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2004 CARDIOVASCULAR AND KIDNEY INVESTIGATORS MEETING

Role of hydrogen peroxide in ACh-induced dilation of human submucosal intestinal microvessels

Cardiovascular Research Center, Digestive Disease Center, Departments of ¹Medicine, ²Surgery, Froedtert Memorial Lutheran Hospital, Veterans Affairs Medical Center, Medical College of Wisconsin, Milwaukee, Wisconsin

Submitted 6 July 2004 ; accepted in final form 27 August 2004

The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several mediators of vasodilation, which include prostacyclin (PGI₂), nitric oxide, and endothelium-derived hyperpolarizing factor (EDHF). We have recently defined the role of nitric oxide and PGI₂ in the dilation of submucosal intestinal arterioles from patients with normal bowel function. However, significant endothelium-dependent dilator capacity to ACh remained after inhibiting both these mediators. The current study was designed to examine the potential role of EDHF in human intestinal submucosal arterioles. ACh elicited endothelium-dependent relaxation in the presence of inhibitors of nitric oxide synthase and cyclooxygenase (23 ± 10%, n = 6). This ACh-induced relaxation was inhibited and converted to constriction by catalase (–53 ± 10%, n = 6) or KCl (–30 ± 3%, n = 7), whereas 17-octadecynoic acid and 6-(2-propargylloxyphenyl) hexanoic acid, two inhibitors of cytochrome P450 monooxygenase, had no significant effect (3 ± 1% and 20 ± 8%, n = 5, respectively). Exogenous H₂O₂ elicited dose-dependent relaxation of intact microvessels (52 ± 10%, n = 7) but caused frank vasoconstriction in arterioles denuded of endothelium (–73 ± 8%, n = 7). ACh markedly increased the dichlorofluorescein fluorescence in intact arterioles in the presence of nitric oxide synthase and cyclooxygenase inhibitors compared with control and compared with catalase-treated microvessels (363.6 ± 49, 218.8 ± 10.6, 221.9 ± 27.9, respectively, P < 0.05 ANOVA, n = 5 arbitrary units). No changes in the dichlorofluorescein fluorescence were recorded in vessels treated with ACh alone. These results indicate that endothelial production of H₂O₂ occurs in response to ACh in human gut mucosal arterioles but that H₂O₂ is not an EDHF in this tissue. Rather, we speculate that it stimulates the release of a chemically distinct EDHF.

microcirculation; endothelium-derived hyperpolarizing factor; acetylcholine; cyclooxygenase; vasodilation

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