Potential Mechanisms of Action of Superselective α1-Adrenoceptor Antagonists

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Abstract
This paper reviews the role of alpha(1)-adrenoceptors (ARs) in the aetiology of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). alpha(1)-ARs have been demonstrated to be present and functionally active in the human prostate where the alpha(1A)-AR subtype is involved in the contraction of smooth muscle resulting in dynamic obstruction and related voiding symptoms. Recently there is increasing evidence that extra-prostatic alpha(1)-ARs may also contribute to the development of LUTS/BPH. It appears that alpha(1)-ARs are also present in the human detrusor where the alpha(1D)-AR subtype predominates and potentially plays a role in storage symptoms. This is supported by data from the rat indicating a shift in alpha(1)-AR subtype expression from alpha(1A) to alpha(1D )following surgical obstruction. Furthermore, facilitatory alpha(1)-ARs have been detected in peripheral ganglia of animals where activation of these receptors induced bladder contractions and related storage symptoms. Recent research has also detected alpha(1)-ARs in the human spinal cord with a predominance of the alpha(1D)-AR subtype. Animal studies suggest that alpha(1)-ARs in the spinal cord induce bladder contractions by activation of parasympathetic neurons. It may be concluded that voiding symptoms may be related to alpha(1A)-AR mediated smooth muscle contraction in the prostate inducing the dynamic component of obstruction. Storage symptoms may be due to bladder wall hypertrophy secondary to obstruction and/or directly to detrusor instability mediated by alpha(1D)-ARs in the detrusor smooth muscle. alpha(1)-ARs in the spinal cord and/or peripheral ganglia may however also be involved. Since there may be an increase in vascular alpha(1B)-AR subtype expression with ageing it is suggested that blockade of this receptor should be avoided in elderly patients with LUTS/BPH, with the objective of minimising interference with blood pressure regulation. Treatment with superselective alpha(1A)/alpha(1D)-AR-antagonists such as tamsulosin may be indicated to reduce obstruction and both voiding and storage symptoms with minimal risk of cardiovascular side effects, thus it may be considered a first-line medical treatment option in men with LUTS suggestive of BPH.

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