title: Enhanced sensitivity to afferent stimulation and impact of overactive bladder therapies in the conscious, spontaneously hypertensive rat.
abstract: The spontaneously hypertensive rat (SHR) has been proposed as an overactive bladder model, driven, at least partially, by alterations in bladder innervation. To assess the functional role of sensory bladder afferents we evaluated the conscious cystometric response to prostaglandin E(2) (PGE(2)) or acetic acid (AA) bladder infusion. SHR demonstrated a hypersensitivity to PGE(2) and AA, as indicated by a greater reduction in both void volume (VV) and micturition interval (MI) compared with Sprague-Dawley controls. The heightened PGE(2) and AA responses in the SHR were inhibited by capsaicin desensitization, supporting a role for bladder afferents in facilitating the hypersensitivity. Furthermore, we characterized the SHR pharmacologically using overactive bladder therapeutic agents. In the SHR, both darifenacin and oxybutynin (M(3)-selective and nonselective muscarinic antagonists, respectively) reduced micturition pressure (MP) and functional bladder capacity (VV and MI). In sharp contrast, functional bladder capacity was significantly enhanced by β(3)-adrenoceptor agonism [5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL316243)], and by gabapentin, without effect on MP. These data provide the first functional evidence for hypersensitive bladder afferents in the SHR and provide a pharmacological benchmark in this model for overactive bladder therapeutics. These data also support the idea that β(3)-adrenoceptor agonism and gabapentin may provide a more effective overactive bladder therapy than muscarinic antagonism.
authors.affiliation: Metabolic Pathways and Cardiovascular Unit, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
authors.forename: Phani B
authors.initials: PB
authors.lastname: Patra
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Thorneloe
mesh_terms: D019342:Acetic Acid / Q000494:pharmacology / Q000627:therapeutic use; D000344:Afferent Pathways / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003243:Consciousness / Q000187:drug effects / Q000502:physiology*; D015232:Dinoprostone / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D018727:Muscarinic Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D053201:Urinary Bladder, Overactive / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D018727:Muscarinic Antagonists; D015232:Dinoprostone; D019342:Acetic Acid