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Nat Med. 2000 Dec;6(12):1388-94.
Overexpression of the alpha1B-adrenergic receptor causes apoptotic neurodegeneration: multiple system atrophy.

Zuscik MJ, Sands S, Ross SA, Waugh DJ, Gaivin RJ, Morilak D, Perez DM.

Department of Molecular Cardiology NB50, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.

Progress toward elucidating the function of alpha1B-adrenergic receptors (alpha1BARs) in the central nervous system has been constrained by a lack of agonists and antagonists with adequate alpha1B-specificity. We have obviated this constraint by generating transgenic mice engineered to overexpress either wild-type or constitutively active alpha1BARs in tissues that normally express the receptor, including the brain. All transgenic lines showed granulovacular neurodegeneration, beginning in alpha1B-expressing domains of the brain and progressing with age to encompass all areas. The degeneration was apoptotic and did not occur in non-transgenic mice. Correspondingly, transgenic mice showed an age-progressive hindlimb disorder that was parkinsonian-like, as demonstrated by rescue of the dysfunction by 3, 4-dihydroxyphenylalanine and considerable dopaminergic-neuronal degeneration in the substantia nigra. Transgenic mice also had a grand mal seizure disorder accompanied by a corresponding dysplasia and neurodegeneration of the cerebral cortex. Both behavioral phenotypes (locomotor impairment and seizure) could be partially rescued with the alpha1AR antagonist terazosin, indicating that alpha1AR signaling participated directly in the pathology. Our results indicate that overstimulation of alpha1BAR leads to apoptotic neurodegeneration with a corresponding multiple system atrophy indicative of Shy-Drager syndrome, a disease whose etiology is unknown.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11100125&dopt=Abstract




J Urol. 2001 Jan;165(1):38-41.
alpha-Blockade improves symptoms suggestive of bladder outlet obstruction but fails to relieve it.

Rossi C, Kortmann BB, Sonke GS, Floratos DL, Kiemeney LA, Wijkstra H, de la ROSETTE JJ.

Department of Urology, University Medical Centre Nijmegen, Nijmegen, The Netherlands.

PURPOSE: We investigated the effect of the alpha-blockers alfuzosin, terazosin and tamsulosin on urodynamic parameters after 6 months of therapy. MATERIALS AND METHODS: Between February 1992 and June 1998, 163 patients with lower urinary tract symptoms suggestive of bladder outlet obstruction were treated with alfuzosin (60), terazosin (66) and tamsulosin (37). Patients were evaluated with urodynamic studies, including pressure flow analysis, before treatment and after 6 months of therapy. Initially, all patients were also assessed by the International Prostate Symptom Score questionnaire and measurement of urinary flow rate. RESULTS: The majority of patients had no clear improvement in obstructive parameters, regardless of the alpha-blocker used, as urethral resistance factor and detrusor pressure maximum flow rate decreased by only 4 cm. H2O. There was a clear subjective and statistically significant decrease in International Prostate Symptom Score and quality of life scores of 6 and 2 points, respectively. No relevant statistical difference was noted among the effects of the 3 alpha-blockers on relieving symptoms or improving urodynamic parameters of obstruction. CONCLUSIONS: The alpha-blockers are effective for treating symptoms suggestive of bladder outlet obstruction in patients presenting with lower urinary tract symptoms but not for treating the obstruction.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11125359&dopt=Abstract




Expert Opin Investig Drugs. 1999 Dec;8(12):2073-2094.
Subtype selective alpha1-adrenoceptor antagonists for the treatment of benign prostatic hyperplasia.

Forray C, Noble SA.

Synaptic Pharmaceutical Corporation, Paramus, New Jersey 07652, USA.

Benign prostatic hyperplasia (BPH) is highly prevalent in the male population beyond the age of 60. Impairment of urinary flow due to prostate enlargement gives rise to symptoms of 'prostatism' that have a detrimental impact on the quality of life. The current trend in the management of symptomatic BPH favours pharmacotherapy as a first line option, while the number of surgical procedures being performed has experienced a steady decline during the last ten years. Among the pharmacological treatments, the use of alpha1-adrenoceptor blockers has demonstrated to be an effective treatment option for BPH. These agents reduce the adrenergic tone to the prostate and increase urinary flow, with a concomitant reduction of lower urinary tract symptoms. The alpha1-blockers currently approved include compounds such as alfuzosin, terazosin and doxazosin, originally developed for the treatment of hypertension, and more recently tamsulosin, an alpha1-subtype selective drug. The blockade of alpha1-adrenoceptors present in vascular smooth muscle is largely responsible for the most prominent side effects of current drugs, which can be severe and require patients dose titration. The limitation imposed by side effects naturally raises the possibility that complete blockade of prostatic alpha1 receptors is not attained at the maximum tolerated dose. The extensive efforts by the pharmaceutical industry towards the development of uroselective alpha1-blockers, is the subject of this review. Advances in the molecular cloning of genes encoding three alpha1-adrenoceptors led to the identification of the alpha1A-subtype as the predominant receptor responsible for the contraction of prostate smooth muscle. In preclinical animal models, selective alpha1A-antagonists have consistently been found to have minimal cardiovascular effects, thus providing a pharmacological rationale for uroselectivity. It has also become apparent, however, that uroselectivity can emerge in a poorly understood manner from the pharmacodynamic properties of compounds without alpha1A-subtype selectivity. Clinical experience with tamsulosin, an alpha1A/alpha1D selective drug, has failed to demonstrate a significant improvement in efficacy beyond that demonstrated for non-subtype selective alpha1-blockers, and gives support to the notion that alpha1A-selective antagonists might achieve greater efficacy for the treatment of BPH. Given the demonstrated uroselectivity of alpha1A-selective antagonists in preclinical models, it is anticipated that third generation alpha1-blockers will exhibit improved urinary flow efficacy and be better tolerated than tamsulosin. The extent to which the improvement in urinary flow will translate to the relief of symptoms of prostatism, however, remains to be demonstrated in randomised placebo-controlled clinical trials of alpha1A-selective antagonists.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11139841&dopt=Abstract [PubMed - as supplied by publisher]





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