Characterization of the alpha 1-adrenoceptor subtype mediating contractions of the pig internal anal sphincter

K. A. Mills, N. Hausman, R. Chess-Williams

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14 Citations (Scopus)

Abstract

Background and purpose: The internal anal sphincter has been shown to contract in response to α 1-adrenoceptor stimulation and therefore α 1-adrenoceptor agonists may be useful in treating faecal incontinence. This study characterizes the α 1- 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 α 1A-adrenoceptor selective agonist A61603 (pEC 50=7.79±0.04) was 158-fold greater than that for noradrenaline (pEC 50=5.59±0.02). Phenylephrine (pEC 50=5.99±0.05) was 2.5-fold more potent than noradrenaline. The α 1D-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 α 1A-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 α 1A/L-adrenoceptor, most probably the α 1L-adrenoceptor form of this receptor.

Original languageEnglish
Pages (from-to)110-117
Number of pages8
JournalBritish Journal of Pharmacology
Volume155
Issue number1
DOIs
Publication statusPublished - Sep 2008

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Anal Canal
Adrenergic Receptors
Swine
Phenylephrine
Norepinephrine
Prazosin
A 61603
Smooth Muscle
Fecal Incontinence
Pharmacology

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@article{3c4286e0e5494a169174b20c0635791b,
title = "Characterization of the alpha 1-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 α 1-adrenoceptor stimulation and therefore α 1-adrenoceptor agonists may be useful in treating faecal incontinence. This study characterizes the α 1- 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 α 1A-adrenoceptor selective agonist A61603 (pEC 50=7.79±0.04) was 158-fold greater than that for noradrenaline (pEC 50=5.59±0.02). Phenylephrine (pEC 50=5.99±0.05) was 2.5-fold more potent than noradrenaline. The α 1D-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 α 1A-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 α 1A/L-adrenoceptor, most probably the α 1L-adrenoceptor form of this receptor.",
author = "Mills, {K. A.} and N. Hausman and R. Chess-Williams",
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Characterization of the alpha 1-adrenoceptor subtype mediating contractions of the pig internal anal sphincter. / Mills, K. A.; Hausman, N.; Chess-Williams, R.

In: British Journal of Pharmacology, Vol. 155, No. 1, 09.2008, p. 110-117.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

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N2 - Background and purpose: The internal anal sphincter has been shown to contract in response to α 1-adrenoceptor stimulation and therefore α 1-adrenoceptor agonists may be useful in treating faecal incontinence. This study characterizes the α 1- 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 α 1A-adrenoceptor selective agonist A61603 (pEC 50=7.79±0.04) was 158-fold greater than that for noradrenaline (pEC 50=5.59±0.02). Phenylephrine (pEC 50=5.99±0.05) was 2.5-fold more potent than noradrenaline. The α 1D-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 α 1A-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 α 1A/L-adrenoceptor, most probably the α 1L-adrenoceptor form of this receptor.

AB - Background and purpose: The internal anal sphincter has been shown to contract in response to α 1-adrenoceptor stimulation and therefore α 1-adrenoceptor agonists may be useful in treating faecal incontinence. This study characterizes the α 1- 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 α 1A-adrenoceptor selective agonist A61603 (pEC 50=7.79±0.04) was 158-fold greater than that for noradrenaline (pEC 50=5.59±0.02). Phenylephrine (pEC 50=5.99±0.05) was 2.5-fold more potent than noradrenaline. The α 1D-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 α 1A-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 α 1A/L-adrenoceptor, most probably the α 1L-adrenoceptor form of this receptor.

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