Role of platelet-activating factor in hypotension and platelet activation induced by infusion of thrombolytic agents in rabbits.

Abstract

Infusion of the thrombolytic agents streptokinase (SK, 666 units/kg per minute for 60 minutes) and tissue-type plasminogen activator (t-PA, 10 micrograms/kg per minute for 15 minutes) in rabbits induced a significant hypotension and decrease in platelet count that were completely prevented by treatment with platelet-activating factor (PAF) receptor antagonists SDZ 63-675 and WEB 2170. PAF synthesis by vascular tissue was suggested by its extraction from blood-free heart and aorta of rabbits treated in vivo with SK or t-PA but not of control rabbits. In contrast, PAF was not detected in peripheral blood. Ex vivo studies on platelet aggregation response to ADP and PAF performed on platelet-rich plasma obtained before and after SK and t-PA infusion demonstrated an early hyperaggregable phase, abrogated by PAF receptor antagonists and followed by reduced sensitivity of platelets to PAF. The ED50 values for the aggregation of washed rabbit platelets induced by PAF but not thrombin were significantly increased at 60 and 120 minutes after SK and t-PA infusion, suggesting a specific desensitization of platelets to PAF. In contrast to PAF receptor antagonists, aspirin did not significantly modify the hypotension and the platelet hyperaggregability induced by SK or t-PA or the platelet hypoaggregability induced by t-PA. Thrombocytopenia induced by t-PA, but not by SK, was partially prevented by aspirin. The effect of SK, t-PA, and plasmin on the aggregation of washed platelets from untreated rabbits and from humans was also studied. Whereas SK and t-PA were inactive, plasmin induced dose-dependent platelet aggregation that was inhibited by platelet pretreatment with PAF receptor antagonists. In conclusion, the effect of PAF receptor antagonists observed in the present experimental model suggests that the hypotension and activation of platelets induced by SK and t-PA infusion are mediated by PAF.

Platelet-activating factor induces cardioprotection in isolated rat heart akin to ischemic preconditioning: role of phosphoinositide 3-kinase and protein kinase C activation

“…Hearts of group 4 (n ϭ 5) underwent a preconditioning protocol like group 2 hearts, bracketed by a 29-min infusion of the PAF receptor antagonist WEB-2170 (1 ϫ 10 Ϫ9 M; Boheringer Ingelheim), a triazolobenzodiazepine derivative (4,16,27,31). To test the role of the used antagonists per se on I/R damages, in three additional groups of hearts (n ϭ 5 for each group), the antagonists WEB-2170 (group 8), chelerythrine (group 9), or LY-294002 (group 10) were infused for 29 min without PAF and IP.…”

Streptokinase induces intravascular release of platelet-activating factor in patients with acute myocardial infarction and stimulates its synthesis by cultured human endothelial cells.

“…This may depend on the production of thromboxane A2, as suggested by Fitzgerald et al'0 In fact, it has recently been shown that thromboxane A2 mediates and amplifies in vivo many of the biological effects of PAF.58 Experiments performed in rabbits infused with SK and t-PA demonstrated that early thrombocytopenia is PAF dependent and can be prevented by treatment with PAF receptor antagonists. 30 In addition, a local synthesis of PAF and its association with the EC surface may induce platelet/ endothelium and polymorphonuclear neutrophil/endothelium interaction, thus favoring thrombotic reocclusion.31-33 The possible role of PAF in determining thrombotic reocclusion is also supported by experiments performed in dogs, showing that oral administration of a PAF-receptor inhibitor completely prevented reocclusion of femoral arteries after thrombolysis.59 Conversely, the negative effect of PAF may be modulated by the production of prostacyclin, which may inhibit both the synthesis of PAF and its bioactivity.42 It has been reported that whereas thrombolytic agents stimulated the synthesis of prostacyclin,60 plasmin has a potent inhibitory effect on it.61 In conclusion, the beneficial effect of thrombolytic therapy may be limited by production of endogenous mediators, including PAF, that may activate platelets locally and in systemic circulation and that may exert a direct negative inotropic and arrhythmogenic effect.l1820,22,25-27A6 The present results should stimulate further studies intended to determine whether patients with acute myocardial infarction undergoing thrombolytic therapy may benefit from concomitant treatment with PAF-receptor antagonists.…”

“…29 The observation that in rabbits treated with thrombolytic agents, PAF-receptor antagonists prevented the activation of platelets prompted us to hypothesize that PAF synthesis induced by thrombolytic agents may promote the activation of platelets. 30 The local generation of PAF and its association with endothelial cell (EC) surface may lead to platelet and/or leukocyte/endothelium interaction,31-33 thus favoring reocclusion. In the present investigation, we evaluated (1) the intravascular release of PAF in patients with acute myocardial infarction treated or untreated with intravenous SK and (2) the synthesis of PAF by cultured human umbilical vein-derived endothelial cells (ECs) challenged with SK, tissue-type plasminogen activator (t-PA), or plasmin.…”

Stimulation of erythrocyte ceramide formation by platelet-activating factor

“…Platelet-activating factor (PAF), a phospholipid mediator involved in the regulation of inflammation, thrombosis, atherogenesis and cardiovascular function (Bussolino et al, 1989;Montrucchio et al, 1993;Subbanagounder et al, 1999;Montrucchio et al, 2000;Zimmerman et al, 2002;Haynes, et al, 2002;Goggel et al, 2004), is released from erythrocyte progenitor cells upon increase of cytosolic Ca 2+ activity (Dupuis et al, 1997). PAF further activates Ca 2+ -sensitive K + channels (Gardos channels) in the erythrocyte cell membrane (Garay et al, 1986) by sensitising them for the stimulating effects of cytosolic Ca 2+ (Rivera et al, 2002).…”