on September 1, 2005
Published online before print September 1, 2005, doi: 10.1161/01.ATV.0000184757.50141.8d
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Submitted on March 4, 2005
Accepted on August 17, 2005
Novel Mechanism of Vasodilation in Inflammatory Bowel Disease
Ossama A. Hatoum ;
From the Departments of Medicine (O.A.H., D.G.B., H.M., D.D.G.), Surgery (G.T., M.F.O.), and Pharmacology (L.G. W.B.C., D.D.G.), Cardiovascular Center, Digestive Disease Center, Zablocki VA Medical Center, Medical College of Wisconsin, Milwaukee.
* To whom correspondence should be addressed. E-mail: dgutt{at}mcw.edu.
Objective--Endothelium-dependent dilation to acetylcholine (Ach) is reduced in mucosal arterioles from patients with inflammatory bowel disease (IBD). The contributions of both nitric oxide (NO) and endothelial-derived hyperpolarizing factor (EDHF) are decreased. We hypothesized that the remaining dilation results from products of cyclooxygenase.
Methods and Results--High-performance liquid chromatography (HPLC) was used to isolate eicosanoid vasodilator products and videomicroscopy was used to examine vasomotor responses in human mucosal arterioles from subjects with or without IBD undergoing bowel resection surgeries. In subjects without IBD, Ach constricted (-52%±10%) arterioles devoid of endothelium. Indomethacin (INDO) (cyclooxygenase inhibitor) had no effect. In contrast, Ach dose-dependently dilated both intact and endothelial denuded arterioles from patients with IBD. The dilation was converted to constriction by INDO (-54%±9%; P<0.05 versus non-IBD) or by BWA868C (PGD2 receptor antagonist). Only in arterioles from subjects with IBD did Ach produce an arachidonic acid metabolite that comigrated on HPLC with PG D2 (PGD2). Exogenous PGD2 dilated (max=66%±4%) IBD arterioles.
Conclusion--In arterioles from IBD patients, Ach-mediated dilation shifts from endothelial production of NO and EDHF to nonendothelial generation of a PG, likely PGD2. This is a novel dilator mechanism arising from nonendothelial vascular tissue that compensates for loss of endothelium-dependent dilation. PGD2 appears to be important in regulating mucosal blood flow in patients with IBD, with implicating potentially detrimental effects from nonsteroidal antiinflammatory drugs.
Key words: cyclooxygenase • inflammatory bowel disease • microcirculation • prostaglandin • vasodilation
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