Abstract
Neurogenic detrusor overactivity (NDO) is among the most challenging complications of spinal cord injury (SCI). A recent report by us demonstrated an improvement in NDO in SCI rats following chronic systemic treatment with the purine nucleoside inosine. The objective of this study was to investigate the mechanism of action of inosine underlying improvement of NDO. Male Sprague-Dawley rats underwent complete spinal cord transection at T8. Inosine (1 mM) delivered intravesically to SCI rats during conscious cystometry significantly decreased the frequency of spontaneous non-voiding contractions. In isolated tissue assays, inosine (1 mM) significantly decreased the amplitude of spontaneous activity (SA) in SCI bladder muscle strips. This effect was prevented by a pan-adenosine receptor antagonist CGS15943, but not by A1 or A3 receptor antagonists. The A2A antagonist ZM241385 and A2B antagonist PSB603 prevented the effect of inosine. The effect of inosine was mimicked by the adenosine receptor agonist NECA and the A2B receptor agonist BAY60-6583. The inhibition of SA by inosine was not observed in the presence of the BK antagonist, iberiotoxin, but persisted in the presence of KATP and SK antagonists. These findings demonstrate that inosine acts via an A2B receptor-mediated pathway that impinges on specific potassium channel effectors.
Highlights
Micturition[8,9,10]
These findings suggest that inosine can act locally within the bladder via the adenosine A2B receptor to inhibit non-voiding contractions and spontaneous activity, and represents a novel treatment for neurogenic detrusor overactivity
Rats subjected to spinal cord transection for 6.5 wk underwent conscious cystometry during which inosine (1 mM) was instilled into the bladder
Summary
Micturition[8,9,10]. In a rat model of Parkinson’s disease, intravenous, intrathecal or intracerebroventricular administration of an adenosine A2A receptor antagonist reduced the overactive bladder phenotype[9] consistent with central and spinal sites of action. Intravesical administration of an A1 receptor agonist increased the intercontraction interval in rats undergoing cystometry, suggesting involvement of local A1 receptor activation in regulation of micturition[10]. The aim of this study was to investigate the role of adenosine receptor signalling in the ability of inosine to attenuate detrusor overactivity in the context of SCI, and to explore local action of inosine in the bladder. Inosine action on spontaneous activity was prevented in the presence of an inhibitor of the large conductance potassium channel (BK channel) Taken together, these findings suggest that inosine can act locally within the bladder via the adenosine A2B receptor to inhibit non-voiding contractions and spontaneous activity, and represents a novel treatment for neurogenic detrusor overactivity
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