The goal of the proposed studies is to determine the mechanism of Ca2+-sensing receptor (CaSR)-mediated vascular relaxation, control of urinary Na+/Ca2+ excretion and their regulation by protein kinase C (PKC) and G protein-coupled receptor kinase 2 (GRK2) in hypertension. Cardiovascular disease is the leading cause of death and disability in the Western World and hypertension, which is associated with vasoconstriction, endothelial dysfunction, end organ damage and stroke is common in the African American community. We hypothesized that local increases in interstitial calcium concentration induce vasorelaxation by activating the CaSR and subsequent release of a vasodilator(s) to counteract the effects of endothelial dysfunction. We propose to test the hypothesis that the CaSR mediates vascular relaxation and control of urinary Na+/Ca2+ excretion through the NCX in salt-loading/hypertension, a process regulated by PKC and G protein- coupled receptor kinase 2 (GRK2). Salt-loading/hypertension increases expression and signaling of the CaSR to counteract the high vascular tone as well as decrease Na+ but increase Ca2+ excretion to maintain vascular integrity and decrease Na+ retention. The proposed studies will use Dahl salt-resistant (SR), salt- sensitive (SS) and CaSR mutant (SS-CasremMcwi) rats.
Specific aim 1 will employ protein and DNA analysis to determine the effect of salt-loading/hypertension on expression of the CaSR, NCX1, G proteins, PKC isoforms and GRK2 in kidney, dorsal root ganglia (DRG) and mesenteric arteries.
Specific aim 2 will employ wire myography and whole animal studies to determine the effect of salt-loading/hypertension on CaSR signaling and regulation of vascular and renal Na+/Ca2+ exchange and blood pressure in rats. We believe that these studies, when completed, will provide a new information on the mechanisms of CaSR-mediated signaling in salt-sensitive hypertension. The proposed studies are integrative and have the potential of identifying targets for the development of novel dietary strategies to counteract hypertension, in the short-term, and new vasodilator compounds in the long-term. This award will allow us to continue the current studies, which have opened up new directions in determining the role of the CaSR in salt-sensitive hypertension. The proposed studies will also provide training opportunites for under-represented minority students at NCCU to prepare them for future careers in biomedical research.
Clinical trials indicate that high calcium intake and diets high in fruits, vegetables, and low-fat milk lower blood pressure in hypertension. The mechanism for this, however, is unknown. The kidney nephron and the perivascular sensory nerve network on blood vessels express a calcium-sensing receptor that may be involved in the mechanism of blood pressure reduction by dietary calcium. The proposed studies are aimed at understanding the signaling mechanism of the receptor and its regulation in hypertension. The studies may provide new information on the mechanism of calcium-induced vascular relaxation, urinary Na+ and Ca2+ excretion and blood pressure regulation. The findings may lead to identification of targets for the development of novel dietary strategies to reduce hypertension, in the short-term, and new anti-hypertensive drugs in the long-term.
