european urology 50 (2006) 635 642 available at www.sciencedirect.com journal homepage: www.europeanurology.com Editorial 50th Anniversary Alpha antagonists from initial concept to routine clinical practice Christopher Chapple * Department of Urology, Royal Hallamshire Hospital, Sheffield, United Kingdom It is a great honour and a pleasure for me to participate in this celebration of the 50th volume of European Urology by commenting on this landmark review paper by Marco Caine, who was the pioneer of pharmacotherapy for lower urinary tract symptoms (LUTS) suggestive of benign prostatic outlet obstruction (BOO; previously referred to as symptomatic benign prostatic hyperplasia [BPH]), which are so common in ageing men. This paper contains a number of comments that remain equally correct 29 yr later in 2006!. At the present stage our understanding of this field is relatively simplistic and does not take into account the close interdependence and integration that exists between the sympathetic and parasympathetic and perhaps also somatic nervous systems. There is steadily increasing evidence of both peripheral and central interactions between these systems [1]. When Professor Caine wrote this review paper, the emphasis was on voiding dysfunction, as shown by the title disorders of micturition and, indeed, still has been until recently. We now realise that the most bothersome symptoms are those affecting storage and the emphasis of treatment is shifting to encompass both storage and voiding symptoms [2]. At the time Professor Caine wrote this innovative paper and certainly until 15 yr ago, surgery and watchful waiting were the only widely accepted management options for BPH/LUTS and benign prostatic obstruction (BPO). There has been an enormous decline in the popularity of surgery and it is now clearly apparent that medication is the most frequently used treatment modality for BPH/ LUTS. Arguably, this has therefore been the most major change in urologic clinical practice in the last decade. Operative intervention is increasingly considered rather radical from the patient s perspective and not surprisingly many patients feel reluctant to undergo surgery and prefer a less invasive intervention such as medical therapy, before contemplating surgery. Although absolute indications for surgery still exist, in the last decade the number of patients undergoing operations for BPH has decreased by about 60% across Europe. This trend has been encouraged not only by increased patient awareness of the availability of effective contemporary pharmacotherapy, but has also been encouraged by an increased understanding of the complications of surgery, in particular that it can be associated with significant morbidity, such as irreversible incontinence and loss of sexual function with subsequent impairment of a patient s quality of life. Professor Caine and his coworkers were the first to emphasise the importance of the a-adrenergic innervation of the bladder outflow tract and to carry out initial characterisation of these in man. The success of this work is evident if one considers that it is standard knowledge in urology that prostatic smooth muscle tone is dependent on the release of noradrenaline (NA) from adrenergic nerves, thereby stimulating a 1 -adrenoceptors (ARs) on smooth muscle of the prostatic stroma, bladder neck, and urethra. * Tel. +44 114 2712559; Fax: +44 114 2798318. E-mail address: c.r.chapple@sheffield.ac.uk. 0302-2838/$ see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2006.07.005
636 european urology 50 (2006) 635 642 Although storage symptoms are clearly associated with bladder dysfunction, often assumed to be secondary to outflow obstruction, there is no convincing evidence for a direct correlation between the size of the prostate, BOO, and LUTS [2]. Prostatic and urethral a-ars are considered to mediate the dynamic component of obstruction and a 1 -AR antagonists improve both LUTS and flow rate in patients with BPH [3]. Conversely, a direct relationship between the amount of prostatic smooth muscle and dynamic obstruction (as assessed by the response to a 1 -AR blockade) has been demonstrated [4]; therefore, it is logical to assume that these receptors mediate some of the symptoms. On the other hand, many patients who have undergone prostatectomy, which should relieve obstruction, still experience persistent storage symptoms [5]; clearly, mechanisms outside the prostate involving a 1 -ARs may be involved in the pathogenesis of storage symptoms. LUTS can be caused by a number of factors and along with the prostate, there are several possible sites of action of a-ar antagonists: Prostatic stroma-smooth musculature Detrusor, trigone, urethral smooth muscle Detrusor, trigone, urethral urothelium Ganglia Spinal or supraspinal structures within the central nervous system It has become clear that the effects of a-blockers on relieving BOO are moderate at best [6], and this effect alone is insufficient to explain the improvement seen in storage symptoms. Therefore, newer concepts have been advanced, with the suggestion that a 1 -adrenoceptors in the bladder or spinal cord are possible mediators of a-blocker-induced symptom relief [7,8]. Clearly this remains hypothetical and the specific mechanisms by which such effects could occur need to be defined. Although it is now clear that a-ar antagonist effects on BOO are mediated predominantly if not exclusively by a 1A - ARs in the bladder neck and prostate, it remains speculative that clinical effects on the bladder and spinal cord, if they occur, are via an action on a 1D - ARs. This needs to be verified by future research. Despite the observations noted above, it must be concluded that just as suggested by Caine 29 yr ago, the principal motor control of the prostate is still, in 2006, considered to be via an action on a 1 -ARs localised predominantly within the stromal compartment of the prostate. Although Caine introduced the nonselective a 1/2 -antagonist phenoxybenzamine, its use was discontinued because of toxicity and sideeffect issues; nevertheless, he was involved in the initial work using the first a 1 -antagonist prazosin. The legacy of Caine s work is that a 1 -AR antagonists are now well established as the most common treatment for BPH/LUTS. Indeed, systematic analysis of placebo-controlled studies shows that commonly used a 1 -AR antagonists (doxazosin, terazosin, alfuzosin, tamsulosin) are similarly effective and statistically significantly superior to placebo in improving urinary flow and reducing symptoms [3]. References [1] Caine M. The importance of adrenergic receptors in disorders of micturition. Eur Urol 1977;3:1 6. [2] Chapple CR, Roehrborn CG. A shifted paradigm for the further understanding, evaluation and treatment of lower urinary tract symptoms in men: focus on the bladder. Eur Urol 2006;49:651 9. [3] Chapple C, Artibani W, Berges R, et al. New medical developments in the management of LUTS in adult men. In: McConnell J, Abrams P, Denis L, Khoury S, Roehrborn, C, editors. Male Lower Urinary Tract Dysfunction. Jersey, UK: Health Publication Ltd; 2006. p. 143 94. ISBN: 0-9546956-6-6. [4] Shapiro E, Hartano V, Lepor H. The response to alpha blockade in benign prostatic hyperplasia is related to the percent area density of prostate smooth muscle. Prostate 1992;21:297 307. [5] Hald T, et al. In: Abrams P, Khoury S, Wein A, editors. Pathophysiology of the urinary bladder in obstruction and aging. In: Incontinence. First International Consultation on Incontinence. United Kingdom: Health Publication, Plymbridge Distributors; 1999. p. 131 78. [6] Kortmann BBM, Floratos DL, Kiemeney LALM, Wijkstra H, de la Rosette JJMCH. Urodynamic effects of alphaadrenoceptor blockers: a review of clinical trials. Urology 2003;62:1 9. [7] Michel MC. Potential role of a 1 -adrenoceptor subtypes in the aetiology of LUTS. Eur Urol Suppl 2002;1(9):5 13. [8] Roehrborn CG, Schwinn DA. a 1 -Adrenergic receptors and their inhibitors in lower urinary tract symptoms and benign prostatic hyperplasia. J Urol 2004;171:1029 35.
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