The investigators have found that obese hypertensives have increased vascular alpha-adrenergic tone and elevated plasma non-esterified fatty acids (NEFAs). The increased alpha-adrenoceptor tone and NEFAs may be linked , since they have shown that raising NEFAs in lean normotensives enhanced local venoconstrictor and systemic pressor responses to phenylephrine, an alpha 1-adrenoceptor agonist. Indomethacin reversed the augmented venoconstrictor response to phenylephrine when NEFAs were raised locally. This project is designed to test the hypothesis: Fatty acids increase vascular alpha 1-adrenoceptor pressor reactivity. The project has four Aims: 1. Determine if raising NEFAs increases and lower NEFAs reduces pressor reactivity to phenylephrine similarly in volunteers differing by body mass index, body fat distribution, and blood pressure. Vascular alpha 1-adrenoceptor reactivity, assessed by changes in phenylephrine dose which raises mean BP 20 mmHg, is measured on separate days at baseline and after raising NEFAs (intralipid/heparin) and lowering NEFAs (nicotinic acid). 2. Determine if interactions between obesity, fat distribution, hypertension and PD-20 are related to insulin's action on NEFA concentrations and turnover rather than glucose disposal. The studies for Aim 1 will be performed in lean normotensives, lower body obese normotensives (to control for obesity), abdominally obese normotensives (to control for body fat distribution), lean hypertensives (to control for BP), and abdominally obese hypertensives. 3. Determine the effects of cyclo-oxygenase inhibition with indomethacin on pressor responsiveness to phenylephrine when NEFAs are elevated with intralipid/heparin. Changes in the PD-20 induced by intralipid/heparin will be compared to changes on other days when intralipid/heparin is given with indomethacin and also indomethacin alone to block generation of cyclo-oxygenase products. 4 Contrast the effects of raising plasma linoleate, oleate, and palmitate levels with intralipid/heparin to those of selectively raising plasma oleate (triolein/heparin), linoleate (trilinolein/heparin), and saturated NEFAs (coconut oil/heparin) on the PD-20. The investigators propose that these studies could better delineate the short-term effects of specific NEFAs, and possibly cyclo-oxygenase products, in the heightened neurovascular reactivity and tone which characterize obesity hypertension. The studies could provide a basis for longer-term clinical studies on NEFAs and BP regulation as well as basic experiments to elucidate signaling mechanisms.
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