Robert J. Krane

Impaired Neurogenic and Endothelium-Mediated Relaxation of Penile Smooth Muscle from Diabetic Men with Impotence

Relaxation of the smooth muscle of the corpora cavernosa of the penis is necessary for penile erection. To determine the relation of impaired relaxation to impotence in diabetic patients, we performed an in vitro examination of corpus cavernosum tissue obtained at the time of implantation of a penile prosthesis in 21 diabetic and 42 nondiabetic men with impotence. Contraction was induced in isolated strips of corporal smooth muscle by norepinephrine; then relaxation was assessed with electrical stimulation of autonomic nerves and with the administration of three agents: acetylcholine, which is known to be mediated by endothelium-derived relaxing factor; papaverine; and sodium nitroprusside. The latter two act directly on smooth muscle (i.e., they are endothelium-independent). Autonomically mediated relaxation with electrical stimulation was less pronounced in the smooth muscle from diabetic men (n = 18) than in the smooth muscle from nondiabetic men (n = 24; P = 0.001). The degree of impairment increased with the duration of diabetes (r = 0.61, P = 0.007). Endothelium-dependent relaxation was also impaired, as evidenced by a lower degree of muscle relaxation after the administration of acetylcholine in the tissue from diabetic men (n = 16) than in that from nondiabetic men (n = 22; P = 0.001). The adverse effects of diabetes persisted after we controlled for smoking and hypertension. Endothelium-independent relaxation after the administration of nitroprusside and papaverine was similar in tissue from the diabetic and nondiabetic men. We conclude that diabetic men with impotence have impairment in both the autonomic and the endothelium-dependent mechanisms that mediate the relaxation of the smooth muscle of the corpora cavernosa. These findings may provide a rationale for the treatment of diabetic men with impotence by intracavernosal injection of vasodilators to induce endothelium-independent relaxation of the smooth muscle.

Mechanisms of Venous Leakage: A Prospective Clinicopathological Correlation of Corporeal Function and Structure

PURPOSE We investigated the pathophysiology of structurally based corporeal veno-occlusive dysfunction. MATERIALS AND METHODS We prospectively evaluated 24 impotent patients (mean age plus or minus standard error 46 +/- 3 years) who had exposure to vascular risk factors and/or disorders inducing diffuse trabecular structure alterations and who underwent penile prosthesis insertion. Preoperative indexes of veno-occlusive function (flow to maintain, venous outflow resistance and pressure decay measurements using repeat dosing pharmacocavernosometry) were correlated with postoperative erectile tissue computer assisted color histomorphometry (percent trabecular smooth muscle to total erectile tissue area). To develop further study findings and correlate histomorphometric findings with molecular biological properties molecular biological studies (ribonuclease protection analysis, reverse transcription-polymerase chain reaction assay for expression of transforming growth factor-beta 1 messenger [m] ribonucleic acid [RNA] and protein affinity labeling techniques for specific transforming growth factor-beta receptors) were performed in representative patients with high (39 to 43%), intermediate (30 to 37%) and low (13 to 29%) trabecular smooth muscle content (normal 42 to 50%). RESULTS Flow to maintain, venous outflow resistance and pressure decay values significantly correlated with trabecular smooth muscle cell content (r = -0.89, 0.82 and -0.85, respectively). In the high, intermediate and low smooth muscle content subgroups flow to maintain, venous outflow resistance and pressure decay values were 1 to 5, 9 to 30 and 50 to 120 ml. per minute, 17 to 84, 3 to 9 and 1 to 2 mm. Hg/ml. per minute, and 40 to 60, 48 to 80 and 110 to 120 mm. Hg decrease in 30 seconds from 150 mm. Hg, respectively. There were no significant differences in patient age or prevalence of risk factors among the 3 subgroups. Patients representative of all 3 subgroups had transforming growth factor-beta 1 mRNA, auto-induction of transforming growth factor-beta 1 mRNA and induction and/or increased availability of all 3 types of transforming growth factor-beta receptors. CONCLUSIONS The pathophysiology of structurally based corporeal veno-occlusive dysfunction is related to elevated corporeal connective tissue content. Based on our data and those in the literature corporeal fibrosis is hypothesized to develop secondary to abnormalities in the regulation of normal collagen synthesis and degradation, most likely associated with adverse influences of chronic ischemia.

