Identification of a dihydropyridine as a potent alpha1a adrenoceptor-selective antagonist that inhibits phenylephrine-induced contraction of the human prostate.

A number of novel dihydropyridine derivatives based upon 1, 4-dihydro-3-(methoxycarbonyl)-2, 6-dimethyl-4-(4-nitrophenyl)-5-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (4) have been synthesized and tested at cloned human alpha adrenoceptors as well as the rat L-type calcium channel. Within this compound series, 5-(aminocarbonyl)-1,4-dihydro-2, 6-dimethyl-4-(4-nitrophenyl)-3-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (19) displayed good binding affinity and selectivity for the alpha1a adrenoceptor (pKi = 8.73) and potently inhibited (pA2 = 9.23) phenylephrine-induced contraction of the human prostate.

Nitric oxide synthase in dog urethra: a histochemical and pharmacological analysis.

1. To examine the presence of nitric oxide synthase (NOS) activity in female dog urethra, pharmacological experiments were performed using electrical field stimulation (EFS), guanethidine, atropine, NG-nitro-L-arginine methyl ester and L-arginine, NOS immunohistochemistry using specific anti-NOS antibody, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase staining were also performed. 2. EFS caused frequency-dependent contractions in all urethral preparations, but in the presence of guanethidine and atropine, EFS caused significant relaxation in the proximal urethra and was without effect on the distal urethra. 3. In the presence of guanethidine, atropine, and NG-nitro-L-arginine methyl ester, small contractions to EFS were re-established in the proximal urethra, but not in the distal urethra. NG-nitro-D-arginine methyl ester had no such effect. 4. In the presence of guanethidine, atropine, and NG-nitro-L-arginine methyl ester, the addition of L-arginine, restored the EFS-elicited relaxant responses previously seen with guanethidine and atropine alone in the proximal urethra (at 30 Hz; 12.89 +/- 5.27% to -2.44 +/- 4.43%, mean +/- s.e., P < 0.05). D-Arginine had no such effect. 5. In the distal urethra, the addition of NG-nitro-L-arginine methyl ester and then L-arginine had no effect on responses to EFS in preparations treated with guanethidine and atropine. 6. Sodium nitroprusside caused relaxation in both the proximal and distal urethra. The relaxant responses per cm2 cross sectional area in the proximal and distal urethra were 1.23 +/- 0.29, and 2.02 +/- 0.54 g cm-2 cross sectional area (mean +/- s.e.), respectively: there was no significant difference between them. 7. Both NOS and NADPH diaphorase-positive neurones were present in dog urethra, the densities of both being higher in the proximal urethra than in the distal urethra. 8. These results show that female dog urethra possesses NOS nerves and that endogenous NO may play a role in relaxation in the proximal but not the distal urethra.

The stereospecificity of LY253352 for alpha 1-adrenoceptor binding sites in the brain and prostate.

1. The stereospecificity of the enantiomers of LY253352, a potent and selective alpha 1-adrenoceptor antagonist, were studied in the human prostate and canine brain using radioligand receptor binding methods. 2. The mean equilibrium dissociation constant (KD) in the canine brain and human prostatic adenoma was 84.4 pM and 65.4 pM, respectively. 3. The alpha 1-adrenoceptor density in the canine brain was approximately eight fold greater than in the human prostatic adenoma. 4. The mean Ki values of (-)-LY253352 and (+)-LY253352 in the prostate were 0.19 nM and 5.79 nM, respectively. 5. The mean Ki values of (-)-LY253352 and (+)-LY253352 in the brain were 0.29 nM and 34.7 nM, respectively. 6. This study indicates that the stereochemical specificity of the optical isomers of LY253352 is a manifestation of differential affinities of the enantiomers for alpha 1-adrenoceptor binding sites. 7. The differential affinities of (+)-LY253352 in the brain and prostate are suggestive of subtle unique properties of adrenoceptor binding sites in these tissues.

