title: Sympathetic vasoconstrictor regulation of mouse colonic submucosal arterioles is altered in experimental colitis.
abstract: Recent studies suggest that altered neural regulation of the gastrointestinal microvasculature contributes to the pathogenesis of inflammatory bowel disease. Therefore, we employed video microscopy techniques to monitor nerve-evoked vasoconstrictor responses in mouse colonic submucosal arterioles in vitro and examined the effect of 2,4,6-trinitrobenzene sulphonic acid (TNBS) colitis. Nerve stimulation (2-20 Hz) caused frequency-dependent vasoconstrictor responses that were abolished by tetrodotoxin (300 nm) and guanethidine (10 microm). The P2 receptor antagonist suramin (100 microm) or the alpha(1)-adrenoceptor antagonist prazosin (100 nm) reduced the vasoconstriction and the combination of suramin and prazosin completely abolished responses. Nerve-evoked constrictions of submucosal arterioles from mice with TNBS colitis were inhibited by prazosin but not suramin. Superfusion of ATP (10 microm) resulted in large vasoconstrictions in control mice but had no effect in mice with colitis whereas constrictions to phenylephrine (3 microm) were unaffected. P2X(1) receptor immunohistochemistry did not suggest any alteration in receptor expression following colitis. However, Western blotting revealed that submucosal P2X(1) receptor expression was increased during colitis. In contrast to ATP, alphabeta-methylene-ATP (1 microm), which is resistant to catabolism by nucleotidases, constricted control and TNBS arterioles. This indicates that reduced purinergic transmission to submucosal arterioles may be due to increased degradation of ATP during colitis. These data comprise the first description of the neural regulation of mouse submucosal arterioles and identify a defect in sympathetic regulation of the GI vasculature during colitis due to reduced purinergic neurotransmission.
authors.affiliation: Gastrointestinal Diseases Research Unit, Queen's University at Kingston General Hospital, Kingston, Ontario K7L 2V7, Canada. lomaxa@post.queensu.ca
authors.forename: A E
authors.initials: AE
authors.lastname: Lomax
authors.forename: M
authors.initials: M
authors.lastname: O'Reilly
authors.forename: S
authors.initials: S
authors.lastname: Neshat
authors.forename: S J
authors.initials: SJ
authors.lastname: Vanner
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D018663:Adrenergic Agents / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000294:innervation; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D003106:Colon / Q000098:blood supply*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D017615:Enteric Nervous System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D006145:Guanethidine / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000098:blood supply*; D008297:Male; D051379:Mice; D018715:Microscopy, Video; D009638:Norepinephrine / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D058919:Purinergic P2 Receptor Antagonists; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058469:Receptors, Purinergic P2X; D013498:Suramin / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014302:Trinitrobenzenesulfonic Acid; D015854:Up-Regulation; D014661:Vasoconstriction
chemical_list: D018663:Adrenergic Agents; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D058919:Purinergic P2 Receptor Antagonists; D018340:Receptors, Adrenergic, alpha-1; D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; D010656:Phenylephrine; D013779:Tetrodotoxin; D013498:Suramin; D000255:Adenosine Triphosphate; D014302:Trinitrobenzenesulfonic Acid; C002630:alpha,beta-methyleneadenosine 5'-triphosphate; D009638:Norepinephrine; D011224:Prazosin; D006145:Guanethidine