Characterization of the α1-adrenoceptor subtype mediating contractions of the pig internal anal sphincter

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Journal Article

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Interim status: Citation only.

Mills, K. A., Hausman, N., & Chess-Williams, R. (2008). Characterization of the α₁-adrenoceptor subtype mediating contractions of the pig internal anal sphincter. British journal of pharmacology, 155(1), 110-117.

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2008 HERDC submission. FoR Code: 1115

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Background and purpose: The internal anal sphincter has been shown to contract in response to a1-adrenoceptor stimulation and therefore a1-adrenoceptor agonists may be useful in treating faecal incontinence. This study characterizes the a1-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 a1A-adrenoceptor selective agonist A61603 (pEC50¼7.79±0.04) was 158-fold greater than that for noradrenaline (pEC50¼5.59±0.02). Phenylephrine (pEC50¼5.99±0.05) was 2.5-fold more potent than noradrenaline. The a1D-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 a1A-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, Po0.05).

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 a1A/L-adrenoceptor, most probably the a1L-adrenoceptor form of this receptor.

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