Mitogenic activation of human prostate-derived fibromuscular stromal cells by bradykinin.

Biologically active kinin peptides are released from precursor kininogens by kallikreins. Kinins act on kinin receptors to mediate diverse biological functions including smooth muscle contraction, inflammation, pain and mitogenicity. All components of the kallikrein-kinin system exist in human male genital secretions suggesting that these molecules participate in physiological and pathophysiological genitourinary function. The objective of this study was to assess the consequences of kinin action on prostate cells. Primary cultures of prostate secretory epithelial (PE) and prostate fibromuscular stromal (PS) cells were established from human prostate tissue. Transcripts encoding both the human B1 and B2 bradykinin receptor subtypes were detected in human prostate transition-zone tissue and in cultured cells by RT-PCR. In receptor binding assays, the B1 subtype predominated on PE cell membranes and the B2 subtype predominated on PS cell membranes. In PS cells, but not in PE cells, BK induced significant inositol phosphate accumulation and [3H]-thymidine uptake. These responses were mediated through the B2 receptor subtype. The use of signal transduction inhibitors indicated that mitogenic activation by BK occurred through both protein kinase C (PKC) and protein tyrosine kinase dependent mechanisms. PMA (phorbol 12-myristate 13-acetate) produced maximal [3H]-thymidine uptake by PS cells, resulted in cell elongation and caused the alpha-actin fibres present in PS smooth muscle cells to became organized into parallel arrays along the length of the elongated cells. In summary, the prostate contains a functional kallikrein-kinin system, which could be significant in physiological and pathophysiological prostate function.

Muscarinic cholinergic and alpha 2-adrenergic receptors in the epithelium and muscularis of the human ileum.

The aim of this study was to characterize the binding and functional properties of muscarinic cholinergic (MCh) and alpha 2-adrenergic receptors in the human ileum to provide insight into pharmacologic strategies for managing urinary and fecal incontinence after bladder and rectal replacement with intestinal segments. MCh and alpha 2-adrenergic binding sites were characterized in the epithelium and muscularis of eight human ileal segments with 3H-N-methylscopolamine and 3H-rauwolscine, respectively. The dissociation constant for 3H-N-methylscopolamine in the epithelium and muscularis was 0.32 +/- 0.07 nmol/L and 0.45 +/- 0.10 nmol/L, respectively (p = 0.32). The MCh receptor content was approximately eightfold greater in the muscularis compared with the epithelium (p = 0.008). The dissociation constant for 3H-rauwolscine in the muscularis and epithelium was 2.55 +/- 0.42 nmol/L and 2.03 +/- 0.19 nmol/L, respectively (p = 0.29). The alpha 2-adrenoceptor density was twofold greater in the epithelium compared with the muscularis (p = 0.05). Noncumulative concentration-response experiments were performed with carbachol, an MCh agonist, and UK-14304, a selective alpha 2-adrenergic agonist. The epithelium did not contract in the presence of high concentrations of carbachol and UK-14304. The muscularis preparations were responsive only to carbachol. The muscularis contains primarily MCh receptors mediating smooth muscle contraction. The alpha 2-adrenoceptors are localized primarily to the epithelium and may regulate water secretion in the intestine. The distribution and functional properties of ileal MCh and alpha 2-adrenergic receptors provide a theoretic basis for the treatment of incontinence after bladder and rectal replacement with intestinal segments.

Long-term efficacy and safety of terazosin in patients with benign prostatic hyperplasia. Terazosin Research Group.

