H2O2 opens BKCa channels via the PLA2-arachidonic acid signaling cascade in coronary artery smooth muscle

H2O2 is a reactive oxygen species that contracts or relaxes vascular smooth muscle, but the molecular basis of these effects remains obscure. We previously demonstrated that H2O2 opens the large-conductance, calcium- and voltage- activated (BKCa) potassium channel of coronary myocytes (2) and now report physiological and biochemical evidence that the effect of H2O2 on coronary smooth muscle involves the phospholipase A(2) (PLA(2))/arachidonic acid (AA) signaling cascades. H2O2 stimulation of BKCa channel activity was inhibited by arachidonyl trifluoromethyl ketone, an inhibitor of cytosolic PLA(2). Furthermore, H2O2 stimulated release of [H-3] AA from coronary myocytes, and exogenous AA mimicked the effect of H2O2 on BKCa channels. Inhibitors of protein kinase C activity attenuated the effect of H2O2 on BKCa channels, [H-3] AA release, or intact coronary arteries. In addition, the effect of H2O2 or AA on BKCa channels was inhibited by blockers of lipoxygenase metabolism. In contrast, inhibitors of cyclooxygenase or cytochrome P-450 had no effect. We propose that H2O2 relaxes coronary arteries by stimulating BKCa channels via the PLA(2)/AA signaling cascade and that lipoxygenase metabolites mediate this response.