Colonic blood flow responses in experimental colitis: time course and underlying mechanisms.
Human inflammatory bowel diseases (IBD) are associated with significant alterations in intestinal blood flow, the direction and magnitude of which change with disease progression. The objectives of this study were to determine the time course of changes in colonic blood perfusion that occur during the development of dextran-sodium-sulfate (DSS)-induced colonic inflammation and to address the mechanisms that may underlie these changes in blood flow. Intravital microscopy was used to quantify blood flow (from measurements of vessel diameter and red blood cell velocity) in different-sized submucosal arterioles of control and inflamed colons in wild-type (WT) mice. A significant (18-30%) reduction in blood flow was noted in the smallest arterioles (<40 microm diameter) on days 4-6 of DSS colitis. The arteriolar responses to bradykinin in control and DSS-treated WT mice revealed an impaired endothelium-dependent, but not endothelium-independent, vasodilation in the inflamed colon. However, this impaired vasodilatory response to bradykinin after DSS treatment was not evident in mutant mice that overexpress Cu,Zn-superoxide dismutase. Rescue of the bradykinin-induced vasodilation during DSS colitis was also observed in mice that are genetically deficient in the NAD(P)H oxidase subunit gp91(phox). These findings indicate that the decline in blood flow during experimental colitis may result from a diminished capacity of colonic arterioles to respond to endogenous endothelium-dependent vasodilators like bradykinin and that NAD(P)H oxidase-derived superoxide plays a major role in the induction of the inflammation-induced endothelium-dependent arteriolar dysfunction.
Mori
Mikiji
M
Dept. of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA.
Stokes
Karen Y
KY
Vowinkel
Thorsten
T
Watanabe
Naoyuki
N
Elrod
John W
JW
Harris
Norman R
NR
Lefer
David J
DJ
Hibi
Toshifumi
T
Granger
D Neil
DN
D000818:Animals; D001160:Arterioles / Q000502:physiology; D001920:Bradykinin / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced / Q000503:physiopathology*; D003106:Colon / Q000098:blood supply* / Q000187:drug effects; D003864:Depression, Chemical; D016264:Dextran Sulfate; D006339:Heart Rate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D010208:Papaverine / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D014664:Vasodilation / Q000502:physiology
D016264:Dextran Sulfate; D010208:Papaverine; D019255:NADPH Oxidases; D001920:Bradykinin