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.
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