Maryrose P. Sullivan

Tissue Angiotensin II as a Modulator of Erectile Function. I. Angiotensin Peptide Content, Secretion and Effects in the Corpus Cavernosum

PURPOSE Although Angiotensin II (Ang II) is a major modulator of regional blood flow in the extracavernosal segments of the vascular bed, its role in erectile function is unknown. The corpus cavernosum penis is a modified vascular tissue that contains endothelial and smooth muscle cells. In other segments of the vascular bed, these cell types produce Ang II. Therefore, we explored the presence and function of an Ang II producing paracrine system in the corpus cavernosum. METHODS The angiotensin content of the human corpus cavernosum was measured by radioimmunoassay. The distribution pattern of Ang II containing cells within the corpus cavernosum was assessed by an immunohistochemical technique, and the rate of its secretion was determined by superfusion. The effects of Ang II and its antagonist, losartan, on intracavernosal pressure were determined under in vivo conditions, in anesthetized dogs. RESULTS Human corpus cavernosum contained 1178 +/- 223 (SEM) fmol Ang II, 528 +/- 171 fmol Ang I, 475 +/- 67 fmol des-asp-Ang I, and 1897 +/- 371 fmol des-asp-Ang II/gm. tissue (n = 4). Ang II was found mainly in endothelial cells lining blood vessels and smooth muscle bundles within the corpus cavernosum. Superfused cavernosal tissue secreted immuno-reactive Ang II (Ang II(ir)) at a rate of 57 +/- 36.5 fmol Ang II(ir)/gm. tissue/minute (n = 10). The amount of Ang II released per gram of tissue in an hour was 3-fold greater than the Ang II content/gm. tissue, suggesting a local production of Ang II. Papaverine and prostaglandin E1 suppressed Ang II secretion significantly (p <0.001, p = 0.013). The responsiveness to inhibition was a function of the initial rate of Ang II secretion. Tissue samples with a high rate of secretion were less responsive to the inhibitors than tissue that secreted small amounts of Ang II (n = 6). In anesthetized dogs, intra-cavernosal injection of Ang II terminated spontaneous erections, while losartan increased the intracavernosal pressure in a dose dependent manner up to the mean arterial pressure (n = 4). CONCLUSIONS The corpus cavernosum produces and secretes physiologically relevant amounts of Ang II. The rate of Ang II secretion can be modulated by pharmacologic agents that regulate cytosolic calcium levels and are used clinically to treat erectile dysfunction. Intracavernosal injection of Ang II causes contraction of cavernosal smooth muscle and terminates spontaneous erection in anesthetized dog, while administration of an Ang II receptor antagonist results in smooth muscle relaxation and thus erection.

Correlation of American Urological Association Symptom Index With Obstructive and Nonobstructive Prostatism

The precise role of the American Urological Association (AUA) symptom index in the management of benign prostatic hyperplasia (BPH) is not well established. The AUA symptom index has been recommended only for quantifying the symptoms of BPH but not for its diagnosis. However, to our knowledge the ability to discriminate obstructive from nonobstructive BPH using the AUA symptom index has never been investigated. To establish the relationship between the AUA symptom index and prostatic obstruction 125 men (mean age 67.7 +/- 8.4 years) with voiding dysfunction presumably related to BPH were analyzed. Patients were given the AUA symptom questionnaire, following which video urodynamic studies were done, including micturitional urethral pressure profilometry for specifically diagnosing outlet obstruction. The patients were divided into 2 groups: group 1-78 with primary BPH dysfunction and group 2-47 with prostatism of ambiguous etiology. The mean AUA symptom index in group 1 (15.5 +/- 7.1) was not statistically different from that in group 2 (14.8 +/- 7.9). In both groups the mean AUA symptom index in the patients with obstruction (15.3 +/- 7.2 for group 1 and 13.9 +/- 7.9 for group 2) was not statistically different from that in the nonobstructed group (17.0 +/- 5.4 and 16.1 +/- 7.9, respectively). Of the severely symptomatic patients 22% did not have obstruction whereas all mildly symptomatic patients did. No significant correlations were found between the severity of obstruction and the AUA symptom index in either group. These observations indicate that the AUA symptom index cannot discriminate obstructed from nonobstructed BPH cases, not all severely symptomatic BPH patients will have outlet obstruction, a significant proportion of mildly symptomatic BPH patients can have outlet obstruction and voiding dysfunctions in elderly men, regardless of the etiology, produce similar symptoms.

