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.


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.
Apostolidis
A N
AN
Peripheral Neuropathy Unit, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
Yiangou
Y
Y
Brady
C M
CM
Ford
A P
AP
Baecker
P A
PA
Jacques
T S
TS
Freeman
A
A
Fowler
C J
CJ
Anand
P
P
D000283:Administration, Intravesical; D001706:Biopsy / Q000379:methods; D004224:Diterpenes / Q000008:administration & dosage*; D004311:Double-Blind Method; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009498:Neurotoxins / Q000008:administration & dosage*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D011446:Prospective Studies; D001743:Urinary Bladder / Q000201:enzymology* / Q000473:pathology; D001750:Urinary Bladder, Neurogenic / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D004224:Diterpenes; D009498:Neurotoxins; D042461:Vascular Endothelial Growth Factor A; C024353:resiniferatoxin; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III