The explanation for this difference is not known and could be suggestive of an additional role for the NMU2R in the mechanisms by which NMU affects peristalsis

The explanation for this difference is not known and could be suggestive of an additional role for the NMU2R in the mechanisms by which NMU affects peristalsis. sustained or gave way to a subsequent relaxation or was characterised by a simple relaxation during EFS. Regardless of the pattern of response evoked during EFS, termination of electrical stimulation immediately evoked a large-amplitude post-EFS’ contraction. In the forestomach, the initial phasic contraction was sustained during EFS in 35% of preparations whereas in 65% it was followed by muscle relaxation. These were 286% (planned comparisons of the LS means; compared with vehicle controls, em P /em 0.01 at 0.1 and 1? em /em M. All values are meanss.e.m. (vertical lines). Discussion and conclusions NMU is usually highly expressed in STL127705 the enteric nervous system (Domin em et al /em ., 1986; Augood em et al /em ., 1988; Ballesta em et al /em ., 1988; Furness em et al /em ., 1989; Timmermans em et al /em ., 1989), yet the effects of NMU on GI motility has not been adequately addressed, other than demonstrating that it is potent at contracting GI easy muscle (Maggi em et al /em ., 1990; Westfall em et al /em ., 2002; Prendergast em et al /em ., 2006). We have also shown that NMU has the ability to contract the muscle of mouse, isolated from forestomach, directly. In this tissue, the potency of NMU was found to be consistent with that reported by others (Benito-Orfila em et al /em ., 1991; Prendergast em et al /em ., 2006). Nevertheless, the contractions induced by NMU were small; the em E /em max STL127705 value was 10-fold lower than that obtained from the carbachol concentrationCresponse curve. Further, there was no significant difference in the amplitude of NMU-induced contractions between forestomachs of wild-type and NMU2R?/? mice, suggesting that they were mediated via TNFRSF13B NMU1R. This observation is usually consistent with the loss of NMU-induced contractile activity found in NMU1R?/? mouse forestomach (Prendergast em STL127705 et al /em ., 2006). However, of particular interest was the observation that NMU failed to contract colonic easy muscle. This regionally dependent difference in the ability of NMU to contract mouse GI easy muscle is usually consistent with the findings of Benito-Orfila em et al /em . (1991), who observed that NMU was able to contract the circular muscle of stomach, but not that of the ileum or colon, and those of Prendergast em et al /em . (2006), who reported a much lower potency of NMU to contract the longitudinal muscle of rat ileum. A significant and novel obtaining of this study was that NMU potentiated post-EFS contractions in the mouse colon, suggesting that in this region of the gut, NMU exerts prokinetic activity. Comparable changes were not clearly observed in the forestomach, although it is possible that STL127705 any effects of NMU on neuronally-mediated contractions may have been obscured by the marked potency of NMU STL127705 at contracting the muscle and increasing the variability of the responses to EFS. As NMU did not increase the amplitude of carbachol-induced contractions, the clear ability of NMU to increase neuronally mediated contractions of the colon is most likely owing to a prejunctional effect within the enteric ganglia that directly or indirectly modulates cholinergic and/or noncholinergic excitatory or inhibitory transmitter release. As there was no significant difference in the magnitude of the responses to NMU in the wild-type and NMU2R?/? colons, this neuromodulatory effect of NMU may be mediated via NMU1 receptors. Additionally, the concentrations of NMU that facilitated the EFS-evoked contractions were similar to those found to be active in human NMU1R-transfected HEK 293.

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