Impact of systemically active neurohumoral factors on the erectile response of the rat.

INTRODUCTION: Mean arterial pressure (MAP) and specific regulation of penile blood flow are the primary determinants of an erection. While this concept is well recognized, the differential relationship between systemically acting vasoactive factors on arterial pressure and erectile responses is not well described. AIM: The aim of this study was to determine how the modification of systemic levels of neurohumoral factors impacts on the magnitude and efficiency of the erectile response. MAIN OUTCOME MEASURES: The main outcome measures for this study are changes in MAP and intracavernosal pressure (ICP) following electrostimulation of the cavernous nerve. METHODS: Anesthetized adult, male Sprague-Dawley rats were catheterized for measuring MAP (carotid), ICP, and drug administration (vena cava). Erections were induced via cavernous nerve electrostimulation. Vasoactive drug infusions were used to produce changes in MAP levels including: hexamethonium, angiotensin II (ANGII)±hexamethonium, methoxamine±hexamethonium, losartan, MAHMA NONOate, and terbutaline. RESULTS: In general, ICP and MAP were linearly correlated regardless of treatment. Hexamethonium markedly dropped MAP and proportionately decreased the magnitude of the erectile response. ANGII or methoxamine given to hexamethonium-pretreated or untreated rats increased MAP similarly, but produced contrasting effects on erectile responses. ANGII-induced pressor responses were associated with increased erectile responses whereas all methoxamine treatments markedly decreased erectile responses. Depressor changes with losartan or terbutaline, but not MAHMA NONOate, also impacted negatively on the efficiency of the erectile responses at lower arterial pressures. CONCLUSIONS: In general, the magnitude of the erectile responses was found to be dependent upon the level of MAP, although the mechanism by which arterial pressure was changed impacted substantially on the characteristics of the relationship. The major finding was that circulation-wide α-adrenoceptor stimulation was extremely deleterious to erectile responses whereas global stimulation of ANG II receptors was actually proerectile. Overall, the results indicate that neurohumoral specificity in systemic hemodynamic control is also critical in establishing the optimal erectile environment in rats.

A phase 1, single-dose study of fresolimumab, an anti-TGF-ß antibody, in treatment-resistant primary focal segmental glomerulosclerosis.

Primary focal segmental glomerulosclerosis (FSGS) is a disease with poor prognosis and high unmet therapeutic need. Here, we evaluated the safety and pharmacokinetics of single-dose infusions of fresolimumab, a human monoclonal antibody that inactivates all forms of transforming growth factor-ß (TGF-ß), in a phase I open-label, dose-ranging study. Patients with biopsy-confirmed, treatment-resistant, primary FSGS with a minimum estimated glomerular filtration rate (eGFR) of 25 ml/min per 1.73 m(2), and a urine protein to creatinine ratio over 1.8 mg/mg were eligible. All 16 patients completed the study in which each received one of four single-dose levels of fresolimumab (up to 4 mg/kg) and was followed for 112 days. Fresolimumab was well tolerated with pustular rash the only adverse event in two patients. One patient was diagnosed with a histologically confirmed primitive neuroectodermal tumor 2 years after fresolimumab treatment. Consistent with treatment-resistant FSGS, there was a slight decline in eGFR (median decline baseline to final of 5.85 ml/min per 1.73 m(2)). Proteinuria fluctuated during the study with the median decline from baseline to final in urine protein to creatinine ratio of 1.2 mg/mg with all three Black patients having a mean decline of 3.6 mg/mg. The half-life of fresolimumab was ∼14 days, and the mean dose-normalized Cmax and area under the curve were independent of dose. Thus, single-dose fresolimumab was well tolerated in patients with primary resistant FSGS. Additional evaluation in a larger dose-ranging study is necessary.

Plasma organochlorine levels and prostate cancer risk.

