Vascular abnormalities in genetically hypertensive rats begin early in life and reversal of these abnormalities during growth phase can lead to permanent amelioration of hypertension. Despite such findings the factors which affect the early growth and blood pressure responses in these animals have received little attention. Intracellular pH (pHi) is one potential factor which affects the growth and contractility of vascular cells in response to angiotensin II and other factors. Three sets of transporters regulate intracellular pH in vascular smooth muscle cells (VSMCs) as well as in other cells; Na+-H+ exchange and sodium- dependent C1- -HC03- exchange alkalinize VSMCs, whereas sodium- independent C1-HC03-exchange serves to acidify the cell. Our preliminary data suggests that Na+-H+ exchange is mediated by the NHE-1 sodium-proton antiporter and that sodium-independent C1-HC03- exchange is mediated by the anion transporters AE2 and AE3. The hypothesis for this proposal is that the onset of hypertension in genetically hypertensive animals is accompanied or induced by increases in hPi in VSMCs, and that abnormal expression or regulation of the AE and NHE proteins could help determine the hypertensive response in these animals. In order to test this hypothesis we will: 1) determine any linkage between AE2, AE3, and NHE-1 genes and hypertension in SHRSP, WKY, and cross-bred rats; 2) determine the expression of AE2 and NHE mRNAs and proteins in the resistance vessels and aortas of SHRSP and matched Wistar-Kyoto (WKY) rats before, during and after the onset of the initial growth pressure spurt; 3) assess pHi, C1-HC03- exchange, and Na+-H+ exchange in preparations of resistance vessels and aortas and ACE activity in preparations of vessels and hearts of SHRSP and WKY rats before, during and after the initial growth and blood pressure spurt, and determine the effects of angiotension II (AII), and platelet derived growth factor (PDGF) on these parameters; 4) determine intracellular Ca++ in VSMCs from resistance vessels of SHRSP and WKY rats before, during and after the initial growth and blood pressure spurt; and 5) identify the contractile differences in resistance vessels from SHRSP and WKY animals before, during and after the initial growth and blood pressure spurt in response to various manipulations which affect C1-HC03- exchange and Na+-H+ exchange. We will utilize a number of molecular genetic, biochemical, electrophysiological and physiologic techniques currently employed by the project investigators in order to provide a comprehensive analysis of pHi regulator proteins and their role in the development of genetic hypertension.
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