Development of new drugs for bladder storage dysfunction targeting beta3 adrenoceptors and bladder afferent nerves

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(1) The relaxant response to adrenergic stimulation in the human normal detrusor was found to be mediated mainly through β3-adrenoceptors (β3-Ars)^1. This was true also in neurogenic (both hyper reflexic and low-compliant) bladders^1. A selective β3-AR agonist, CL316243 surppressed bladder overactivity induced by intravesical instillation of prostaglandin E2 in conscious rats^2 and bladder overactivity in cerebral infarcted rats^3 without increasing post-residual volume and without significant cardiovascular side effects. These results suggest that selective β3-AR agonists may be used for the treatment of overactive bladder.(2) Intravesical instillation of ATP (0.1-10 mM) caused bladder overactivity in conscious rats. Intravesical instillation of TNP-ATP (0.5-5.0 μM), a P2X_<2/3> antagonist, increased voiding intervals, bladder capacity and micturition volumes and counteracted the ATP-induced overactivity, suggesting increased extracellular ATP has a role in mechanoafferent transduction in the rat bladder though P2X_<2/3> receptors(3) The clinical and urodynamic effects of intravesical instillation of capsaicin (2 mM, 100 ml) in 7 spinal cord injured patients with detrusor hyperreflexia and autonomic dysreflexia, and of resiniferatoxin (RTX, IνM, 100 ml) in 4 patients with overactive bladder (OAB) and 5 patients with interstitial cystitis (IC), were inverstigated. Capsaicin improved both reflexic urinary incontinence and symptoms related to autonomic dysreflexia in all the 7 patients^4. After RTX treatment, 3 of 4 with OAB and 4 of 5 with IC showed symptomatic improvement. The beneficial effect emerged more quickly after RTX treatment than after capsaicin, and lasted for at least 3 months after either of the two drugs. No adverse effects were found.