A case-control study was conducted to determine the association between plasma organochlorine levels and prostate cancer risk. Male clinic patients scheduled for prostate core biopsy or seeing their urologist for other conditions from 1997 through 1999 in Kingston, Ontario were eligible, excluding those with an earlier cancer. Age frequency matched controls (n=329) were compared with 79 incident prostate cancer cases. Before knowledge of diagnosis, the patients completed a questionnaire and donated 15 ml of blood for the measurement of 14 PCBs, and 13 organochlorine pesticides by gas chromatography. At least 70% of patients had detectable levels of nine PCB congeners and seven pesticides, and these chemicals were included in the risk analysis adjusted for total lipids. Geometric means for these PCB congeners, total PCBs, and p,p'-DDE are slightly lower for cases than controls, whereas the levels of p,p'-DDT and other pesticides are virtually equal. Adjusting for age and other confounders in multivariable logistic regression, odds ratios (ORs) are consistently below 1.0 for PCB congeners and total PCBs. For pesticides, most ORs are very close to the null. This study suggests that long-term low-level exposure to organochlorine pesticides and PCBs in the general population does not contribute to increased prostate cancer risk.

Phase II study of nitric oxide donor for men with increasing prostate-specific antigen level after surgery or radiotherapy for prostate cancer.

OBJECTIVES: To evaluate the effect of low-dose glyceryl trinitrate (GTN) on men with biochemical recurrence of prostate cancer after primary therapy. Preclinical, proof-of-principle studies have demonstrated that nitric oxide signaling plays a significant role in the hypoxia-induced progression of prostate cancer. METHODS: A prospective, open-label clinical trial of men with an increasing prostate-specific antigen (PSA) level after surgery or radiotherapy was conducted. Men with PSA recurrence were enrolled in a 24-month trial investigating the effect of a low-dose, slow-release transdermal GTN patch. The PSA doubling time (PSADT) was compared before and after treatment initiation, as well as with a matched control group that received no immediate treatment for their PSA recurrence. RESULTS: A total of 29 patients were enrolled in the study. Of the 29 patients, 62% completed the 24-month protocol, with 10% experiencing clinical disease progression. The calculated PSADT of the treatment group before initiating GTN was 13.3 months, not significantly different from that of the matched control group at 12.8 months. In an intention-to-treat analysis, the end-of-study PSADT for the treatment group was significantly different at 31.8 months (P < .001). CONCLUSIONS: We report the first clinical trial of a GTN patch in patients with prostate cancer. The prolongation of the PSADT and the safety of the drug, coupled with the corresponding preclinical in vitro and in vivo data documenting the ability of nitric oxide to attenuate hypoxia-induced progression of prostate cancer, warrant further testing in a placebo-controlled study.

Restoration of female genital vasocongestive arousal responses in young and aged rats.

INTRODUCTION: Treatments of aged, male hypertensive rats that induce vascular remodeling or that normalize endothelial function are known to produce sustained improvements in erectile function. Whether the treatments targeting these processes benefit female genital vasocongestive arousal (GVA) responses is currently not known. AIM: To determine whether the actions of nitric oxide (NO) are critical to the apomorphine (APO)-generated GVA responses in both intact and ovariectomized OVX young adult female rats (before any aging-associated decreases in the responses). In addition, we also investigated whether the diminished GVA responses in aged rats could be restored, at least in part, using an antihypertensive treatment, which is known to enhance erectile responses and improve general vascular function in male rats. METHODS: In female Wistar rats, APO-induced GVA responses (80 microg/kg, subcutaneously [sc], 30 minutes) were assessed by videomonitoring following various treatments. Young adult females were ovariectomized or were treated with the nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (30 mg/kg, iv), followed by an NO mimetic, sodium nitroprusside (10 microg/kg/minute, intravenous). Aged females (18 months) were treated for 2 weeks with the angiotensin converting enzyme (ACE) inhibitor, enalapril (30 mg/kg/day, orally) plus low sodium (0.04%). MAIN OUTCOME MEASURES: APO-induced GVA responses in female rats. RESULTS: There was an age-associated reduction in sexual responses in normotensive rats that was greatly enhanced (fourfold) by brief, aggressive antihypertensive treatment. The enhanced vasocongestive responses persisted for a 5-week off-treatment. Both OVX and NOS inhibition significantly decreased sexual responses by approximately 80% in young female rats. Systemic administration of an NO mimetic recovered vasocongestive responses in the NOS-blocked rats, but not in OVX animals. CONCLUSIONS: Although mechanisms were not established, the major findings were that brief aggressive ACE inhibitor treatment markedly improved sexual responses in aged female rats, and systemic delivery of an NO mimetic recovered sexual responses in globally NOS-blocked animals.

