Faculty Bibliography

PURPOSE: To evaluate the contractile effect of endothelin-1 (ET-1) on prostatic urethral pressure and to characterize the effect of the selective ETA receptor antagonist PD155080 on ET-1 mediated prostatic urethral pressure. MATERIALS AND METHODS: The effect of intravenous ET-1 administration on canine urethral pressure was determined in the presence and absence of PD155080. The affinity of PD155080 for endothelin-mediated contraction was determined using antagonist dissociation studies. Saturation and competition binding studies were performed using [125I] ET-1 in both human and canine prostate. RESULTS: ET-1 bolus injection elicited shallow and prolonged increases the prostatic urethral pressure. Pretreatment with PD155080 totally abolished the urethral contractile response to ET-1. Specific [125I] ET-1 binding was saturable and of high affinity. Two ET receptor subtypes (ETA receptor, ETB receptor) have been identified in human prostate. The ratio of ETA to ETB receptors was approximately 1.5:1 in both human and canine prostates. Isometric tension studies revealed that PD155080 shifted the ET-1 dose-response curves to the right and exhibited no effect on the ETB receptor selective agonist sarafotoxin dose-response curves. CONCLUSION: ET-1 mediates prostate smooth muscle tone and may play a role in the pathophysiology and treatment of benign prostatic hyperplasia (BPH)

OBJECTIVES: In an effort to avoid allogeneic transfusions, many patients scheduled for radical retropubic prostatectomy (RRP) participate in preoperative autologous donation (PAD) programs. Yet, PAD programs are costly, time-consuming, and not without risks. Perioperative administration of recombinant human erythropoietin (Epoetin alfa) also has been shown to reduce patients exposure to allogeneic transfusion. This study sought to compare the costs and transfusion rates associated with either PAD or perioperative Epoetin alfa in patients undergoing RRP. METHODS: The study population consisted of 120 men randomized to one of two treatment groups. Patients in group 1 donated up to 3 U of autologous blood preoperatively, provided that their hematocrit (HCT) was 33% or higher. Patients in group 2 received 600 IU/kg of Epoetin alfa on days -14 and -7 preoperatively, provided that their HCT was 46% or lower. RESULTS: Overall, 107 (89%) of 120 patients underwent RRP. In group 1, 5 (9.6%) of 52 patients received a total of 12 U of allogeneic blood (0.23 U/patient). In group 2, 5 (9.6%) of 52 patients received a total of 10 U of allogeneic blood (0.19 U/patient). Three patients in group 1 but no patients in group 2 experienced an adverse event. The average costs related to PAD and pharmacologic administration per patient were $540 in group 1 and $657 in group 2. Participation in PAD required an average of 5 hours more per patient compared with Epoetin alfa administration. CONCLUSIONS: Preoperative Epoetin alfa therapy is safe, well tolerated, and equally effective as PAD in reducing allogeneic blood transfusion requirements. Epoetin alfa therapy also is comparable in cost to PAD and offers patients greater convenience and less of a time commitment

BACKGROUND: Although quantitative morphometry of benign prostatic hyperplasia (BPH) has been described, there is a paucity of information on the morphometry of the nonhyperplastic prostate. This study determines the histologic composition of prostates obtained from males, ages 2 days to 40 years, in order to provide insights into the morphometry of the 'normal' gland. METHODS: The histologic composition of 45 prostates was obtained from autopsies of males with age groups stratified to reflect the neonatal, childhood, peripubertal, adolescent, and young adult periods. Double immunoenzymatic staining and computer image analysis were used to determine the mean area densities of the smooth muscle (SM), connective tissue (CT), glandular epithelium (E), and lumen (L). RESULTS: A progressive decrease in SM area density throughout childhood, prepuberty, and puberty was seen. The density of SM significantly increased following puberty and throughout adolescence and early adulthood. There was a concomitant increase in CT from the neonatal period throughout childhood, prepuberty, and puberty, and a decrease after puberty and throughout adolescence and early adulthood. Since the changes in SM and CT were inversely related, the percent contribution of the stromal compartment to the total gland remained constant. CONCLUSIONS: The stromal to epithelial ratio remains constant from birth to age 40 in nonhyperplastic glands and is similar to the ratios in asymptomatic and symptomatic BPH tissues

