title: Prostaglandin E2 excitatory effects on rat urinary bladder: a comparison between the β-adrenoceptor modulation of non-voiding activity in vivo and micro-contractile activity in vitro.
abstract: Prostaglandin E2 (PGE2) is well known to modulate urinary bladder functions, but it is also thought to be involved in the pathophysiology of lower urinary tract dysfunctions, since high levels of PGE2 have been found in overactive bladder (OAB) patients. β-Adrenoceptors are major players in detrusor muscle relaxation, and the selective β3-adrenoceptor (AR) agonist mirabegron was recently approved for the treatment of overactive bladder (OAB). β-Adrenoceptor modulation of PGE2 excitatory effects on bladder detrusor muscle was investigated by i.v. mirabegron after intravesical PGE2 infusion in conscious rats. Non-voiding activity (NVA) was assessed under isovolumetric conditions. In addition, mirabegron and isoprenaline (0.01-10 μM) were studied on PGE2-increased micro-contractile activity during isometric tension recordings of intact isolated bladder muscle strips. Our investigations showed that PGE2 dramatically increased NVA in vivo and spontaneous micro-contractions in vitro. In vivo administration of mirabegron (0.1, 0.3 and 3 mg/kg) reduced PGE2-augmented NVA in dose-dependent manner, while the PGE2-increased micro-contractions in isolated bladder strips were poorly inhibited. Isoprenaline inhibited PGE2-augmented micro-contractions in a concentration-dependent manner and had a higher potency compared to mirabegron. The apparent pKB of 7.25 for metoprolol at the isoprenaline concentration-response curve for PGE2-augmented micro-contractions suggests a β1-AR-mediated.
authors.affiliation: Drug Discovery Science & Management-Europe, Astellas Pharma Europe B.V., Sylviusweg 62, 2300 AH, Leiden, The Netherlands, claudia-granato@astellas.com.
authors.forename: C
authors.initials: C
authors.lastname: Granato
authors.forename: C
authors.initials: C
authors.lastname: Korstanje
authors.forename: V
authors.initials: V
authors.lastname: Guilloteau
authors.forename: C
authors.initials: C
authors.lastname: Rouget
authors.forename: S
authors.initials: S
authors.lastname: Palea
authors.forename: J I
authors.initials: JI
authors.lastname: Gillespie
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D015232:Dinoprostone / Q000494:pharmacology* / Q000502:physiology; D005260:Female; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D053201:Urinary Bladder, Overactive / Q000378:metabolism / Q000503:physiopathology; D014554:Urination / Q000187:drug effects*
chemical_list: D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D015232:Dinoprostone