URODYNAMIC CHARACTERIZATION OF NONOBSTRUCTIVE VOIDING DYSFUNCTION IN SYMPTOMATIC ELDERLY MEN

PURPOSE The pathogenesis of lower urinary tract symptoms in men without bladder outlet obstruction has not been well characterized. Therefore, we defined the urodynamic abnormalities associated with symptomatic nonobstructive voiding dysfunction, and determined the relationship between age and type of dysfunction. MATERIALS AND METHODS Video urodynamic studies of symptomatic men without outlet obstruction were examined. The criterion for a normal bladder outlet was a pressure gradient across the prostatic urethra of 5 cm. water or less in the absence of distal stricture. A maximum isometric contraction pressure less than 60 cm. water was regarded as impaired detrusor contractility. Detrusor instability was defined as involuntary detrusor contractions during filling or the inability to suppress a detrusor contraction after initiation of flow. Patients were categorized into 4 groups based on the urodynamic findings. RESULTS Of 193 men (mean age 69.6+/-10.5 years) 40.9% had detrusor instability (group 1), 31.1% had impaired contractility (group 2), 10.8% had detrusor instability and impaired contractility (group 3), and 17.1% were urodynamically normal (group 4). Average patient age was significantly lower in group 4 than all other groups. Bladder capacity was lowest in group 1, and group 3 had the lowest voiding efficiency. Maximum flow rate, bladder compliance and symptom scores were not different among the 4 groups. The prevalence of detrusor instability with and without impaired contractility increased, while the proportion of patients without urodynamic abnormalities decreased with age. Bladder contractility did not correlate with age. CONCLUSIONS The nonobstructed patient population comprises several groups that are functionally distinct while symptomatically similar. Thus, treatment of nonobstructed cases based on symptoms may lead to inappropriate pharmacological therapy and unsuccessful clinical outcomes.

Detrusor Contractility and Compliance Characteristics in Adult Male Patients With Obstructive and Nonobstructive Voiding Dysfunction

PURPOSE To understand better the contractility and compliance characteristics of the detrusor in patients with varying degrees of outlet obstruction, we analyzed urodynamic studies in elderly men with obstructive and nonobstructive voiding dysfunction. MATERIALS AND METHODS All patients were evaluated with video urodynamics, including cystometry, isometric tests, voiding profilometry and post-void residual measurement. Bladder compliance, detrusor contractility, detrusor reserve, detrusor instability and the severity of outlet obstruction were determined in each patient. Patients were stratified into 4 groups: urodynamically normal, detrusor instability, outlet obstruction and outlet obstruction with detrusor instability. RESULTS A significant correlation was found between the maximum isometric contraction pressure and the severity of obstruction in 168 patients. Maximum isometric contraction pressure was significantly greater in patients with than without obstruction, independent of detrusor instability. Although compliance was not significantly different among the groups, the proportion of patients with poor compliance (less than 30 ml./cm. water) was lowest in the normal group. The detrusor reserve was significantly less in patients with chronic retention (post-void residual more than 200 ml.) than in those with lower post-void residuals. CONCLUSIONS The increase in detrusor contractility with increasing outlet obstruction suggests a compensatory response to obstruction. Furthermore, a decrease in bladder compliance does not appear to be a consistent finding in patients with outlet obstruction, although the proportion of patients with poor compliance is higher in the group with obstruction and/or detrusor instability than in those with normal urodynamic findings. The decrease in detrusor reserve in patients with high post-void residual volumes suggests that the detrusor reserve reflects the degree of detrusor decompensation.

