Elsevier

Urology

Volume 71, Issue 2, February 2008, Pages 341-345
Urology

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

https://doi.org/10.1016/j.urology.2007.10.025Get rights and content

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.

Section snippets

Material and Methods

We used adult female Sprague-Dawley rats (250 to 350 g). All experiments were conducted in accordance with institutional guidelines and approved by the University of Pittsburgh Institutional Animal Care and Use Committee.

Cystometry

During awake cystometry, all spinalized rats showed NVCs before large amplitude voiding bladder contractions occurred (Fig. 1). The amplitude of NVCs increased as the bladder was filled with saline infusion. The mean amplitude and mean number of NVCs per voiding cycle were 17.3 ± 3.6 cmH2O and 4.1 ± 0.6, respectively (Table 1). ABT-627 (1 mg/kg, iv) significantly decreased the amplitudes of NVCs to 13.3 ± 1.3 cmH2O (P <0.01, n = 6) and the number of NVCs to 2.6 ± 0.6 (P <0.05, n = 6), whereas

Comment

The present study revealed that the protein and mRNA levels of ET-1 in the bladder are significantly increased in chronic SCI rats compared with spinal cord intact rats and that inhibition of ETA receptors, but not ETB receptors, suppressed bladder overactivity as evidenced by a reduction in the number and mean amplitude of NVCs in SCI rats. Thus, upregulation of the endothelin mechanism through increased expression of ET-1 and subsequent activation of ETA receptors in the bladder could

Conclusions

The present results indicate that inhibition of ETA receptors can inhibit nonvoiding bladder contractions associated with increased levels of ET-1 in the bladder in SCI rats. Thus, ETA receptor antagonists could be useful for the treatment of bladder overactivity in neurogenic diseases such as SCI.

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This work was supported by NIH Grants DK57267, DK68557 and HD39768. ET receptor antagonists were kindly provided by Abbott.

1

J.B. Nelson is a paid consultant to Abbott.

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