HYDROGEN-PEROXIDE RELAXES PORCINE CORONARY-ARTERIES BY STIMULATING BKCA CHANNEL ACTIVITY

It has been known for a number of years that neutrophils and macrophag es secrete H2O2 while fighting disease, and the levels obtained within the vasculature under these conditions can reach several hundred micr omolar. Because the effect of H2O2 on vascular smooth muscle is not fu lly understood, the present study examined the cellular effects of H2O 2 on coronary arteries. Under normal ionic conditions, H2O2 relaxed ar teries that were precontracted with prostaglandin F-2 alpha or histami ne (EC50 = 252 +/- 22 mu M). The effect of H2O2 was concentration depe ndent and endothelium independent. In contrast, H2O2 did not relax art eries contracted with 80 mM KCl, suggesting involvement of K+ channels . Single-channel patch-clamp recordings revealed that H2O2 increased t he activity of the large-conductance (119 pS), Ca2+- and voltage-activ ated K+ (BKCa) channel. This response was mimicked by arachidonic acid and inhibited by eicosatriynoic acid, a lipoxygenase blocker, suggest ing involvement of leukotrienes. Further studies on intact arteries de monstrated that eicosatriynoic acid not only blocked the vasodilatory response to H2O2 but unmasked a vasoconstrictor effect that was revers ed by blocking cyclooxygenase activity with indomethacin. These findin gs identify a novel effector molecule, the BKCa channel, which appears to mediate the vasodilatory effect of H2O2, and suggest that a single signaling pathway, arachidonic acid metabolism, can mediate the vasod ilatory and vasoconstrictor effects of H2O2 and possibly other reactiv e oxygen species.