Calcium-independent phospholipase A(2)-derived arachidonic acid is essential for endothelium-dependent relaxation by acetylcholine

J Pharmacol Exp Ther. 2002 Sep;302(3):918-23. doi: 10.1124/jpet.302.3.918.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylcholine / antagonists & inhibitors
  • Acetylcholine / pharmacology*
  • Animals
  • Arachidonic Acid / metabolism*
  • Endothelium, Vascular / physiology*
  • Enzyme Inhibitors / pharmacology
  • Fatty Acids / pharmacology
  • Group VI Phospholipases A2
  • In Vitro Techniques
  • Male
  • Muscle Contraction / drug effects
  • Muscle Relaxation / drug effects
  • Muscle, Smooth, Vascular / physiology*
  • Nitric Oxide / pharmacology
  • Nitric Oxide / physiology
  • Phospholipases A / antagonists & inhibitors
  • Phospholipases A / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Vasodilator Agents / antagonists & inhibitors
  • Vasodilator Agents / pharmacology*


  • Enzyme Inhibitors
  • Fatty Acids
  • Vasodilator Agents
  • Arachidonic Acid
  • Nitric Oxide
  • Phospholipases A
  • Group VI Phospholipases A2
  • Acetylcholine