Overactivity and structural changes in the chronically ischemic bladder

PURPOSE Our aim was to study the effect of chronic ischemia on bladder contraction and detrusor smooth muscle reactivity. The relationship between structural damage and functional changes in the chronically ischemic bladder was also investigated. MATERIAL AND METHODS Male New Zealand White rabbits were divided into arterial injury (AI), hypercholesterolemia (Hch) and control groups. The AI group (n = 18) underwent balloon endothelial injury of the iliac arteries and received a 0.5% cholesterol diet. The Hch group (n = 8) received a 0.5% cholesterol diet alone. The control group (n = 8) received a regular diet. After 16 weeks, iliac artery and bladder wall blood flows were recorded. Cystometrograms and arteriography were obtained and bladder tissues were processed for isometric tension measurement in the organ bath and for histological evaluation. RESULTS At 16 weeks, blood flow through the iliac arteries was significantly reduced in the AI group compared with the Hch and control groups. In the AI group, 8 animals developed severe bladder ischemia (SBI) defined as greater than 60% decrease in bladder blood flow, 7 animals developed moderate bladder ischemia (MBI) defined as 40 to 60% decrease in bladder blood flow, and 3 animals failed to develop significant bladder ischemia (<40% decrease in bladder blood flow). In the control animals, bladder blood flow increased prior to contraction, decreased during contraction and rebounded to baseline levels after contraction. In animals with MBI and SBI, the increase in bladder blood flow prior to contraction and the rebound of blood flow after contraction, both seen in control animals, were diminished. Detrusor overactivity (significant increase in the frequency of spontaneous bladder contractions) was observed in the MBI group and impaired bladder contraction in the SBI group. In the organ bath, bladder strips from the MBI group demonstrated increased contractile response to carbachol and electrical field stimulation (EFS) while bladder strips from the SBI group showed impaired contractility. Hch alone produced only short-lived ischemia during bladder contraction and caused significantly lesser functional changes compared with those seen in MBI. Histological examination showed atherosclerotic occlusion in the iliac arteries and bladder microcirculation and marked disruption of urothelium in the MBI and SBI groups. Severe fibrosis was seen in bladder tissue from the SBI group, moderate fibrosis in tissue from the MBI group and mild fibrosis in tissue from the Hch group. CONCLUSIONS Our studies show that chronic MBI is associated with detrusor overactivity and increased smooth muscle contractility to carbachol and EFS while chronic SBI is associated with impaired detrusor contraction. The mechanism of chronic ischemia-induced bladder dysfunction is not known and may involve multiple physiologic and structural changes in the bladder nerves, receptors and contractile components. Our studies suggest that ischemia-induced structural damage in the urothelium and possible chronic exposure of the underlying tissue and nerves to the urine may also play a role in MBI-induced detrusor overactivity. SBI-induced impairment of bladder contraction may involve, in part, extensive fibrosis and loss of bladder smooth muscle. Histopathophysiologic changes in bladder tissue from our MBI model are similar to those seen in patients with detrusor instability, suggesting that chronic ischemia may play a role in the development of idiopathic detrusor instability.