Recovery of erectile function in aging hypertensive and normotensive rats using exercise and caloric restriction.

INTRODUCTION: Using aging spontaneously hypertensive rats (SHR), we established that antihypertensive drugs can improve erections and penile vascular structure, and lower arterial pressure. Using kidney cross-transplantations, our findings revealed that the benefit of this treatment resulted from drug-induced changes specific to the penile circulation, and not to the kidney-mediated lowering of pressure. AIM: The objective of the present study was to determine whether increased exercise and/or caloric restriction (CR) can reverse the decline in sexual responses in aging hypertensive and normotensive rats. METHODS: From 30 to 40 weeks, food intake was restricted (10-40%), and SHR, Wistar, and Sprague-Dawley rats ran on treadmills (30 minutes/day, 5 days/week). Exercise was withdrawn at 40 weeks, and CR was stopped at 50 weeks. Using a separate group of older Wistars (56 weeks) and Sprague-Dawley rats (67 weeks), the effects of 10% CR or exercise plus 10-40% CR on erectile function were determined. MAIN OUTCOME MEASURE: Apomorphine-induced erectile responses and body weight were monitored weekly. RESULTS: An age-related decline in erections was seen from 15 to 29 weeks of age in all strains. This decline paralleled increases in body weight, particularly in the normotensive strains. Exercise and CR induced a 10% weight loss in normotensive rats and improved erections in all animals. In SHR, increased erections occurred without decreasing body weight. Body weight and erectile responses were maintained by CR alone after exercise was withdrawn, but erectile function rapidly declined soon after CR was stopped and paralleled increases in body weight. In aged Wistar and Sprague-Dawley rats treated with exercise and CR, erectile function was also significantly improved. CONCLUSIONS: Similar to previous studies, erectile function progressively decreased with age in both hypertensive and normotensive rats. Erectile responses were found to be substantially improved by an intervention involving exercise and CR, but not necessarily involving weight loss.

Pesticides and polychlorinated biphenyls as potential risk factors for erectile dysfunction.

While it is biologically plausible that environmental chemicals such as pesticides and polychlorinated biphenyls (PCBs) with suspected hormone disrupting properties may have an impact on risk of erectile dysfunction (ED), few epidemiologic studies have assessed this potential association. In a clinic-based case-control study in Kingston, Ontario, consenting subjects completed a questionnaire and donated 15 mL of blood for analysis of organochlorines and lipids by gas chromatography. Exposures were compared for 101 cases with ED and 234 comparable control subjects. For most PCB congeners and organochlorine pesticides, geometric mean levels are similar for cases and controls. Multivariate logistic regression results do not show an increased or decreased risk of ED associated with levels of most detectable environmental substances after adjustment for age, total lipids, and confounders. Levels of 2 of the ubiquitous chlorinated pesticides, oxychlordane and trans-nonachlor, which are highly correlated, appear to associate with a reduced risk of ED, but the role of chance cannot be ruled out. To our knowledge, this study is the first to investigate the possible relationship between plasma levels of organochlorines and ED risk, and results do not provide evidence of an association.

Predictive validity of five comorbidity indices in prostate carcinoma patients treated with curative intent.

BACKGROUND: Comorbidity is important to consider in clinical research on curative prostate carcinoma because of the role of competing risks. Five chart-based comorbidity indices were assessed for their ability to predict survival. METHODS: This was a case-cohort study of prostate carcinoma patient cohort treated with curative intent in Toronto and Southeast Cancer Care Ontario regions between 1990 and 1996; the subcohort was drawn from these men, whereas cases were cohort members who died from causes other than prostate carcinoma. Comorbidity data were obtained from medical charts (269 subjects). Vital status, age, area of residence, and socioeconomic status information were available. Predictive validity was quantified by the percent variance explained (PVE) over and above age using proportional hazards modeling. RESULTS: The Chronic Disease Score (CDS) (PVE = 11.3%; 95% confidence interval [95% CI], 3.5-22.8%), Index of Coexistent Disease (ICED) (PVE = 9.0%; 95% CI, 2.9-17.9%), Cumulative Illness Rating Scale (CIRS) (PVE = 7.2%; 95% CI, 1.4-17.1%), Kaplan-Feinstein Index (PVE = 4.9%; 95% CI, 0.6-12.8%), and Charlson Index (PVE = 3.8%; 95% CI, 0.3-10.9%) each explained some outcome variability beyond age. PVE differences among indices were not statistically significant. A comorbidity identified at the time of cancer diagnosis was the cause of death in 59.2% of cases (75% for cardiac or vascular causes). CONCLUSIONS: The better-performing, more comprehensive indices (CDS, ICED, and CIRS) would be useful in measuring and controlling for comorbidity in this setting. The CDS was easiest to apply and explained the most outcome variability.

