In recent decades one of the major forces driving lower urinary tract research has been the aim of discovering the origins of bladder dysfunction and developing new therapeutic agents for treatment of conditions such as detrusor overactivity (DO). It is now becoming clear that the simplistic view of the control of detrusor function is far more complicated and involves complex interactions between various components of the bladder. With limited access to human tissue, animal models have been used for investigating the underlying mechanisms that control the detrusor function under pathological states. The aim of this project was to investigate the physiology and pathophysiology of bladder function in the streptozotocin (STZ)-induced diabetic rat model, 1, 4, 8 and 12-weeks post STZ injection. This was achieved by a combination of pharmacological, molecular biology and immunostaining techniques. Antimuscarinic drugs are the current pharmacological agents available for treatment of DO; however, there is much controversy surrounding the muscarinic mediated responses of the bladders from animal models of DO. Therefore, the muscarinic receptor mediated smooth muscle contractions were investigated in detrusor strips from the diabetic rat. An increased agonist mediated response was detected in detrusor strips from 1-week diabetic rats, which was mediated by M3-muscarinic receptor subtype. Basal spontaneous activity (SA) was detected in detrusor strips from control (nondiabetic) and diabetic but not in 12-week diabetic tissues. 1-week diabetic tissues showed increased amplitude of basal SA compared to all other groups. Since increased amplitude of SA of the bladder is thought to be associated with DO, the mechanisms that may be regulating these contractions were explored. SA could be induced/modulated by low concentrations of muscarinic receptor agonist carbachol (CCH). Once again, the amplitude of CCH-induced SA was significantly bigger in 1-week diabetic tissues compared to all other groups. No role for the mucosa in mediating the CCH-induced SA was demonstrated; however, the mucosa may have a role in 12-week diabetic tissues. The role of various potassium (K+) channels in modulating the SA was also investigated. Results demonstrated that opening of large conductance calcium activated potassium channels (BK Ca) reduced the amplitude of CCH-induced SA in both control (non-diabetic) and diabetic groups, whilst blocking these channels resulted in an increased basal SA in all groups except 12-week diabetic tissues. A decreased expression of BK Ca channel subunits' mRNA was detected in all diabetic bladders. Opening of ATP sensitive K+ channels (K ATP) only decreased the frequency of CCH-induced SA. Blocking K ATP channels had no effect on basal SA in all tissues. A reduced expression of K ATP channel subunits' mRNA was also detected in diabetic rat bladders. Recently a specialised type of cell, termed interstitial cells (ICs) has become the focus of research. It is postulated that they are involved in mediating the mechanosensory function of this organ. In this study, ICs were also identified in the rat urinary bladder using molecular biology and immunostaining. ICs were shown to play a role in mediating the CCH-induced SA of detrusors from rats, since their inhibition resulted in reduced SA in both control (non-diabetic) and diabetic tissues. Marked differences were seen between 1-week and 12-week diabetic rat bladders and it was concluded that 1-week diabetic rats can be used as a model of DO.In conclusion, the data presented in this thesis, indicates that complex mechanisms and physiological processes are present in the urinary bladder. It is clear that little is known about the detailed integrated physiology of the bladder wall and the structures involved in mediating the detrusor contractility.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:503750 |
| Date | January 2009 |
| Creators | Vahabi, Bahareh |
| Contributors | Sellers, Donna ; Mckay, Neil ; Lawson, Kim ; Woodroofe, Nicola |
| Publisher | Sheffield Hallam University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://shura.shu.ac.uk/20829/ |
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