PURPOSE: We determined if total prostate volume, transition zone volume or transition zone index is correlated with the severity of clinical benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: A total of 93 men 52 to 85 years old, who were referred to a urology outpatient facility for treatment of clinical BPH, elevated serum prostate specific antigen or abnormal digital rectal examination, underwent measurement of total prostate and transition zone volume at transrectal ultrasonography. All men were requested to undergo uroflowmetry and complete the American Urological Association (AUA) symptom score. RESULTS: The pairwise correlations between AUA symptom score, versus total prostate and transition zone volumes and transition zone index were not statistically or clinically significant. A weak pairwise relationship was observed between peak flow rate versus total prostate volume (r2 = 0.160), transition zone volume (r2 = 0.156) and transition zone index (r2 = 0.147). The pairwise relationships between AUA symptom scores versus all prostate volumes were not statistically significant for subjects with mild (score 8 or less) or moderate to severe (score more than 8) symptoms. CONCLUSIONS: Total prostate and transition zone volumes, and transition zone index are not directly related to AUA symptom score and only weakly related to peak flow rate. These findings provide further evidence that the total prostate, total BPH and relative BPH volumes are not useful determinants of the severity of clinical BPH

OBJECTIVES: To determine if men with normal peak urinary flow rates (PFR) and prostatism respond to terazosin. METHODS: Forty-one men over the age of 50 years with an American Urological Association (AUA) symptom score greater than 8, postvoid residual urine volume (PVR) less than 300 mL, and no clinical or biochemical evidence of prostate cancer were treated with terazosin independent of the baseline PFR. The effect of terazosin on the AUA symptom score and PFR were compared for subjects with a PFR of 15 mL/s or less (group I) and those with a PFR greater than 15 mL/s (group II). RESULTS: The baseline age, AUA symptom score, prostate volume, and PVR were not significantly different between the two groups. The mean changes in AUA symptom score were -45.0% and -49.5% for groups I and II, respectively. The mean changes in PFR were 7.0% and -26.6% for groups I and II, respectively. CONCLUSIONS: The effect of terazosin on AUA symptom score is independent of baseline PFR, indicating that the mechanism of action of terazosin is not exclusively mediated by reduction of bladder outlet obstruction. Randomized controlled studies are required to confirm this provocative observation

PURPOSE: To localize the mRNAs and receptor binding sites for the alpha 1a/A, alpha 1b/B and alpha 1d/D- adrenoceptor (AR) subtypes in the rat, monkey and human urinary bladder and prostate. MATERIALS AND METHODS: alpha 1-AR mRNAs were localized on slide mounted tissue sections by in situ hybridization using [35S]-labeled subtype specific oligonucleotide probes. alpha 1-AR receptor binding sites were localized on slide mounted tissue sections by competitive displacement of [3H]-prazosin using subtype selective ligands. RESULTS: Only the alpha 1a-AR subtype mRNA was discernible by in situ hybridization. The alpha 1a-AR mRNA was localized in all smooth muscle areas of the rat, monkey and human urinary bladder and prostate. High levels of alpha 1a mRNA were detected in bladder dome and bladder base urothelium. Competitive displacement studies using the alpha 1A-AR selective ligand SNAP 5272 revealed that the alpha 1A-AR represented over 80% of the total alpha 1-AR in monkey bladder and prostate. In general, localization of the alpha 1A-AR corresponded to the alpha 1a-AR mRNA localization, that is, receptor protein was localized to smooth muscle areas of the bladder dome, trigone and base and prostate. One notable exception was the bladder urothelium, which contained high levels of alpha 1a-AR mRNA, but undetectable levels of alpha 1A-AR protein. The alpha 1a-AR mRNA appeared to be transcribed but not translated in bladder urothelium. CONCLUSIONS: The alpha 1A-AR represents the major subtype in the smooth muscle of rat, monkey and human urinary systems. Selective alpha 1A-AR agents are therefore potentially useful in the treatment of multiple urinary smooth muscle related disorders

