Partial urethral obstruction (PUO), a common urologic pathology in men and children, can be associated with detrusor overactivity (DO), but the exact molecular mechanisms responsible for the altered contractile phenotypes have not been fully elucidated.
Our study is the first to determine by direct patch-clamp current measurement that PUO, to recapitulate many of the pathological characteristics of benign prostatic hyperplasia (BPH), is associated with an approximate 5-fold decrease in bladder myocyte Maxi-K channel activity. Similar to others we report a 40% decrease in Maxi-K α subunit expression which correlates with the observed decrease in Maxi-K activity, but uniquely as much as a 5-fold increase in expression of Maxi-K β subunit which we hypothesize may be a compensatory response. Based upon our previous finding of increased detrusor overactivity (DO) in similar male PUO rats, we suggest the Maxi-K channel as a therapeutic target to treat BPH associated lower urinary tract symptoms (LUTS).
OBJECTIVES: To examine the effect of partial urethral obstruction (PUO) on bladder smooth muscle outward potassium current and the contribution of the large-conductance calcium-activated potassium (Maxi-K, BKCa) channel to this activity in smooth muscle cells isolated from bladders of sham-operated and PUO male rats using whole-cell patch clamp recording techniques. To determine the effect of PUO on the expression of the Maxi-K channel α and β1 subunits and in vitro detrusor contractility.
MATERIALS AND METHODS: Twenty adult male Sprague-Dawley rats were divided equally into two groups and subjected to surgical ligation of the urethra (PUO) or sham surgery (SHAM). After 2 weeks, the detrusors from PUO and SHAM rats were used for molecular analyses (mRNA and protein quantification of Maxi-K subunits) or organ bath contractility studies, or myocytes were isolated for conventional whole-cell patch clamp analyses.
RESULTS: PUO increased bladder mass 2.5-fold and detrusor strips exhibited a more tonic-type contraction and increased contractility compared with controls (SHAM). Iberiotoxin (300 nM) sensitive Maxi-K channel current comprised about 40% of the outward whole-cell current in SHAM bladders but only about 8% in PUO bladders. Expression of the α subunit of the Maxi-K channel was significantly decreased ∼40% while the expression of the β1 subunit was increased ∼2-fold at the mRNA level. The increase in β1 expression was confirmed by Western blotting.
CONCLUSIONS: Our findings show that obstruction of the rat bladder is associated with decreased Maxi-K channel activity of bladder smooth muscle cells, determined via direct current measurement. Increased expression of the β1 subunit points to a compensatory reaction to decreased Maxi-K channel activity. Maxi-K channel openers or gene therapy may therefore provide therapeutic benefit for the overactive bladder.
Written by:
Aydin M, Wang HZ, Zhang X, Chua R, Downing K, Melman A, Disanto ME. Are you the author?
Department of Urology, Albert Einstein College of Medicine, New York Department of Surgery/Division of Urology, Cooper Medical School of Rowan University, Camden, NJ, USA.
Reference: BJU Int. 2012 Oct;110(8 Pt B):E402-8.
doi: 10.1111/j.1464-410X.2012.11137.x
PubMed Abstract
PMID: 22520450
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