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Title: Enteral arginine does not increase superior mesenteric arterial blood flow and but induces mucosal growth in neonatal pigs

item PUIMAN, PATRYCJA - Erasmus Medical Center
item STOLL, BARBARA - Children'S Nutrition Research Center (CNRC)
item VAN GOUDOEVER, JOHANNES - Erasmus Medical Center
item Burrin, Douglas - Doug

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/16/2010
Publication Date: 11/24/2010
Citation: Puiman, P.J., Stoll, B., Van Goudoever, J.B., Burrin, D.G. 2011. Enteral arginine does not increase superior mesenteric arterial blood flow and but induces mucosal growth in neonatal pigs. Journal of Nutrition. 141(1):63-70.

Interpretive Summary: In the United States, a significant number of infants are born premature and have poor intestinal function. Many of these premature infants have been shown to have low levels of the amino acid, arginine, in their blood stream. The low level of arginine may lead to depressed blood flow to the intestine since arginine is used to form nitric oxide, which is a key molecule necessary for normal blood flow. Arginine may also be important for intestinal cell growth because it is required for survival of these cells. We hypothesized that feeding supplemental arginine to the newborn intestine would stimulate blood flow and promote growth of the epithelial cells in neonatal piglets, which were used as an animal model of the infant. We found that across a broad range of dietary intakes, supplemental arginine did not affect intestinal blood flow. This lack of blood flow response to dietary arginine occurred in piglets that were nourished exclusive via the intravenous route, called total parenteral nutrition, and those given a small amount of enteral nutrition, called partial enteral nutrition. We also tested whether feeding the substrates needed for intestinal arginine synthesis would lead to increased intestinal blood flow. This experiment showed that key arginine substrates, especially the amino acid citrulline, did not increase intestinal blood flow even though this supplement caused a marked increase in blood arginine level. We also tested whether giving dietary arginine to neonatal piglets for four days would stimulate intestinal cell growth. This study showed that feeding arginine increased intestinal growth, but was not affected when we blocked the production of nitric oxide with a chemical inhibitor. We conclude that feeding arginine does not increase neonatal intestinal blood flow, but does induce growth of the intestinal mucosa via a mechanism that does not involve nitric oxide. These findings are important to gastroenterologists as we continue to learn more about possible nutritional supplements for premature infants.

Technical Abstract: Arginine is an essential amino acid in neonates synthesized by gut epithelial cells and a precursor for nitric oxide (NO) that regulates vasodilatation and blood flow. Arginine supplementation has been shown to improve intestinal integrity in ischemia-reperfusion models and low plasma levels are associated with necrotizing enterocolitis. We hypothesized that enteral arginine is a specific stimulus for neonatal intestinal blood flow and mucosal growth under conditions of total parenteral nutrition (TPN) or partial enteral nutrition (PEN). We first tested the dose-dependence and specificity of acute (3 h) enteral arginine infusion on superior mesenteric artery (SMA) blood flow in pigs fed TPN or PEN. We then determined whether chronic (4 d) arginine supplementation of PEN increases mucosal growth and if this was affected by treatment with the NO synthase inhibitor, L-NAME. Acute enteral arginine infusion increased plasma arginine dose-dependently in both TPN and PEN groups, but the plasma response was markedly higher in PEN vs TPN. Baseline SMA blood flow was 90% higher in PEN vs. TPN (2.37 vs 1.23 L x kg-1 x h-1), but was not affected by acute infusion individually of arginine, citrulline, or other major gut fuels. Chronic dietary arginine supplementation in PEN induced mucosal growth in the intestine, but this effect was not prevented by treatment with L-NAME. Intestinal crypt cell proliferation, protein synthesis and phosphorylation of mTOR and p70S6K were not affected by dietary arginine. We conclude that partial enteral feeding, but not acute enteral arginine, increases SMA blood flow in the neonatal pig. Furthermore, supplementing arginine in partial enteral feeding modestly increased intestinal mucosal growth and was NO independent.