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Platelet activating factor receptor antagonist improves survival and attenuates eicosanoid release in severe
J R Fletcher1, A G DiSimone, M A Earnest
1Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee.
Abstract:
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.
Insights
Platelet activating factor (PAF) plays a key role in endotoxemia, causing severe symptoms. Blocking PAF receptors with BN52021 significantly improved survival rates in endotoxemic rats.
Area of Science:
- Pharmacology
- Immunology
- Pathophysiology
Background:
- Exogenous platelet activating factor (PAF) induces hypotension, plasma extravasation, metabolic acidosis, and death.
- These PAF-induced effects mimic those observed in endotoxemia and with eicosanoids.
Purpose of the Study:
- To investigate the role of PAF receptor activation in rat endotoxemia.
- To determine the effects of a specific PAF receptor antagonist (BN52021) on hemodynamic changes, eicosanoid production, and survival.
Main Methods:
- Administration of endotoxin to rats to induce severe endotoxemia.
- Pretreatment with BN52021, a specific PAF receptor antagonist.
- Monitoring hemodynamic parameters, measuring prostaglandin release (TxB2, PGE2), and assessing survival rates.
Main Results:
- Endotoxin administration caused significant hypotension, prostaglandin release, and mortality.
- Pretreatment with BN52021 significantly attenuated hypotension and prostaglandin release.
- BN52021 significantly improved survival rates in endotoxemic rats (p < 0.01).
Conclusions:
- PAF receptor activation appears to be an early event in the pathophysiology of endotoxemia.
- Eicosanoid release during endotoxemia may be linked to PAF synthesis and receptor activation.
- These findings suggest a potential interaction between PAF and eicosanoids, with PAF effects possibly mediated via the cyclo-oxygenase pathway in endotoxemia.
