Hui Q. Pan, Dan Li Lin, Lindsay Eggers, David Sypert, Vincent M. Monnier, Firouz Daneshgari and Margot S. Damaser

Departments of Biomedical Engineering and Urology, Cleveland Clinic, Cleveland OH, and Louis Stokes Cleveland VA Medical Center, Cleveland, OH and Dept of Pathology, Case Western Reserve University, Cleveland, OH

Introduction: Diabetes Mellitus (DM) increases the risk of stress urinary incontinence (SUI), contributing to the high prevalence of SUI among women. The injury of the pudendal nerve (PN) during vaginal delivery has been postulated as a mechanism of SUI in women. Further, accumulation of advanced glycation endproducts (AGEs) in the peripheral nerves has been linked to diabetic neuropathy. However, the relationship between DM, birth trauma and SUI is poorly understood.

Objective: The aims of this study were to determine: 1. If PN injury in DM animals results in increased severity of SUI symptoms; and 2. If the severity of SUI in DM animals are associated with increased accumulation of AGEs.

Methods: Sixty six female virgin Sprague-Dawley rats were divided into DM, diuretic (DU) and untreated control (C) groups with 22 each. Each group was subdivided into PN crush (PNC) and sham PNC (SPNC) groups. DM rats (8 weeks prior to PNC) were induced by injection (i.p) of Streptozotocin (35 mg/kg). DU rats were given 5% sucrose in their drinking water for 8 weeks. For PNC, the PN was crushed twice bilaterally by closing a Castroviejo needle holder over it for 30 seconds. For SPNC, rats underwent a dorsal skin incision only. All rats underwent awake cystometry (CMG) and leak point pressure (LPP) testing 4 days after PNC or SPNC. The bladder, urethra, vagina and PN were dissected and tested for accumulation of AGEs using gas chromatography/mass spectrometry (6/group) or embedded in paraffin (5/group) for histological assessment.

Results: DM rats with SPNC had significantly increased voiding pressure and volume voided during CMG compared to both DU and C rats with SPNC. The duration of void was not significantly different in DM rats with SPNC compared to DU and C rats with SPNC. DM rats with PNC demonstrated decreased voiding pressure and duration of void compared to DM rats with SPNC. The volume voided by DM rats with PNC was not significantly different from that of DM rats with SPNC. The abdominal pressure increase to leakage during LPP testing was significantly decreased after PNC compared to SPNC and there were no differences between the C, DU, and DM groups after either PNC or SPNC. Furosine and carboxymethyl-lysine (CML) were significantly increased in all tissues tested in DM rats compared to C and DU rats and were not significantly different between PNC and SPNC subgroups. Carboxyethyl-lysine (CEL) or 2-amino-adipic acid, an oxidation marker, showed no significant differences between the groups. Bladders and vaginas of DM rats weighed significantly more than those of DU and C rats. Bladders of DU rats weighed significantly more than those of C rats. Bladder lumen and wall thickness were increased in DM rats compared to DU and C rats. Pathology of the EUS was increased in rats with PNC compared to rats with SPNC in all groups.

Conclusions: DM rats with SPNC exhibit increased voiding pressure and increased urinary volumes typical of diabetic cystopathy. DM rats with PNC likely have a highly distensible urethra, enabling them to void the same increased volumes in a shorter time and with less voiding pressure. PNC leads to decreased urethral resistance as demonstrated by LPP testing in all groups. Therefore, PN injury may play an important role in the development of SUI in DM and elevated levels of some AGEs may contribute to the dysfunction.

Acknowledgements: NIH R21-DK070905 and RR&D Service of the VA

UroToday.com Coverage of SUFU 2007

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