Therapeutic Effects of Endothelin-A Receptor Antagonist on Bladder Overactivity in Rats with Chronic Spinal Cord Injury

Teruyuki Ogawa, Kurumi Sasatomi, Shiro Hiragata, Satoshi Seki, Osamu Nishizawa, Christopher J. Chermansky, Beth Pflug, Joel B. Nelson, Michael B. Chancellor, Naoki Yoshimura

Research output: Contribution to journalArticle

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Abstract

Objectives: We investigated the effects of suppression of endothelin-A (ETA) receptors on bladder function and ET-1 levels in the bladder in rats with chronic spinal cord injury (SCI). Methods: We transected the spinal cord of female Sprague-Dawley rats at the level of Th 8-9. Awake cystometrograms were performed 4 weeks after spinal cord transection. We evaluated cystometric parameters such as mean amplitudes of nonvoiding contractions (NVCs), the number of NVCs, voided volume, voiding efficiency, and micturition pressure before and after intravenous (iv) injection of ABT-627, an ETA antagonist, or A-19261, an ETB antagonist, in SCI animals. Four weeks after spinalization, we also measured the protein and mRNA levels of ET-1 in the bladder using enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). Results: ABT-627 (1 mg/kg, iv) but not A-192621 (10 mg/kg, iv) significantly decreased the amplitude of NVCs and the number of NVCs in SCI rats. There were no significant changes in pressure threshold, maximum voiding pressure, voided volume, or voiding efficiency. ELISA analysis for ET-1 showed significantly elevated protein concentrations in SCI rats compared with spinal cord intact rats. Significant upregulation of the ET-1 mRNA was also noted in SCI bladders. Conclusions: These results suggest that upregulation of ET-1 is involved in the mechanism inducing bladder overactivity in chronic SCI rats, and that an ETA receptor antagonist can suppress SCI-induced bladder overactivity as indicated by a reduction in NVCs. Thus, ETA receptor inhibition could be an effective treatment for neurogenic bladder overactivity in pathological conditions such as SCI.

Original languageEnglish (US)
Pages (from-to)341-345
Number of pages5
JournalUrology
Volume71
Issue number2
DOIs
StatePublished - Feb 2008
Externally publishedYes

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Therapeutic Uses
Spinal Cord Injuries
Urinary Bladder
Endothelin A Receptors
Pressure
A 192621
Spinal Cord
Up-Regulation
Enzyme-Linked Immunosorbent Assay
Endothelin A Receptor Antagonists
Neurogenic Urinary Bladder
Messenger RNA
Urination
Intravenous Injections
Sprague Dawley Rats
Real-Time Polymerase Chain Reaction
Proteins

ASJC Scopus subject areas

  • Urology

Cite this

Ogawa, T., Sasatomi, K., Hiragata, S., Seki, S., Nishizawa, O., Chermansky, C. J., ... Yoshimura, N. (2008). Therapeutic Effects of Endothelin-A Receptor Antagonist on Bladder Overactivity in Rats with Chronic Spinal Cord Injury. Urology, 71(2), 341-345. https://doi.org/10.1016/j.urology.2007.10.025

Therapeutic Effects of Endothelin-A Receptor Antagonist on Bladder Overactivity in Rats with Chronic Spinal Cord Injury. / Ogawa, Teruyuki; Sasatomi, Kurumi; Hiragata, Shiro; Seki, Satoshi; Nishizawa, Osamu; Chermansky, Christopher J.; Pflug, Beth; Nelson, Joel B.; Chancellor, Michael B.; Yoshimura, Naoki.

In: Urology, Vol. 71, No. 2, 02.2008, p. 341-345.

