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

Abstract

Objectives-We investigated the effects of suppression of ET A receptors on bladder function and ET-1 levels in the bladder in rats with chronic spinal cord injury (SCI).Methods-The spinal cord of female Spraque-Dawley rats was transected at the level of Th 8-9. Awake cystometrograms were performed 4 weeks after spinal cord transection. Cystometric parameters such as mean amplitudes of non-voiding contractions (NVCs), the number of NVCs, voided volume, voiding efficiency, and micturition pressure were evaluated before and after intravenous (i.v.) injection of ABT-627, an ET A antagonist, or A-19261, an ETB antagonist, in SCI animals. Four weeks after spinalization, the protein and mRNA levels of ET-1 in the bladder were also measured using enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). Results-ABT-627(1 mg/kg, i.v.), but not A-192621 (10 mg/kg, i.v.), 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 ET A receptor antagonist can suppress SCI-induced bladder overactivity as indicated by a reduction in NVCs. Thus, ET A receptor inhibition could be an effective treatment for neurogenic bladder overactivity in pathological conditions such as SCI.

Neuropeptides in Lower Urinary Tract Function

“…Endothelin-1 and endothelin receptors, ET A and ET B , contribute to LUT function under normal and pathological conditions (Ukai et al, 2006; Ogawa et al, 2008; Ukai et al, 2008). In the LUT, endothelin-1 facilitates detrusor smooth muscle contraction in various species including rabbit, rat, dogs and humans and stimulates proliferation of the prostate and urinary bladder (Maggi et al, 1989; Garcia-Pascual et al, 1990; Persson et al, 1992; Langenstroer et al, 1997; Ogawa et al, 2004).…”

“…Additional beneficial effects of repeated administration of endothelin-converting enzyme inhibitor in BOO rats included normalization of: bladder weight, micturition pressures and voiding durations (Schroder et al, 2004). Suppression of ET A receptors by intravenous infusion of ABT-627 in rats with complete spinal cord transection (thoracic 8–9) significantly decreased the amplitude and number of non-voiding bladder contractions without changing bladder pressures, void volumes or voiding efficiency (Ogawa et al, 2008). No effects on bladder function were observed when rats with spinal cord transection were similarly treated with an ET B receptor antagonist, A-192621 (Ogawa et al, 2008).…”

“…Suppression of ET A receptors by intravenous infusion of ABT-627 in rats with complete spinal cord transection (thoracic 8–9) significantly decreased the amplitude and number of non-voiding bladder contractions without changing bladder pressures, void volumes or voiding efficiency (Ogawa et al, 2008). No effects on bladder function were observed when rats with spinal cord transection were similarly treated with an ET B receptor antagonist, A-192621 (Ogawa et al, 2008). Thus, endothelin and ET A receptors may be a novel therapeutic target to ameliorate the effects of bladder overactivity associated with BOO.…”

Endothelin-1 concentrations in the internal jugular and azygous veins in multiple sclerosis patients: the results of a pilot study

“…It is known that ET-1 is involved in the regulation of urinary bladder, and an increased blood ET-1 concentration can result in urinary bladder hyperactivity [19][20][21]. Intraventricular injection of ET-1 in animal experiments resulted in neurological symptoms comprising nystagmus, ocular clonus, tonic hindlimb extension, and generalised motor disturbances, the so-called barrel-rolling [22][23][24].…”

Neurogenic Bladder: Current Pharmacologic Trends

“…Intravesical endothelin-1 induces DO in healthy rats [9]. Ogawa et al [10] measured bladder endothelin-1 and investigated effects of an endothelin-A receptor antagonist on DO in SCI rats. Four weeks after spinal cord transection, cystometry in conscious rats and healthy controls was performed before and after ABT-627 administration (endothelin-A receptor antagonist) or A-19261 (endothelin-B receptor antagonist).…”