Benign prostatic hyperplasia (BPH) develops in one out of four men. In excess of $1 billion is spent to relieve bothersome symptoms of BPH due to an overactive bladder (OAB). These symptoms may include urgency, frequency, nocturia and urge incontinence. Symptoms can be relieved by local anesthetics and minimally invasive procedures that blunt sensory input from the bladder and urethra yet fail to un-obstruct. Using the partial urethral ligation model in rodents, investigators postulate that OAB may originate from changes in muscle and nerves in the lower urinary tract. Obstructed (OBS) rats exhibit urinary frequency and detrusor overactivity temporally correlated to the development of afferent hypertrophy, an enhanced spinal reflex, and a rise in nerve growth factor (NGF). Immunity to NGF prevents both neural plasticity and OAB. Therefore, NGF acting as a cytokine is thought to participate in these events, NGF's ability to influence afferent excitability is thought to derive, in part, from altering Na conductances, which in turn depends on Na channel isoform expression. Data suggests that afferents from OBS rats exhibit decreased immunohistochemical (IHC) staining for the Nay1.8 isoform. This Na alpha subunit gives rise to tetrodotoxin resistant (TTX-R) sodium (Na) currents in C-fiber afferents. Moreover, an antisense (AS) but not mismatch oligodeoxynucleotide (ODN) against this isoform reduces OAB. We postulate that in OBS rats 1) increased afferent excitability exists, 2) OAB and afferent excitability are due to an alteration in sodium (Na) conductance, 3) knockdown of Na channel isoform(s) using intrathecal AS ODN reduces afferent hyperexcitability and OAB, and 4) NGF participates in the genesis of enhanced afferent excitability, alterations in Na channel function and/or isoform expression. These hypotheses will be tested by determining whether obstruction compared to sham surgery 1) alters electrical properties of labeled afferent bladder neurons based on patch clamp analysis, 2) changes expression of Na channel isoforms using IHC and Western blotting, and 3) whether alterations in excitability or protein expression are reversible with deligation and normalization of voiding behavior. The ability of NGF to orchestrate these events will be elucidated by noting if NGF immunity or trkA antagonists prevent changes in electrical properties and protein expression in OBS compared to controls. Insight into these cellular processes could be exploited to develop afferent based treatments for OAB employing pharmacologic, molecular or gene based strategies.
| Batts, Timothy W; Klausner, Adam P; Jin, Zhicheng et al. (2006) Increased expression of heat shock protein 20 and decreased contractile stress in obstructed rat bladder. J Urol 176:1679-84 |
