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Modulation of peristalsis by SUR1-type KATP channel ligands in the mouse isolated colon Pinacidil and cromakalim, SUR2-type KATP channel openers, inhibit peristalsis in the mouse colon by a glibenclamide-insensitive mechanism (McCurrie et al., 2003). The aim of this study was to investigate the effects of pharmacological manipulations designed to alter SUR1-type KATP channel activity on peristalsis in the mouse isolated colon. Segments of proximal colon (3cm in length, next to the caecum) were obtained from BKW mice of either sex (38-42g), cannulated at the oral and anal ends and secured horizontally in a water-jacketed bath containing Krebs’ solution at 37ºC, gassed with 95% O2 and 5% CO2. Regular peristalsis was obtained with intraluminal pressures of 3-4 cm of water. The volume ejected during each peristaltic wave, rate of peristalsis and tone of the tissue were measured as described previously (Tuladhar et al., 2002). All drugs were added to the serosal side and concentration-response curves to diazoxide were constructed by cumulative addition of diazoxide at 6-8 minute intervals once regular peristalsis was obtained. The experiments were repeated in the presence of glibenclamide (0.01, 0.1 and 1μM added to the reservoir). Values shown are mean±s.e.mean with n indicating the number of animals. Statistical comparisons between the different treatments were made using one way ANOVA followed by Bonferroni Dunnett’s t test. The KATP channel opener diazoxide (1-100μM) did not alter the tone of the tissues but inhibited peristalsis in a concentration-dependent manner and abolished peristalsis in all tissues by 100μM. The pEC50 values for changes in the ejection volume and the rate of peristalsis were 4.84±0.16 (n=7) and 4.72±0.13 (n=7) respectively. Glibenclamide had no significant effect on the diazoxide concentration-response curve at 0.01μM (pEC50 values for changes in the ejection volume and the rate of peristalsis were 4.48±0.18, n=6, P>0.05 and 4.43±0.12, n=6, P>0.05 respectively) but produced a significant antagonism of the diazoxide responses at 0.1μM (pEC50 values for changes in the ejection volume and the rate of peristalsis were 3.98±0.11, N=6, P<0.01 and 4.06±0.18, N=6, P<0.01) and 1μM (pEC50values for changes in ejection volume and rate of peristalsis were 3.73±0.08, N=8, P<0.001 and 3.58±0.07, N=8, P<0.001 respectively). Glibenclamide (0.1-1μM, n=14), on its own, had no significant effect on the volume ejected, tone or rate of peristalsis. The inhibition of peristalsis by diazoxide and antagonism of this response by low concentrations of glibenclamide (0.1-1μM) indicate an involvement of SUR1-type KATP channels. SUR1-type KATP channels modulating peristalsis are likely to be located on the enteric neurons as diazoxide affected both the ejection volume and rate of peristalsis but did not affect the tone of the tissues.
McCurrie, JR et al. (2003). J Pharm Pharmacol, 55, 220 Suppl. |
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