Lipids Stimulate the Production of 6-keto-prostaglandin F _1α in Human Dorsal Hand Veins

Abstract

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...

Mechanism of lipid enhancement of α1-adrenoceptor pressor sensitivity in hypertension

“…In previous studies in dorsal hand veins of healthy normotensive subjects, we observed a lipid-associated enhancement in a 1 vasoreactivity [9] and endothelium-dependent venodilation abolished by indomethacin [10]. Subsequent studies revealed the local generation of the stable prostacyclin derivative, 6-keto-PGF 1a induced by lipids [25]. Complementary invitro studies showed that 2 cis-unsaturated fatty acids, oleic and linoleic acid enhanced in 6-keto-PGF 1a corresponding with increased calcium influx into cultured vascular smooth muscle cells, which presumably activated phopholipase A2 with the release of arachidonic acid and the generation of eicosanoid products.…”

Effects of Danhong Injection (丹红注射液) and its main components on anticoagulation and fibrinolysis in cultured vein endothelial cells

“…Therefore, the level of 6-keto-PGF1α, a stable metabolite produced by PGI 2 , can not only refl ect the condition of platelet aggregation inhibition, but also reflect the injury degree of vascular VECs. (28,29) The present research shows that VECs secretion function and fibrinolysis function were regulated in the daiclzein group and Danhong Injection group as compared with hypoxia group.…”

Reduced venous endothelial responsiveness after oral lipid overload in healthy volunteers

“…Our results showed that the dose of phenylephrine needed to reach ED 70% was higher after the OLO, characterizing an α 1 -adrenergic response alteration, which is demonstrated for the first time in healthy adults. Studies of venous endothelial function in response to the infusion of free fatty acids showed increased α 1 -adrenergic reactivity [32] together with an increased pressoric response, probably due to increased intracellular Ca 2+ activated by phospholipase A 2 [33]. In these studies, increased α 1 -adrenergic reactivity was characterized by the lower dose of phenylephrine needed to achieve the vasoconstrictor and pressoric response.…”