TY - JOUR
T1 - Calcium-independent phospholipase A2-derived arachidonic acid is essential for endothelium-dependent relaxation by acetylcholine
AU - Seegers, Hélène C.
AU - Gross, Richard W.
AU - Boyle, Walter A.
PY - 2002/9
Y1 - 2002/9
N2 - 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- (l-naphthalenyl)-2H-pyran-2-one (BEL; μM1 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 ni-tric-oxide synthase inhibitor (Nω-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.
AB - 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- (l-naphthalenyl)-2H-pyran-2-one (BEL; μM1 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 ni-tric-oxide synthase inhibitor (Nω-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.
UR - http://www.scopus.com/inward/record.url?scp=0036721414&partnerID=8YFLogxK
U2 - 10.1124/jpet.302.3.918
DO - 10.1124/jpet.302.3.918
M3 - Article
C2 - 12183647
AN - SCOPUS:0036721414
SN - 0022-3565
VL - 302
SP - 918
EP - 923
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -