H(2)O(2) opens BK(Ca) channels via the PLA(2)-arachidonic acid signaling cascade in coronary artery smooth muscle.
H(2)O(2) 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 H(2)O(2) 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 H(2)O(2) on coronary smooth muscle involves the phospholipase A(2) (PLA(2))/arachidonic acid (AA) signaling cascades. H(2)O(2) stimulation of BK(Ca) channel activity was inhibited by arachidonyl trifluoromethyl ketone, an inhibitor of cytosolic PLA(2). Furthermore, H(2)O(2) stimulated release of [(3)H]AA from coronary myocytes, and exogenous AA mimicked the effect of H(2)O(2) on BK(Ca) channels. Inhibitors of protein kinase C activity attenuated the effect of H(2)O(2) on BK(Ca) channels, [(3)H]AA release, or intact coronary arteries. In addition, the effect of H(2)O(2) 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 H(2)O(2) relaxes coronary arteries by stimulating BK(Ca) channels via the PLA(2)/AA signaling cascade and that lipoxygenase metabolites mediate this response.
Department of Physiology and Biophysics, Wright State University School of Medicine, Dayton, Ohio 45435, USA.
R S
RS
Barlow
A M
AM
El-Mowafy
R E
RE
White
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D007537:Isometric Contraction / Q000502:physiology; D051036:Large-Conductance Calcium-Activated Potassium Channels; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009281:Naphthalenes / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010741:Phospholipases A / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D024681:Potassium Channels, Calcium-Activated; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013552:Swine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D002722:Chlorobenzenes
D016718:Arachidonic Acid; D004791:Enzyme Inhibitors; D006861:Hydrogen Peroxide; D007211:Indoles; D051036:Large-Conductance Calcium-Activated Potassium Channels; D016859:Lipoxygenase Inhibitors; D009281:Naphthalenes; D010741:Phospholipases A; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; C060893:MK-886; D002722:Chlorobenzenes; C058819:calphostin C