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 E2 (PGE2) or acetic acid (AA) bladder infusion. SHR demonstrated a hypersensitivity to PGE2 and AA, as indicated by a greater reduction in both void volume (VV) and micturition interval (MI) compared with Sprague-Dawley controls. The heightened PGE2 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 (M3-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 β3-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 β3-adrenoceptor agonism and gabapentin may provide a more effective overactive bladder therapy than muscarinic antagonism.
Footnotes
This research was funded by GlaxoSmithKline Pharmaceuticals.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.180885.
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ABBREVIATIONS:
- SHR
- spontaneously hypertensive rat
- PGE2
- prostaglandin E2
- AA
- acetic acid
- VV
- void volume
- MI
- micturition interval
- MP
- micturition pressure
- SD
- Sprague-Dawley
- CL-316243
- 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate.
- Received February 21, 2011.
- Accepted April 25, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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