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.
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