The primary goal of this research continues to be elucidation of intracellular metal ion (Na+, K+, free Mg2+ & free Ca2+) metabolism in normal and pathological states. We seek to understand how the regulation of intracellular concentrations of essential metal ions goes astray in health disorders, especially hypertension diabetes. Our main research tool is NMR spectroscopy. Our laboratory played a key role in the development of NMR methods for measuring intracellular Na+ (using a membrane-impairment extracellular shift reagent to differentiate between intra- and extracellular ions) and free Mg2+ (by analyzing 31P NMR chemical shifts of intracellular ATP), and for simultaneous measurement of heavy metals and intracellular free Ca2+ (by 19F NMR of fluorinated probe molecules introduced into the cell). The choice of cells and issues for our research is based on the criteria of availability and physiological significance. It includes human peripheral blood cells (erythrocytes and platelets), intact rat kidney and heart in-vivo or perfused in vitro, and perfused rat aorta which is a readily accessible model for vascular smooth muscle cells. The following specific aims will be pursued: (l) To test the hypothesis that intracellular potassium deficit is relevant in hypertension, and arises due to increased K+ efflux via calcium-activated potassium channels; 2) To test the hypothesis that an abnormality in renal sodium transport due to hyperactivity of renal Na+:H+ transport accompanies vascular ionic changes in salt-sensitive, but not in salt-resistant, essential hypertension: 3) To investigate the effects of diabetes on intracellular [Na+], [K+], free [Ca2+], free [Mg2+] and pH in elected target tissues (kidney, heart and vasculature) in diabetic rat models;(4) To investigate the potential ole of hyperglycemia in causing diabetes associated intracellular ionic abnormalities, especially in the vascular tissue; and (5) To investigate increased vulnerability of diabetic and hypertensive kidney and myocardium to ischemic damage, and the protective effect of magnesium ions. It is hoped that the proposed investigations of intracellular ions in hypertension and diabetes will eventually lead to better strategies for he management of these health disorders.
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