Abstract-The dyslipidemia in obese hypertensive persons may contribute to their increased vascular ␣-adrenergic receptor reactivity and tone. To further examine this notion, we conducted 2 studies of pressor sensitivity to phenylephrine, an ␣ 1 -adrenergic receptor agonist, in lean normotensive subjects. In the first study (nϭ6), pressor responses to phenylephrine were obtained before and during a saline and heparin infusion. On another day, pressor reactivity to phenylephrine was measured before and during infusion of 20% Intralipid at 0.5 mL ⅐ m Ϫ2 ⅐ min Ϫ1 with heparin at 1000 U/h to increase lipoprotein lipase activity and raise nonesterified fatty acids (NEFAs). In the second study (nϭ8), baseline reactivity to phenylephrine was obtained on 2 separate days and repeated after raising NEFAs and triglycerides either with 0.8 mL ⅐ m Ϫ2 ⅐ min Ϫ1 of 20% Intralipid alone or together with heparin. The infusion of saline and heparin did not significantly change plasma NEFAs from baseline (516Ϯ90 versus 512Ϯ108 mol/L, respectively; PϭNS) or the dose of phenylephrine required to raise mean blood pressure by 20 mm Hg ([PD 20PE ]; 1.00Ϯ0.14 versus 0.95Ϯ0.10 Across all study conditions, changes in levels of triglycerides and NEFAs correlated with changes in mean arterial pressure responses to phenylephrine, especially at the 0.4-g ⅐ kg Ϫ1 ⅐ min Ϫ1 infusion rate of phenylephrine (rϭ0.64, PϽ0.01 and rϭ0.54, PϽ0.01, respectively). These data suggest that raising levels of plasma NEFAs and/or triglycerides enhances ␣ 1 -adrenoceptor-mediated pressor sensitivity. The findings suggest that lipid abnormalities in obese hypertensives, which include elevated NEFAs and triglycerides, contribute to greater vascular ␣ 1 -adrenergic reactivity. (Hypertension. 1998;32:693-698.) Key Words: fatty acids Ⅲ phenylephrine Ⅲ receptors, adrenergic Ⅲ blood pressure I nsulin resistance is associated with a cluster of cardiovascular risk factors including hypertension, but the intermediary mechanisms linking metabolic and hemodynamic abnormalities are not well defined.1-7 Abdominally obese hypertensive persons have increased vascular ␣-adrenergic tone and reactivity, 8 as well as increased plasma concentrations 9 and turnover of nonesterified fatty acids (NEFAs) that are highly resistant to suppression by insulin.10 Evidence implicates abnormalities of NEFAs as one potential pathogenetic link between abdominal obesity and hypertension. 3,9 -12 We observed a positive correlation between plasma fatty acids during euglycemic clamp and blood pressure (BP) in obese subjects that was independent of hyperinsulinemia and insulin-mediated glucose disposal. 10 In minipigs, raising fatty acid levels increases systemic vascular resistance and BP. 13Our previous research has shown that raising fatty acids in the dorsal hand vein of normal volunteers to concentrations observed in obese hypertensives significantly increases venoconstrictor responses to phenylephrine as well as a neuroreflex stimulus.11,14 These observations raise the possibility that the e...

Abstract-Obese hypertensives have increased nonesterified fatty acids (NEFAs) and ␣-adrenergic vascular reactivity.Raising NEFAs locally with intralipid and heparin augments dorsal hand venoconstrictor responses to phenylephrine, an ␣ 1 -adrenoceptor agonist. The enhanced venoconstrictor responses were reversed by indomethacin. The findings suggest that raising NEFAs leads to the generation of cyclooxygenase (COX) product(s) that enhance vascular reactivity. To test this notion, 6-keto-PGF 1␣ and TxB 2 , the stable metabolites of prostaglandin H 2 (PGH 2 ); prostacyclin (PGI 2 ); and thromboxane (TxA 2 ), were measured Ϸ1.5 to 2 cm downstream of a dorsal hand vein infusion of intralipid and heparin (nϭ10) or saline and heparin (nϭ5) for 2 hours each. During the third hour, intralipid and heparin (experimental) and saline and heparin (control) were continued, and either saline (control) or indomethacin (intervention) were infused. Intralipid and heparin raised local 6-keto PGF 1␣ concentrations by 350% to 500% (PϽ0.005), but saline and heparin did not (PϭNS). TxB 2 levels did not change significantly with any infusion. Infusion of indomethacin during the third hour of intralipid and heparin lowered plasma 6-keto-PGF 1␣ (PϽ0.05), whereas infusion of saline with intralipid and heparin did not (PϭNS). Oleic and linoleic acids at 100 mol/L, increased 6-keto-PGF 1␣ in vascular smooth muscle cells (VSMCs) through a protein kinase C and extracellular, signal-regulated kinase independent pathway. However, oleic and linoleic acids increased intracellular Ca 2ϩ in VSMCs. The data indicate that NEFAs induce the production of COX products, perhaps via Ca 2ϩ -dependent activation of phospholipase A 2 . The COX product(s) may contribute to increased vascular ␣-adrenergic reactivity among insulin-resistant individuals when NEFAs are elevated. Key Words: fatty acids Ⅲ prostaglandins Ⅲ muscle, vascular, smooth Ⅲ cyclooxygenase O bese hypertensives have increased vascular ␣-adrenergic reactivity and tone as well as elevated non-esterified fatty acids (NEFAs) which are resistant to suppression by insulin. [1][2][3] In lean normotensives, raising NEFAs with intralipid and heparin enhances local and systemic sensitivity to phenylephrine, an ␣ 1 -adrenoceptor agonist. 4 -6 In the hand vein studies, raising NEFAs locally enhanced ␣ 1 -adrenergic vasoconstriction and endotheliumdependent dilation via an indomethacin-sensitive mechanism, which implicates cyclooxygenase (COX) product(s) in the altered vascular reactivity. 6 cis-Unsaturated NEFAs, eg, oleic acid, activate a sequential signaling pathway that includes protein kinase C (PKC), reactive oxygen species (ROS), and extracellular signal-regulated kinases (ERKs). 7,8 ERKs can induce a Ca 2ϩ -independent activation of phospholipase A 2 with hydrolysis of arachidonic acid from complex lipids, 9 leading to the subsequent generation of eicosanoid products. Alternatively, linoleic but not oleic acid can be elongated and desaturated to arachidonic acid. 10 Arachidonic acid is converted b...