IL-1β alters hemodynamics in newborn intestine: role of endothelin

Abstract

Studies were carried out to determine the effects of IL-1β on newborn intestinal hemodynamics. IL-1β increased the release of ET-1 by primary endothelial cells in a dose-dependent manner; as well, it reduced expression of the endothelin (ET) type B (ETB) receptor on endothelial cells and increased expression of the ET type A (ETA) receptor on vascular smooth muscle cells. IL-1β increased endothelial cell endothelial nitric oxide (NO) synthase (eNOS) expression but did not enhance eNOS activity as evidenced by release of NOxinto conditioned medium in response to acetylcholine or shear stress. The effects of IL-1β on flow-induced dilation were evaluated in terminal mesenteric arteries in vitro. Pretreatment with IL-1β (1 ng; 4 h) significantly attenuated vasodilation in response to flow rates of 100 and 200 μl/min. This effect was mediated, in part, by the endothelin ETAreceptor; thus selective blockade of ETAreceptors with BQ610 nearly restored flow-induced dilation. In contrast, exogenous ET-1 only shifted the diameter-flow curve downward without altering the percent vasodilation in response to flow. The effects of IL-1β on ileal oxygenation were then studied using in vivo gut loops. Intramesenteric artery infusion of IL-1β upstream of the gut loop caused ileal vasoconstriction and reduced the arterial-venous O2difference across the gut loop; consequently, it reduced ileal oxygenation by 60%. This effect was significantly attenuated by pretreatment with BQ610. These data support a linkage between the proinflammatory cytokine IL-1β and vascular dysfunction within the intestinal circulation, mediated, at least in part, by the ET system.