Depressed contractile responses to neurokinin A in idiopathic but not neurogenic overactive human detrusor muscle

Donna J. Sellers, Christopher R. Chapple, Douglas P. Douglas, Russell Chess-Williams

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13 Citations (Scopus)

Abstract

Objective: The role of tachykinins such as neurokinin A in regulating bladder function is unclear, but NK2 receptors seem to mediate contraction in the human bladder and it has been suggested that these peptides may have a role in the pathophysiology of bladder dysfunction. The present study investigates neurokinin receptor-mediated contractility of detrusor muscle in the idiopathic overactive and neurogenic overactive bladder and investigates the neurokinin receptor subtypes involved. Methods: Human bladder was obtained from patients undergoing cystectomy (normal) or clam cystoplasty (idiopathic overactive) and from patients with spinal injuries (neurogenic overactive). Strips of isolated detrusor muscle were mounted in physiological Krebs-bicarbonate solution and cumulative concentration-response curves to 1 nM to 300 μM neurokinin A (NKA) were obtained in the absence and presence of neurokinin receptor antagonists, either the NK2 receptor-selective antagonist SR 48968 or the NK3 receptor-selective antagonist SB 223412. Results: NKA evoked concentration-dependent contraction of normal, idiopathic, and neurogenic overactive detrusor strips. In idiopathic overactive detrusor muscle, NKA-induced contraction was significantly reduced relative to normal detrusor (0.031 ± 0.005 mg/g, n = 11 versus 0.193 ± 0.039 mg/g, n = 7). Sensitivity to the peptide was also significantly (p < 0.01) reduced in idiopathic overactive detrusor, with mean pEC50 values (concentration producing 50% maximal response) of 6.62 ± 0.16 (n = 11) compared to 7.47 ± 0.19 (n = 7) in normal detrusor. In contrast, NKA-induced responses of neurogenic overactive detrusor were similar to those in normal detrusor, with a mean maximum contraction of 0.199 ± 0.036 mg/g (n = 10) and mean pEC50 value of 7.85 ± 0.16 (n = 10). NKA curves in all groups were shifted to the right by the NK2 receptor-selective antagonist SR 48968 with high affinity, pKB values being similar in normal, idiopathic, and neurogenic overactive detrusor (8.85 + 0.08, n = 14; 8.97 ± 0.13, n = 12; 8.73 ± 0.12, n = 8, respectively). In contrast the NK3 receptor-selective antagonist SB 223412 had a minimal effect on NKA responses and affinity values were low (pKB 5.81 ± 0.11, n = 12 in normal; 5.75 ± 0.08, n = 12 in idiopathic overactive, and 5.77 ± 0.13, n = 11 in neurogenic overactive). Conclusion: These data indicate that NKA-induced responses are impaired in detrusor muscle from idiopathic overactive human bladder, but not in detrusor muscle from neurogenic overactive bladder. The NK2 receptor subtype appears to mediate NKA responses in the normal, idiopathic overactive, and neurogenic overactive detrusor. This is important evidence suggesting a difference between the bladder pathophysiology observed in idiopathic versus neurogenic overactive detrusor.

Original languageEnglish
Pages (from-to)510-518
Number of pages9
JournalEuropean Urology
Volume49
Issue number3
DOIs
Publication statusPublished - Mar 2006
Externally publishedYes

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Neurokinin A
Overactive Urinary Bladder
Muscles
Urinary Bladder
Neurogenic Urinary Bladder
Tachykinins
Spinal Injuries
Peptides
Bivalvia
Cystectomy
Bicarbonates

