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Characterization of the alpha1-adrenoceptor subtype mediating contractions of the pig internal anal sphincter.

ABSTRACT: BACKGROUND AND PURPOSE: The internal anal sphincter has been shown to contract in response to alpha1-adrenoceptor stimulation and therefore alpha1-adrenoceptor agonists may be useful in treating faecal incontinence. This study characterizes the alpha1-adrenoceptor subtype responsible for mediating contraction of the internal anal sphincter of the pig. EXPERIMENTAL APPROACH: The potency of agonists and the affinities of several receptor subtype selective antagonists were determined on smooth muscle strips for the pig internal anal sphincter. Cumulative concentration-response curves were performed using phenylephrine and noradrenaline. KEY RESULTS: The potency of the alpha1A-adrenoceptor selective agonist A61603 (pEC50=7.79+/-0.04) was 158-fold greater than that for noradrenaline (pEC50=5.59+/-0.02). Phenylephrine (pEC50=5.99+/-0.05) was 2.5-fold more potent than noradrenaline. The alpha1D-adrenoceptor selective antagonist BMY7378 caused rightward shifts of the concentration-response curves to phenylephrine and noradrenaline, yielding low affinity estimates of 6.59+/-0.15 and 6.33+/-0.13, respectively. Relatively high affinity estimates were obtained for the alpha1A-adrenoceptor selective antagonists, RS100329 (9.01+/-0.14 and 9.06+/-0.22 with phenylephrine and noradrenaline, respectively) and 5-methylurapidil (8.51+/-0.10 and 8.31+/-0.10, respectively). Prazosin antagonized responses of the sphincter to phenylephrine and noradrenaline, yielding mean affinity estimates of 8.58+/-0.10 and 8.15+/-0.08, respectively. The Schild slope for prazosin with phenylephrine was equal to unity (1.01+/-0.24), however the Schild slope using noradrenaline was significantly less than unity (0.50+/-0.11, P<0.05). CONCLUSION AND IMPLICATIONS: The results suggest that contraction of circular smooth muscle from the pig internal anal sphincter is mediated via a population of adrenoceptors with the pharmacological characteristics of the alpha1A/L-adrenoceptor, most probably the alpha1L-adrenoceptor form of this receptor.

SUBMITTER: Mills K

PROVIDER: S-EPMC2527848 | biostudies-other | 2008 Sep

REPOSITORIES: biostudies-other

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Project description:Background & aimsThe anal sphincters and puborectalis are imaged routinely with an endoanal magnetic resonance imaging (MRI) coil, which does not assess co-aptation of the anal canal at rest. By using a MRI torso coil, we identified a patulous anal canal in some patients with anorectal disorders. We aimed to evaluate the relationship between anal sphincter and puborectalis injury, a patulous anal canal, and anal pressures.MethodsWe performed a retrospective analysis of data from 119 patients who underwent MRI and manometry analysis of anal anatomy and pressures, respectively, from February 2011 through March 2013 at the Mayo Clinic. Anal pressures were determined by high-resolution manometry, anal sphincter and puborectalis injury was determined by endoanal MRI, and anal canal integrity was determined by torso MRI. Associations between manometric and anatomic parameters were evaluated with univariate and multivariate analyses.ResultsFecal incontinence (55 patients; 46%) and constipation (36 patients; 30%) were the main indications for testing; 49 patients (41%) had a patulous anal canal, which was associated with injury to more than 1 muscle (all P ≤ .001), and internal sphincter (P < .01), but not puborectalis (P = .09) or external sphincter (P = .06), injury. Internal (P < .01) and external sphincter injury (P = .02) and a patulous canal (P < .001), but not puborectalis injury, predicted anal resting pressure. A patulous anal canal was the only significant predictor (P < .01) of the anal squeeze pressure increment.ConclusionsPatients with anorectal disorders commonly have a patulous anal canal, which is associated with more severe anal injury and independently predicted anal resting pressure and squeeze pressure increment. It therefore is important to identify a patulous anal canal because it appears to be a marker of not only anal sphincter injury but disturbances beyond sphincter injury, such as damage to the anal cushions or anal denervation.

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Characterization of the alpha1-adrenoceptor subtype mediating contractions of the pig internal anal sphincter.

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