The main objective of this proposal is to test the hypothesis that hyperinsulinemia, comparable to that found in obese hypertensives, any cause chronic hypertension via alterations in renal function. Our studies will focus mainly on the possibility that the hyperinsulinemia initiates hypertension by increasing renal tubular sodium reabsorption, similar to the effect of mineralocorticoids. Our approach will employ animal experimentation, studies in humans, and a theoretical analysis of the effects of insulin on renal function and arterial pressure. The animal experiments are designed to determine whether there is a cause and effect relationship between chronic hyperinsulinemia in dogs with normal kidneys and with various degrees of functional renal reserve, caused by reduced renal mass or increased sodium intake. Studies are also designed to evaluate the importance of changes in activity of the renin-angiotensin system (RAS), aldosterone, the sympathetic nervous system, and atrial natriuretic factor (ANF) in modulating insulin-sodium-blood pressure interrelationships. The relative importance of the direct intrarenal and extrarenal actions of insulin in causing chronic hypertension will also be quantitated. And finally, these studies will evaluate the intrarenal mechanisms, including changes in renal hemodynamics and tubular reabsorption, by which insulin influences renal excretion chronically and the role of extrarenal mechanisms, such as the RAS, aldosterone, the sympathetic nervous system, and ANF in modulating insulin's renal actions. All of these studies will be conducted in chronically instrumented conscious dogs using techniques recently developed in our laboratory that allow us to accurately estimate changes in renal function and systemic hemodynamics for along periods of time. The clinical studies are designed primarily to determine whether insulin resistance, which occurs in peripheral tissues of obese hypertensives, also occurs in the renal tubule. In these experiments, the effects of insulin on renal sodium reabsorption will be evaluated in normotensive and hypertensive non-obese and obese individuals. A systems analysis of the interrelationships between insulin, body fluid homeostasis, and arterial pressure regulation will be developed. The experiments will provide much of the quantitative data needed to develop this analysis and the mathematical analysis will, in turn, be important in evaluating the validity of our hypotheses and in suggesting new areas for experimentation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL039399-04
Application #
3356223
Study Section
Special Emphasis Panel (SRC (04))
Project Start
1987-07-01
Project End
1992-04-30
Budget Start
1990-05-01
Budget End
1991-04-30
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Mississippi Medical Center
Department
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Brands, M W; Harrison, D L; Keen, H L et al. (1997) Insulin-induced hypertension in rats depends on an intact renin-angiotensin system. Hypertension 29:1014-9
Summers, R L; Montani, J P; Woodward, L H et al. (1997) Theoretical analysis of the mechanisms of chronic hyperinsulinemia. Comput Biol Med 27:249-56
Hall, J E (1997) Mechanisms of abnormal renal sodium handling in obesity hypertension. Am J Hypertens 10:49S-55S
Alonso-Galicia, M; Brands, M W; Zappe, D H et al. (1996) Hypertension in obese Zucker rats. Role of angiotensin II and adrenergic activity. Hypertension 28:1047-54
Hall, J E; Guyton, A C; Brands, M W (1996) Pressure-volume regulation in hypertension. Kidney Int Suppl 55:S35-41
Keen, H L; Brands, M W; Alonso-Galicia, M et al. (1996) Chronic adrenergic receptor blockade does not prevent hyperinsulinemia-induced hypertension in rats. Am J Hypertens 9:1192-9
Hall, J E; Brands, M W; Shek, E W (1996) Central role of the kidney and abnormal fluid volume control in hypertension. J Hum Hypertens 10:633-9
Brands, M W; Lee, W F; Keen, H L et al. (1996) Cardiac output and renal function during insulin hypertension in Sprague-Dawley rats. Am J Physiol 271:R276-81
Van Vliet, B N; Hall, J E; Mizelle, H L et al. (1995) Reduced parasympathetic control of heart rate in obese dogs. Am J Physiol 269:H629-37
Hall, J E; Brands, M W; Zappe, D H et al. (1995) Insulin resistance, hyperinsulinemia, and hypertension: causes, consequences, or merely correlations? Proc Soc Exp Biol Med 208:317-29

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