Obesity increases the prevalence of hypertension (Ht) more in men <45 years old vs. other age and gender subgroups. Three studies test three related hypotheses: (1) The threefold higher prevalence of Ht in obese (body mass index >27kg/m2) younger men, vs. age-matched normal weight (BMI <25.5 kg/m2) men, is associated with greater upper body (waist:hip ratio (WHR)) and visceral (computerized tomography of the abdomen) fat, hyperinsulinemia (insulin AUC during a 3-hour oral GTT), and salt-sensitivity (mean blood pressure (MBP, mmHg) calculated from 24-hr ambulatory monitoring on 200mEq/d NaC1 >5mmHg above MBP on 20mEq/d NaC1). (2) Salt-sensitive Ht (SS-Ht) in obese young men is characterized by failure to reduce forearm (FAVR) and total systemic vascular resistance (TSR) rather than an excessive rise in forearm blood blow (plethysmography) and cardiac output (thoracic impedance). Maladjustment of vascular resistance to salt is explained by dysregulation of sympathetic drive (plasma norepinephrine (NE) and direct sympathetic nerve recording) and eicosanoid metabolism (hemodynamic response to indomethacin) which enhance vascular alpha-tone (response to prazosin) and angiotensin II-dependent tone (response to captopril) while impairing vasodilator responses to ischemia. (3) Post-prandial insulin (PPI) levels contribute to SS-Ht by (a) increasing sympathetic drive (plasma NE and 3H-NE kinetics) (b) enhancing proximal tubular Na+ reabsorption (Li+ clearance) and (c) depressing systemic prostacyclin production (urinary 2,3-dinor-6-keto-PGF1alpha). PPI characteristic of both lean (roughly 100uU/ml) and obese subjects (approximately 300uU/ml) will be induced in both groups by insulin clamp at 40 and 80 mU/m2/min, respectively. The three objectives are to: (1) define the relationship of adiposity, body fat distribution and hyperinsulinemia to salt-sensitivity status and the excess prevalence of hypertension in men <45 years old in Study 1; (2) determine the physiologic mechanisms of SS-Ht in Study 2 and; (3) verify the biologic mechanisms by which physiologic levels of insulin promote SS-Ht in Study 3. Significance: Hypertensive patients are characterized by upper body obesity and hyperinsulinemia. The proposed studies should determine pathophysiologic mechanisms linking anthropometric variables and insulin metabolism to hemodynamic regulation.