COMBINATION OF SYMPTOM SCORE, FLOW RATE AND PROSTATE VOLUME FOR PREDICTING BLADDER OUTFLOW OBSTRUCTION IN MEN WITH LOWER URINARY TRACT SYMPTOMS

PURPOSE The severity of lower urinary tract symptoms associated with benign prostatic enlargement correlates poorly with bladder outlet obstruction. Since urodynamic studies are presumed to be relatively complex, invasive and not cost-effective, they are not routinely performed by physicians treating men with lower urinary tract symptoms. As a result, a large number of patients are treated for bladder outlet obstruction when in fact obstruction may not be present. Since other noninvasive methods have not been effective for predicting bladder outlet obstruction, we investigated whether a combination of prostate volume, uroflowmetry and the American Urological Association (AUA) symptom index would be reliable for predicting this condition. MATERIALS AND METHODS We prospectively evaluated 204 men with a mean age plus or minus standard deviation of 66.7 +/- 7.5 years who presented with lower urinary tract symptoms. Each patient completed an AUA symptom index questionnaire and underwent uroflowmetry, post-void residual urine volume measurement, pressure flow study and transrectal ultrasound of the prostate to estimate prostatic volume. We constructed receiver operating characteristics curves using various threshold values for maximum urine flow and prostate volume. Threshold values for maximum urine flow and prostate volume were used alone and combined with the AUA symptom index for predicting bladder outlet obstruction. We selected a cutoff value for maximum urine flow of 10 or less ml. per second and prostate volume of 40 gm. or greater, and used these values with an AUA symptom index of greater than 20 to predict bladder outlet obstruction in the group overall. RESULTS Differences in the mean symptom index score in men with and without bladder outlet obstruction were not statistically significant. There was no obstruction in 19%, 28.9% and 35% of those with severe, moderate and mild symptoms, respectively. The selected cutoff values of maximum urine flow, prostate volume and symptom score combined correctly predicted obstruction in all 39 patients. Therefore, our combination of cutoff values proved to be highly accurate for predicting bladder outlet obstruction. Sensitivity, specificity, and positive and negative predictive values were 26%, 100%, 100% and 32%, respectively. CONCLUSIONS Our study showed that combining the AUA symptom index, maximum urine flow and prostate volume reliably predicted bladder outlet obstruction in a small subset of patients only. Although bladder outlet obstruction was correctly predicted by our threshold values of AUA symptom index, maximum urine flow and prostate volume in only 39 men (26%) with obstruction, these patients represent a substantial group in any large urological practice treating male lower urinary tract symptoms.

EFFECT OF RADICAL PROSTATECTOMY ON SENSORY THRESHOLD AND PRESSURE TRANSMISSION

PURPOSE The mechanisms involved in post-radical prostatectomy incontinence remain unclear despite previous anatomical and functional studies. In addition, the factors responsible for the restoration of continence are not well studied. To improve our understanding of the alterations in continence mechanisms, we prospectively investigated the temporal changes in urodynamic parameters after radical prostatectomy. MATERIALS AND METHODS Cystometry, urethral pressure profilometry and posterior urethral sensory threshold measurements were performed in patients undergoing radical prostatectomy. Preoperative pressure transmission was determined by the maximal urethral pressure divided by the maximal abdominal pressure during cough maneuvers at a bladder volume of 200 ml. Postoperative sensory threshold, pressure transmission (% of pressure transmission), maximal urethral closure pressure and functional sphincter length were measured 6 weeks and 6 months after prostatectomy. These parameters were compared between continent and incontinent patients. RESULTS Preoperative and postoperative urodynamic studies were completed in 34 patients. The continence rate after 6 weeks was 18% (6 patients) and improved to 82% (28) after 6 months. Preoperatively sensory threshold was 16 +/- 11 mA. After 6 weeks and 6 months, respectively, sensory threshold was significantly higher in incontinent (84 +/- 11 mA., 70 +/- 8 mA.) compared to continent (65 +/- 8 mA., 41 +/- 12 mA.) patients. Preoperative proximal urethral sensory threshold was not correlated with degree of postoperative incontinence determined by pad tests. Pressure transmission was not different in continent and incontinent patients postoperatively. After 6 weeks and 6 months, respectively, pressure transmission was 77% and 91% in continent, and 37% and 58% in incontinent patients (p = 0.04, p = 0.03). Maximal urethral closure pressure was significantly higher in continent patients (35 +/- 6 cm. H2O) compared to incontinent patients (11 +/- 9 cm. H2O). Sphincter length decreased from 50 mm. preoperatively to 24 mm. after 6 weeks and 25 mm. after 6 months. There was no difference in sphincter length between continent and incontinent patients. CONCLUSIONS Posterior urethral sensitivity and pressure transmission are impaired immediately after prostatectomy. An improvement in these parameters after 6 months is associated with the restoration of continence. These observations suggest that urinary continence after radical prostatectomy depends on the integrity of posterior urethral sensation and the efficiency of pressure transmission.

