Endothelin 1 and prostacyclin attenuate increases in hydraulic permeability caused by platelet-activating factor in rats.

We have previously documented that endothelin-1 (ET-1) and prostacyclin (PGI2) decrease basal state hydraulic permeability (Lp). The aim of this study was to investigate the ability of ET-1 and PGI2 to modulate trans-endothelial fluid flux during situations in which Lp was artificially elevated with platelet activating factor (PAF). We hypothesized that ET-1 and PGI2 administration before PAF exposure would prevent the increase in Lp secondary to PAF. Additionally, in a potentially more clinically relevant situation, we also hypothesized that ET-1 and PGI2 administration after PAF exposure would attenuate the increase in Lp secondary to PAF. Microvascular Lp was measured in rat mesenteric post-capillary venules. Exposure to 10 nM PAF increased Lp 4-fold (p<0.001). If the administration of 80 pM ET-1 or 10 μM PGI2 was completed prior to PAF exposure, no PAF-associated increase in Lp was observed (p<0.001). The administration of ET-1 or PGI2 after PAF exposure attenuated the peak increase in Lp due to PAF alone by 55% and 57%, respectively (p<0.001). We conclude that ET-1 and PGI2 administration prior to PAF exposure prevents PAF-induced elevations in Lp, and in a more clinically relevant situation, ET-1 and PGI2 administered after PAF exposure attenuates the PAF-induced increase in Lp. ET-1 and PGI2 receptors may provide important therapeutic targets for decreasing the microvascular fluid leak-associated morbidity resulting from shock and sepsis.