Alpha1A/L-adrenoceptors mediate contraction of the circular smooth muscle of the pig urethra

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Abstract

1 Sympathetically mediated urethral tone is essential for the maintenance of continence and involves the activation of postjunctional α1- adrenoceptors. This study characterizes the α1-adrenoceptor subtypes responsible for mediating contraction of the urethral circular smooth muscle of the pig. 2 The potency order of a number of agonists and the affinities of several receptor selective antagonists were determined on pig-isolated circular smooth muscle strips in the presence of cocaine (1 μm) and corticosterone (10 μm) to inhibit amine uptake and propranolol (1 μm) to antagonize β-adrenoceptors. 3 The potency order for agonists was N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl] methanesulphonamide (A61603) > noradrenaline = phenylephrine = M6434 > methoxamine with pEC50 values of 7.3, 5.8, 5.7, 5.6 and 5.0 respectively. 4 The α1D-adrenoceptor-selective antagonist 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione (BMY7378) caused rightward shifts of the concentration-response curves to noradrenaline, yielding a low affinity estimate (6.6) for the urethral receptor. The α1A-adrenoceptor-selective antagonists, RS100329 and 5-methylurapidil, gave relatively high affinity estimates (9.6 and 8.8 respectively) for this receptor. All three antagonists produced Schild plots with slopes close to unity but did reduce maximum responses at higher concentrations. Prazosin antagonized responses of the urethra to noradrenaline, yielding a mean affinity estimate of 9.0. Although the Schild plot for prazosin again had a slope of unity, this drug also reduced maximum responses to noradrenaline at all concentrations examined (10-100 nm). N-[2-(2- cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α,α-dimethyl-1H-indole-3- ethanamide (RS17053), which discriminates between responses mediated via α1A (high affinity) and α1L-adrenoceptors (low affinity) at concentrations up to 3 μm, failed to antagonize responses of the urethra. 5 These results suggest that contraction of urethral circular smooth muscle in the pig is mediated via a single population of adrenoceptors with the pharmacological characteristics of the α1A/L- adrenoceptor, most probably the α1L-adrenoceptor.

Original languageEnglish
Pages (from-to)345-353
Number of pages9
JournalAutonomic and Autacoid Pharmacology
Volume26
Issue number4
DOIs
Publication statusPublished - Oct 2006

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Urethra
Adrenergic Receptors
Smooth Muscle
Swine
Norepinephrine
Prazosin
A 61603
Methoxamine
Phenylephrine
Corticosterone
Cocaine
Propranolol
Amines
Maintenance
Pharmacology

Cite this

@article{375250839eb24055be9f72e1a0a16266,
title = "Alpha1A/L-adrenoceptors mediate contraction of the circular smooth muscle of the pig urethra",
abstract = "1 Sympathetically mediated urethral tone is essential for the maintenance of continence and involves the activation of postjunctional α1- adrenoceptors. This study characterizes the α1-adrenoceptor subtypes responsible for mediating contraction of the urethral circular smooth muscle of the pig. 2 The potency order of a number of agonists and the affinities of several receptor selective antagonists were determined on pig-isolated circular smooth muscle strips in the presence of cocaine (1 μm) and corticosterone (10 μm) to inhibit amine uptake and propranolol (1 μm) to antagonize β-adrenoceptors. 3 The potency order for agonists was N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl] methanesulphonamide (A61603) > noradrenaline = phenylephrine = M6434 > methoxamine with pEC50 values of 7.3, 5.8, 5.7, 5.6 and 5.0 respectively. 4 The α1D-adrenoceptor-selective antagonist 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione (BMY7378) caused rightward shifts of the concentration-response curves to noradrenaline, yielding a low affinity estimate (6.6) for the urethral receptor. The α1A-adrenoceptor-selective antagonists, RS100329 and 5-methylurapidil, gave relatively high affinity estimates (9.6 and 8.8 respectively) for this receptor. All three antagonists produced Schild plots with slopes close to unity but did reduce maximum responses at higher concentrations. Prazosin antagonized responses of the urethra to noradrenaline, yielding a mean affinity estimate of 9.0. Although the Schild plot for prazosin again had a slope of unity, this drug also reduced maximum responses to noradrenaline at all concentrations examined (10-100 nm). N-[2-(2- cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α,α-dimethyl-1H-indole-3- ethanamide (RS17053), which discriminates between responses mediated via α1A (high affinity) and α1L-adrenoceptors (low affinity) at concentrations up to 3 μm, failed to antagonize responses of the urethra. 5 These results suggest that contraction of urethral circular smooth muscle in the pig is mediated via a single population of adrenoceptors with the pharmacological characteristics of the α1A/L- adrenoceptor, most probably the α1L-adrenoceptor.",
author = "K. Bagot and R. Chess-Williams",
year = "2006",
month = "10",
doi = "10.1111/j.1474-8673.2006.00374.x",
language = "English",
volume = "26",
pages = "345--353",
journal = "Journal of Autonomic Pharmacology",
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}

Alpha1A/L-adrenoceptors mediate contraction of the circular smooth muscle of the pig urethra. / Bagot, K.; Chess-Williams, R.

