Abstract 1260
Neonatal Disease Oriented Research: Intestinal Development Platform, Saturday, 5/1
Mechanical reduction of flow into the newborn intestinal circulation causes a progressive increase in gut vascular resistance which occurs over 5 hours. The early increase is mediated by loss of endogenous NO production, while the latter increase can be attenuated by blockade of constrictor receptors (ie., endothelin ETA, angiotensin AT1, and α1 receptors). This latter effect is paradoxical inasmuch as blockade of these receptors under normal conditions has no effect. To test the hypothesis that exposure to low flow conditions alters the binding affinity of constrictor receptors, gut loops from 3- and 35-day old swine were exposed to 5 hours of flow reduction (50% of baseline) in vivo. The mesenteric artery was then removed and cut into rings which were hung for isometric tension recording. Duplicate rings were administered increasing amounts of a single agonist (AII, ET1 or NE); thereafter, receptor affinity was determined as the ED50 for each agonist. *p<.01. (Table) Binding affinity increased after exposure to low flow conditions, (↓ED50), but only in the newborn. AT1, ETA and α1receptors are all coupled to a G11/q protein and this coupling increases receptor affinity. The increased binding affinity noted after exposure to low flow conditions might reflect a change in receptor-G protein coupling. To test this possibility, GTPase activity, a marker of receptor-G protein coupling, was determined in response to AII, ET1 and NE using membrane prepared from newborn mesenteric artery vascular smooth muscle. GTPase activity increased for all agonist-receptor pairs after low flow perfusion: AII 5.2±0.4 to 9.9±0.7, ETl 4.4±0.2 to 8.3±0.7, NE 4.7±0.3 to 8.9±0.7 (in pmol/min/mg, all p<.01 v control. Conclusion: exposure to flow flow conditions increases binding affinity of the AT1, ETA and α1 receptors in mesenteric artery in an age-specific manner, likely 2° to enhanced G protein coupling. Speculation: The increased receptor-G protein coupling may be caused by a reduction of NO within the gut microvasculature, as constitutive NO production decreases during low flow (see companion abstract by Reber & Nowicki), and it has been established that NO interferes with receptor-G protein coupling. The increased binding affinity of constrictor receptors may be an important mechanism in the etiology of necrotizing enterocolitis, as it would serve as an amplification system whereby modest, localized areas of flow reduction, caused, for example, by PAF or bacteria-related cytokines, rapidly enlarge and intensify.
