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(Hypertension. 2001;38:858.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Lipids Stimulate the Production of 6-keto-prostaglandin F₁ in Human Dorsal Hand Veins

Adetola Haastrup; Crystal A. Gadegbeku; Da Zhang; Yurii V. Mukhin; Eddie L. Greene; Ayad A. Jaffa; Brent M. Egan

From the Departments of Pharmacology and Medicine, Medical University of South Carolina, Charleston.

Correspondence to Brent M. Egan, MD, Division of Clinical Pharmacology, Medical University of South Carolina, 96 Jonathan Lucas St, PO Box 250623, CSB 826, Charleston, SC 29425. E-mail eganbm{at}musc.edu

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-PGF₁ and TxB₂, the stable metabolites of prostaglandin H₂ (PGH₂); prostacyclin (PGI₂); and thromboxane (TxA₂), were measured 1.5 to 2 cm downstream of a dorsal hand vein infusion of intralipid and heparin (n=10) or saline and heparin (n=5) 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 PGF₁ concentrations by 350% to 500% (P<0.005), but saline and heparin did not (P=NS). TxB₂ levels did not change significantly with any infusion. Infusion of indomethacin during the third hour of intralipid and heparin lowered plasma 6-keto-PGF₁ (P<0.05), whereas infusion of saline with intralipid and heparin did not (P=NS). Oleic and linoleic acids at 100 µmol/L, increased 6-keto-PGF₁ 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 Ca²⁺ in VSMCs. The data indicate that NEFAs induce the production of COX products, perhaps via Ca²⁺-dependent activation of phospholipase A₂. The COX product(s) may contribute to increased vascular -adrenergic reactivity among insulin-resistant individuals when NEFAs are elevated.

Key Words: fatty acids • prostaglandins • muscle, vascular, smooth • cyclooxygenase

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