Lipids stimulate the production of 6-keto-prostaglandin F1α in human dorsal hand veins

Obese hypertensives have increased nonesterified fatty acids (NEFAs) and alpha -adrenergic vascular reactivity. Raising NEFAs locally with intralipid and heparin augments dorsal hand venoconstrictor responses to phenylephrine, an alpha (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 alpha) and TxB(2), the stable metabolites of prostaglandin H-2 (PGH(2)); prostacyclin (PGI(2)); and thromboxane (TxA(2)), were measured approximate to1.5 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 PGF(1 alpha), concentrations by 350% to 500% (P<0.005), but saline and heparin did not (P=NS). 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<alpha>) (P<0.05), whereas infusion of saline with intralipid and heparin did not (P=NS). Oleic and linoleic acids at 100 <mu>mol/L, increased 6-keto-PGF(1 alpha) 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 A(2) The COX product(s) may contribute to increased vascular alpha -adrenergic reactivity among insulin-resistant individuals when NEFAs are elevated.