Continuous occlusion test to determine detrusor contractile performance

PURPOSE A study was conducted to determine the merits of the continuous occlusion test as a method of detrusor contractility assessment by comparing it with other stop tests and with contractility derived from pressure-flow analysis. MATERIALS AND METHODS The continuous occlusion test was performed in elderly men by occluding the bladder outlet before the onset of a detrusor contraction and it was repeated to assess reproducibility. The magnitude of the isovolumetric contraction, maximum slope of the detrusor contraction, and duration of detrusor activation were determined. Voluntary and mechanical stop tests were performed during the mid voiding phase. Continuous occlusion test parameters were compared with the pressure-flow contractility parameters. RESULTS The continuous occlusion test was evaluated in 159 patients. The maximum isovolumetric contraction pressure of the continuous occlusion test was significantly higher than that of the voluntary stop test (49 patients). Continuous occlusion test contractility parameters were reproducible. The maximum isovolumetric contraction pressure and the maximum slope of the detrusor contraction of the continuous occlusion test significantly correlated with the estimated maximum isovolumetric contraction pressure and estimated velocity of shortening (derived from pressure-flow), respectively (r = 0.79, p < 0.0001 and r = 0.385, p = 0.016, 39 patients). The watts factor was well correlated with maximum isovolumetric contraction pressure (r = 0.75, 39 patients). CONCLUSIONS Our study suggests that the continuous occlusion test can be used as an effective alternative method of assessing detrusor contractility.

Bladder Tissue Regeneration Using Acellular Bi-Layer Silk Scaffolds in a Large Animal Model of Augmentation Cystoplasty

Acellular scaffolds derived from Bombyx mori silk fibroin were investigated for their ability to support functional tissue regeneration in a porcine model of augmentation cystoplasty. Two bi-layer matrix configurations were fabricated by solvent-casting/salt leaching either alone (Group 1) or in combination with silk film casting (Group 2) to yield porous foams buttressed by heterogeneous surface pore occlusions or homogenous silk films, respectively. Bladder augmentation was performed with each scaffold group (6 × 6 cm(2)) in juvenile Yorkshire swine for 3 m of implantation. Augmented animals exhibited high rates of survival (Group 1: 5/6, 83%; Group 2: 4/4, 100%) and voluntary voiding over the course of the study period. Urodynamic evaluations demonstrated mean increases in bladder capacity over pre-operative levels (Group 1: 277%; Group 2: 153%) which exceeded nonsurgical control gains (144%) encountered due to animal growth.In addition, animals augmented with both matrix configurations displayed increases in bladder compliance over pre-operative levels(Group 1: 357%; Group 2: 338%) similar to growth-related elevations observed in non-surgical controls (354%) [corrected]. Gross tissue evaluations revealed that both matrix configurations supported extensive de novo tissue formation throughout the entire original implantation site which exhibited ultimate tensile strength similar to nonsurgical counterparts. Histological and immunohistochemical analyses showed that both implant groups promoted comparable extents of smooth muscle regeneration and contractile protein (α-smooth muscle actin and SM22α) expression within defect sites similar to controls. Parallel evaluations demonstrated the formation of a transitional, multi-layered urothelium with prominent cytokeratin, uroplakin, and p63 protein expression in both matrix groups. De novo innervation and vascularization processes were evident in all regenerated tissues indicated by synaptophysin-positive neuronal cells and vessels lined with CD31 expressing endothelial cells. Ex vivo organ bath studies demonstrated that regenerated tissues supported by both silk matrices displayed contractile responses to carbachol, α,β-methylene-ATP, KCl, and electrical field stimulation similar to controls. Our data detail the ability of acellular silk scaffolds to support regeneration of innervated, vascularized smooth muscle and urothelial tissues within 3 m with structural, mechanical, and functional properties comparable to native tissue in a porcine model of bladder repair.

