Modulation of bladder α1-adrenergic receptor subtype expression by bladder outlet obstruction

Christian Hampel, Paul C. Dolber, Michael P. Smith, Sandra L. Savic, Joachim W. Thüroff, Karl B. Thor, Debra A. Schwinn

Research output: Contribution to journalArticle

144 Citations (Scopus)

Abstract

Purpose: α1-Adrenergic receptor (α1AR) antagonists are effective for relieving obstructive and irritative symptoms in patients with bladder outlet obstruction. While the α1aAR is responsible for prostate smooth muscle relaxation and outlet obstruction relief, to our knowledge the mechanisms underlying the relief of irritative symptoms remain to be determined. Therefore, we investigated mechanisms by which bladder α1AR subtypes may be involved in this process. Materials and Methods: We studied 42 rats, including 6 unoperated controls, 17 sham operated controls and 19 obstructed animals. Animals were characterized for baseline voiding pattern, followed by surgical intervention or sham surgery to establish obstruction (1.09 mm. restricted opening). After 6 weeks to enable the development of detrusor hypertrophy, voiding behavior was reexamined, the animals were sacrificed and bladder tissue was immediately placed in liquid nitrogen. α1AR subtype messenger (m)RNA using quantitative competitive reverse transcriptase-polymerase chain reaction and protein expression was determined using radioligand binding with the α1AR antagonist [125iodine2-(- [4-hydroxyphenyl]-ethylaminomethyl)tetralone (saturation analysis for total α1AR density and competition analysis with BMY7378 and 5-methylurapidel to determine α1AR subtypes). Results: In this model 6-week surgical obstruction produced a 6.3-fold increase in bladder weight versus sham operation (p <0.001), concurrent with increased voiding frequency versus before obstruction (p <0.004). Although bladder α1AR density did not increase overall with obstruction, striking changes in α1AR subtype expression occurred. In control animals 70% of α1AR mRNA was the α1a subtype, 5% were α1b and 25% were α1d, whereas in obstructed animals bladder α1AR expression changed to 23% α1a, 2% α1b and 75% α1d. Changes in α1AR mRNA expression were of similar magnitude throughout the bladder dome, mid body and base. Parallel changes were also evident at the protein level with 100% α1aAR expression in control animals changing to new onset α1dAR expression (mean plus or minus standard error of mean 36% ± 7%) in animals with a 5-fold or greater increase in bladder weight. Conclusions: Our findings indicate a remarkable increase in bladder α1dAR mRNA and protein expression after 6 weeks of obstruction and resultant detrusor hypertrophy. This finding is potentially important since α1dARs have 10 to 100-fold higher affinity for the endogenous neurotransmitter norepinephrine than the α1a or α1bAR subtypes. These findings imply that targeting α1d may provide a new therapeutic approach for controlling bladder irritative symptoms and possibly detrusor overactivity associated with bladder outlet obstruction.

Original languageEnglish (US)
Pages (from-to)1513-1521
Number of pages9
JournalJournal of Urology
Volume167
Issue number3
StatePublished - 2002
Externally publishedYes

Fingerprint

Urinary Bladder Neck Obstruction
Adrenergic Receptors
Urinary Bladder
Messenger RNA
Adrenergic Antagonists
Hypertrophy
Tetralones
Weights and Measures
Proteins
Muscle Relaxation
Reverse Transcriptase Polymerase Chain Reaction
Smooth Muscle
Neurotransmitter Agents
Prostate
Norepinephrine
Nitrogen

Keywords

  • Adrenergic
  • Bladder
  • Bladder neck obstruction
  • Receptors

ASJC Scopus subject areas

  • Urology

Cite this

Hampel, C., Dolber, P. C., Smith, M. P., Savic, S. L., Thüroff, J. W., Thor, K. B., & Schwinn, D. A. (2002). Modulation of bladder α1-adrenergic receptor subtype expression by bladder outlet obstruction. Journal of Urology, 167(3), 1513-1521.

Modulation of bladder α1-adrenergic receptor subtype expression by bladder outlet obstruction. / Hampel, Christian; Dolber, Paul C.; Smith, Michael P.; Savic, Sandra L.; Thüroff, Joachim W.; Thor, Karl B.; Schwinn, Debra A.

In: Journal of Urology, Vol. 167, No. 3, 2002, p. 1513-1521.

