H2O2 opens BK(Ca) channels via the PLA2-arachidomic acid signaling cascade in coronary artery smooth muscle

H2O2 opens BK(Ca) channels via the PLA2-arachidonic acid signaling cascade in coronary artery smooth muscle. Am J Physiol Heart Circ Physiol 279: H475-H483, 2000. - 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 (BK(Ca)) 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 A2 (PLA2)/arachidonic acid (AA) signaling cascades. H2O2 stimulation of BK(Ca) channel activity was inhibited by arachidonyl trifluoromethyl ketone, an inhibitor of cytosolic PLA2. Furthermore, H2O2 stimulated release of [3H]AA from coronary myocytes, and exogenous AA mimicked the effect of H2O2 on BK(Ca) channels. Inhibitors of protein kinase C activity attenuated the effect of H2O2 on BK(Ca) channels, [3H]AA release, or intact coronary arteries. In addition, the effect of H2O2 or AA on BK(Ca) 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 BK(Ca) channels via the PLA2/AA signaling cascade and that lipoxygenase metabolites mediate this response.