ATHEROSCLEROSIS-INDUCED CHRONIC ISCHEMIA CAUSES BLADDER FIBROSIS AND NON-COMPLIANCE IN THE RABBIT

PURPOSE The overall goal was to determine whether chronic ischemia and hypercholesterolemia interfere with bladder function and structure. The roles of atherosclerosis-induced chronic ischemia and hypercholesterolemia in bladder fibrosis and non-compliance were studied in the rabbit. The relationship between ischemia-induced changes in the expression of transforming growth factor-beta1 (TGF-beta1) and basic fibroblast growth factor (bFGF) and the severity of bladder fibrosis was also investigated. MATERIALS AND METHODS Male New Zealand White rabbits were divided into chronic bladder ischemia (CBI, n = 11), hypercholesterolemia (Hch, n = 8) and control (n = 8) groups. The CBI group underwent balloon endothelial injury of the iliac arteries and received a 0.5% cholesterol diet. The Hch group received a 0.5% cholesterol diet alone. The control group was placed on a regular diet. After 16 weeks, iliac artery and bladder wall blood flow measurements, cystometrograms (CMG) and aorto-iliac arteriograms were obtained in all animals. Iliac arteries and bladder tissues were processed for histological staining and computer-assisted histomorphometric image analysis. The expressions of TGF-beta1 and bFGF in bladder tissue were determined by immunohistochemical staining utilizing monoclonal antibodies. RESULTS At 16 weeks, arteriography and histology showed significant diffuse atherosclerotic occlusive disease of the aorto-iliac arteries in the CBI group. Iliac artery and bladder wall blood flows were significantly decreased in the CBI group compared with the Hch and control groups. Atherosclerosis-induced CBI shifted the volume-pressure curve to the left and caused severe bladder fibrosis. Hypercholesterolemia also caused fibrosis and non-compliance but to a much lesser extent compared with those caused by CBI. In histomorphometry, the percentage of detrusor smooth muscle was moderately decreased in the Hch group and severely decreased in the CBI group compared with the control group. In immunohistochemical stains of bladder tissues, bFGF expression was similar in the three groups of animals. TGF-beta1 expression was significantly greater in bladder tissues from the CBI group compared with the Hch and control groups. CONCLUSIONS Our studies show that atherosclerosis-induced chronic ischemia increases TGF-beta1 expression in the bladder leading to fibrosis, smooth muscle atrophy and non-compliance. Hypercholesterolemia also interferes with bladder structure and compliance but to a significantly lesser extent compared with CBI. Our studies suggest that arterial insufficiency and hypercholesterolemia, common aging-associated disorders, may play important roles in the pathophysiology of voiding dysfunction in the elderly.

Neurourologic Abnormalities in Multiple Sclerosis

Multiple sclerosis is a demyelinating disease of the central nervous system, often producing abnormalities in sexual function and urinary control. Eighty-six patients with this disorder were referred to our neurourologic facilities for evaluation (45 women and 41 men). Symptomatic voiding dysfunction was present in 84 patients (97 per cent). Sexual dysfunction was present in 29 of the 41 men (71 per cent). Neurourologic evaluation was performed by rapid-fill carbon dioxide cystometry and perineal floor needle electromyography. Several neurourologic patterns were identified in multiple sclerosis patients: the most common cystometry pattern was detrusor hyperreflexia (76 per cent) and the most common electromyography finding was vesico-sphincter dyssynergia (50 per cent). Voiding symptoms alone were not found to correlate with neurourologic findings. The presence of bilateral extensor plantar reflexes was found to indicate the possibility of vesico-sphincter dyssynergia. The addition of sacral-evoked responses to the neurourologic evaluation was useful in the identification and localization of occult sacral cord pathology and was of special significance to men with sexual dysfunction undergoing evaluation for neurogenic impotence. The combination of abnormal perineal electromyography, abnormal sacral latency and detrusor hyperreflexia was suggestive of multilevel spinal cord dysfunction and, possibly, has diagnostic as well as therapeutic significance. Neurourologic patterns were found to change in 4 of 9 patients re-evaluated because of symptom changes or poor treatment responses. Neurourologic testing in multiple sclerosis patients may be used to identify pathologic lesions, characterize sexual and voiding dysfunctions, corroborate neurologic diagnosis in doubtful cases and form a basis for rational treatment planning.

