The goal of the proposed studies is to expand upon a recent breakthrough in our understanding of the mechanisms that couple changes in whole organism Ca2+ homeostasis with alterations in vascular function.
Three specific aims will test the hypothesis that dynamic change sin the concentration of Ca/2+ occur in interstitial space of tissues involved in transcellular Ca2+ movement; these changes modulate arterial tone by causing sensory nerve dependant relaxation of resident resistance arteries; and the relaxation occurs secondary to Ca2+-induced activation of a receptor for extracellular Ca2+ that is coupled with the release of vasodilator transmitter. Preliminary data that support this hypothesis include the finding that under physiologic conditions, interstitial Ca2+ in the duodenal sub-mucosa undergoes dynamic changes between 1 and 2mM, that Ca2+ in this range causes nerve mediated relaxation of isolated mesenteric arteries, and molecular evidence that perivascular dilator nerve express a Ca2+ receptor (CaR) that is homologous with the parathyroid and renal CaRs that couple changes in extracellular Ca/2+ with alterations in cell function.
Specific aim 1 will use an in situ microdialysis method to test the hypothesis that the concentration of interstitial Ca2+ (Ca/isf) in tissues involved in transcellular Ca2+ movement; i.e., the duodenum, kidney, and femur, undergoes dynamic changes in response to physiologic or pharmacologic stimuli including intake of varying levels of dietary Ca/2+. parathyroid hormone-induced Ca2+ mobilization, and sub-chronic treatment with 1,25 (OH)2 vitamin D3.
Specific aim 2 will use wire myography and video dimension analysis-based arteriography to test the hypothesis that Ca/2+-induced dilation occurs in resistance arteries isolated from tissues involved in transcellular movement of Ca/2+.
Specific aim 3 will use natural and synthetic ligands of the Ca/2+ receptor, a postnatal development model, and the CaR knockout mouse to test the hypothesis that the perivascular sensory nerve CaR mediates nerve dependent relaxation induced by Ca/2+. We anticipate that these studies will provide (a) new information about the physiologic role that this novel Ca/2+-activated dilator system plays in linking hole animal Ca/2+ homeostasis and cardiovascular function, (b) a critical test of the hypothesis that the Ca/2+-induced dilation is mediated by a sensory nerve CaR, and (c) may provide the basis for the development of novel pharmacologic means of manipulating blood pressure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL064761-01S1
Application #
6204367
Study Section
General Medicine B Study Section (GMB)
Project Start
1999-07-01
Project End
2003-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
1
Fiscal Year
2000
Total Cost
$44,744
Indirect Cost
Name
North Carolina Central University
Department
Type
Organized Research Units
DUNS #
072026321
City
Durham
State
NC
Country
United States
Zip Code
27707
Pointer, Mildred A; Eley, Shaleka; Anderson, Lauren et al. (2015) Differential Effect of Renal Cortical and Medullary Interstitial Fluid Calcium on Blood Pressure Regulation in Salt-Sensitive Hypertension. Am J Hypertens 28:1049-55
Sesay, John S; Gyapong, Reginald N K; Najafi, Leila T et al. (2015) G?i/o-dependent Ca(2+) mobilization and G?q-dependent PKC? regulation of Ca(2+)-sensing receptor-mediated responses in N18TG2 neuroblastoma cells. Neurochem Int 90:142-51
Spruiell, Krisstonia; Jones, Dominique Z; Cullen, John M et al. (2014) Role of human pregnane X receptor in high fat diet-induced obesity in pre-menopausal female mice. Biochem Pharmacol 89:399-412
Awumey, Emmanuel M; Bridges, Lakeesha E; Williams, Cicely L et al. (2013) Nitric-oxide synthase knockout modulates Ca²?-sensing receptor expression and signaling in mouse mesenteric arteries. J Pharmacol Exp Ther 346:38-47
Pointer, Mildred A; Daumerie, Geraldine; Bridges, LaKessha et al. (2012) Physiological stress increases renal injury in eNOS-knockout mice. Hypertens Res 35:318-24
Bridges, Lakeesha E; Williams, Cicely L; Pointer, Mildred A et al. (2011) Mesenteric artery contraction and relaxation studies using automated wire myography. J Vis Exp :
Awumey, Emmanuel M; Hill, Sylvie K; Diz, Debra I et al. (2008) Cytochrome P-450 metabolites of 2-arachidonoylglycerol play a role in Ca2+-induced relaxation of rat mesenteric arteries. Am J Physiol Heart Circ Physiol 294:H2363-70
Heyeraas, Karin J; Haug, Sivakami R; Bukoski, Richard D et al. (2008) Identification of a Ca2+-sensing receptor in rat trigeminal ganglia, sensory axons, and tooth dental pulp. Calcif Tissue Int 82:57-65
Eley, Shaleka L; Allen, Crystal M; Williams, Cicely L et al. (2008) Action of thiazide on renal interstitial calcium. Am J Hypertens 21:814-9
Awumey, Emmanuel M; Howlett, Allyn C; Putney Jr, James W et al. (2007) Ca(2+) mobilization through dorsal root ganglion Ca(2+)-sensing receptor stably expressed in HEK293 cells. Am J Physiol Cell Physiol 292:C1895-905

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