The focus of this competitive grant renewal is on the cellular and subcellular etiologies for the contractile dysfunctions induced by partial outlet obstruction in rabbits, the relevance of these findings to bladder dysfunction secondary to BPH in men, and using this information to develop novel and effective therapies for treatment of BPH induced obstructive bladder dysfunction. The response of the rabbit bladder to partial outlet obstruction can be separated into compensated and decompensated function. Compensated function is characterized by relatively normal function, increased but stable bladder mass, and stable contractile function. Decompensation is characterized by a further progressive increase in bladder mass, and deterioration in the contractile, metabolic, and functional status. The transition from compensation to decompensation, and progression to end- stage decompensation is mediated by progressive denervation, mitochondrial dysfunction, and dysregulation of intracellular calcium (Ca+2) storage and release from the sarcoplasmic reticulum (SR). Hypothesis: Ischemia/reperfusion injury is a major etiology for bladder dysfunction i.e., decompensation, following partial outlet obstruction in rabbits and benign prostatic hyperplasia (BPH) in humans. Ischemia/reperfusion causes both dysregulation of Ca+2 homeostasis and free radical generation which result in, respectively, activation of Ca+2-dependent hydrolytic enzymes and membrane lipid peroxidation. Therapeutic strategies which prevent Ca+2 -overload, reduce the concentration of free radicals, and / or protect cellular membranes will reduce the progression of decompensation.
Specific aims : 1. To generate evidence for the hypothesis that ischemia/reperfusion is a major etiological factor for bladder decompensation secondary to partial outlet obstruction. 2. To accumulate evidence that the above hypothesis for the progression of bladder decompensation observed in the rabbit secondary to partial outlet obstruction is relevant to the progression of bladder dysfunction secondary to BPH in men. 3. To test potential therapies in the obstructed rabbit bladder model directed at: a) reducing the generation of free radicals and peroxidation damage, b) reducing the calcium- overload induced by ischemia/reperfusion, and c) protecting the neuronal and smooth muscle subcellular membranes from hydrolytic damage.
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