OBJECTIVES: To evaluate long-term efficacy and safety of terazosin, a selective alpha 1 blocker, in the treatment of benign prostatic hyperplasia (BPH). METHODS: This was a long-term (42 months), open-label, multicenter study with patients evaluated at 1- to 6-month intervals. Twenty-three outpatient clinics throughout the United States and Canada participated in the study. A total of 494 men with symptomatic BPH, lacking absolute indications for surgery, were enrolled in this study; 298 were transferred into the study from randomized, placebo-controlled studies of terazosin and 196 had no prior terazosin therapy. Terazosin was given starting at 1 mg/d and titrated upward until symptoms were relieved or a maximum dose of 20 mg/d was achieved, whichever came first. RESULTS: Peak urinary flow rates at all visits were significantly higher than baseline values, with mean improvements ranging from 1.0 to 4.0 mL/s. At 3 months, 40% of patients exhibited a 30% or greater improvement in peak flow rate; this improvement was maintained through 42 months. Boyarsky symptom scores improved significantly at all visits; mean total score improved by at least 4.0 points (40%) at all visits beyond 3 months. The most common adverse events resulting in premature termination from the study were dizziness (6.7%), asthenia (3.8%), and somnolence (2.0%). CONCLUSIONS: This study suggests that terazosin is well tolerated and effective in longterm treatment of patients with BPH.

Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Tamsulosin Investigator Group.

OBJECTIVES: To evaluate the efficacy and safety of two once-daily doses of tamsulosin, the first selective alpha1A-antagonist studied in clinical trials. METHODS: Patients with benign prostatic hyperplasia (BPH) were randomized to receive either tamsulosin (0.4 and 0.8 mg/day) or placebo (n = 756). Primary efficacy parameters were improvement in the total American Urological Association (AUA) symptom score and peak urinary flow (Qmax). Secondary efficacy parameters were improvement in measurements at individual double-blind visits corresponding to the primary efficacy parameters; percentage of patients with a 3-mL/s increase in Qmax; total AUA irritative, obstructive, and bother scores; individual AUA symptom scores; total, irritative, obstructive, and individual Boyarsky symptom scores; average urinary flow rate and other uroflowmetric parameters; and investigator's global assessment. RESULTS: Statistically significant improvements in all efficacy parameters were observed in tamsulosin-treated compared with placebo-treated patients. Additionally, the 0.4-mg/day dose demonstrated a rapid onset of action (4 to 8 hours) based on Qmax after the first dose of double-blind medication. A review of the safety parameters demonstrated excellent tolerance at 1 week after the initial 0.4-mg/day dose and continued tolerance during the additional 12 weeks of 0.4- and 0.8-mg/day dosing. The incidence of positive orthostatic test results in the tamsulosin groups was comparable to that observed in the placebo group. Adverse events were comparable in the 0.4-mg/day tamsulosin and placebo groups and were somewhat higher in the 0.8-mg/day tamsulosin group. CONCLUSIONS: Tamsulosin was effective, safe, and well tolerated in the target BPH population at both the 0.4- and 0.8-mg/day dose levels, without the blood pressure-lowering effects typical of nonselective alpha-adrenergic antagonists.

Long-term evaluation of tamsulosin in benign prostatic hyperplasia: placebo-controlled, double-blind extension of phase III trial. Tamsulosin Investigator Group.

OBJECTIVES: To evaluate the long-term efficacy and safety of once-daily tamsulosin (0.4 and 0.8 mg), a unique selective alpha1A-adrenoceptor antagonist in patients with benign prostatic hyperplasia (BPH). METHODS: This trial extended a 13-week, Phase III multicenter placebo-controlled, double-blind outpatient trial for an additional 40 weeks. Of 618 patients, 418 (68%) continued into the extension phase on the same double-blind medication and dose. The primary efficacy parameters were total American Urological Association (AUA) symptom score and maximum urinary flow (Qmax). RESULTS: The mean changes in AUA symptom score from baseline to end point were statistically significant in all groups (P <0.001). Significant improvements were observed in Qmax for both tamsulosin groups but not for the placebo group. The statistically significant improvements from baseline in efficacy parameters observed for each tamsulosin group at the end of the 13-week Phase III trial were maintained during the long-term extension phase. Tamsulosin at both dosages was well tolerated as maintenance therapy. Clinically significant orthostatic hypotension was not observed. Vital sign changes in either hypertensive or normotensive patients were not clinically significantly different across the three groups. CONCLUSIONS: Tamsulosin once-daily at 0.4 or 0.8 mg was shown to be effective, safe, and well tolerated in the target BPH population during long-term use.

