Hydrogen peroxide relaxes porcine coronary arteries by stimulating BKCa channel activity

Department of Physiology and Biophysics, Wright State University School of Medicine, Dayton, Ohio 45435 It has been known for a number of years that neutrophils and macrophages secrete H 2 O 2 while fighting disease, and the levels obtained within the vasculature under these conditions can reach several hundred micromolar. Because the effect of H 2 O 2 on vascular smooth muscle is not fully understood, the present study examined the cellular effects of H 2 O 2 on coronary arteries. Under normal ionic conditions, H 2 O 2 relaxed arteries that were precontracted with prostaglandin F 2 or histamine (EC 50 = 252 ± 22 µM). The effect of H 2 O 2 was concentration dependent and endothelium independent. In contrast, H 2 O 2 did not relax arteries contracted with 80 mM KCl, suggesting involvement of K + channels. Single-channel patch-clamp recordings revealed that H 2 O 2 increased the activity of the large-conductance (119 pS), Ca 2+ - and voltage-activated K + (BK Ca ) channel. This response was mimicked by arachidonic acid and inhibited by eicosatriynoic acid, a lipoxygenase blocker, suggesting involvement of leukotrienes. Further studies on intact arteries demonstrated that eicosatriynoic acid not only blocked the vasodilatory response to H 2 O 2 but unmasked a vasoconstrictor effect that was reversed by blocking cyclooxygenase activity with indomethacin. These findings identify a novel effector molecule, the BK Ca channel, which appears to mediate the vasodilatory effect of H 2 O 2 , and suggest that a single signaling pathway, arachidonic acid metabolism, can mediate the vasodilatory and vasoconstrictor effects of H 2 O 2 and possibly other reactive oxygen species. lipoxygenase; cyclooxygenase