Lau, DHW; (2012) Investigating the role of peripheral serotonergic, purinergic and nitric oxide/cGMP pathways in the normal and pathological erectile process and the effect of Vardenafil on diabetic nephropathy. Doctoral thesis , UCL (University College London).

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Abstract

Serotonin (5-HT, 5-hydroxytrptamine), purinergic and nitric oxide (NO)/ cyclic guanosine monophosphate (cGMP) pathways have been implicated in human penile erection and erectile dysfunction (ED) and the later also involved in the pathogenesis of diabetic nephropathy (DN). The role and characterisation of the peripheral serotonergic and purinergic pathway in corpus cavernosal smooth muscle (CCSM) function was investigated. Electrical field stimulation of human and rabbit CCSM strips demonstrated the presence of neuronally-derived 5-HT acting on 5-HT(2A) receptors. Organ bath studies also showed that 5-HT caused CCSM contraction via 5-HT(1A), (1B), (2A) and (4) receptor subtypes, which was inhibited by doxazosin (an α-1 receptor antagonist known to have 5-HT inhibitory action). Immunohistochemistry and Western Blot analysis confirmed the presence of these 5-HT receptor subtypes in human CCSM. The effect of 5-HT and sodium nitroprusside (SNP; NO donor) on CCSM function from normal, diabetic and partial bladder outlet obstructed (PBOO) rabbit models were also assessed as these pathological models are associated with ED. There was no difference in 5-HT-induced CCSM contractions between the control and pathological models. In contrast, SNP-mediated relaxations were impaired in diabetic and PBOO rabbits. Vardenafil (phosphodiesterase type-5 inhibitor) improved the impaired CCSM relaxation in both models. Immunohistochemistry also identified the presence of purinergic P2Y6 receptors in human CCSM, which when activated induced tissue relaxation. Finally, the effect oral vardenafil treatment has on established renal impairment in diabetic rabbits was investigated. Vardenafil increased cGMP accumulation and improved renal function in DN. These findings suggests that targeting the peripheral serotonergic and purinergic pathways may be useful therapeutic options in treating ED. In addition, the use of vardenafil may be beneficial in the management of DN.

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