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Hydrogen peroxide induces endothelium-dependent and -independent coronary arteriolar dilation: role of cyclooxygenase and potassium channels

Department of Medical Physiology, Cardiovascular Research Institute, College of Medicine, Texas A&M University System Health Science Center, College Station, Texas 77843-1114

Submitted 28 June 2003 ; accepted in final form 2 July 2003

Hydrogen peroxide, a relatively stable reactive oxygen species, is known to elicit vasodilation, but its underlying mechanism remains elusive. Here, we examined the role of endothelial nitric oxide (NO), prostaglandin, cytochrome P-450-derived metabolites, and smooth muscle potassium channels in coronary arteriolar dilation to abluminal H₂O₂. Pig subepicardial coronary arterioles (50–100 µm) were isolated and pressurized without flow for in vitro study. Arterioles developed basal tone and dilated dose dependently to H₂O₂ (1–100 µM). Disruption of th endothelium and inhibition of cyclooxygenase (COX) by indomethacin produced identical attenuation of vasodilation to H₂O₂. Conversely, the vasodilation to H₂O₂ was not affected by either the NO synthase inhibitor N^G-nitro-L-arginine methyl ester or the cytochrome P-450 enzyme blocker miconazole. Inhibition of the COX-1, but not the COX-2 pathway, attenuated H₂O₂-induced dilation similarly to indomethacin. The production of prostaglandin E₂ (PGE₂), but not prostaglandin I₂, from coronary arterioles was significantly increased by H₂O₂. Furthermore, inhibition of PGE₂ receptors with AH-6809 attenuated vasodilation to H₂O₂ similar to that produced by indomethacin. In the absence of a functional endothelium, H₂O₂-induced dilation was attenuated, in an identical manner, by a depolarizing agent KCl and a calcium-activated potassium (K_Ca) channel inhibitor iberiotoxin. However, PGE₂-induced dilation was not affected by iberiotoxin. The endothelium-independent dilation to H₂O₂ was also insensitive to the inhibition of guanylyl cyclase, lipoxygenase, ATP-sensitive potassium channels, and inward rectifier potassium channels. These results suggest that H₂O₂ induces endothelium-dependent vasodilation through COX-1-mediated release of PGE₂ and also directly relaxes smooth muscle by hyperpolarization through K_Ca channel activation.

oxidative stress; prostaglandins; smooth muscle; hyperpolarization

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