Fourth International Consultation On Incontinence (ICI) - Cell Biology Committee Highlights

Main Category: Urology / Nephrology
Article Date: 24 Jul 2008 - 2:00 PDT

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Chris Fry, MD, Committee Chair

PARIS, FRANCE (UroToday.com) - Dr. Fry began the second presentation by noting the rapid advances in our understanding of the role of the urothelium and suburothelium in bladder function and symptomatology since the last consultation. This committee addressed 8 separate areas in their report. Dr. Fry began by describing the barrier function of the urothelium and noted this may be disrupted in pathological states. Bacterial invasion can result in sequestering of bacteria for months, despite treatment. Dr. Fry stated that alterations in this barrier function can produce release of neurotransmitters such as ATP into the local environment. Several molecules have been identified which can be released by stretch of the urothelium including ATP, acetylcholine, nitric oxide and others. Any or all of these molecules may play a role in bladder sensation.

Dr. Fry highlighted an elegant study by Hawthorn et al (2000) in which carbachol-induced contraction of isolated muscle strips was measured in intact strips and denuded (urothelium removed) strips. The presence of urothelium was shown to have a negative inotropic effect. This suggests that an intact urothelium may assist in bladder relaxation while damage to the urothelium may promote overactivity.

Dr. Fry briefly reviewed our current knowledge regarding the calcium dependent and calcium independent contractile mechanisms involved in detrusor smooth muscle contraction. A continuing area of interest involves the Rho-kinase calcium independent pathway and it was noted that this is an area of ongoing interest with respect to drug targeting. With respect to receptors, the importance of the M3 was reaffirmed, although the M2 subtype may become more important in pathological states such as outlet obstruction. Beta3 receptor agonists continue to show promise in treating OAB, but Dr. Fry questioned the significance of purinergic receptors such as P2X1.

Next, Dr. Fry outlined causes of spontaneous activity which is thought to lead to detrusor overactivity and/or OAB; these causes include neurogenic, myogenic, urotheliogenic and autonomous. The urotheliogenic etiology was supported by a study showing different electrical responses in intact and denuded muscle strips in response to UTP and Carbachol. Another study was shown highlighting the synergy between muscarinic and adrenergic responses in the bladder trigone.

Dr. Fry next turned to the committee's findings regarding the cell biology of the urethra. The role of alpha1-a receptors in contractile response and nitric oxide in relation was described. NO induced relaxation may become defective in certain disease states such as diabetes and outlet obstruction. Again, there were interesting findings related to estrogen which showed that lack of estrogen can lead to decreased resting urethral tone, however, estrogen supplementation reduces urethral closure pressures. Dr. Fry then presented data on decreasing rhabdosphincter muscle density with aging and how myoblast implants are an emerging potential treat for urethral dysfunction. He also reviewed the role of neurotransmitters in Onuf's nucleus, particularly serotonin and norepinephrine and how pharmacomodulation may be useful in treating SUI through this mechanism.

The committee reviewed our current understanding of the molecular pathways of the major neurotransmitters involved in lower urinary tract physiology including the muscarinic, adrenergic and nitric oxide pathways.

Dr. Fry next addressed the biomechanical properties of the bladder and noted the difference between cellular dysfunction and biomaterial failure in disorders of detrusor contraction. Greater collagen concentration is noted in several pathological states including outlet obstruction, detrusor overactivity and stress incontinence. There is an increased ratio of type III: type I collagen in poorly compliant bladders. Dr. Fry stated that these biomechanical changes may be more responsible for the clinical findings in disease states than cellular changes.

Dr. Fry briefly reviewed the anatomy and physiology of the lower GI tract with attention to the rectum and anal sphincter complex. The rectum and external sphincter responds to noradrenaline while the internal sphincter relaxes with cholinergic stimulation.

Dr. Fry presented interesting findings in the next section on molecular targets in the lower urinary tract including studies on endothelin receptors, TRPA ion channels and glutamate receptor antagonists. One of the more interesting topics here was the discussion involving the endoplasmic reticulum stress response which may be triggered by hypoxia or mechanical stress. This stress response leads to a number of downstream changes that cause apoptosis of detrusor myocytes. This, in turn, may lead to the changes we see in bladder outlet obstruction bladders or aging bladders. This stress response may be attenuated by treatment with 4-PBA, a low molecular weight fatty acid.

Finally, Dr. Fry highlighted the recent work in tissue engineering and clinical applications in lower urinary tract disease. The newest findings include the importance of omental wraps of autologous tissue-engineered bladder substitutes. Moon et al (2008) has shown that "conditioning" culture grown bladder cells by progressive mechanical stretching improves contractile function. Lastly, Dr. Fry discussed the emerging treatment with urethral myoblast implants and how they may be used in the treatment of urethral stricture disease and stress incontinence.

Moderated by William C. de Groat, Ph.D., Professor, and L. Denis, MD, at the Fourth International Consultation on Incontinence (ICI) - July 5 - 8, 2008. Palais des Congres, Paris, France.

Written by William Jaffe, MD, a Contributing Editor with UroToday.

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