The Study On The Role Of T-type Ca～(2+) Channels In The Generation Of Detrusor Excitability And The Pathogenesis Of Detrusor Instability

The detrusor instability, a common condition in bladder dysfunction, causes significant morbidity in sufferers and a great financial expense to health care providers. The condition is associated with symptoms of urinary frequency, urgency and urge incontinence.and even leads to hydronephrosis or hydroureter hydroureteronephroiss, and the impairment of the renal functions in those serious cases. Detrusor instability has features as variant etiologies, high incidence and poor treatment outcomes etc. The exact etiology of detrusor instability has not been unwinded and the main controversy is focused on whether it is neurogenic or myogenic causes. The latest accumulated evidences indicate that detrusor instability is closely related with the spontaneously enhanced excitability of detrusor and the end stage of detrusor instability is the increased excitability of detrusor smooth muscle cells, which is believed to be due to a myogenic alteration of excitability.The detrusor smooth muscle cell is a sort of excitable one, and the generation of its excitation is regulated by a variety of factors, among which the Ca2+ signal plays a key role. The premise of excitation of the detrusor smooth muscle cell is the influx of theextracellular Ca ion, then leads to the alteration of the membrabe potential, and activates the voltage-gated ion channels, and results in the membrane depolarization, simultaneously, other Ca2+-dependent ion channels and receptors also activated by Ca2+ ion, serving as a second messenger, jointly participate in the initiation of the action potential. The influx of Ca2+ ion into the cytoplasm is mainly controlled by way of the Ca2+ channels and there are dense L-type Ca2+ channels in the detrusor cell membrane. Based on the above evidence, the application of L-type Ca2+ channel inhibitors has long been put forward clinically in the treatment of detrusor instability, though this kind of therapy could ameliorate some symptoms, it cann't completely erase the generation of detrusor instability.T-type Ca2+ channel is a low-voltage activated ion channel, with rapid inactivation and relatively slower close kinetics in their gating behaviors. At the period of the resting membrane potential range, it can produce a "widow" current that facilitates the membrane depolarization, and plays a vital role at the stage of initiation of the action potential. At thesame time, T-type Ca2+ channel has three isoforms(subtypes) of a jG-. & \H and a ,1, and these isoforms manifestate diversity characteristics in both gating kinetics and functions. It has been confirmed that the T-type Ca2+ channel play a key role for excitability in the cardiac pacemaker cells and neurons, and some pathological circumstances also existed with an enhanced expression of T-type Ca2+ current.At present, it has not been covered whether the excitability transformation at unstable detrusor myocytes correlated with the constitution and disfunction of T-type Ca2+ channel. Relevant odds and ends reports about the role of T-type Ca2+ channel was covered in the development of excitation at normal detrusor myocytes in the recently years. In 2001 year, it was discovered that detrusor myocytes was present with T-type Ca2+ span membrance current, and in 2003 year, muscle strip experiment proved the excitability of detrusor were drastically reduced by the addition of T-type Ca2+ channel blocker.We carried out our experiment as follows: Frist, The commonly used unstable detrusor animal model (BOO model) was investigated by regular urodynamical method and then the optimal period for assessing the model was determined. Based on this result, the expressions of T-type Ca2+ channels between normal detrusor and unstable detrusor tissues were probed using RT-PCR protocol to see if T-type Ca2+ channels could be the etiology of detrusor instability; Second, The T-type Ca2+ currents were recorded via patch-clamp on the freshly dispersed and cultured normal detrusor myocytes with the end to explore the roles of these currents in the initiation of detrusor myocytes ex...