Role of cytoplasmic phospholipase A2 in endothelium-derived hyperpolarizing factor dilations of rat middle cerebral arteries

Very little is known regarding the mechanism of action for the endothelium-derived hyperpolarizing factor (EDHF) response in cerebral vessels. The authors tested two hypotheses: (1) activation of the cytoplasmic form of phospholipase A(2) (cPLA(2)) is involved with EDHF-mediated dilations in rat middle cerebral arteries; and (2) activation of the cPLA, involves an increase in endothelial Ca2+ through activation of phospholipase C. Middle cerebral arteries were isolated from the rat, pressurized to 85 mm Hg, and luminally perfused. The EDHF response was elicited by luminal application of uridine triphosphate (UTP) after NO synthase and cyclooxygenase inhibition (10(-5) mol/L N-nitro-L-arginine methyl ester and 10(-5) mol/L indomethacin, respectively). AACOCF(3) and PACOCF(3), inhibitors of cPLA(2) (Ca2+-sensitive) and Ca2+-insensitive PLA(2) (iPLA(2)), dose dependently attenuated the EDHF response. A selective inhibitor for iPLA(2), haloenol lactone suicide substrate, had no effect on the EDHF response. The EDHF response elicited by UTP was accompanied by an increase in endothelial Ca2+ (144 to 468 nmol/L), and the EDHF dilation was attenuated with U73122, a phospholipase C inhibitor. The authors conclude that the EDHF response elicited by luminal UTP in rat middle cerebral arteries involved activation of phospholipase C, an increase in endothelial Ca2+, and activation of cPLA(2).