelet activating factor (PAF) antagonists on nephrotoxicity induced by gentamicin (GENTA) and cisplatin (DDP) in rats. PAF infusion provoked a 56% decline in single nephron (SN) GFR due to a decrease in glomerular plasma flow (QA, 55%), glomerular transcapillary hydraulic pressure (delta P, 13%), and glomerular ultrafiltration coefficient (Kf, 37%). Four days after a single dose of DDP (6 mg/kg, i.p.) we observed non-oliguric acute renal failure (ARF) with reduced SNGFR (45%), QA (46%) and delta P (10%) and unchanged Kf. GENTA administration for 10 days (40 mg/kg, i.p. daily) induced a decline in SNGFR (40%), QA (41%) and Kf (41%). Chronic treatment with a GENTA + PAF antagonist (BN 52021) partially prevented the decline in SNGFR (22%) by an amelioration in QA (25%) and Kf (13%). However, simultaneous treatment with DDP and BN 52063 completely prevented the ARF induced by DDP, normalizing all parameters of renal function. Thus, PAF may be a potential mediator involved in the nephrotoxicity induced by GENTA and DDP.     

Effect of platelet-activating factor antagonists (BN-52021, WEB-2170, and BB-882) on bacterial translocation in acute pancreatitis

Bacterial translocation is an important source of pancreas infection in acute pancreatitis. The effect of platelet-activating factor (PAF) in the pathogenesis of acute pancreatitis has been proved in various studies. The aim of this study was to determine whether potent PAF antagonists influence bacterial translocation in acute pancreatitis. Acute pancreatitis was induced in 62 Wistar rats by injection of 2.5% sodium taurocholate into the biliopancreatic duct. The rats treated with PAF factor antagonists received intravenous injection of WEB-2170 (10 mg/kg), lexipafant (5 mg/kg), and BN-52021 (5 mg/kg) 30 minutes before induction of acute pancreatitis. Six hours after induction of acute pancreatitis, bacteriologic cultures and histologic scoring of tissues were performed. There was a statistically significant reduction in bacterial translocation to the mesenteric lymph nodes and liver but not to the pancreas of the rats treated with PAF antagonists. No significant increase in the intestinal bacterial population of any group was found. There were no statistical differences between the pancreatic histologic scores of the groups. PAF antagonists reduced bacterial translocation to distant sites other than the pancreas, preventing the bacterial dissemination that occurs in the early phase of acute pancreatitis and may have beneficial effects on the evolution of this disease.     

Effect of platelet-activating factor antagonist on cyclosporine nephrotoxicity. Glomerular hemodynamics evaluation

In order to evaluate the effect of platelet-activating factor (PAF) antagonist BN 52021 (5 mg/kg i.v.) on cyclosporine (50 mg/kg i.v.) nephrotoxicity, euvolemic Munich-Wistar rats were submitted to micropuncture studies. BN 52021 alone did not change the total (1.08 +/- 0.07 vs. 1.04 +/- 0.06 ml/min) or single nephron (SN) (29.1 +/- 50 vs. 31.3 +/- 4.0 nl/min) and glomerular filtration rate. The CsA administration caused a decline on GFR (0.47 +/- 0.07 vs. 0.96 +/- 0.04 ml/min, P less than 0.05) and on SNGFR (14.0 +/- 3.5 vs. 27.9 +/- 3.4 ml/min, P less than 0.05). An increase in afferent (RA) and efferent (RE) arteriolar resistances, 180% and 360%, respectively, that caused a decrease on glomerular plasma flow rate (QA) from 100.99 +/- 17.09 to 44.37 +/- 13.37 nl/min (P less than 0.05) was observed. Moreover, the glomerular ultrafiltration coefficient (Kf) declined by 70% (0.096 +/- 0.003 to 0.031 +/- 0.10 ml/sec mmHg, P less than 0.05). The previous BN 52021 administration on rats treated with CsA blunted its effects on superficial nephrons. The SNGFR (22.3 +/- 3.0 vs. 28.0 +/- 25 nl/min), QA (72.2 +/- 5.9 vs. 91.7 +/- 12.1 nl/min) and KF (0.038 +/- 0.009 vs. 0.048 +/- 0.005 nl/s mmHg) remained unaltered. By contrast, the total renal function was not prevented by BN 52021 treatment: GFR 0.45 +/- 0.12 vs. 0.94 +/- 0.05 ml/min (P less than 0.05). Thus, this study suggests that PAF may participate in CsA nephrotoxicity. Furthermore, the protective effect of BN 52021 on superficial nephrons may indicate that BN 52021 is a drug that can minimize the impairment of renal function induced by CsA.     