Comparison of AUA symptom index in unselected males and females between fifty-five and seventy-nine years of age.

A symptom index for benign prostatic hyperplasia (BPH) was recently developed and validated by the Multidisciplinary Measurements Committee of the American Urologic Association, Inc. (AUA). The AUA symptom index ascertains the severity of seven nonspecific urinary symptoms associated with clinical BPH. The objective of the present study was to determine the influence of aging and gender on the AUA symptom index. Approximately 750 individuals attended a health fair at Froedtert Memorial Lutheran Hospital which included exhibits related to surgical and medical disease processes affecting the aging population. A nurse specialist randomly invited male and female attendees to complete the self-administered AUA symptom index and two additional inquiries related to age and gender. A total of 101 males and 96 females between fifty-five and seventy-nine years of age completed the AUA symptom index. The mean age of the males and females completing the AUA symptom index was 69.3 +/- 0.5 years and 68.2 +/- 0.6 years, respectively (p = 0.14). The mean AUA symptom scores in the male and female groups were 6.7 +/- 0.5 and 7.5 +/- 0.6, respectively. The difference between the mean AUA symptom scores in the male and female groups was not statistically significant (p = 0.35). The differences between AUA symptom scores were also not significantly different between males and females in five consecutive advancing-age groups between fifty-five and seventy-nine years of age. The percentage of males with mild, moderate, and severe symptoms was 64 percent, 32 percent, and 4 percent, respectively. The percentage of females with mild, moderate, and severe symptoms was 61 percent, 35 percent, and 4 percent, respectively. The present study suggests that prostatism-like symptoms are a manifestation of aging, and that the AUA symptom index is not BPH-specific.

Relationship between prostatic epithelial volume and serum prostate-specific antigen levels.

OBJECTIVES: The present study was designed to determine the relationship between serum prostate-specific antigen (PSA) levels and prostatic epithelial volumes. METHODS: Forty-two men between the ages of 50 and 79 years of age with either an abnormal digital rectal examination (DRE) or a serum PSA level > 4 ng/dL underwent transrectal ultrasonography (TRUS) and ultrasound-guided random systematic biopsy of the prostate. The volumes of the peripheral zone (PZ) and transition zone (TZ) were calculated, assuming that the total prostate and TZ are ellipsoidal structures. Six random systematic biopsies were directed into the PZ and four random systematic biopsies were directed into the TZ under ultrasound guidance. Among the 42 patients undergoing prostatic biopsy, adenocarcinoma of the prostate was identified in 21 (50%). Tissue sections obtained from the biopsy specimens of the subjects without histologic evidence of prostate cancer were stained with Mallory trichrome stain, and the percentage area density of epithelium in the biopsy cores was determined using computer-assisted color image analysis. The relationships between serum PSA and total, PZ, and TZ epithelial volumes, and serum PSA and total, PZ, and TZ prostatic volumes were determined using regression analysis. RESULTS: The difference between the mean percentage epithelial density of the PZ (17.79 +/- 1.40%) and TZ (10.32 +/- 0.82%) was statistically significant (p < 0.0001). The mean volumes of epithelium in the PZ and TZ were 4.25 +/- 0.47 cc and 3.39 +/- 0.45 cc, respectively. The p and r2 values for the relationship between serum PSA and total prostatic volume were 0.016 and 0.260, respectively. Statistically significant correlations were also observed between serum PSA levels and TZ epithelial volumes (p = 0.0009; r2 = 0.449) and serum PSA levels and TZ volumes (p = 0.007; r2 = 0.329). Statistically significant correlations were not observed between serum PSA levels and the following parameters: PZ volume, PZ epithelial volume, and total prostatic epithelial volume. CONCLUSIONS: Although the PZ contains a significantly greater area density and absolute volume of epithelium than the TZ, the serum PSA level is most strongly correlated only with the volume of epithelium in the TZ.

