Calcium-independent phospholipase A(2)-derived arachidonic acid is essential for endothelium-dependent relaxation by acetylcholine.
The role of calcium-independent phospholipase A(2) (iPLA(2))-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 microM; p < 0.01), a highly selective suicide substrate inhibitor of iPLA(2). 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 microM) had a direct endothelium-dependent relaxing action, which was inhibited by the nitric-oxide synthase inhibitor (N(omega)-nitro-L-arginine; 100 microM), 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 microM) or cytochrome P450 monooxygenase (17-octadecynoic acid; 10 microM) pathways; and both actions of AA-Me were enhanced following preincubation with the cyclooxygenase inhibitor indomethacin (10 microM; p < 0.05). The results of the present study indicate that iPLA(2)-produced AA plays an essential role in ACh-mediated endothelium-dependent relaxation in rat mesenteric resistance arteries.
Department of Anesthesiology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Hélène C
HC
Seegers
Richard W
RW
Gross
Walter A
WA
Boyle
D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology; D054522:Group VI Phospholipases A2; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D005227:Fatty Acids; D014665:Vasodilator Agents; D016718:Arachidonic Acid; D009569:Nitric Oxide; D010741:Phospholipases A; D054522:Group VI Phospholipases A2; D000109:Acetylcholine