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Central 5-HT containing pathways have been shown to play an important role in the control of micturition with a focus on 5-HT receptor influence on the parasympathetic outflow to the bladder, and somatic outflow to the external urethral sphincter (EUS) in the rat. 5-HTjA and 5-HT7 receptors have been revealed to be physiologically involved in the control of micturition. Moreover, from the literature, activation of the 5-HT2 receptor, specifically 5-HT2C receptor has been observed to be inhibitory on the micturition reflex, although no physiological role for this receptor subtype has yet been established. Using reportedly selective 5-HT2 receptor agonists and antagonists, the present work reveals the excitatory actions of the 5-HT2A receptor on the external urethral sphincter and the micturition reflex, the inhibitory actions of the 5-HT2C receptor in micturition and the involvement of 5-HT2B receptors in mediating urethral smooth muscle contraction. Further, data from the present study demonstrates that 5-HT2A receptors excite the external urethral sphincter at the level of the sacral spinal cord and further supports the view that the inhibitory action of the 5-HT2C receptors on micturition is centrally mediated. Molecular evidence regarding expression of 5-HT2 receptor subtypes in the lower urinary tract of the rat is also provided in the present study, with 5-HT2A, 5- HT2B and 5-HT2C receptor mRNA expression observed in the rat bladder, urethra and brain respectively. Overall, this thesis provides evidence for the involvement of 5-HT2 receptors in the control of micturition, although it is still unclear as to the physiological role of this receptor family in the control of micturition.

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The use of medical devices in the urinary tract is limited by infection. Consequences of catheter-associated urinary tract infection include an increase in mortality, perhaps due to secondary bacteraemia and septicaemia is, as well as increased expenditure on the replacement of catheters. Infection with urease-producing bacteria such as Proteus mirablis results in hydrolysis of urea in ammonia and carbon dioxide, and precipitation of magnesium and calcium salts which can result in the blockage of urinary medical devices, resulting in urine bypassing the catheter. This thesis aims to present a proof-of-concept of a pH-triggered multilayer catheter coating, capable of reacting to the presence of infection In vivo to reduce bacterial adherence to a urinary biomaterial. The methyl methacrylate polymers, Eudragit Preparation 415SF and Eudragit L1OO, were investigated as potential urinary catheter coatings. Eudragit Preparation 415SF is soluble at pH values above pH 7. Eudragit L lOO is soluble at pH values above pH 6. It was hypothesised that the tell-tale increase in pH as a result of infection with urease-producing bacteria like P. mirabilis would trigger a shedding of these surface layers, reducing bacterial adherence. By loading these polymer coatings with antibacterial agents and functional excipients, active agent could be released into the surrounding area, providing a secondary means of reducing bacterial activity. Initial studies developed formulations of Eudragit Preparation 41SSF and Eudragit L100, loaded with levofloxacin or nalidixic acid as model antibiotics, that could be processed using bench-top hot-melt extruders. Drug release studies in phosphate buffered saline at pH values representative of healthy and infected urine (pH 6.2 and ph. 7.8, respectively) demonstrated the pH-responsive properties of these formulations. When challenged with bacteria in artificial urine, the response of these formulations to the pH change caused by infection with urease-producing bacteria was demonstrated, with significantly reduced bacterial adherence with levofloxacin-containing formulations.