Cite this

@article{6b842e9ca646447eb0b6d4e8be89bfad,
title = "Depressed contractile responses to neurokinin A in idiopathic but not neurogenic overactive human detrusor muscle",
abstract = "Objective: The role of tachykinins such as neurokinin A in regulating bladder function is unclear, but NK2 receptors seem to mediate contraction in the human bladder and it has been suggested that these peptides may have a role in the pathophysiology of bladder dysfunction. The present study investigates neurokinin receptor-mediated contractility of detrusor muscle in the idiopathic overactive and neurogenic overactive bladder and investigates the neurokinin receptor subtypes involved. Methods: Human bladder was obtained from patients undergoing cystectomy (normal) or clam cystoplasty (idiopathic overactive) and from patients with spinal injuries (neurogenic overactive). Strips of isolated detrusor muscle were mounted in physiological Krebs-bicarbonate solution and cumulative concentration-response curves to 1 nM to 300 μM neurokinin A (NKA) were obtained in the absence and presence of neurokinin receptor antagonists, either the NK2 receptor-selective antagonist SR 48968 or the NK3 receptor-selective antagonist SB 223412. Results: NKA evoked concentration-dependent contraction of normal, idiopathic, and neurogenic overactive detrusor strips. In idiopathic overactive detrusor muscle, NKA-induced contraction was significantly reduced relative to normal detrusor (0.031 ± 0.005 mg/g, n = 11 versus 0.193 ± 0.039 mg/g, n = 7). Sensitivity to the peptide was also significantly (p < 0.01) reduced in idiopathic overactive detrusor, with mean pEC50 values (concentration producing 50{\%} maximal response) of 6.62 ± 0.16 (n = 11) compared to 7.47 ± 0.19 (n = 7) in normal detrusor. In contrast, NKA-induced responses of neurogenic overactive detrusor were similar to those in normal detrusor, with a mean maximum contraction of 0.199 ± 0.036 mg/g (n = 10) and mean pEC50 value of 7.85 ± 0.16 (n = 10). NKA curves in all groups were shifted to the right by the NK2 receptor-selective antagonist SR 48968 with high affinity, pKB values being similar in normal, idiopathic, and neurogenic overactive detrusor (8.85 + 0.08, n = 14; 8.97 ± 0.13, n = 12; 8.73 ± 0.12, n = 8, respectively). In contrast the NK3 receptor-selective antagonist SB 223412 had a minimal effect on NKA responses and affinity values were low (pKB 5.81 ± 0.11, n = 12 in normal; 5.75 ± 0.08, n = 12 in idiopathic overactive, and 5.77 ± 0.13, n = 11 in neurogenic overactive). Conclusion: These data indicate that NKA-induced responses are impaired in detrusor muscle from idiopathic overactive human bladder, but not in detrusor muscle from neurogenic overactive bladder. The NK2 receptor subtype appears to mediate NKA responses in the normal, idiopathic overactive, and neurogenic overactive detrusor. This is important evidence suggesting a difference between the bladder pathophysiology observed in idiopathic versus neurogenic overactive detrusor.",
author = "Sellers, {Donna J.} and Chapple, {Christopher R.} and Douglas, {Douglas P.} and Russell Chess-Williams",
year = "2006",
month = "3",
doi = "10.1016/j.eururo.2005.11.028",
language = "English",
volume = "49",
pages = "510--518",
journal = "European Urology",
issn = "0302-2838",
publisher = "Elsevier",
number = "3",

}

Depressed contractile responses to neurokinin A in idiopathic but not neurogenic overactive human detrusor muscle. / Sellers, Donna J.; Chapple, Christopher R.; Douglas, Douglas P.; Chess-Williams, Russell.

In: European Urology, Vol. 49, No. 3, 03.2006, p. 510-518.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Depressed contractile responses to neurokinin A in idiopathic but not neurogenic overactive human detrusor muscle

AU - Sellers, Donna J.

AU - Chapple, Christopher R.

AU - Douglas, Douglas P.

