Author(s): Xue B, Hausmann M, Mller MH, Pesch T, Karpitschka M,
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Abstract Evidence exists that visceral afferent sensitivity is subject to regulatory mechanisms. We hypothesized that afferent sensitivity is decreased in the small intestine during intestinal inflammation by an inducible nitric oxide synthase (iNOS)-dependent mechanism. C57BL/6 mice were injected twice with vehicle or 60 mg kg(-1) indomethacin subcutaneously to induce intestinal inflammation. Afferent sensitivity was recorded on day 3 from a 2-cm segment of jejunum in vitro by extracellular multi-unit afferent recordings from the mesenteric nerve bundle. In subgroups (n = 6), iNOS was inhibited selectively by L-N6-(1-iminoethyl)-lysine (L-NIL) given either chronically from day 1-3 (3 mg kg(-1) twice daily i.p.) or acutely into the organ bath (30 micromol L(-1)). The indomethacin-induced increase of macroscopic and microscopic scores of intestinal inflammation (both P < 0.05) were unchanged after pretreatment with L-NIL. Peak afferent firing following bradykinin (0.5 micromol L(-1)) was 55 +/- 8 impulse s(-1) during inflammation vs 97 +/- 7 impulse s(-1) in controls (P < 0.05). Normal firing rate was preserved following L-NIL pretreatment (112 +/- 16 impulse s(-1)) or acute administration of L-NIL (108 +/- 14 impulse s(-1)). A similar L-NIL dependent reduction was observed for 5-HT (250 micromol L(-1)) and mechanical ramp distension from 20 to 60 cmH(2)O (both P < 0.05). Intraluminal pressure peaks were decreased to 0.66 +/- 0.1 cmH(2)O during inflammation compared to 2.51 +/- 0.3 in controls (P < 0.01). Afferent sensitivity is decreased by an iNOS-dependent mechanism during intestinal inflammation which appears to be independent of the inflammatory response. This suggests that iNOS-dependent nitric oxide production alters afferent sensitivity during inflammation by interfering with signal transduction to afferent nerves rather than by attenuating intestinal inflammation.
This article was published in Neurogastroenterol Motil
and referenced in Pharmaceutica Analytica Acta