Lower urinary tract disease: what are we trying to treat and in whom?

The diseases of the lower urinary tract are traditionally divided into abnormalities of storage and abnormalities of emptying. The targets for therapy were the organs most responsible for influencing storage and emptying. Modern understanding places the symptomatic status of the patient as the overriding criterion for treatment. It also accommodates a broader understanding of multiple and overlapping systems. Symptoms of voiding dysfunction have been clearly shown to be associated with symptoms of other genitourinary disease, for example, erectile dysfunction (ED). Treatment of voiding dysfunction has also been shown to have effects (adverse or beneficial) in these other domains. Thus, the symptoms of lower urinary tract disease (LUTD) that have to be considered now as targets relevant to these therapies include ED, ejaculatory dysfunction, sexual desire, sexual pain disorders and female sexual dysfunction. The anatomic, neural and endocrine systems that support these symptomatic functions and dysfunctions span the range from the urogenital smooth muscle to the hypothalamus, the bladder sensory output to the micturition centre and growth factors to androgens. Potentially important targets also include vascular and spinal structures, sex hormones and nitric oxide as well as the obvious genes, enzymes and receptors. The epidemiological studies prove the convergence of LUTD when viewed through the lens of the current patient-related outcomes and problem constructs. This convergence serves as a clear guidance to include wide ranging outcome instruments in all future studies with compounds being investigated for the treatment of LUTD. Out of these will come evidence of expected and unexpected collateral effects. The convergence should open the possibility to a different business model for developing therapeutic concepts. The blockbuster drug for a monolithic indication may be supplemented by agents with single or multiple pathway activity with smaller parallel targets. Using an approach based on patient reported outcomes to therapeutic targets not only widens the range of conditions, but also the patient types who can be considered as having LUTD.

Smoking and other lifestyle factors in relation to erectile dysfunction.

OBJECTIVE: To assess the association between erectile dysfunction (ED) and various lifestyle and medical factors, including smoking and cardiovascular disease (CVD) medications, among men attending urology clinics in Kingston, Canada. SUBJECTS AND METHODS: We conducted a case-control study of men aged 50-80 years in Kingston, Ontario who agreed to participate at visits to urology clinics during 1997-99. We compared 101 men with clinically diagnosed ED and 234 controls with various benign urological conditions. All men completed a questionnaire on lifestyle and medical factors. RESULTS: Men with ED were twice as likely to be former smokers (odds ratio 2.2, 95% confidence interval, 1.2-3.9), and cumulative smoking in pack-years suggests a dose-response pattern with the risk of ED. Having diabetes was associated with double the risk of ED, and increased alcohol intake appeared to increase the risk. CONCLUSION: There was a greater risk of ED among former smokers, and the suggestion of a dose-response relationship with cumulative smoking.

Dietary patterns and risk of prostate cancer in Ontario, Canada.

Dietary patterns reflect combinations of dietary exposures, and here we examine these in relation to prostate cancer risk. In a case-control study, 80 incident primary prostate cancer cases and 334 urology clinic controls were enrolled from 1997 through 1999 in Kingston, Ontario, Canada. Food-frequency questionnaires were completed prior to diagnosis and assessed intake in the 1-year period 2-3 years prior to enrollment. Among controls, dietary intake was used in principal components analyses to identify patterns that were then evaluated with all subjects in relation to prostate cancer risk using unconditional logistic regression, controlling for age. Four dietary patterns were identified: Healthy Living, Traditional Western, Processed and Beverages. Increased prostate cancer risk is apparent in relation to the Processed pattern, composed of processed meats, red meats, organ meats, refined grains, white bread, onions and tomatoes, vegetable oil and juice, soft drinks and bottled water. The OR for the highest tertile compared to baseline is 2.75 (95% CI 1.40-5.39), with a dose-response pattern (trend test p < 0.0035). Our results suggest that a dietary pattern including refined grain products, processed meats and red and organ meats contributes to increased prostate cancer risk. Since dietary information was collected before subjects knew their diagnosis, recall bias was avoided.

