Sodium channels are required during in vivo sodium chloride hyperosmolarity to stimulate increase in intestinal endothelial nitric oxide production

• Published in: American journal of physiology. Heart and circulatory physiology 2005-01, Vol.288 (1), p.H89-H95
• Main Authors: Zani, Brett G, Bohlen, H. Glenn
• Format: Article
• Language: English
• Subjects: Amiloride - pharmacology; Animals; Arterioles - metabolism; Arterioles - physiology; Biological Transport - drug effects; Bumetanide - pharmacology; Endothelium, Vascular - metabolism; Intestines - metabolism; Nitric Oxide - biosynthesis; Osmolar Concentration; Rats; Rats, Sprague-Dawley; Regional Blood Flow - drug effects; Sodium - metabolism; Sodium Channels - physiology; Sodium Chloride - metabolism; Sodium-Calcium Exchanger - antagonists & inhibitors; Thiourea - analogs & derivatives; Thiourea - pharmacology
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00644.2004

Department of Cellular and Integrative Physiology, School of Medicine, Indiana University, Indianapolis, Indiana Submitted 29 June 2004 ; accepted in final form 19 August 2004 NaCl hyperosmolarity increases intestinal blood flow during food absorption due in large part to increased NO production. We hypothesized that in vivo, sodium ions enter endothelial cells during NaCl hyperosmolarity as the first step to stimulate an increase in intestinal endothelial NO production. Perivascular NO concentration ([NO]) and blood flow were determined in the in vivo rat intestinal microvasculature at rest and under hyperosmotic conditions, 330 and 380 mosM, respectively, before and after application of bumetanide (Na + -K + -2Cl – cotransporter inhibitor) or amiloride (Na + /H + exchange channel inhibitor). Suppressing amiloride-sensitive Na + /H + exchange channels diminished hypertonicity-linked increases in vascular [NO], whereas blockade of Na + -K + -2Cl – channels greatly suppressed increases in vascular [NO] and intestinal blood flow. In additional experiments we examined the effect of sodium ion entry into endothelial cells. We proposed that the Na + /Ca 2+ exchanger extrudes Na + in exchange for Ca 2+ , thereby leading to the calcium-dependent activation of endothelial nitric oxide synthase (eNOS). We blocked the activity of the Na + /Ca 2+ exchanger during 360 mosM NaCl hyperosmolarity with KB-R7943; complete blockade of increased vascular [NO] and intestinal blood flow to hyperosmolarity occurred. These results indicate that during NaCl hyperosmolarity, sodium ions enter endothelial cells predominantly through Na + -K + -2Cl – channels. The Na + /Ca 2+ exchanger then extrudes Na + and increases endothelial Ca 2+ . The increase in endothelial Ca 2+ causes an increase in eNOS activity, and the resultant increase in NO increases intestinal arteriolar diameter and blood flow during NaCl hyperosmolarity. This appears to be the major mechanism by which intestinal nutrient absorption is coupled to increased blood flow. endothelial nitric oxide synthase; sodium/calcium exchanger; sodium-potassium-chloride cotransporter; sodium-hydrogen exchanger 1 Address for reprint requests and other correspondence: H. G. Bohlen, Dept. of Cellular and Integrative Physiology, Indiana Univ. School of Medicine, 635 Barnhill Dr., MS 426, Indianapolis, IN 46202 (E-mail: gbohlen{at}iupui.edu )