Perianastomotic injection of autologous fat at the time of radical retropubic prostatectomy.

OBJECTIVES: The present study represents the first attempt to improve urinary continence following radical prostatectomy (RP) by perianastomotic injection of autologous fat at the time of the surgical procedure. METHODS: A total of 15 consecutive men with clinically localized carcinoma of the prostate underwent nerve-sparing radical retropubic prostatectomy (RRP) with perianastomotic injection of autologous fat. The autologous fat was obtained using a liposuction cannula connected to a power aspirator. The fat was harvested from the adipose tissue immediately adjacent to the lower midline incision. After the pelvic floor musculature was perforated, a total of 30 mL of autologous fat was injected through a 12 gauge angiocatheter under cystoscopic guidance. RESULTS: There were no complications resulting from the harvesting or injection of the autologous fat. All of the patients were evaluated for 6 months. Of the 15 patients, 12 (80%) achieved total urinary control within 6 months. The average time required to achieve total urinary continence was 89 days. None of the patients experienced total or nocturnal incontinence. Of the 3 patients with stress urinary incontinence (SUI), 2 required 2 small pads per day and 1 required 3 pads per day. Only 1 patient reported that the level of bother resulting from the incontinence was severe. CONCLUSIONS: The preliminary experiences with the perianastomotic fat injection at the time of RRP are encouraging. Determining the ultimate safety and effectiveness of this technique requires longer follow-up in expanded series of patients.

Preoperative recombinant human erythropoietin injection versus preoperative autologous blood donation in patients undergoing radical retropubic prostatectomy.

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.

Effects of nitric oxide on human and canine prostates.

OBJECTIVES: To determine whether nitric oxide (NO) is a mediator of prostatic smooth muscle activity. METHODS: Pharmacologic experiments using electrical field stimulation (EFS) were performed on strips of human and canine prostate. RESULTS: EFS alone elicited frequency-dependent contractions in preparations of human and canine prostates. The greatest contractile activity was achieved at 30 Hz. In the presence of 10(-5) M guanethidine (GUA) and 2 x 10(-6) M atropine (ATR), EFS elicited relaxation of canine prostate strips relative to baseline tension. A weak biphasic response consisting of initial relaxation and subsequent contraction relative to baseline tension was observed in the human prostate strips exposed to similar conditions. The smooth muscle activity observed in the presence of GUA plus ATR was attributed to nonadrenergic, noncholinergic (NANC) nerve transmission. 10(-4) M L-NG-nitroarginine methylester (NAME) significantly increased EFS-elicited NANC smooth muscle activity both in human and canine prostates. L-arginine, 10(-2) M, reversed the effect of L-NAME in human and canine prostates. Sodium nitroprusside, 10(-4) M, a donor of NO, caused relaxation of both human and canine prostates. The mean magnitude of the relaxant response/cross-sectional area in human prostate (2.64 +/- 0.4 g/cm2) was significantly greater than in the canine prostate (1.09 +/- 0.17 g/cm2) (P < 0.005). CONCLUSIONS: These results provide compelling evidence that NO plays a role in mediating contractile function of human and canine prostates.

Laboratory assessment of terazosin and alpha-1 blockade in prostatic hyperplasia.

The alpha-1 adrenergic innervation of the human prostate has been studied using radioligand receptor binding methods and in vitro contractile experiments. The density of alpha-1 adrenergic binding sites is of the same order of magnitude as alpha-2 adrenergic and muscarinic-cholinergic (MCh) receptors in the human prostate adenoma. The contractile response of human prostate adenomas to selective alpha-1, alpha-2, and MCh agonists indicated that smooth muscle contraction of the human prostate is mediated by alpha-1 adrenoceptors. The selective affinities of terazosin for alpha-1 and alpha-2 binding sites were determined using competitive displacement assays. Terazosin was shown to have a four hundred-fold greater affinity for alpha-1 binding sites. The concentration of terazosin-inhibiting phenylephrine-induced contractions suggested that terazosin inhibits prostate smooth muscle contraction via alpha-1 adrenoceptors.

