Blockage of UDP-sensitive P2Y6 receptors as a novel therapeutic strategy to control urine storage symptoms in men with bladder outlet obstruction

  • I. Silva
    Correspondence
    Corresponding author.
    Affiliations
    Laboratório de Farmacologia e Neurobiologia

    Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas de Abel Salazar – Universidade do Porto (ICBAS-UP)
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  • F. Ferreirinha
    Affiliations
    Laboratório de Farmacologia e Neurobiologia

    Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas de Abel Salazar – Universidade do Porto (ICBAS-UP)
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  • M.T. Magalhães-Cardoso
    Affiliations
    Laboratório de Farmacologia e Neurobiologia

    Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas de Abel Salazar – Universidade do Porto (ICBAS-UP)
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  • M. Silva-Ramos
    Affiliations
    Laboratório de Farmacologia e Neurobiologia

    Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas de Abel Salazar – Universidade do Porto (ICBAS-UP)

    Serviço de Urologia, CHP, Porto, Portugal
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  • P. Correia-de-Sá
    Affiliations
    Laboratório de Farmacologia e Neurobiologia

    Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas de Abel Salazar – Universidade do Porto (ICBAS-UP)
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      Deregulation of purinergic bladder signalling may contribute to persistent detrusor overactivity in patients with bladder outlet obstruction. UDP-sensitive P2Y6 receptors activation indirectly increases the voiding frequency in rats by releasing ATP from the urothelium (Timóteo et al., 2014), but this mechanism was never tested in the human bladder. Here, we examined the role of the P2Y6 receptor on TTX-insensitive non-neuronal ATP and [3H]ACh release from the human mucosa of control organ donors and benign prostatic hyperplasia (BPH) patients. The ATP/[3H]ACh ratio was 5-fold higher in urothelial strips from BPH patients than control men. The selective P2Y6 receptor agonist, PSB0474 (100 nM), augmented by a similar proportion ATP and [3H]ACh release from the urothelium of both groups; the facilitatory effect of PSB0474 was prevented by MRS2578 (50 nM) and by carbenoxolone (10 μM), which block the P2Y6 receptor and pannexin-1 hemichannels, respectively. Blockade of P2X3 (and/or P2X2/3) receptors with A317491 (100 nM) also attenuated release facilitation by PSB0474 in control men, but not in BPH patients. Immunolocalization studies showed that P2Y6, P2X2 and P2X3 receptors are present in choline acetyltransferase (ChAT) positive urothelial cells. In contrast to P2Y6 staining, immunoreactivity against ChAT, P2X2 and P2X3 decreased in the urothelium of BPH patients. Activation of the P2Y6 receptor amplifies mucosal ATP release underlying bladder overactivity in BPH patients. Therefore, we propose the selective P2Y6 receptor blockage as a novel therapeutic strategy to control persistent storage symptoms in obstructed patients. IS is in receipt of a PhD fellowship by FCT (SFRH/BD/88855/2012).
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