Retrograde leak point pressure for evaluating postradical prostatectomy incontinence

OBJECTIVES To evaluate a technique of measuring the retrograde leak point pressure (RLPP) for assessing men with postradical prostatectomy stress urinary incontinence (SUI). METHODS We measured RLPP in adult men by retrograde infusion of the distal urethra while simultaneously recording intraurethral pressure. The reproducibility of this test, and its dependence on urethral infusion rate, bladder volume, and anterior urethral catheter position, were evaluated. RLPP and abdominal leak point pressure (ALPP) measurements were performed in postradical prostatectomy patients. RLPP was compared with ALPP and with severity of incontinence determined by pad usage. RESULTS Repeated RLPP measurements were not significantly different and did not change with bladder volume up to half capacity or with the location of the catheter in the anterior urethra. The differences between RLPP measurements with infusion rates of 2, 4, and 8 mL/min were also not significant. Twenty-seven men were evaluated 6 to 108 months after surgery. Of these, 22 (81%) demonstrated SUI. Mean RLPP in men without SUI (79.2 +/- 14 cm H2O) was significantly higher than in men with SUI (51.9 +/- 13 cm H2O, P < 0.01). In men with SUI, ALPP and RLPP were significantly correlated, and ALPP (49.8 +/- 24 cm H2O) was not significantly different from RLPP (51.9 +/- 13 cm H2O) Pad use and RLPP were also significantly related. CONCLUSIONS RLPP measurements are reproducible and simple to perform. The pressure at which leakage occurs is easily identifiable as the plateau pressure. RLPP correlates significantly with the lowest of multiple ALPP measurements in men with SUI. This technique represents a reliable urodynamic alternative for evaluating men with postradical prostatectomy SUI.

Urodynamic Risk Factors for Renal Dysfunction in Men With Obstructive and Nonobstructive Voiding Dysfunction

PURPOSE Urodynamic investigation of men with lower urinary tract symptoms, usually attributed to benign prostatic hyperplasia, often reveals bladder outlet obstruction, detrusor instability and/or diminished vesical compliance. We investigated whether these urodynamic abnormalities alone or in combination contribute to renal dysfunction. MATERIALS AND METHODS A total of 161 men with lower urinary tract symptoms was evaluated by urodynamics, and outlet obstruction, detrusor instability and decreased compliance (30 ml./cm. water or less) were noted. Serum blood urea nitrogen (BUN) and creatinine were measured. Cases were categorized according to the urodynamic diagnosis. Mean values of serum BUN and creatinine as well as the incidence of elevated BUN and creatinine were compared among groups. RESULTS Of the cohort 54 men (34%) had elevated BUN and 19 (12%) had elevated serum creatinine. No significant correlation was found between the degree of obstruction and BUN or creatinine level. Mean serum BUN and creatinine, and the incidence of abnormal laboratory tests did not significantly differ among those with outlet obstruction, detrusor instability, both conditions or neither condition. However, in patients with outlet obstruction and detrusor instability there was a significantly increased incidence of azotemia in the subgroup with diminished compliance (78%) versus the subgroup with normal compliance (36%). CONCLUSIONS In men with voiding dysfunction of a nonneurogenic etiology outlet obstruction with or without detrusor instability does not appear to be a risk factor for elevated BUN and creatinine. However, when decreased bladder compliance is associated with a combination of outlet obstruction and detrusor instability, this risk is substantially increased.