Hydrogen peroxide relaxes porcine coronary arteries by stimulating BKCa channel activity.
It has been known for a number of years that neutrophils and macrophages secrete H2O2 while fighting disease, and the levels obtained within the vasculature under these conditions can reach several hundred micromolar. Because the effect of H2O2 on vascular smooth muscle is not fully understood, the present study examined the cellular effects of H2O2 on coronary arteries. Under normal ionic conditions, H2O2 relaxed arteries that were precontracted with prostaglandin F2alpha or histamine (EC50 = 252 +/- 22 microM). The effect of H2O2 was concentration dependent and endothelium independent. In contrast, H2O2 did not relax arteries contracted with 80 mM KCl, suggesting involvement of K+ channels. Single-channel patch-clamp recordings revealed that H2O2 increased the activity of the large-conductance (119 pS), Ca2+- and voltage-activated K+ (BKCa) 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 H2O2 but unmasked a vasoconstrictor effect that was reversed by blocking cyclooxygenase activity with indomethacin. These findings 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 vasodilatory and vasoconstrictor effects of H2O2 and possibly other reactive oxygen species.
Barlow
R S
RS
Department of Physiology and Biophysics, Wright State University School of Medicine, Dayton, Ohio 45435, USA.
White
R E
RE
D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D015237:Dinoprost / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D024681:Potassium Channels, Calcium-Activated; D013552:Swine; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D005231:Fatty Acids, Unsaturated; D051036:Large-Conductance Calcium-Activated Potassium Channels; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; C026603:5,8,11-eicosatriynoic acid; D016718:Arachidonic Acid; D006632:Histamine; D015237:Dinoprost; D006861:Hydrogen Peroxide; D007213:Indomethacin