Endothelin-1 ET_B Receptors Are Developmentally Regulated in Postnatal Swine Intestine

Abstract 1256 Neonatal Disease Oriented Research: Intestinal Development Platform, Saturday, 5/1

Endothelin-1 (ET1) binds to two receptors: ET_A and ET_B. The ET_A receptor, located on vascular smooth muscle, mediates vasoconstriction. The ET_B receptor, located on the endothelium, mediates vasodilation via activation of ecNOS, which produces NO. To determine the ontogeny of ET_B receptors in postnatal intestine, endothelium-intact rings of mesenteric artery from 3- or 35-d old swine were suspended for isometric tension recording in myographs and then administered ET1 or S6c, a selective ET_B agonist, under control conditions or in the presence of BQ610 (selective ET_A antagonist), BQ788 (selective ET_B antagonist) or LNMMA (blocks endogenous NO synthesis). Agents were given to relaxed rings stretched to the optimal point on their length tension curve, or to rings which were precontracted with phenylephrine. Data are M±SE, n=, and are expressed as a percent of 40 mM KCl contraction for relaxed rings, or as % relaxation for contracted rings. *p<0.1 vs control, ^p<0.1 vs 3-d old. (Table) ET1 given to relaxed rings caused the expected vasoconstriction; however, application of ET1 to precontracted rings caused vasodilation, which was of greater magnitude in 3-d and was eliminated by selective ET_B blockade or by NO synthesis inhibition. Dilation in response to S6c was greater in 3- than 35-d rings, and was also eliminated by BQ788 or LNMMA. Mechanical removal of the endothelium eliminated ET1 and S6c dilations, confirming the endothelial location of the ET_B receptors. Conclusion: Endothelial ET_B receptors are developmentally regulated, being present in newborn, but not older intestine. Speculation: The presence of endothelial ET_B receptors may be an important adaptive mechanism in newborn intestine. ET1 is essential for angiogenesis, a process clearly present in growing newborn intestine. The presence of endothelial ET_B receptors would offset the vasoconstrictive action of ET1, allowing it to be present in the microvascular environment to stimulate angiogenesis without causing vasoconstriction. However, loss of endothelial cell function, as might occur following ischemia-reperfusion, might selectively eliminate the ET_B receptors. The now-unbalanced ET_A receptor could cause significant vasoconstriction, which could act as a mechanism contributing to necrotizing enterocolitis.

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