Safety and Efficacy Outcome of Mentor Alpha-1 Inflatable Penile Prosthesis Implantation for Impotence Treatment

PURPOSE We investigated safety and efficacy outcome pertaining to the Mentor Alpha-1, 3-piece inflatable penile prosthesis for impotence treatment. MATERIALS AND METHODS A 2-phase, multi-institutional, large scale retrospective study, with independently analyzed medical record (phase I) and questionnaire (phase II) data from consecutive eligible patients of 7 physician investigators was performed from March to October 1993. RESULTS In phase I there were no morbidities of any type in 394 of the 434 patients (90.8%) (mean age 61 years, range 24 to 88) who underwent Alpha-1 implantation (mean followup 22.2 months, range 0.67 to 44.5). The risk of prosthesis malfunction (fluid leak and auto-inflation) was 2.5%. No cylinder aneurysms were reported. A total of 93.1% of Alpha-1 devices was free from explantation (4.4%) or revision surgery (2.5%) for approximately 2 years from the original implant date. Kaplan-Meier actuarial analyses revealed that cumulative survival of the Alpha-1 prostheses at 12, 24 and 36 months was 98 +/- 1%, 93 +/- 2% and 85 +/- 7% until device malfunction, and 91 +/- 2% 83 +/- 4% and 75 +/- 7% until surgical intervention (revision or explantation). In phase II 89% of the men claimed fulfilled expectations with the Alpha-1 prosthesis as impotence treatment. Satisfaction responses 80% or greater were noted with regard to intercourse ability and confidence, and device rigidity and function. Implantation did not result in greater than 80% satisfaction in partner relationships or feelings (as judged by the patient), social or work confidence, or intercourse frequency. Factors adversely affecting satisfaction included partner feelings of dissatisfaction (as judged by the patient), specific physician investigators and need for explantation/revision surgery. CONCLUSIONS In 1 of the largest multi-institutional implant outcome studies thus far performed, safety and efficacy data concerning the Alpha-1 contemporary inflatable device were found markedly improved over earlier inflatable prostheses and now compare favorably with historical data from noninflatable rod type devices.

Arterial Priapism: Diagnosis, Treatment and Long-Term Followup

We report on the long-term followup of 7 patients 11 to 50 years old treated for arterial priapism following perineal or penile trauma with arteriographic evidence of contrast medium extravasating from a lacerated cavernous artery into surrounding erectile tissue lacunae (an arterial-lacunar fistula). All patients underwent medical record review and completed a mailed questionnaire. The priapism erections were described as devoid of pain or tenderness, incompletely but constantly rigid and able to increase rigidity with sexual stimulation. Bright red corporeal aspirates were observed in all cases. Color flow Doppler ultrasound findings of focal areas of high flow turbulence correlated with diagnostic arteriography (correlation coefficient 1.00). Initial treatment by mechanical or pharmacological means was unsuccessful when performed. Superselective transcatheter embolization of the ipsilateral common penile artery resolved the priapism in all cases. The interval from onset to resolution of priapism was 4 to 126 days. Full erectile function return was delayed from 2 weeks to 5 months, most likely from resolving clot lysis. Full erection quality was restored in 6 of 7 patients with persistent function and restored frequency of intercourse at 6 to 67 months. Reestablished cavernous artery flow in previously embolized arteries was demonstrated on followup ultrasonography. Surgical treatment was not required in any case. We conclude that arterial priapism occurs in the absence of neurogenic-mediated relaxation, and is sustained by high oxygen tension and shear stress associated with the cavernous artery laceration. Embolization therapy offers effective management of the pathophysiology with high preservation of premorbid erectile function.

Cavernosal expandability is an erectile tissue mechanical property which predicts trabecular histology in an animal model of vasculogenic erectile dysfunction