Platelet activating factor receptor antagonist improves survival and attenuates eicosanoid release in severe endotoxemia.

Exogenous platelet activating factor (PAF) causes hypotension, plasma extravasation, metabolic acidosis, and death. These effects are similar to those of endotoxin as well as the eicosanoids. A specific PAF receptor antagonist, BN52021, was used to determine its effects on the hemodynamic events, the eicosanoid production, and on survival in severe rat endotoxemia. Endotoxin alone significantly produced hypotension, prostaglandins (TxB2, PGE2) release, and death. In contrast pretreatment with BN52021, a specific PAF receptor antagonist, significantly altered the hypotension, significantly attenuated the eicosanoid release, and improved the survival rate (p less than 0.01). These findings suggest that PAF receptor activation is an early event in endotoxemia. Eicosanoid release in endotoxemia could be related to PAF synthesis and PAF receptor activation. These findings support the hypothesis that there may be an intimate relationship between PAF and the eicosanoids and that in endotoxemia some of the effects of PAF may be mediated via the cyclo-oxygenase pathway.     

Failure of salmeterol to inhibit circulating white cell responses and bronchoconstriction induced by platelet activating factor.

BACKGROUND: Platelet activating factor (PAF) is a potent mediator of inflammation. Inhalation of PAF causes acute bronchoconstriction and a transient fall in white blood cell count in humans. Salmeterol inhibits pulmonary inflammation induced by PAF in guinea pigs. METHODS: The effect of salmeterol on effects induced by PAF was investigated in eight normal subjects who inhaled salmeterol (50 micrograms) twice daily or a matched placebo for one week before challenge with PAF. Blood samples were taken from a forearm catheter for total white cell and neutrophil counts before and for 30 minutes after administration of PAF (48 micrograms) through a Mefar dosimeter. Blood films were stained for unsegmented neutrophils before and after treatment with PAF on a placebo day. RESULTS: Mean baseline total white cell counts and neutrophil counts did not differ on the two days. Mean baseline sGaw was significantly higher after inhaled salmeterol (1.84 (95% C1 1.45-2.23) s-1kPa-1) than after placebo (1.53 (1.24-1.82)). After placebo mean total white cell counts, neutrophil counts, and sGaw were reduced to 60 (43-78)%, 39 (14-64)%, and 82 (71-93)% of baseline respectively five minutes after inhaled PAF. After salmeterol treatment mean reductions five minutes after inhaled PAF were 59 (45-73)%, 40 (19-61)%, and 82 (71-93)% of baseline respectively. At 30 minutes after treatment with PAF the neutrophil count rebounded to 143 (82-204)% of baseline after placebo and to 127 (93-161)% after inhaled salmeterol. There was no significant difference in the percentage of immature neutrophils before and after treatment with PAF (2.0 (0.5-2.6)% compared with 3.9 (2.2-5.6)%. CONCLUSIONS: Treatment with salmeterol did not inhibit reduction in total white cell count or neutrophil count, rebound neutrophilia, acute bronchoconstriction, or transient flushing after inhalation of PAF. These results conflict with the inhibitory effect of salmeterol on lung inflammation in guinea pigs but are consistent with the lack of effect of salbutamol in humans. Salmeterol does not have an anti-PAF effect in vivo in humans.     

