Parallel changes in bladder suburothelial vanilloid receptor TRPV1 and pan-neuronal marker PGP9.5 immunoreactivity in patients with neurogenic detrusor overactivity after intravesical resiniferatoxin treatment.

OBJECTIVE: To compare PGP9.5 and transient receptor potential vanilloid receptor (TRPV1) suburothelial immunoreactivity between controls and patients with spinal neurogenic detrusor overactivity (NDO) before and after treatment with intravesical resiniferatoxin, as suburothelial PGP9.5-staining nerve fibres decrease in patients with spinal NDO who respond to intravesical capsaicin, and TRPV1 is present on these suburothelial nerve fibres in normal and overactive human urinary bladder. PATIENTS AND METHODS: Patients with refractory NDO were enrolled in a prospective, randomized, parallel-group, double-blind, placebo-controlled trial using escalating doses of resiniferatoxin to a maximum of 1 micro mol/L. Flexible cystoscopic bladder biopsies obtained at baseline, 4 weeks after each instillation and at the time of maximum clinical response were compared with biopsies taken from control subjects. Frozen sections were incubated with rabbit antibodies to TRPV1 and PGP9.5, and assessed using standard immunohistochemical methods. PGP9.5 nerve density was analysed using a nerve-counting graticule by an observer unaware of sample origin. Another two independent observers unaware of each other's results used a random grading scale to evaluate TRPV1 nerve fibre density and intensity. The immunohistochemistry results were compared with histology findings (haematoxylin-eosin), and the Mann-Whitney test used to assess any differences (P < 0.05 significant) and the Pearson test for correlation. RESULTS: There were eight controls and 20 patients with spinal NDO, 14 (five clinical responders and nine not) who received the maximum dose of resiniferatoxin. There were more PGP9.5 and TRPV1 nerve fibres in patients with NDO than in controls (P = 0.007 and 0.002, respectively). Immunoreactivity before resiniferatoxin was similar in both groups for both PGP9.5 and TRPV1. In responders there were fewer PGP9.5 and TRPV1-positive fibres after treatment (P = 0.008 for each) but no change in those not responding. Changes after treatment for TRPV1 correlated well with those for PGP9.5 (r = 0.88, P < 0.001). CONCLUSIONS: The decrease of PGP9.5 and TRPV1 immunoreactive nerve fibres in responders to resiniferatoxin (to levels in control tissues) suggests that the increased numbers of nerve fibres in patients with NDO are mainly of sensory origin and express TRPV1. As baseline nerve fibre values were similar in responders and nonresponders, an additional factor may account for the difference in treatment outcome.

Endothelial nitric oxide synthase expression in neurogenic urinary bladders treated with intravesical resiniferatoxin.

OBJECTIVE: To investigate endothelial nitric oxide synthase (eNOS) immunoreactivity in bladder biopsies from patients with neurogenic detrusor overactivity (NDO) before and after treatment with intravesical resiniferatoxin, and compare this with control material; the distribution of two other vascular markers, von Willebrand Factor (vWF) and the vascular endothelial growth factor (VEGF), was also studied. PATIENTS AND METHODS: Flexible cystoscopic bladder biopsies from eight controls investigated for asymptomatic microhaematuria and 19 patients with refractory spinal NDO enrolled in a clinical trial of intravesical treatment with escalating doses of resiniferatoxin were immunostained with polyclonal rabbit antibodies for eNOS, vWF and VEGF. Fewer baseline NDO specimens (eight) were available for vWF and VEGF staining. Computerized image analysis was used to quantify immunoreactivity, and the Mann-Whitney test for statistical analysis. RESULTS: eNOS immunoreactivity was found in the suburothelium and less often in the urothelium, with a distribution indicating a location in small blood vessels at the urothelium-suburothelium junction. Immunostaining for vWF showed a similar location. There was a trend to higher eNOS values before treatment in those responding than in those not responding to resiniferatoxin (P = 0.059), and a significant reduction in eNOS immunoreactivity after successful treatment (P = 0.016). VEGF staining was weaker but there was a significant increase in pretreatment biopsies of responders to resiniferatoxin (P = 0.048). Clinical and histopathology features were similar in both groups. CONCLUSIONS: The trend for higher eNOS expression in patients with NDO who responded to resiniferatoxin suggests that increased vasculature or vasodilatation in the suburothelium may be necessary for successful intravesical treatment. Further studies with more patients are required to confirm this relationship and to examine the mechanisms underlying changes in vasculature with levels of bladder overactivity.

Erectile and urinary dysfunction may be the presenting features in patients with multiple system atrophy: a retrospective study.

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by parkinsonism and cerebellar, autonomic, urinary, and/or pyramidal dysfunction. Urinary and erectile dysfunction (ED) symptoms are prominent early features in men with MSA. Autonomic failure, considered until recently to be the cause of ED in these men, is commonly expressed through symptoms of orthostatic hypotension (OH). The aim of this retrospective study is to examine the chronological relationship between the development of urogenital symptoms and those of OH in patients diagnosed with MSA and discuss its significance in the aetiology of ED in these patients. A total of 71 male patients, referred to a Uro-Neurology department with a diagnosis of 'probable MSA', were reviewed in terms of 'autonomic' symptoms only--OH and lower urinary tract symptoms, accompanied by ED--present at the time of their referral. Laboratory investigations including anal sphincter EMG and/or autonomic function tests (AFTs) were performed in 75 and 90% of the patients, respectively. At presentation, urinary complaints were recorded in 96% of patients and ED in all patients that this was inquired about. The onset of ED had preceded the onset of bladder symptoms in 58% and the onset of OH symptoms in 91% of these men. Bladder symptoms also preceded symptoms of OH in 76% of patients. Sphincter EMG was abnormal in 91% and AFTs in 77% of the patients tested. Almost all patients with abnormal EMG had troublesome urinary symptoms. AFTs showed similar sensitivity relating to symptoms. At presentation, urogenital symptoms are common in patients with probable MSA and are often not accompanied by symptoms of OH. The earlier occurrence of ED in men with MSA suggests a lack of a causal relationship to hypotension. The notion that MSA possibly affects the dopaminergic mechanism of erectile function is discussed.