BACKGROUND. alpha(1)-adrenoceptor antagonists (blockers) are now commonly used in the treatment of the symptoms of lower urinary tract obstruction. Originally phenoxybenzamine, a non-selective antagonist at both alpha(1)- and alpha(2)-adrenoceptors, was used by Marco Caine. In an attempt to minimize side effects, selective alpha(1)-antagonists, e.g, prazosin, were subsequently developed. More recently, agents such as alfuzosin, doxazosin, terazosin, and tamsulosin have been introduced and claims of ''uroselectivity'' and ''prostate'' selectivity have emerged. METHODS. This review attempts to put these claims into perspective and represents a comprehensive analysis of all pre-clinical and clinical data including several papers from the Japanese literature. An attempt is made to define what is meant by selectivity at various levels including the test tube, in the laboratory animal and, most importantly, in the clinical context of the whole patient. CONCLUSIONS. The conclusions are interpreted within the context of the subdivision of the alpha(1)-adrenoceptor into alpha(1A), alpha(1B), and alpha(1D) subtypes. (C) 1997 Wiley-Liss, Inc

PURPOSE: To characterize the functional effect of endothelin-1 (ET1) and endothelin-3 (ET3), immunohistochemically localize ET1-like immunoreactivity, and measure the tissue levels of immunoreactive endothelin (irET) in canine genitourinary (GU) tissues. MATERIALS AND METHODS: Canine GU tissues were characterized by measuring ET1 levels using a RIA, immunohistochemical staining of ET1 and isometric tension studies. RESULTS: Immunoreactive endothelin was present, to varying degrees, in the vas deferens, ureter, prostate, bladder and urethra. Functionally, ET1 demonstrated the typical concentration response characteristics in the canine bladder base, bladder body, and prostate. The maximal tension (Emax) measured following ET1 challenge was approximately 20-fold greater in the bladder body (0.67 +/- 0.21 g/mm.2) and bladder base (0.48 +/- 0.18 g/mm.2) as compared to the prostate 0.04 +/- 0.001 g/mm.2 The Emax of ET3 in the bladder body (0.31 +/- 0.12 g/mm.2) and bladder base (0.19 +/- 0.08 g/mm.2) was significantly lower than the corresponding Emax of ET1. No measurable contractile response was elicited by ET3 in the canine prostate. Immunohistochemical staining localized the ET-like immunoreactivity to the glandular epithelium of the prostate and the transitional epithelium of the bladder. CONCLUSIONS: Endothelins are ubiquitous in the canine lower GU tract with predominant localization to the epithelial elements. Endothelins are also functionally active in canine GU tissues, but the specific role of endothelins in the physiology and pathophysiology of GU tissues requires further investigation

OBJECTIVES: To evaluate changes in the smooth muscle and connective tissue development in the obstructed and normal fetal bladder. METHODS: The smooth muscle and connective tissue composition of 19 fetal urinary bladders, including those of 9 fetuses with anatomic obstruction and 10 controls free of urologic disease, were analyzed by light microscopy and computer-assisted color image analysis. RESULTS: The bladder wall thickness was markedly increased in obstructed fetuses throughout gestation as compared with that in controls. The disparity in bladder wall thickness increased rapidly during gestation. The percent area density of smooth muscle and connective tissue as well as the ratio of smooth muscle to connective tissue remained the same in the obstructed and normal control fetal bladders. CONCLUSIONS: Although bladder outlet obstruction is associated with a marked increase in bladder wall thickness, the percent of smooth muscle and connective tissue comprising the mural histology remains relatively constant as compared with that of normal fetal controls. This study suggests that bladder outlet obstruction in the fetus is not associated with excess collagen deposition but rather with an increased amount of bladder with normal cellular content and a concomitant increase in smooth muscle development