Urologic Diseases Research Updates
Prostate Enlargement with Bladder Overactivity Associated with Decreased Big Potassium Channel Activity
Big potassium (BK) channels—otherwise known as large conductance calcium- and voltage-activated potassium channels—are cell membrane signaling proteins involved in regulating muscle contractions. A recent study funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) indicates a relationship between BK channel activity in the bladder detrusor—the thin layer of muscle in the bladder wall that contracts to expel urine—and detrusor overactivity (DO) related to prostate enlargement.
The prostate gland surrounds the urethra. When the prostate enlarges with benign prostatic hyperplasia (BPH), it constricts the urethra, obstructs urine flow during bladder emptying, and causes the bladder to retain urine. To compensate for decreased urethral diameter, the detrusor thickens to more forcefully expel urine. As a consequence, some men develop a condition called overactive bladder (OAB) in which the detrusor contracts as the bladder fills. These abnormal contractions, called DO, cause urinary urgency, the sensation of needing to urinate right away, and urinary frequency, the need to urinate more often.
The researchers wanted to find out if increased detrusor contractions in patients with BPH-induced OAB are related to altered BK channel activity. Using a rabbit model to simulate the effects of BPH-induced urethral obstruction, the researchers surgically induced partial bladder outlet obstruction (PBOO), significantly increasing detrusor thickness and frequency of urination. They then measured contractions and BK channel protein content in detrusor tissue samples. Compared with controls, the amount of detrusor BK protein in the PBOO group decreased while spontaneous detrusor contractions increased.
A decrease in BK channel expression was also seen in bladder tissue taken from men with BPH and DO. BK channel activity in bladder samples from men with BPH but without DO was comparable to samples from men without BPH. However, among samples from men with BPH, those from men who also had DO contained significantly less BK channel protein than tissues from men without DO. In lab experiments, samples from men with DO and BPH had significantly more spontaneous contractions.
“These findings in BPH patients with DO, as well as in the animal model for PBOO, suggest that loss of BK channel expression leads to DO,” wrote Samuel Chacko, D.V.M., Ph.D., director of basic urological research, University of Pennsylvania School of Medicine, and co-authors in their report, which appeared in the June 2010 issue of American Journal of Physiology-Renal Physiology.
To determine if the relationship between PBOO and BK channel downregulation was causal, the researchers measured the level of phosphorylation of myosin light chain (MLC20), a component of the protein myosin that serves as the molecular motor for muscle contraction. In laboratory experiments with cultured detrusor cells, they found that blocking the cells’ BK channel expression increased MLC20 phosphorylation—a mechanism by which myosin function is turned on or off.
Increased MLC20 phosphorylation through depletion of BK channel function contributes to enhanced detrusor muscle contraction and DO, the authors concluded. The study helps clarify the complex physiology of bladder muscle contraction and BPH-related symptoms and provides avenues for future exploration of better preventive and treatment strategies.
About 50 percent of men in their 50s have BPH. Between 26 and 46 percent of men will have BPH-related moderate to severe lower urinary tract symptoms between the ages of 40 and 79. Despite their high prevalence, benign diseases of the prostate are poorly understood and can be difficult to treat.
To learn more about NIDDK-supported prostate research, see the NIDDK Prostate Strategic Plan, available at www2.niddk.nih.gov/Research/ScientificAreas/Urology.
The National Kidney and Urologic Diseases Information Clearinghouse, part of the NIDDK, has fact sheets and booklets about prostate problems. For more information or to obtain free copies, visit www.urologic.niddk.nih.gov.
NIH Publication No. 11–5743