thromboxane-b2 and bepafant

Platelet-activating factor (PAF) is an endogenous phospholipid which may be an important mediator of shock and inflammation. Recent evidence suggests that PAF plays a role in the development of ischemic colitis and inflammatory bowel disease. Its effects are mediated by second messengers, including the arachidonic acid metabolites. Using an ex vivo isolated left colon rabbit perfusion model, our aims were to determine whether exogenously administered trinitrobenzene sulfonic acid (TNB), which produces experimental colitis, stimulates both PAF and eicosanoid release in the colon, and if so, whether this effect can be blocked by a PAF antagonist. Colonic inflammation was induced by the intracolonic administration of 0.25 ml of 50% ethanol containing 30 mg of TNB. Tissue and perfusate concentrations of the eicosanoids, [prostaglandin E (PGE2), 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TXB2), leukotriene B4 (LTB4)] and the autocoid PAF were measured by ELISA. During TNB infusion there was a significant increase in tissue levels of PAF compared to control colons. Additional studies performed pretreating the colons with the PAF receptor antagonist WEB-2170 prior to TNB infusion blocked PAF release. TNB stimulated release of luminal eicosanoids except LTB4 and suppressed release of tissue prostanoids. Pretreatment with WEB-2170 prior to TNB inhibited luminal eicosanoids, and inhibited PGE2 and prostacyclin, but not TX tissue suppression. Inhibition of TNB-stimulated PAF release by WEB-2170 suggests that PAF may play a role in TNB-induced colitis and this phenomenon may mediate tissue injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Azepines; Colitis; Colon; Dinoprostone; Eicosanoids; Gastrointestinal Contents; Leukotriene B4; Platelet Activating Factor; Rabbits; Second Messenger Systems; Thromboxane B2; Triazoles; Trinitrobenzenesulfonic Acid

Rats were treated with the platelet activating factor receptor antagonist WEB 2170 (15 mg/kg/day) in three different protocols to evaluate a possible role of platelet activating factor in an experimental proliferative model of glomerular disease. The glomerular immune injury was initiated by the i.v. administration of a rabbit anti-rat thymocyte antiserum. Anti-rat thymocyte antiserum induces a proliferative glomerulonephritis with reduction of glomerular filtration rate (614 +/- 94) compared with controls (1,120 +/- 192 microL/min/100 g body wt) when studied at day 7. Treatment of rats with WEB 2170 over 8 days (starting at day -1; protocol 1) ameliorated the loss in glomerular filtration rate (936 +/- 82 microL/min/100 g body wt) in nephritic rats at day 7; however, it had no effect on controls (1,142 +/- 104 microL/min/100 g body wt). Interventional treatment with WEB 2170 (starting at day 4 after anti-rat thymocyte antiserum; protocol 2) also improved glomerular function when glomerular filtration rate was already reduced (410 +/- 41 microL/min/100 g body wt) at day 4. The platelet activating factor receptor antagonist given at day 7 after induction of disease (protocol 3) did not improve impaired glomerular filtration rate. Preinterventional and interventional treatment with WEB 2170 reduced the infiltration of polymorphonuclear granulocytes in glomeruli. Interventional treatment with WEB 2170 also reduced glomerular morphologic damage in nephritic glomeruli. The data demonstrate a beneficial effect of the platelet activating factor receptor antagonist in this animal model of proliferative glomerulonephritis which suggests that platelet activating factor might play an important role in the mediation of this disease.

Topics: Animals; Antilymphocyte Serum; Azepines; Dinoprostone; Disease Models, Animal; Glomerular Filtration Rate; Glomerular Mesangium; Glomerulonephritis; Inulin; Male; Platelet Membrane Glycoproteins; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Thromboxane B2; Triazoles

Theophylline (p less than 0.05) and ketotifen (p greater than 0.05) markedly reduced, but the lipoxygenase inhibitors and PAF receptor antagonists were without any influence on the endothelin-1 (ET-1 1 nmol/kg i.v.) induced increase of pulmonary inflation pressure of anaesthetised and ventilated guinea-pigs. The ET-1 induced increase in mean arterial blood pressure as well as the secondary TXB2 release into bronchoalveolar lavage fluid or plasma was not decreased. TXB2 release cannot be the only mechanism of bronchopulmonary ET-1 effects in guinea-pigs in vivo.

Topics: Aminophylline; Animals; Azepines; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Bronchoconstrictor Agents; Diterpenes; Endothelins; Ginkgolides; Guinea Pigs; Ketotifen; Lactones; Lipoxygenase Inhibitors; Lung; Male; Masoprocol; Platelet Activating Factor; Platelet Aggregation Inhibitors; Theophylline; Thromboxane B2; Triazoles; Umbelliferones; Vasoconstriction; Vasoconstrictor Agents