Obese hypertensives have elevated plasma non-esterified fatty acids (NEFAs) including oleic acid. Oleic acid induces a PKC-dependent increase of reactive oxygen species in vascular smooth muscle cells. In volunteers consuming diets low in anti-oxidants for 3 weeks, raising plasma NEFAs with an infusion of Intralipid and heparin increased blood pressure (BP) about l4/8 mmHg and elevated plasma F2-isoprostanes, an index of oxidative stress, p
SPECIFIC AIM : Determine the effects of isocaloric high and low anti-oxidant diets with equal daily amounts of Na* (3000 mg), K+ (4000 mg), Ca2+ (1000 mg), and Mg2+ (500 mg) and fiber for 4 weeks each on BP and plasma isoprostanes at baseline and during a 4-hour infusion of Intralipid and heparin to raise plasma NEFAs in obese, dyslipidemic hypertensive and lean normotensive volunteers. METHODS: Complete data will be obtained on 30 lean (BMI <25 kg/m2), healthy normotensive (BP <130/85 mmHg) subjects with normal glucose and lipid values and 30 obese, non-diabetic patients with the risk factor cluster (BMI >27 kg/m2, triglycerides >150 mg/dl, HDL-C <45 mg/dl, BP 130-159/85-99). Subjects are studied first on their usual diets, then randomized to either the low or high anti-oxidant diet for 4 weeks prior to the second study. They undergo a third study after 4 weeks on the complementary phase of the high or low anti-oxidant diet. Each study includes a two-day assessment. On day one, volunteers have measurements of glucose and NEFAs under fasting conditions and during a 15-minute insulin tolerance test to assess insulin action. A 24-hour BP monitor is placed. On day two, subjects undergo testing that includes hemodynamics (BP, heart rate, stroke volume, cardiac output, calculated vascular resistance, arterial compliance) and indices of oxidative stress (plasma and urine F2-isoprostanes and other secondary markers). Anti-oxidant capacity will be assessed by assaying the ferric reducing activity of plasma (FRAP) and by measuring reduced and oxidized glutathione in plasma and RBCs. Plasma NEFAs, lipids, and insulin will be obtained. Measurements will be obtained in the fasting state and during a 4-hour infusion of Intralipid and heparin to raise plasma NEFAs. SIGNIFICANCE: The mechanisms by which obesity raises BP are not well defined. Evidence supports the notion that resistance to insulin's NEFAs lowering action contributes to elevated BP through oxidant-sensitive mechanisms. This study is designed to clarify the capacity of dietary anti-oxidants to modulate BP and measures of oxidative stress under basal, fasting conditions and in response to acute dyslipidemia under controlled laboratory conditions. We believe the information generated by the proposed studies has the potential for elucidating biological mechanisms underlying obesity-associated hypertension and the potential for dietary anti-oxidants to modulate BP.
