title: Stimulation of large-conductance calcium-activated potassium channels inhibits neurogenic contraction of human bladder from patients with urinary symptoms and reverses acetic acid-induced bladder hyperactivity in rats.
abstract: We have analysed the effects of large-conductance calcium-activated potassium channel (BK) stimulation on neurogenic and myogenic contraction of human bladder from healthy subjects and patients with urinary symptoms and evaluated the efficacy of activating BK to relief bladder hyperactivity in rats. Bladder specimens were obtained from organ donors and from men with benign prostatic hyperplasia (BPH). Contractions elicited by electrical field stimulation (EFS) and carbachol (CCh) were evaluated in isolated bladder strips. in vivo cystometric recordings were obtained in anesthetized rats under control and acetic acid-induced hyperactive conditions. Neurogenic contractions of human bladder were potentiated by blockade of BK and small-conductance calcium-activated potassium channels (SK) but were unaffected by the blockade of intermediate calcium-activated potassium channels (IK). EFS-induced contractions were inhibited by BK stimulation with NS-8 or NS1619 or by SK/IK stimulation with NS309 (3µM). CCh-induced contractions were not modified by blockade or stimulation of BK, IK or SK. The anti-cholinergic agent, oxybutynin (0.3µM) inhibited either neurogenic or CCh-induced contractions. Neurogenic contractions of bladders from BPH patients were less sensitive to BK inhibition and more sensitive to BK activation than healthy bladders. The BK activator, NS-8 (5mg/kg; i.v.), reversed bladder hyperactivity induced by acetic acid in rats, while oxybutynin was ineffective. NS-8 did not significantly impact blood pressure or heart rate. BK stimulation specifically inhibits neurogenic contractions in patients with urinary symptoms and relieves bladder hyperactivity in vivo without compromising bladder contractile capacity or cardiovascular safety, supporting its potential therapeutic use for relieving bladder overactivity.
authors.affiliation: Serviço de Urologia. Hospital Santo Antonio, Porto, Portugal.
authors.forename: José M
authors.initials: JM
authors.lastname: La Fuente
authors.affiliation: Servicio de Histología. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
authors.forename: Argentina
authors.initials: A
authors.lastname: Fernández
authors.affiliation: Servicio de Histología. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Cuevas
authors.affiliation: Laboratorio de Estructura y Función de Proteínas, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: González-Corrochano
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline R&D, Stevenage, Herts SG1 2NY, United Kingdom.
authors.forename: Mao Xiang
authors.initials: MX
authors.lastname: Chen
authors.affiliation: Servicio de Histología. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain. Electronic address: javier.angulo@hrc.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Angulo
mesh_terms: D019342:Acetic Acid; D000328:Adult; D000368:Aged; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000502:physiology; D011470:Prostatic Hyperplasia / Q000503:physiopathology*; D051381:Rats; D001743:Urinary Bladder / Q000503:physiopathology; D001750:Urinary Bladder, Neurogenic / Q000503:physiopathology*; D053201:Urinary Bladder, Overactive / Q000139:chemically induced / Q000503:physiopathology*; D055815:Young Adult
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels; D002217:Carbachol; D019342:Acetic Acid
keywords: Anti-muscarinics; Apamin (PubChem CID: 16218850); BK activators; Benign prostatic hyperplasia; Bladder overactivity; Ca(2+)-activated K(+) channels; Carbachol (PubChem CID: 5831); Glibenclamide (PubChem CID: 3488); Human bladder; Iberiotoxin (PubChem CID: 16132435); NS-8 (PubChem CID: 10176749); NS1619 (PubChem CID: 52948538); NS309 (PubChem CID: 11637204); Oxybutynin (PubChem CID: 4634); Pinacidil (PubChem CID: 4826); TRAM-34 (PubChem CID: 656734)