Effect of terazosin on prostatism in men with normal and abnormal peak urinary flow rates.

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.

Comparison of the cellular composition of benign prostatic hyperplasia in Chinese and Caucasian-American men.

OBJECTIVES: To compare the cellular composition of benign prostatic hyperplasia (BPH) in Chinese and Caucasian-American men. METHODS: Surgical specimens of the prostate were obtained from 9 Chinese and 8 Caucasian-American men undergoing cystoprostatectomy for invasive transitional cell carcinoma. The mean ages of the Chinese and Caucasian-American men were 66.8 years and 66.4 years, respectively (P = 0.94). The mean prostate weight of the Chinese and Caucasian-American men was 53.4 g and 32.1 g, respectively (P = 0.01). Double immunoenzymatic staining with antibodies against actin and prostatic acid phosphatase and computer-assisted color image analysis were performed on whole-mount tissue sections. The percent area density of smooth muscle (SM), connective tissue (CT), epithelium (E), and epithelial lumen (L) were obtained by analyzing 30 fields from each specimen. RESULTS: The mean percent area density of SM, CT, E, and L in the prostate of Chinese men was 32%, 9.1%, 10.8%, and 48.5%, respectively. The mean percent area density of SM, CT, E, and L in the prostate of Caucasian-American men was 52.5%, 27.9%, 12.8%, and 7%, respectively. Overall, the prostates of Chinese men contained significantly more glandular lumen and significantly less SM and CT. CONCLUSIONS: The present study demonstrates that the cellular composition of BPH in the prostates of Caucasian-American and Chinese men is different. These cellular differences may account for previously observed differences in the incidence of clinical BPH.

A prospective randomized comparison of transurethral resection to visual laser ablation of the prostate for the treatment of benign prostatic hyperplasia.

OBJECTIVES: Transurethral resection of the prostate (TURP) represents the accepted standard of surgical therapy for the management of symptomatic bladder outlet obstruction due to benign prostatic hyperplasia (BPH). However, this is a major operative procedure associated with significant perioperative morbidity. Visual laser ablation of the prostate (VLAP) utilizing a neodymium:yttrium-aluminum-garnet laser represents a new technologic approach to the surgical management of BPH. We compared the relative safety and efficacy of these two surgical approaches in a prospective, randomized trial. METHODS: At 6 investigational sites in the United States, 115 men with symptomatic BPH more than 50 years of age and not in retention, were randomly assigned to undergo either TURP (59 patients) of VLAP (56 patients). VLAP patients received a mean of 10,200 J of energy delivered in a mean of 5.5 intraprostate laser applications. At preoperative baseline, 3 months, 6 months, and 1 year postoperatively, all patients underwent clinical evaluations, including ultrasonic prostatic volume determination, standardized American Urological Association (AUA)-6 symptom score, peak urine flow, postvoid residual urine volume, and quality-of-life assessment. RESULTS: Compared to TURP, the VLAP procedure required less time (23.4 versus 45.2 minutes; P < 0.01) and shorter hospitalization (1.8 versus 3.1 days, P < 0.01). VLAP was associated with a significantly lower rate of serious treatment-related complications compared to TURP (10.7% versus 35.6%; P < 0.01). Only One (2.2%) patient undergoing VLAP experienced a greater than 2.2 g/dL decrease in hemoglobin compared to 40% of TURP patients (P = 0.01). No patient in the VLAP group required blood transfusion compared with 3.4% of those undergoing TURP. Of the 115 patients, clinical outcomes measured at 1 year showed a mean improvement in AUA-6 symptom scores of -9.0 for VLAP compared with -13.3 for TURP (P < 0.04), mean increase in peak urinary flow rate of 5.3 cc/s for VLAP compared with 7.0 cc/s for TURP (P = 0.27), and mean decrease in postvoid residual urine volume of -55.4 cc for VLAP compared with -138.8 cc for TURP (P < 0.01). At 1 year, 78.2% of patients undergoing VLAP indicated that their quality of life was improved compared with 93.0% of patients undergoing TURP (P = 0.03). When compared with TURP, treatment of BPH with VLAP is associated with less hemoglobin decrease, a lower likelihood of serious complication, and requires less procedure time and a shorter hospital stay. Through a 1-year follow-up, VLAP produced significant improvement over baseline in objective and subjective outcome measures. However, for 1-year improvement in AUA-6 symptom score, postvoid residual urine volume, and quality of life, VLAP was less effective than TURP. CONCLUSIONS: In this initial study in the United States, with relatively low-energy laser applications, VLAP did not result in as complete a removal of prostatic tissue as did TURP. Considering the lower morbidity, shorter procedure and hospitalization times, and the degree of effectiveness that was achieved even at the low-energy doses used in this study, VLAP appears to be a viable and safe alternative to standard TURP.

