Dissertation Information for Brett Greer ZaniNAME:
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SCHOOL: ADVISORS: COMMITTEE MEMBERS: MPACT Status: Incomplete - Not_Inspected Title: Endothelial sodium channels and extracellular L-arginine are required to activate endothelial nitric oxide synthase during various physiological stimuli Abstract: Sodium chloride hyperosmolarity increases intestinal blood flow during food absorption due in large part to increased nitric oxide production. I hypothesized that in vivo , sodium ions enter endothelial cells during NaCl hyperosmolarity as the first step to stimulate an increase in intestinal endothelial nitric oxide production. The perivascular NO concentration ([NO]) and blood flow were determined in the in vivo rat intestinal microvasculature. Suppressing Na + /K + /2Cl - channels greatly suppressed increases in vascular [NO] and intestinal blood flow. Blocking the activity of the Na + /Ca + exchanger caused a decrease in vascular [NO] and intestinal blood flow to hyperosmolarity. These results indicate that during NaCl hyperosmolarity, sodium ions enter endothelial cells predominantly through Na + /K + /2Cl - channels. The Na + /Ca + exchanger then extrudes Na + and increases endothelial Ca +2 . The increase in endothelial Ca +2 demonstrated an increase in eNOS activity, and the resultant increase in nitric oxide increases intestinal arteriolar diameter and blood flow during NaCl hyperosmolarity. In endothelial cells, 70-95% of extracellular L-arginine uptake has been attributed to the cationic amino acid transporter-1 protein (CAT-1). I tested the hypothesis that extracellular L-arginine entry into endothelial cells via CAT-1 plays a crucial role in endothelial nitric oxide (NO) production. Extracellular L-arginine transport into endothelial cells by CAT-1 was competitively inhibited during conditions of NaCl hyperosmolarity, low oxygen, and flow increase. Prior studies indicate each of these perturbations cause NO-dependent vasodilation. Suppression of extracellular L-arginine transport significantly inhibited increases in vascular [NO] and intestinal blood flow to hyperosmolarity, low oxygen, and increased flow. These results suggest that L-arginine from the extracellular space is accumulated by CAT-1 to support the increased NO production that in turn increases intestinal arteriolar diameter and blood flow during various physiological stimuli. CAT-1 mediated transport of extracellular L-arginine into endothelial cells appears to be a crucial component for normal endothelial cell response to a wide range of physiological stimuli. |
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