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Vol. 302, Issue 3, 918-923, September 2002

Calcium-Independent Phospholipase A2-Derived Arachidonic Acid Is Essential for Endothelium-Dependent Relaxation by Acetylcholine

Hélène C. Seegers , Richard W. Gross and Walter A. Boyle

Department of Anesthesiology (H.C.S., W.A.B.) and Division of Bioorganic Chemistry and Molecular Pharmacology (R.W.G.), Department of Medicine, Washington University, St. Louis, Missouri; and Academic Rheumatology (H.C.S.), University of Nottingham, City Hospital, Nottingham, United Kingdom

The role of calcium-independent phospholipase A2 (iPLA2)-produced arachidonic acid (AA) in acetylcholine (ACh)-mediated, endothelium-dependent vascular relaxation was investigated. ACh-induced relaxation of phenylephrine-constricted isolated rat mesenteric resistance arteries was attenuated following pretreatment with (E)-6-(bromomethylene)tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one (BEL; 1 µM; p < 0.01), a highly selective suicide substrate inhibitor of iPLA2. Following BEL, the ACh relaxation could be completely restored following pretreatment with picomolar quantities of the cell-permeant methyl ester analog of AA (arachidonic acid methyl ester, AA-Me). Higher amounts of AA-Me (1 µM) had a direct endothelium-dependent relaxing action, which was inhibited by the nitric-oxide synthase inhibitor (Nomega -nitro-L-arginine; 100 µM), independent of ACh, and unaffected by BEL. Neither the ACh relaxation restoring action nor the direct relaxing action of AA-Me was affected by preincubation with inhibitors of the lipoxygenase (esculetin, 10 µM) or cytochrome P450 monooxygenase (17-octadecynoic acid; 10 µM) pathways; and both actions of AA-Me were enhanced following preincubation with the cyclooxygenase inhibitor indomethacin (10 µM; p < 0.05). The results of the present study indicate that iPLA2-produced AA plays an essential role in ACh-mediated endothelium-dependent relaxation in rat mesenteric resistance arteries.

0022-3565/02/3023-0918$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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