Causes of erectile dysfunction.

Erectile dysfunction (ED) arises as a result of a collision of circumstances among any of a number of factors (e.g., risk factors, causes, probable associations), each with its own primary power to affect the outcome. Furthermore, each of the components has its own timing as part of a complex effort of compensation and adjustment that often obscures the individual details. In the end, ED results from a failure of local tissues or systemic supply and control structures. The power of any individual "cause" to degrade erectile function is an important but as-yet unquantified property. The power of a small abnormality over a long or critical period (e.g., organogenesis), or many small contributions, or multiple risk factors will certainly be greater than the sum of the individual elements. Without a full quantitation of pathways and their potential influence, one can compare the importance of causative factors only in limited ways. Not surprisingly, it is the presence of a multiplicity of unidentified or poorly understood causative factors that accounts in large measure for the current inability to cure and prevent ED. There are two other important properties of a putatively causative factor for ED--reversibility and preventability--and these are strongly influenced by the time of onset and the duration of impact. Thus, a critical understanding that comes from recognizing the importance of the temporal associations of component factors is that the causes of ED in an individual may be guessed at but cannot be fully disclosed by an analysis of a "snapshot" of the disease taken at the time of diagnosis.

Long-term penile incarceration by a metal ring resulting in urethral erosion and chronic lymphedema.

A patient presented with a metal ring around the base of his penis. The ring had been placed 3 years prior to presentation. Intra-operative findings revealed a ventral erosion with complete transection of the urethra and massive fixed lymphedema of the penile skin distal to the ring. Treatment consisted of removal of the ring with metal shears and bolt cutters. Small reduction of the edema was seen 3 months following removal, and the patient refused further treatment. The most interesting part of the outcome was the preservation of penile urethral voiding although intromission was not possible.

Nitric oxide-mediated regulation of hypoxia-induced B16F10 melanoma metastasis.

Tumour hypoxia is associated with resistance to therapy and with increased invasion and metastatic potential. Recent studies in our laboratory have shown that the hypoxic up-regulation of tumour cell invasiveness and chemoresistance is in part due to reduced nitric oxide (NO) signaling. Using B16F10 murine melanoma cells, we demonstrate here that the increased metastatic potential associated with exposure to hypoxia is mediated by a reduction in cGMP-dependent NO-signaling. Pre-incubation of B16F10 cells in hypoxia (1% vs. 20% O(2)) for 12 hr increased lung colonization ability by over 4-fold. This effect of hypoxia on metastasis was inhibited by co-incubation with low concentrations of the NO-mimetic drugs glyceryl trinitrate (GTN) and diethylenetriamine NO adduct (DETA/NO). In a manner similar to hypoxia, pharmacological inhibition of NO synthesis resulted in a significant increase in lung nodule formation, an effect that was prevented by co-incubation with GTN. An important NO-signaling pathway involves the activation of soluble guanylyl cyclase and the consequential generation of cGMP. Culture in the presence of a non-hydrolysable cGMP analogue (8-Br-cGMP) abrogated the hypoxia-induced lung nodule formation, suggesting that the effects of NO on metastasis are mediated via a cGMP-dependent pathway. These findings suggest that a novel mechanism whereby hypoxia regulates metastatic potential involves a downstream inhibition of cGMP-dependent NO signaling.

Endocrine causes of impotence (nondiabetes).

The endocrine system has a major role in erections in normal men and it can also be a cause of significant morbidity. The relationship between serum testosterone measurement and erectile function is complex. Androgen treatment should certainly be considered in patients without prostate cancer but with a clinical picture that suggests a relevant contribution of hypogonadism to the ED. Other, nondiabetic, endocrine abnormalities may need to be considered in the management or the patient with ED.