PURPOSE Reliable, clinically available, non-invasive measurements able to predict trabecular histology without the need for erectile tissue biopsy would improve impotence management, since the percentage of trabecular smooth muscle content has been shown to be associated with corporal veno-occlusive dysfunction. The purpose was to identify whether the erectile tissue mechanical property, cavernosal expandability, correlated with the percentage of trabecular smooth muscle content in an animal model of hypercholesterolemia and ischemic-induced corporal fibrosis. MATERIALS AND METHODS New Zealand White rabbits (6 to 7 months old, 3 to 3.5 kg.), were divided into control (n = 7), hypercholesterolemic (n = 5, 0.5% cholesterol diet) and atherosclerotic groups (n = 8, 0.5% cholesterol diet with balloon de-endothelialization). At 16 weeks, the corpora cavernosa were removed en bloc and submerged in physiologic salt solution, and volume-pressure data were plotted at 20 mm. Hg pressure intervals under trabecular smooth muscle relaxation. Cavernosal expandability, X, (the measure of the ability to achieve high corporal expansion at relatively low intracavernosal pressure) and tunical distensibility, V(E)/V(F), (relative volume of fully erect to flaccid penis) were calculated. Erectile tissue was assessed by computer-assisted color histomorphometry with Massons trichrome stained sections (30 to 45 high power fields/animal) to assess percentage of trabecular smooth muscle content. RESULTS The overall mean percentage of trabecular smooth muscle content and mean cavernosal expandability values were 45.4 +/- 1.6, 39.2 +/- 0.9, 33.9 +/- 0.6 and 0.0165 +/- 3.04 x 10(-3), 0.0116 +/- 1.63 x 10(-3), 0.0118 +/- 1.26 x 10(-3) mm. Hg(-1) for the control, hypercholesterolemic and atherosclerotic groups, respectively (r = 0.87). Significant differences in trabecular smooth muscle content were observed among all 3 groups, and in cavernosal expandability, between control and atherosclerotic groups, as well as between control and hypercholesterolemic groups but not between atherosclerotic and hypercholesterolemic groups. CONCLUSIONS The erectile tissue mechanical property, cavernosal expandability, correlated with erectile tissue structural quality. Since cavernosal histology has been shown to predict corporal veno-occlusive function, it is hypothesized that the measurement of cavernosal expandability may become a valuable functional clinical parameter in the diagnosis and treatment of men with erectile dysfunction.

Neurourologic Findings in Parkinson’s Disease

A total of 30 patients with an established diagnosis of Parkinsons disease and symptomatic voiding dysfunction underwent neurourologic evaluation. Detrusor hyperreflexia associated with appropriate sphincter relaxation was found to be the most common urodynamic pattern, occurring in 75 per cent of the cases. Two types of increased electromyogram activity at the time of detrusor contraction were identified: 1) pseudo-dyssynergia (7 per cent)--a voluntary contraction of the perineal floor in an attempt to prevent leakage and 2) sphincter bradykinesia (11 per cent)--a manifestation of skeletal muscle hypertonicity characteristic of parkinsonism. On the basis of these observations it is assumed that the effect of the basal ganglia on micturition is inhibitory in nature. The diagnostic and therapeutic approach to the parkinsonian patient with voiding dysfunction is discussed.

Implications of prostate micrometastases in pelvic lymph nodes: An archival tissue study

OBJECTIVES In the United States, radical retropubic prostatectomy for adenocarcinoma usually includes a staging pelvic lymphadenectomy. If frozen section analysis of the lymph nodes fails to reveal any evidence of metastases, the prostate is removed. We have previously noted that as many as 56% of patients undergoing radical prostatectomy demonstrate rising serum prostate-specific antigen (PSA) levels by 4 years postoperatively. This report was designed to determine whether micrometastases undetectable by conventional pathologic methods: could have accounted for these biochemical failures. METHODS A retrospective analysis of formalin-fixed paraffin-embedded pelvic lymph node material was undertaken using a reverse transcription-polymerase chain reaction (RT-PCR)-based assay designed to amplify messenger RNA from PSA. All specimens were obtained from a group of 57 patients with prostate cancer who had undergone staging pelvic lymphadenectomy at the time of radical prostatectomy, and whose long-term follow-up was known. RESULTS Although all of these nodes appeared to be free of tumor by conventional pathologic methods, a RT-PCR assay was used to identify evidence of prostate metastases in 44% of evaluable samples. Of these, 14 of 16 went on to manifest rising serum PSA values by 5 years postoperatively. CONCLUSIONS These results suggest that molecular staging of pelvic lymph nodes prior to planned therapy for clinically organ-confined prostate cancer may better distinguish between patients with local disease and those for whom local therapy alone will not be curative. To our knowledge, this is the first large-scale retrospective gene expression study published.