Strategies to modulate the deleterious effects of endothelin in hepatic ischemia-reperfusion.

Abstract

This study evaluates whether bosentan (endothelin [ET] receptor antagonist) or preconditioning (mechanism that inhibits the postischemic ET release) could reduce the microvascular disorders and the injurious effects of tumor necrosis factor (TNF) associated with hepatic ischemia-reperfusion (I/R). Hepatic I/R was induced in rats and the effects of bosentan or preconditioning on the deleterious effects of ET in hepatic I/R were evaluated. Transaminase and TNF levels in plasma; edema, vascular permeability, lactate, ET, and TNF levels in liver; and edema and myeloperoxidase activity levels in lung were measured after hepatic reperfusion. The administration of bosentan or the induction of preconditioning previous to I/R attenuated the increase in vascular permeability, edema and lactate levels observed in liver after I/R. However, the addition of ET before preconditioning abolished its benefits. Preconditioning prevented both the increase in hepatic TNF and its release from the liver into the systemic circulation. This resulted in an attenuation of liver and lung damage. Addition of ET or TNF to the preconditioned group abolished the benefits of preconditioning, whereas the previous inhibition of TNF release with GdCl3 in the preconditioned group pretreated with ET did not modify the effects of preconditioning. The inhibition of ET with bosentan prevented the increase of both hepatic and plasma TNF, thus attenuating the liver and lung injury, whereas TNF addition abolished the benefits of bosentan. These findings suggest that both bosentan and preconditioning, by inhibition of ET could attenuate the microvascular disorders and the deleterious effect of TNF on the liver and lung elicited by hepatic I/R.