The mechanism underlying the high incidence of hypertension (HTN) in obesity and in noninsulin dependent diabetes mellitus (NIDDM) has not been clarified. Our hypothesis is that hyperinsulinemia and insulin resistance contribute to the pathogenesis of HTN of these states. We suggest that insulin increases blood pressure by enhancing sympathetic nervous system (SNS) outflow by altering sodium balances via absorptive processes including activation of Na+/K+ ATPase, by modifying the renin-angiotensin system, and by altering vascular responsivity through changes in Mg++ and through mitogenic effects on vessels. In addition, HTN per se causes insulin resistance and hyperinsulinemia, thus establishing a vicious cycle of events. Nine projects to explore these relationships are planned: 1) In a clinical module, a group of patients will be studied over time who are lean or obese, NIDDM or normal, and hypertensive or normotensive. Glucose and insulin kinetics, SNS, Na+ handling, renin, and various eicosanoids will be measured and correlated. 2) The effect of insulin and the hypertensive state on SNS will be studied both centrally and peripherally in Wistar-Kyoto and SHR rats. 3) The effect of insulin on vascular and cardiac cell growth in culture and on Na+/H+ antiporter and Na/K ATPase activity and gene expression will be quantitated both in vivo and in vitro. 4) The effect of insulin on vascular reactivity and angiotensin II (AII) and norepinephrine action will be studied. 5) We will determine by the role of Magnesium deficiency on vascular reactivity, platelet aggregation, and response to AII. 6) Systemic and renal production of prostacyclin and lipoxygenase (LO) products will be measured in the various clinical groups, during insulin clamp studies, and in a continuum of NIDDM patients with micro and macroalbuminuria. Using renin secreting cells and tissues as a specialized vascular model, the effect of the diabetic state on eicosanoid metabolism, AII action, and role of various growth factors on renin secretion will be explored. 7) Prorenin processing in NIDDM will be determined at the cellular and molecular level. 8) The effects of HTN and insulin on key cardiac protein gene expression and cell mitogenesis will be quantitated. 9) The role of the microcirculation or insulin sensitivity and receptor biology will be researched. The interaction of the various investigators, the presence of the clinical modules and animal core will allow us to extend knowledge and treat this attractive hypothesis in a manner that a series of independent projects could not accomplish.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL044404-04
Application #
2221464
Study Section
Special Emphasis Panel (SRC (HX))
Project Start
1990-09-30
Project End
1995-11-30
Budget Start
1993-12-01
Budget End
1994-11-30
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Southern California
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Berger, M E; Ormsby, B L; Bunnag, P et al. (1998) Increased functional Na(+)-K+ pump activity in the vasculature of fructose-fed hyperinsulinemic and hypertensive rats. Hypertens Res 21:73-80
Bunnag, P; Hori, M T; Ormsby, B et al. (1997) Impaired in vivo adrenergic responses in diet-induced hypertensive rats. Hypertens Res 20:17-21
Zhang, Y; Mircheff, A K; Hensley, C B et al. (1996) Rapid redistribution and inhibition of renal sodium transporters during acute pressure natriuresis. Am J Physiol 270:F1004-14
Azuma, K K; Balkovetz, D F; Magyar, C E et al. (1996) Renal Na+/H+ exchanger isoforms and their regulation by thyroid hormone. Am J Physiol 270:C585-92
McDonough, A A; Zhang, Y; Shin, V et al. (1996) Subcellular distribution of sodium pump isoform subunits in mammalian cardiac myocytes. Am J Physiol 270:C1221-7
Quinones, M J; Leor, J; Kloner, R A et al. (1996) Avoidance of immune response prolongs expression of genes delivered to the adult rat myocardium by replication-defective adenovirus. Circulation 94:1394-401
Antonipillai, I; Nadler, J; Vu, E J et al. (1996) A 12-lipoxygenase product, 12-hydroxyeicosatetraenoic acid, is increased in diabetics with incipient and early renal disease. J Clin Endocrinol Metab 81:1940-5
Natarajan, R; Lanting, L; Gonzales, N et al. (1996) Formation of an F2-isoprostane in vascular smooth muscle cells by elevated glucose and growth factors. Am J Physiol 271:H159-65
Leor, J; Quinones, M J; Patterson, M et al. (1996) Adenovirus-mediated gene transfer into infarcted myocardium: feasibility, timing, and location of expression. J Mol Cell Cardiol 28:2057-67
Nadler, J L; Rude, R K (1995) Disorders of magnesium metabolism. Endocrinol Metab Clin North Am 24:623-41

Showing the most recent 10 out of 50 publications