Research output: Contribution to journalArticle

Hampel, C, Dolber, PC, Smith, MP, Savic, SL, Thüroff, JW, Thor, KB & Schwinn, DA 2002, 'Modulation of bladder α1-adrenergic receptor subtype expression by bladder outlet obstruction', Journal of Urology, vol. 167, no. 3, pp. 1513-1521.
Hampel C, Dolber PC, Smith MP, Savic SL, Thüroff JW, Thor KB et al. Modulation of bladder α1-adrenergic receptor subtype expression by bladder outlet obstruction. Journal of Urology. 2002;167(3):1513-1521.
Hampel, Christian ; Dolber, Paul C. ; Smith, Michael P. ; Savic, Sandra L. ; Thüroff, Joachim W. ; Thor, Karl B. ; Schwinn, Debra A. / Modulation of bladder α1-adrenergic receptor subtype expression by bladder outlet obstruction. In: Journal of Urology. 2002 ; Vol. 167, No. 3. pp. 1513-1521.
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abstract = "Purpose: α1-Adrenergic receptor (α1AR) antagonists are effective for relieving obstructive and irritative symptoms in patients with bladder outlet obstruction. While the α1aAR is responsible for prostate smooth muscle relaxation and outlet obstruction relief, to our knowledge the mechanisms underlying the relief of irritative symptoms remain to be determined. Therefore, we investigated mechanisms by which bladder α1AR subtypes may be involved in this process. Materials and Methods: We studied 42 rats, including 6 unoperated controls, 17 sham operated controls and 19 obstructed animals. Animals were characterized for baseline voiding pattern, followed by surgical intervention or sham surgery to establish obstruction (1.09 mm. restricted opening). After 6 weeks to enable the development of detrusor hypertrophy, voiding behavior was reexamined, the animals were sacrificed and bladder tissue was immediately placed in liquid nitrogen. α1AR subtype messenger (m)RNA using quantitative competitive reverse transcriptase-polymerase chain reaction and protein expression was determined using radioligand binding with the α1AR antagonist [125iodine2-(- [4-hydroxyphenyl]-ethylaminomethyl)tetralone (saturation analysis for total α1AR density and competition analysis with BMY7378 and 5-methylurapidel to determine α1AR subtypes). Results: In this model 6-week surgical obstruction produced a 6.3-fold increase in bladder weight versus sham operation (p <0.001), concurrent with increased voiding frequency versus before obstruction (p <0.004). Although bladder α1AR density did not increase overall with obstruction, striking changes in α1AR subtype expression occurred. In control animals 70{\%} of α1AR mRNA was the α1a subtype, 5{\%} were α1b and 25{\%} were α1d, whereas in obstructed animals bladder α1AR expression changed to 23{\%} α1a, 2{\%} α1b and 75{\%} α1d. Changes in α1AR mRNA expression were of similar magnitude throughout the bladder dome, mid body and base. Parallel changes were also evident at the protein level with 100{\%} α1aAR expression in control animals changing to new onset α1dAR expression (mean plus or minus standard error of mean 36{\%} ± 7{\%}) in animals with a 5-fold or greater increase in bladder weight. Conclusions: Our findings indicate a remarkable increase in bladder α1dAR mRNA and protein expression after 6 weeks of obstruction and resultant detrusor hypertrophy. This finding is potentially important since α1dARs have 10 to 100-fold higher affinity for the endogenous neurotransmitter norepinephrine than the α1a or α1bAR subtypes. These findings imply that targeting α1d may provide a new therapeutic approach for controlling bladder irritative symptoms and possibly detrusor overactivity associated with bladder outlet obstruction.",
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AU - Dolber, Paul C.

AU - Smith, Michael P.

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AU - Thüroff, Joachim W.

AU - Thor, Karl B.

AU - Schwinn, Debra A.