In: Autonomic and Autacoid Pharmacology, Vol. 26, No. 4, 10.2006, p. 345-353.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Alpha1A/L-adrenoceptors mediate contraction of the circular smooth muscle of the pig urethra

AU - Bagot, K.

AU - Chess-Williams, R.

PY - 2006/10

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N2 - 1 Sympathetically mediated urethral tone is essential for the maintenance of continence and involves the activation of postjunctional α1- adrenoceptors. This study characterizes the α1-adrenoceptor subtypes responsible for mediating contraction of the urethral circular smooth muscle of the pig. 2 The potency order of a number of agonists and the affinities of several receptor selective antagonists were determined on pig-isolated circular smooth muscle strips in the presence of cocaine (1 μm) and corticosterone (10 μm) to inhibit amine uptake and propranolol (1 μm) to antagonize β-adrenoceptors. 3 The potency order for agonists was N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl] methanesulphonamide (A61603) > noradrenaline = phenylephrine = M6434 > methoxamine with pEC50 values of 7.3, 5.8, 5.7, 5.6 and 5.0 respectively. 4 The α1D-adrenoceptor-selective antagonist 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione (BMY7378) caused rightward shifts of the concentration-response curves to noradrenaline, yielding a low affinity estimate (6.6) for the urethral receptor. The α1A-adrenoceptor-selective antagonists, RS100329 and 5-methylurapidil, gave relatively high affinity estimates (9.6 and 8.8 respectively) for this receptor. All three antagonists produced Schild plots with slopes close to unity but did reduce maximum responses at higher concentrations. Prazosin antagonized responses of the urethra to noradrenaline, yielding a mean affinity estimate of 9.0. Although the Schild plot for prazosin again had a slope of unity, this drug also reduced maximum responses to noradrenaline at all concentrations examined (10-100 nm). N-[2-(2- cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α,α-dimethyl-1H-indole-3- ethanamide (RS17053), which discriminates between responses mediated via α1A (high affinity) and α1L-adrenoceptors (low affinity) at concentrations up to 3 μm, failed to antagonize responses of the urethra. 5 These results suggest that contraction of urethral circular smooth muscle in the pig is mediated via a single population of adrenoceptors with the pharmacological characteristics of the α1A/L- adrenoceptor, most probably the α1L-adrenoceptor.

AB - 1 Sympathetically mediated urethral tone is essential for the maintenance of continence and involves the activation of postjunctional α1- adrenoceptors. This study characterizes the α1-adrenoceptor subtypes responsible for mediating contraction of the urethral circular smooth muscle of the pig. 2 The potency order of a number of agonists and the affinities of several receptor selective antagonists were determined on pig-isolated circular smooth muscle strips in the presence of cocaine (1 μm) and corticosterone (10 μm) to inhibit amine uptake and propranolol (1 μm) to antagonize β-adrenoceptors. 3 The potency order for agonists was N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl] methanesulphonamide (A61603) > noradrenaline = phenylephrine = M6434 > methoxamine with pEC50 values of 7.3, 5.8, 5.7, 5.6 and 5.0 respectively. 4 The α1D-adrenoceptor-selective antagonist 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione (BMY7378) caused rightward shifts of the concentration-response curves to noradrenaline, yielding a low affinity estimate (6.6) for the urethral receptor. The α1A-adrenoceptor-selective antagonists, RS100329 and 5-methylurapidil, gave relatively high affinity estimates (9.6 and 8.8 respectively) for this receptor. All three antagonists produced Schild plots with slopes close to unity but did reduce maximum responses at higher concentrations. Prazosin antagonized responses of the urethra to noradrenaline, yielding a mean affinity estimate of 9.0. Although the Schild plot for prazosin again had a slope of unity, this drug also reduced maximum responses to noradrenaline at all concentrations examined (10-100 nm). N-[2-(2- cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α,α-dimethyl-1H-indole-3- ethanamide (RS17053), which discriminates between responses mediated via α1A (high affinity) and α1L-adrenoceptors (low affinity) at concentrations up to 3 μm, failed to antagonize responses of the urethra. 5 These results suggest that contraction of urethral circular smooth muscle in the pig is mediated via a single population of adrenoceptors with the pharmacological characteristics of the α1A/L- adrenoceptor, most probably the α1L-adrenoceptor.

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