Chapple, Christopher R.; (1990) The importance of neural factors in the presentation and treatment of prostatic obstruction. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Symptomatic bladder outlet obstruction due to prostatic enlargement is a common problem in urological practice. Hyperactive detrusor function, "detrusor instability", occurs in up to 80% of patients presenting with prostatic obstruction and in most cases it resolves post-operatively when the obstruction has been relieved. This dysfunction is generally regarded as a modern concept but, in 1786, John Hunter recognised the complex nature of prostatic obstruction and reported: “The disease of the bladder arising from obstruction alone, is increased irritability, and its consequences, by which the bladder becomes quick in its action and thick and strong in its coats." Animal models have confirmed the relationship between obstruction and instability. Several hypotheses have been proposed to explain this link and include; (1) post-junctional hypersensitivity possibly related to denervation, (2) altered adrenoceptor function, (3) afferent nerve dysfunction, (4) an imbalance of peptide neuro-transmitters, and (5) a primary or acquired myogenic deficit. The principal motor control of the intraprostatic musculature is mediated by the sympathetic nervous system; however, the mechanism of action and specific localisation of prostatic adrenoceptors and the importance of non-adrenergic neurotransmission in man is poorly understood. A study of patients with symptomatic prostatic obstruction was undertaken to investigate the influence of neural pathways in determining the pathogenesis and clinical presentation of prostatic and detrusor dysfunction. Sixty-two patients were investigated using modern urodynamic techniques and sub-divided into three groups; control, stable obstructed and unstable obstructed. Biopsies of prostate, bladder neck and bladder muscle were taken at the time of surgery, and pharmacological, autoradiographic and histochemical studies performed. The prostate, bladder and bladder neck were found to be innervated by a complex network of noradrenaline-, acetylcholine-, neuropeptide-, and amine-containing nerves. Separate quantitative analyses of these neurons were carried out and corrections applied to compensate for muscle hypertrophy and hyperplasia. The histological findings were complemented wherever possible by biochemical assay of neuro transmitters. There was a significant reduction in the acetylcholinesterase positive innervation of the obstructed bladder compared with control, which was most marked in tissue from patients with detrusor instability. A similar reduction in the non-adrenergic, non-cholinergic sensorimotor neurotransmitters was evident. Biochemical changes within the detrusor included an increase in noradrenaline content and a decrease in the putative sensory neurotransmitter substance P. Detrusor muscle strips from obstructed patients showed increased contraction in response to acetylcholine, suggesting that denervation hypersensitivity might contribute to the pathogenesis of post-obstructive detrusor instability. Normal detrusor muscle relaxed in response to noradrenaline. In contrast, detrusor muscle from unstable obstructed patients contracted; a response most marked in detrusor muscle from patients who had presented in acute retention. In vitro prostatic muscle-strip experiments confirmed that contraction of prostatic muscle is produced by adrenoceptor stimulation. Radioligand binding assays endorsed the results of these experiments by demonstrating a clear excess of α1 receptors over α2 receptors in histologically normal and adenomatous prostate. Auto-radiography showed the precise localization of the two types of adrenoceptor and confirmed the predominance of α1 receptors within prostatic musculature. The complexity and potential importance of the autonomic nervous system in the pathogenesis and symptomatic expression of prostate-mediated bladder outflow obstruction, is demonstrated by this work. Marked changes in the innervation of both the prostate and bladder accompany obstructive benign enlargement of the prostate. The characterisation and localisation of the prostatic adrenoceptor is of considerable relevance since it validates the therapeutic use of selective prostatic α1 blockade in the clinical management of obstructed patients. Preliminary immunohistochemical studies of bladder, bladder neck and prostate are presented, which provide an histological basis for further functional investigative studies.

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