Effects of alpha-adrenergic agonist on neobladder water and electrolyte transport.

OBJECTIVE: Nocturnal urinary incontinence and nocturia are problematic for patients with continent neobladders. Clonidine, an alpha 2-adrenergic agonist, increases water absorption across rabbit ileum; human intestine contains a substantial density of alpha 2-adrenergic receptors. We studied the effect of neobladder clonidine instillation and catheterization (to reduce urine-bowel contact time) on nocturnal water and electrolyte reabsorption. METHODS: A total of 8 patients with Indiana neobladders constructed after radical cystectomy were studied at a mean of 11.3 months postoperatively under standardized diet and fluid intake. RESULTS: Topical clonidine or catheterization failed to alter nocturnal urine volume, free-water clearance, or absolute excretions of electrolytes in Indiana neobladders; however, the absolute excretion of urine urea nitrogen and osmoles was significantly increased in the catheterized urine collections compared with the baseline urine collections (paired t-test, p = 0.0022 and 0.0091, respectively). CONCLUSIONS: Bowel comprising neobladders loses its capacity to significantly alter urinary electrolyte composition by prolonged contact, which may explain the rarity of significant acid-base disturbances in patients with continent neobladders. Unfortunately, topical clonidine does not diminish nocturnal urine volumes, but increased excretion of urea and osmoles with overnight neobladder catheterization may prove beneficial in patients who suffer azotemia or hyperosmolarity.

Characterization and localization of nitric oxide synthase in the human prostate.

OBJECTIVES: To characterize nitric oxide synthase (NOS), which catalyzes nitric oxide (NO) production, in the human prostate using biochemical and immunohistochemical techniques. METHODS: NOS catalytic assay and NOS immunohistochemistry were performed on histologically verified nonmalignant prostate tissue obtained from the peripheral and transition zones of seven radical prostatectomy specimens. RESULTS: Biochemical analysis revealed NOS activity in the human prostate, with a greater amount in the peripheral zone than in the transition zone (P < 0.01). In both prostate zones, NOS was immunohistochemically localized to nerve fibers and ganglia coursing throughout the smooth musculature of the stroma and to subepithelial nerve plexuses. NOS immunoreactivity was also localized to glandular epithelium. CONCLUSIONS: The presence, activity, and distribution of NOS were described in two regions of the human prostate. The present evidence implicates NO in the automatic innervation and physiology of the human prostate. It is proposed that NO may modulate smooth muscle tone and secretory functions in the human prostate, although functional studies are needed to support these hypotheses.

Smooth muscle development in the obstructed fetal bladder.

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.