Effects of Nifedipine and Platelet Activating Factor Antagonist (BN 52021) in Glycerol-Induced Acute Renal Failure in Rats

We studied the actions of nifedipine and the platelet activating factor (PAF) antagonist BN 52021 on renal and tubular function in glycerol-induced acute renal failure (Gly-ARF). The tubular handling of sodium was evaluated through the lithium clearance method in awake rats in metabolic cages. The sequential analysis of tubular function 3, 6, 12, and 24 h after Gly-ARF showed a sharp decrease in fractional proximal Na reabsorption (FPR_Na—control 74.1 ± 12.5%, 3 h: 79.5 ± 6.0%; 6 h: 41.8 ± 15.9%; 12 h: 22.9 ± 17.9%; and 24 h: 31.1 ± 16.2% (p < 0.001) while fractional distal Na reabsorption (FDR_Na) did not change during the study. The effect of nifedipine (20 mg/kg p.o.) and BN 52021 (1 mg/kg i.p.) were evaluated 24 h after the induction of Gly-ARF. Both drugs attenuated the reduction in creatinine clearance (control 431.8 ± 108.2, glycerol 96.7 ± 43.8, glycerol plus nifedipine 264.9 ± 103.5, and glycerol plus BN 52021 188.9 ± 69.8 μL/min/100 g, p < 0.001). However, only nifedipine could keep FPR_Na higher than untreated rats (58.3 ± 13.2 vs. 31.1 ± 16.2%, p < 0.05) and reduced the tubular necrosis on histologic semiquantitative analysis. Our data showed that nifedipine and BN 52021 could protect against filtration failure in Gly-ARF but that only nifedipine reduced the proximal tubular lesion.     

血小板活化因子及其受体对颈髓损伤后血脊髓屏障损害的分子机制研究

目的：探讨血小板活化因子（ＰＡＦ）及其受体对颈髓损伤后血脊髓屏障损害的分子机制。方法：采用蛛网膜下腔注射ＰＡＦ及静脉注射ＰＡＦ受体拮抗剂ＢＮ５２０２１，应用地高辛标记ｃＤＮＡ探针原位杂交技术检测颈髓损伤后颈髓血管内皮细胞细胞间粘附分子－１ｍＲＮＡ（ＩＣＡＭ－１ｍＲＮＡ）和内皮细胞白细胞粘附分子－１ｍＲＮＡ（ＥＬＡＭ－１ｍＲＮＡ）表达。观察ＰＡＦ及其受体拮抗剂对颈髓损伤后血脊髓屏障、ＩＣＡＭ－１ｍＲＮＡ、ＥＬＡＭ－１ｍＲＮＡ表达的影响。结果：伤后颈髓血管内皮细胞ＩＣＡＭ－１ｍＲＮＡ、ＥＬＡＭ－１ｍＲＮＡ表达、伊文思蓝含量、水含量呈不同程度的增加；ＰＡＦ可使伤后血管内皮细胞ＩＣＡＭ－１ｍＲＮＡ、ＥＬＡＭ－１ｍＲＮＡ表达、伊文思蓝含量、水含量增加更为显著，ＰＡＦ受体拮抗剂可抑制ＩＣＡＭ－１ｍＲＮＡ、ＥＬＡＭ－１ｍＲＮＡ表达，降低颈髓组织伊文思蓝含量及水含量。结论：ＰＡＦ通过增加伤后颈髓血管内皮细胞粘附分子的表达是导致血脊髓屏障损害的重要分子基础。ＰＡＦ受体对伤后血管内皮细胞细胞粘附分子的表达具有调控作用。     

血小板活化因子在烧伤合并内毒素血症早期肺损伤中的作 …

目的 探讨血小板活化因子（ＰＡＦ）肿瘤坏死因子（ＴＮＦ）等在烧伤合并内毒素血症早期肺损伤中的作用及意义。方法 采用２０％ＴＢＳＡⅢ度烧伤合并内毒素注射复制大鼠早期肺损伤模型,检测血浆ＰＡＦ、ＴＮＦ含量等,观察肺组织病理形态学变化并应用ＰＡＦ受体拮抗剂防治早期肺损伤。结果 ＰＡＦ是烧伤合并内毒素血症早期先于ＴＮＦ出现变化的炎症介质,血浆ＰＡＦ浓度与早期肺操作程度呈正相关,注射ＰＡＦ受体拮抗剂ＢＮ５０