| THE INTERACTION BETWEEN ADRENERGIC AND CHOLINERGIC SYSTEMS IN REGULATING PROSTATE SMOOTH MUSCLE TONE AND CONTRACTILITY.
Professor C H Fry, B Blake-James Institute of Urology & Nephrology, UCL London |
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Final summary report, November 2006
Purpose of the project: Growth of the prostate gland restricts the outflow from the urinary bladder, thus making it more difficult to pass urine, and also is associated with a number of bladder disorders, such as detrusor overactivity. The muscular component of the prostate is influenced by a branch of the autonomic nervous system through the release of a neurotransmitter, noradrenaline, such that an increase of activity will increase prostate tone and exacerbate the above symptoms. This is recognised therapeutically through the development of drugs that reduce the ability of noradrenaline to bind to the muscular fraction. The other branch of the autonomic nervous system – the parasympathetic branch – has been intensively studied in its action on the bladder, but its influence on the prostate has received little attention. This is important as there are many drugs (antimuscarinic agents) to reduce bladder overactivity, but their action on the prostate has received scant attention. The aim of this project was to study the effect of muscarinic and antimuscarinic agents on human prostate tissue to determine if they exert any action on this tissue. We used ‘chips’ of tissue obtained from men undergoing partial removal their prostate to relieve the symptoms associated with prostate growth.
Study findings: The significant functional observation was that muscarinic agents alone exerted little effect on prostate tissue, however they greatly enhanced and sensitised the contractile response to sympathetic agents (i.e. those agents that mimic the effect of noradrenaline). We found also that this synergistic effect was not found in all prostate chip samples, but was especially marked in those obtained from the part of the prostate that most closely surrounds the urethra, that carries urine from the bladder. Thus a combination of these two classes of transmitters would greatly increase the muscular tone of the prostate. It was also possible to identify the particular sub-class of receptors that respond to the muscarinic agonists to cause this synergy. This was done by functional experiments to block the synergistic effect, and also by molecular means to identify this sub-type of receptor to the muscular fraction of the prostate gland. Some initial experiments were carried out to identify the actual mechanisms of this synergy and implicated the necessity of an interaction between different cell types in the prostate tissue.
Implications of the study: The clinical implications of this study are very significant. Antimuscarinic agents are the mainstay of treatment for many types of overactive bladder, but their use in men with prostate growth is not widespread. This is because it was assumed that they would have no direct effect on the prostate and might cause retention of urine in the bladder. However, this study has indicated that these drugs will have a beneficial effect on the prostate to reduce tone and so relieve associated bladder symptoms. We carried out a parallel meta-analysis of clinical date and found that antimuscarinic agents were not associated with an increased incidence of urinary retention. We would propose therefore that antimuscarinic agents would have a beneficial effect on alleviating the symptoms associated with prostate obstruction of the lower urinary tract, especially when used in combination with current therapies.
CH Fry, B Blake-James - November 2006.
Final report dated 27 November 2006
Project 2004/10