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N2 - Purpose: α1-Adrenergic receptor (α1AR) antagonists are effective for relieving obstructive and irritative symptoms in patients with bladder outlet obstruction. While the α1aAR is responsible for prostate smooth muscle relaxation and outlet obstruction relief, to our knowledge the mechanisms underlying the relief of irritative symptoms remain to be determined. Therefore, we investigated mechanisms by which bladder α1AR subtypes may be involved in this process. Materials and Methods: We studied 42 rats, including 6 unoperated controls, 17 sham operated controls and 19 obstructed animals. Animals were characterized for baseline voiding pattern, followed by surgical intervention or sham surgery to establish obstruction (1.09 mm. restricted opening). After 6 weeks to enable the development of detrusor hypertrophy, voiding behavior was reexamined, the animals were sacrificed and bladder tissue was immediately placed in liquid nitrogen. α1AR subtype messenger (m)RNA using quantitative competitive reverse transcriptase-polymerase chain reaction and protein expression was determined using radioligand binding with the α1AR antagonist [125iodine2-(- [4-hydroxyphenyl]-ethylaminomethyl)tetralone (saturation analysis for total α1AR density and competition analysis with BMY7378 and 5-methylurapidel to determine α1AR subtypes). Results: In this model 6-week surgical obstruction produced a 6.3-fold increase in bladder weight versus sham operation (p <0.001), concurrent with increased voiding frequency versus before obstruction (p <0.004). Although bladder α1AR density did not increase overall with obstruction, striking changes in α1AR subtype expression occurred. In control animals 70% of α1AR mRNA was the α1a subtype, 5% were α1b and 25% were α1d, whereas in obstructed animals bladder α1AR expression changed to 23% α1a, 2% α1b and 75% α1d. Changes in α1AR mRNA expression were of similar magnitude throughout the bladder dome, mid body and base. Parallel changes were also evident at the protein level with 100% α1aAR expression in control animals changing to new onset α1dAR expression (mean plus or minus standard error of mean 36% ± 7%) in animals with a 5-fold or greater increase in bladder weight. Conclusions: Our findings indicate a remarkable increase in bladder α1dAR mRNA and protein expression after 6 weeks of obstruction and resultant detrusor hypertrophy. This finding is potentially important since α1dARs have 10 to 100-fold higher affinity for the endogenous neurotransmitter norepinephrine than the α1a or α1bAR subtypes. These findings imply that targeting α1d may provide a new therapeutic approach for controlling bladder irritative symptoms and possibly detrusor overactivity associated with bladder outlet obstruction.

AB - Purpose: α1-Adrenergic receptor (α1AR) antagonists are effective for relieving obstructive and irritative symptoms in patients with bladder outlet obstruction. While the α1aAR is responsible for prostate smooth muscle relaxation and outlet obstruction relief, to our knowledge the mechanisms underlying the relief of irritative symptoms remain to be determined. Therefore, we investigated mechanisms by which bladder α1AR subtypes may be involved in this process. Materials and Methods: We studied 42 rats, including 6 unoperated controls, 17 sham operated controls and 19 obstructed animals. Animals were characterized for baseline voiding pattern, followed by surgical intervention or sham surgery to establish obstruction (1.09 mm. restricted opening). After 6 weeks to enable the development of detrusor hypertrophy, voiding behavior was reexamined, the animals were sacrificed and bladder tissue was immediately placed in liquid nitrogen. α1AR subtype messenger (m)RNA using quantitative competitive reverse transcriptase-polymerase chain reaction and protein expression was determined using radioligand binding with the α1AR antagonist [125iodine2-(- [4-hydroxyphenyl]-ethylaminomethyl)tetralone (saturation analysis for total α1AR density and competition analysis with BMY7378 and 5-methylurapidel to determine α1AR subtypes). Results: In this model 6-week surgical obstruction produced a 6.3-fold increase in bladder weight versus sham operation (p <0.001), concurrent with increased voiding frequency versus before obstruction (p <0.004). Although bladder α1AR density did not increase overall with obstruction, striking changes in α1AR subtype expression occurred. In control animals 70% of α1AR mRNA was the α1a subtype, 5% were α1b and 25% were α1d, whereas in obstructed animals bladder α1AR expression changed to 23% α1a, 2% α1b and 75% α1d. Changes in α1AR mRNA expression were of similar magnitude throughout the bladder dome, mid body and base. Parallel changes were also evident at the protein level with 100% α1aAR expression in control animals changing to new onset α1dAR expression (mean plus or minus standard error of mean 36% ± 7%) in animals with a 5-fold or greater increase in bladder weight. Conclusions: Our findings indicate a remarkable increase in bladder α1dAR mRNA and protein expression after 6 weeks of obstruction and resultant detrusor hypertrophy. This finding is potentially important since α1dARs have 10 to 100-fold higher affinity for the endogenous neurotransmitter norepinephrine than the α1a or α1bAR subtypes. These findings imply that targeting α1d may provide a new therapeutic approach for controlling bladder irritative symptoms and possibly detrusor overactivity associated with bladder outlet obstruction.

KW - Adrenergic

KW - Bladder

KW - Bladder neck obstruction

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