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1 Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: dgutt{at}mcw.edu.
The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several mediators of vasodilation, which include prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor (EDHF). We have recently defined the role of nitric oxide and prostacyclin in the dilation of submucosal intestinal arterioles from patients with normal bowel function. However significant endothelium-dependent dilator capacity to acetylcholine remained after inhibiting both these mediators. The current study was designed to examine the potential role of EDHF in human intestinal submucosal arterioles. Acetylcholine (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 two inhibitors of cytochrome P450 monooxygenase, 17-octadecynoic acid and 6-(2-propargylloxyphenyl) hexanoic acid, had no significant effect (3 ± 1% and 20 ± 8%, n = 5, respectively). Exogenous hydrogen peroxide 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 DCF fluorescence in intact arterioles in the presence of nitric oxide synthase and cyclooxygenase inhibitors, compared to control and compared to catalase treated microvessels (363.6 ± 49, 218.8 ± 10.6, 221.9 ± 27.9, respectively P< 0.05 ANOVA, n=5). No changes in the DCF fluorescence were recorded in vessels treated with Ach alone. These results indicate that endothelial production of hydrogen peroxide 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 release of a chemically distinct EDHF.
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