title: Impairment of ATP hydrolysis decreases adenosine A1 receptor tonus favoring cholinergic nerve hyperactivity in the obstructed human urinary bladder.
abstract: This study was designed to investigate whether reduced adenosine formation linked to deficits in extracellular ATP hydrolysis by NTPDases contributes to detrusor neuromodulatory changes associated with bladder outlet obstruction in men with benign prostatic hyperplasia (BPH). The kinetics of ATP catabolism and adenosine formation as well as the role of P1 receptor agonists on muscle tension and nerve-evoked [(3)H]ACh release were evaluated in mucosal-denuded detrusor strips from BPH patients (n = 31) and control organ donors (n = 23). The neurogenic release of ATP and [(3)H]ACh was higher (P < 0.05) in detrusor strips from BPH patients. The extracellular hydrolysis of ATP and, subsequent, adenosine formation was slower (t (1/2) 73 vs. 36 min, P < 0.05) in BPH detrusor strips. The A(1) receptor-mediated inhibition of evoked [(3)H]ACh release by adenosine (100 μM), NECA (1 μM), and R-PIA (0.3 μM) was enhanced in BPH bladders. Relaxation of detrusor contractions induced by acetylcholine required 30-fold higher concentrations of adenosine. Despite VAChT-positive cholinergic nerves exhibiting higher A(1) immunoreactivity in BPH bladders, the endogenous adenosine tonus revealed by adenosine deaminase is missing. Restoration of A1 inhibition was achieved by favoring (1) ATP hydrolysis with apyrase (2 U mL(-1)) or (2) extracellular adenosine accumulation with dipyridamole or EHNA, as these drugs inhibit adenosine uptake and deamination, respectively. In conclusion, reduced ATP hydrolysis leads to deficient adenosine formation and A(1) receptor-mediated inhibition of cholinergic nerve activity in the obstructed human bladder. Thus, we propose that pharmacological manipulation of endogenous adenosine levels and/or A(1) receptor activation might be useful to control bladder overactivity in BPH patients.
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.|Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, R. Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.|Serviço de Urologia, Centro Hospitalar do Porto (CHP), Porto, Portugal.
authors.forename: M
authors.initials: M
authors.lastname: Silva-Ramos
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.|Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, R. Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
authors.forename: I
authors.initials: I
authors.lastname: Silva
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.|Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, R. Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
authors.forename: M
authors.initials: M
authors.lastname: Faria
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.|Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, R. Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
authors.forename: M T
authors.initials: MT
authors.lastname: Magalhães-Cardoso
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.|Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, R. Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
authors.forename: J
authors.initials: J
authors.lastname: Correia
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.|Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, R. Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
authors.forename: F
authors.initials: F
authors.lastname: Ferreirinha
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal. farmacol@icbas.up.pt.|Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, R. Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal. farmacol@icbas.up.pt.
authors.forename: P
authors.identifier: http://orcid.org/0000-0002-6114-9189
authors.initials: P
authors.lastname: Correia-de-Sá
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000227:Adenine Nucleotides / Q000378:metabolism; D000241:Adenosine / Q000378:metabolism; D000243:Adenosine Deaminase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D001081:Apyrase / Q000378:metabolism; D004576:Electromyography; D005260:Female; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D010275:Parasympathetic Nervous System / Q000187:drug effects*; D043682:Receptor, Adenosine A1 / Q000187:drug effects*; D001748:Urinary Bladder Neck Obstruction / Q000503:physiopathology*
chemical_list: D000227:Adenine Nucleotides; D015703:Antigens, CD; D043682:Receptor, Adenosine A1; D019830:Adenosine-5'-(N-ethylcarboxamide); D000255:Adenosine Triphosphate; D000243:Adenosine Deaminase; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine; D000109:Acetylcholine
keywords: ATP catabolism; Acetylcholine release; Adenosine A1 receptors; Bladder outlet obstruction; Ectonucleotidases; Human urinary bladder