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Investigations into the role of endothelin, nitric oxide and prostaglandins in the pathogenesis of diabetic cystopathy

Mumtaz, Faiz Hassan; (2001) Investigations into the role of endothelin, nitric oxide and prostaglandins in the pathogenesis of diabetic cystopathy. Doctoral thesis (M.D), UCL (University College London). Green open access

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Abstract

Endothelin-1 (ET-1) and its receptors (ETA and ETB) have been identified on the urothelium and smooth muscle of the urinary bladder. ET-1 has potent smooth muscle contractile and mitogenic properties. In contrast, the nitric oxide (NO)-cyclic-guanine 3'5' monophosphate (cGMP) pathway mediates bladder outlet smooth muscle relaxation. In addition, the prostaglandin (PG)-cyclic-adenosine 3'5' monophosphate (cAMP) pathway regulates urinary tract smooth muscle tone. The role of these mediators in the pathogenesis of diabetic cystopathy has not been elucidated. Detrusor, bladder neck and urethral tissue from control and six month alloxan-induced diabetic New Zealand White (NZW) rabbits were obtained. Using organ bath, autoradiographic, histochemical, biochemical and tissue culture techniques, the role of these mediators in the pathogenesis of diabetic cystopathy was investigated. These studies demonstrate: 1) Impaired bladder neck and urethral smooth muscle responses to ET-1 and NO in diabetes mellitus (DM) despite a significantly increased expression of ETB receptors and NO synthase (NOS) binding sites. This upregulation may be a compensatory pathophysiological response to smooth muscle dysfunction and/or to alterations in the bioactivity of ET-1 and NO in DM. 2) Decreased formation of cGMP and cAMP by the diabetic smooth muscle that may be a consequence of a decrease in NO and PG bioactivity, respectively. 3) Increased muscarinic receptor-linked PGE2 and PGI2 production by the diabetic detrusor and bladder outlet. This may be a compensatory response to a hypotonic bladder and impaired bladder outlet relaxation in response to NO. 4) Inhibited diabetic smooth muscle cell proliferation by ETA and ETB receptor antagonists indicating a mitogenic role for ET-1 in detrusor hyperplasia. The ET, NO and PG pathways may contribute to the pathogenesis of diabetic cystopathy. The experimental model described may be useful for the evaluation of pharmacological interventions in diabetic cystopathy.

Type: Thesis (Doctoral)
Qualification: M.D
Title: Investigations into the role of endothelin, nitric oxide and prostaglandins in the pathogenesis of diabetic cystopathy
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Health and environmental sciences; Diabetic cystopathy
URI: https://discovery.ucl.ac.uk/id/eprint/10106545
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