Mechanism of Bladder Overactivity in Pelvic Ischemia

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DESCRIPTION (provided by applicant): Overactive bladder incorporates to a variety of lower urinary tract symptoms (LUTS) including urinary frequency, urge incontinence, nocturia and pelvic pain. The incidence of bladder overactivity and LUTS increases with age. Clinical studies suggest that the prevalence of bladder overactivity and LUTS among Veterans is almost five fold higher than its incidence in the general population. It has been reported that Veterans with overactive bladder have a worse quality of life score in comparison with Veterans without overactive bladder. In most cases, overactive bladder symptoms are associated with insomnia, anxiety, fatigue, and even depression. Factors predisposing to the development of bladder overactivity and LUTS are poorly understood. In the elderly male, bladder outlet obstruction due to benign prostatic hyperplasia (BPH) has long been blamed. However, urodynamic studies have shown that in approximately one third to more than one-half of cases, LUTS in the elderly are not associated with BPH or bladder outlet obstruction suggesting other possibilities. The specific features of non-obstructed bladder contributing to LUTS remain essentially unknown. We attempt to introduce the concept that aging-associated bladder ischemia is an independent factor in the development of non-obstructed non-neurogenic overactive bladder. Our concept is supported by clinical evidence of a close correlation between bladder ischemia and LUTS in the elderly patients. Blood flow recording with transrectal color Doppler ultrasonography has revealed a significant decrease in bladder blood flow in the elderly patients in comparison with asymptomatic younger controls. It was shown that decreased bladder blood flow significantly correlates with the severity of LUTS in these patients. Ischemia is one of the leading causes of smooth muscle spasm in the stomach, intestine, uterus, and bronchioles. Our studies with a rabbit model have shown that atherosclerosis-induced pelvic ischemia results in bladder overactivity and increased voiding frequency. In preliminary studies, we found that chronic bladder ischemia activated redox survival signaling via phosphoinositide 3-kinase (PI3-Kinase)/protein kinase B (Akt) pathway in smooth muscle cells and nerve fibers. Oxidative stress in cultured smooth muscle cells upregulated redox survival signaling via PI3-kinase and Akt expression and evoked two vital responses to promote survival: 1) Increase in mitochondrial density and respiration rate. 2) Increase in smooth muscle cell Ca++ uptake. These redox survival responses augmented smooth muscle contractions and were associated with bladder overactivity and voiding dysfunction. Inhibition of PI3-Kinase diminished bladder smooth muscle overreactivity to contractile stimuli. Based on these observations, we hypothesize that: "Activation of redox survival signaling via PI3-kinase/Akt pathway in bladder ischemia stimulates smooth muscle and neural mitochondrial respiration and promotes smooth muscle cell Ca++ uptake resulting in excessive contractile activity and voiding dysfunction". Our overall goal is to explore the role of ischemia and redox signaling in bladder overactivity using our well-established animal and cell culture model systems." Our specific aims are: 1) To define redox regulation of bladder smooth muscle contractility via PI3-kinase/Akt survival pathway and mitochondrial respiratory chain under the ischemic conditions. 2) To define regulation of smooth muscle cell PI3-kinase/Akt survival pathway, mitochondrial respiration and Ca++ uptake by neural redox elements in bladder ischemia. 3) To define regulation of smooth muscle cell PI3-kinase/Akt survival pathway, mitochondrial respiration, and Ca++ uptake by redox-modified muscarinic receptors in bladder ischemia. 4) To develop therapeutic strategies targeting redox signaling, redox elements and modified receptors to prevent or reverse augmented smooth muscle contractions and bladder overactivity in pelvic ischemia. The proposed studies will elucidate some of the highly controversial aspects of non-obstructed non-neurogenic overactive bladder and may lead to newer therapeutic strategies against bladder overactivity in the elderly population.