Research output: Contribution to journalArticle

Ogawa, T, Sasatomi, K, Hiragata, S, Seki, S, Nishizawa, O, Chermansky, CJ, Pflug, B, Nelson, JB, Chancellor, MB & Yoshimura, N 2008, 'Therapeutic Effects of Endothelin-A Receptor Antagonist on Bladder Overactivity in Rats with Chronic Spinal Cord Injury', Urology, vol. 71, no. 2, pp. 341-345. https://doi.org/10.1016/j.urology.2007.10.025
Ogawa, Teruyuki ; Sasatomi, Kurumi ; Hiragata, Shiro ; Seki, Satoshi ; Nishizawa, Osamu ; Chermansky, Christopher J. ; Pflug, Beth ; Nelson, Joel B. ; Chancellor, Michael B. ; Yoshimura, Naoki. / Therapeutic Effects of Endothelin-A Receptor Antagonist on Bladder Overactivity in Rats with Chronic Spinal Cord Injury. In: Urology. 2008 ; Vol. 71, No. 2. pp. 341-345.
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abstract = "Objectives: We investigated the effects of suppression of endothelin-A (ETA) receptors on bladder function and ET-1 levels in the bladder in rats with chronic spinal cord injury (SCI). Methods: We transected the spinal cord of female Sprague-Dawley rats at the level of Th 8-9. Awake cystometrograms were performed 4 weeks after spinal cord transection. We evaluated cystometric parameters such as mean amplitudes of nonvoiding contractions (NVCs), the number of NVCs, voided volume, voiding efficiency, and micturition pressure before and after intravenous (iv) injection of ABT-627, an ETA antagonist, or A-19261, an ETB antagonist, in SCI animals. Four weeks after spinalization, we also measured the protein and mRNA levels of ET-1 in the bladder using enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). Results: ABT-627 (1 mg/kg, iv) but not A-192621 (10 mg/kg, iv) significantly decreased the amplitude of NVCs and the number of NVCs in SCI rats. There were no significant changes in pressure threshold, maximum voiding pressure, voided volume, or voiding efficiency. ELISA analysis for ET-1 showed significantly elevated protein concentrations in SCI rats compared with spinal cord intact rats. Significant upregulation of the ET-1 mRNA was also noted in SCI bladders. Conclusions: These results suggest that upregulation of ET-1 is involved in the mechanism inducing bladder overactivity in chronic SCI rats, and that an ETA receptor antagonist can suppress SCI-induced bladder overactivity as indicated by a reduction in NVCs. Thus, ETA receptor inhibition could be an effective treatment for neurogenic bladder overactivity in pathological conditions such as SCI.",
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AB - Objectives: We investigated the effects of suppression of endothelin-A (ETA) receptors on bladder function and ET-1 levels in the bladder in rats with chronic spinal cord injury (SCI). Methods: We transected the spinal cord of female Sprague-Dawley rats at the level of Th 8-9. Awake cystometrograms were performed 4 weeks after spinal cord transection. We evaluated cystometric parameters such as mean amplitudes of nonvoiding contractions (NVCs), the number of NVCs, voided volume, voiding efficiency, and micturition pressure before and after intravenous (iv) injection of ABT-627, an ETA antagonist, or A-19261, an ETB antagonist, in SCI animals. Four weeks after spinalization, we also measured the protein and mRNA levels of ET-1 in the bladder using enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). Results: ABT-627 (1 mg/kg, iv) but not A-192621 (10 mg/kg, iv) significantly decreased the amplitude of NVCs and the number of NVCs in SCI rats. There were no significant changes in pressure threshold, maximum voiding pressure, voided volume, or voiding efficiency. ELISA analysis for ET-1 showed significantly elevated protein concentrations in SCI rats compared with spinal cord intact rats. Significant upregulation of the ET-1 mRNA was also noted in SCI bladders. Conclusions: These results suggest that upregulation of ET-1 is involved in the mechanism inducing bladder overactivity in chronic SCI rats, and that an ETA receptor antagonist can suppress SCI-induced bladder overactivity as indicated by a reduction in NVCs. Thus, ETA receptor inhibition could be an effective treatment for neurogenic bladder overactivity in pathological conditions such as SCI.

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