(Verbatim from the application): This proposal will study mechanisms through which the intestinal microvasculature supports the absorptive and secretory functions of the bowel. During nutrient absorption, the intestinal villus and submucosal layer interstitium becomes hypertonic due to NaCl absorption. This laboratory has demonstrated sodium hyperosmolarity stimulates nitric oxide formation in vessel walls and crypt gland cells in the submucosa. The increased nitric oxide (NO) detected with microelectrodes contributes to the arteriolar vasodilation associated with intestinal absorption. How sodium hyperosmolarity stimulates the endothelial cells to increase their NO formation in unknown. However, the mechanism is linked to a specific attribute of sodium rather than hyperosmolarity per se. Hyperosmolarity due to a non-permeable, non-electrolyte molecule, such as mannitol, is a poor stimulus both for NO formation and arteriolar dilation compared to equivalent sodium chloride hyperosmolarity. We propose that sodium ions enter the endothelial and crypt gland cells through the Na+ - K+ - 2Cl- cotransport system used to maintain cell volume and the Na+ - H+ antiport. The excess intracellular sodium would compromise extrusion of calcium ions, gradually elevating the calcium concentration that leads to increased NO formation. Isolated intestinal arterioles will be used to document the increased calcium ion concentration in endothelial cells during NaCl hyperosmolarity. We propose that crypt glands require a large increase in blood flow and oxygen extraction to support the elevated metabolic rate associated with active transport of a hypertonic, sodium-rich solution to the bowel lumen during intestinal absorption. As NO is both a potent secretagogue and vasodilator, if crypt glands form NO in response to NaCl hyperosmolarity, the NO would stimulate secretion of the hypertonic interstitial fluid to the bowel lumen and dilate blood vessels to increase oxygen delivery needed for active transport of ions. As NaCl hyperosmolarity also stimulates arteriolar and venular endothelial cells to increase NO formation, sodium hyperosmolarity acting through increased NO formation could help coordinate the complex microvascular, absorptive and secretory functions of the bowel during nutrient absorption.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL020605-23
Application #
6536770
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Lin, Michael
Project Start
1980-08-01
Project End
2005-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
23
Fiscal Year
2002
Total Cost
$172,600
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Physiology
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Bohlen, Harold Glenn (2015) Nitric oxide and the cardiovascular system. Compr Physiol 5:808-23
Bohlen, H Glenn (2013) Is the real in vivo nitric oxide concentration pico or nano molar? Influence of electrode size on unstirred layers and NO consumption. Microcirculation 20:30-41
Bohlen, H Glenn (2011) Rapid and slow nitric oxide responses during conducted vasodilation in the in vivo intestine and brain cortex microvasculatures. Microcirculation 18:623-34
Zhou, Xiaosun; Bohlen, H Glenn; Unthank, Joseph L et al. (2009) Abnormal nitric oxide production in aged rat mesenteric arteries is mediated by NAD(P)H oxidase-derived peroxide. Am J Physiol Heart Circ Physiol 297:H2227-33
Bohlen, H G; Zhou, X; Unthank, J L et al. (2009) Transfer of nitric oxide by blood from upstream to downstream resistance vessels causes microvascular dilation. Am J Physiol Heart Circ Physiol 297:H1337-46
Payne, Gregory A; Bohlen, H Glenn; Dincer, U Deniz et al. (2009) Periadventitial adipose tissue impairs coronary endothelial function via PKC-beta-dependent phosphorylation of nitric oxide synthase. Am J Physiol Heart Circ Physiol 297:H460-5
Pezzuto, Laura; Bohlen, H Glenn (2008) Extracellular arginine rapidly dilates in vivo intestinal arteries and arterioles through a nitric oxide mechanism. Microcirculation 15:123-35
Bohlen, H Glenn (2008) Metalloproteinases damage the insulin receptor to cause insulin resistance in spontaneously hypertensive rats. Hypertension 52:215-7
Zhou, Xiaosun; Bohlen, H Glenn; Miller, Steven J et al. (2008) NAD(P)H oxidase-derived peroxide mediates elevated basal and impaired flow-induced NO production in SHR mesenteric arteries in vivo. Am J Physiol Heart Circ Physiol 295:H1008-H1016
Bauser-Heaton, Holly D; Song, Jin; Bohlen, H Glenn (2008) Cerebral microvascular nNOS responds to lowered oxygen tension through a bumetanide-sensitive cotransporter and sodium-calcium exchanger. Am J Physiol Heart Circ Physiol 294:H2166-73

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