AU - Chess-Williams, Russell

PY - 2006/3

Y1 - 2006/3

N2 - Objective: The role of tachykinins such as neurokinin A in regulating bladder function is unclear, but NK2 receptors seem to mediate contraction in the human bladder and it has been suggested that these peptides may have a role in the pathophysiology of bladder dysfunction. The present study investigates neurokinin receptor-mediated contractility of detrusor muscle in the idiopathic overactive and neurogenic overactive bladder and investigates the neurokinin receptor subtypes involved. Methods: Human bladder was obtained from patients undergoing cystectomy (normal) or clam cystoplasty (idiopathic overactive) and from patients with spinal injuries (neurogenic overactive). Strips of isolated detrusor muscle were mounted in physiological Krebs-bicarbonate solution and cumulative concentration-response curves to 1 nM to 300 μM neurokinin A (NKA) were obtained in the absence and presence of neurokinin receptor antagonists, either the NK2 receptor-selective antagonist SR 48968 or the NK3 receptor-selective antagonist SB 223412. Results: NKA evoked concentration-dependent contraction of normal, idiopathic, and neurogenic overactive detrusor strips. In idiopathic overactive detrusor muscle, NKA-induced contraction was significantly reduced relative to normal detrusor (0.031 ± 0.005 mg/g, n = 11 versus 0.193 ± 0.039 mg/g, n = 7). Sensitivity to the peptide was also significantly (p < 0.01) reduced in idiopathic overactive detrusor, with mean pEC50 values (concentration producing 50% maximal response) of 6.62 ± 0.16 (n = 11) compared to 7.47 ± 0.19 (n = 7) in normal detrusor. In contrast, NKA-induced responses of neurogenic overactive detrusor were similar to those in normal detrusor, with a mean maximum contraction of 0.199 ± 0.036 mg/g (n = 10) and mean pEC50 value of 7.85 ± 0.16 (n = 10). NKA curves in all groups were shifted to the right by the NK2 receptor-selective antagonist SR 48968 with high affinity, pKB values being similar in normal, idiopathic, and neurogenic overactive detrusor (8.85 + 0.08, n = 14; 8.97 ± 0.13, n = 12; 8.73 ± 0.12, n = 8, respectively). In contrast the NK3 receptor-selective antagonist SB 223412 had a minimal effect on NKA responses and affinity values were low (pKB 5.81 ± 0.11, n = 12 in normal; 5.75 ± 0.08, n = 12 in idiopathic overactive, and 5.77 ± 0.13, n = 11 in neurogenic overactive). Conclusion: These data indicate that NKA-induced responses are impaired in detrusor muscle from idiopathic overactive human bladder, but not in detrusor muscle from neurogenic overactive bladder. The NK2 receptor subtype appears to mediate NKA responses in the normal, idiopathic overactive, and neurogenic overactive detrusor. This is important evidence suggesting a difference between the bladder pathophysiology observed in idiopathic versus neurogenic overactive detrusor.

AB - Objective: The role of tachykinins such as neurokinin A in regulating bladder function is unclear, but NK2 receptors seem to mediate contraction in the human bladder and it has been suggested that these peptides may have a role in the pathophysiology of bladder dysfunction. The present study investigates neurokinin receptor-mediated contractility of detrusor muscle in the idiopathic overactive and neurogenic overactive bladder and investigates the neurokinin receptor subtypes involved. Methods: Human bladder was obtained from patients undergoing cystectomy (normal) or clam cystoplasty (idiopathic overactive) and from patients with spinal injuries (neurogenic overactive). Strips of isolated detrusor muscle were mounted in physiological Krebs-bicarbonate solution and cumulative concentration-response curves to 1 nM to 300 μM neurokinin A (NKA) were obtained in the absence and presence of neurokinin receptor antagonists, either the NK2 receptor-selective antagonist SR 48968 or the NK3 receptor-selective antagonist SB 223412. Results: NKA evoked concentration-dependent contraction of normal, idiopathic, and neurogenic overactive detrusor strips. In idiopathic overactive detrusor muscle, NKA-induced contraction was significantly reduced relative to normal detrusor (0.031 ± 0.005 mg/g, n = 11 versus 0.193 ± 0.039 mg/g, n = 7). Sensitivity to the peptide was also significantly (p < 0.01) reduced in idiopathic overactive detrusor, with mean pEC50 values (concentration producing 50% maximal response) of 6.62 ± 0.16 (n = 11) compared to 7.47 ± 0.19 (n = 7) in normal detrusor. In contrast, NKA-induced responses of neurogenic overactive detrusor were similar to those in normal detrusor, with a mean maximum contraction of 0.199 ± 0.036 mg/g (n = 10) and mean pEC50 value of 7.85 ± 0.16 (n = 10). NKA curves in all groups were shifted to the right by the NK2 receptor-selective antagonist SR 48968 with high affinity, pKB values being similar in normal, idiopathic, and neurogenic overactive detrusor (8.85 + 0.08, n = 14; 8.97 ± 0.13, n = 12; 8.73 ± 0.12, n = 8, respectively). In contrast the NK3 receptor-selective antagonist SB 223412 had a minimal effect on NKA responses and affinity values were low (pKB 5.81 ± 0.11, n = 12 in normal; 5.75 ± 0.08, n = 12 in idiopathic overactive, and 5.77 ± 0.13, n = 11 in neurogenic overactive). Conclusion: These data indicate that NKA-induced responses are impaired in detrusor muscle from idiopathic overactive human bladder, but not in detrusor muscle from neurogenic overactive bladder. The NK2 receptor subtype appears to mediate NKA responses in the normal, idiopathic overactive, and neurogenic overactive detrusor. This is important evidence suggesting a difference between the bladder pathophysiology observed in idiopathic versus neurogenic overactive detrusor.

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