The goals of this project continue to be: 1) to develop an understanding of the system which controls extracellular K and K balance, and 2) to analyze the effects of changes in K within the pathophysiological range on cardiovascular and renal function. Achieving these goals is closely relevant to a large fraction of the health care problems dealt with by the medical community each day. In fact, one-third of all general medical in- patients receive K supplementation to correct conditions associated with improper K regulation. Furthermore, one of the most commonly prescribed antihypertensive medications, hydrochlorothiazide, taken daily by a large percentage of the 10% of the general population with hypertension, frequently produces hypokalemia nad K depletion. And finally, hypokalemia is a consistent sequelae to general anesthesia, surgical stress, myocardial infarction, and traumatic states in general, while hyperkalemia is a hallmark of circulatory shock. Although the effects of extreme K concentrations beyond the pathophysiological range are known to have severe cardiovascular and renal consequences, very little is known about the effects of variations in K within this range so frequently encountered in clinical medicine. This gap in our understanding of the effects of K within the clinically relevant range, and of the control system which must regulate K are the targets of the project in this application. The studies of the cardiovascular effects include analyses of changes in cardiac mechanics during chronic K depletion, a quantitative study of the effects of K depletion on cardiac arrhythmia, a study of the effects of rapid decreases in K on coronary blood flow regulation, and a test of the hypothesis that the syndrome of post-exercise sudden cardiac death is caused by the rapid decrease in K which occurs in the first minutes after the cessation of exercise. The renal hemodynamics and renin release resulting from long-term hyperkalemia, the effects of changes in K on the relationship between sodium intake nad arterial blood pressure, and we will study the long-term effects of calcium entry blockers on renal hemodynamic and renin release regulation, with emphasis on developing and understanding why calcium entry blocker therapy is ineffective in high renin hypertension. The analyses of the system which regulates K are designed to support the development of a mathematical model-hypothesis of the control system, analogous to the one developed previously with support of this grant concerning the long-term control of K over periods of days and weeks. During this coming project period we will conduct both experimental and mathematical analyses of the control system, working towards a complete understanding of the system which regulates K during conditions such as anesthesia, surgical stress, myocardial infarction, severe exercise, and other acutely traumatic conditions.
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