Ischemic Etiology of Obstructive Bladder Dysfunction

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DESCRIPTION (provided by applicant): The rabbit model of chronic partial outlet obstruction has proven to be an excellent model for the study of the pathophysiology of human obstructed bladder disease secondary to benign prostatic hyperplasia (BPH). In the rabbit model and in obstructed human bladder tissue, we have identified four defining characteristics of the decompensated (dysfunctional) bladder: 1) cholinergic denervation; 2) mitochondrial dysfunction; 3) decreased sarcoplasmic reticulum (SR) Ca2+ATPase (SERCA) content and activity; and 4) progressive connective tissue (CT) synthesis and redistribution. Results of our recent studies revealed that the rabbit urinary bladders response to partial outlet obstruction is non-uniform, areas of transient focal hypoxia appeared in the bladder wall during the organs initial rapid growth response to obstruction, before any decrease in net bladder blood flow (BF) was observed. Furthermore, these hypoxic foci were clearly visible within the smooth muscle (SM) compartment during compensated bladder function in chronically obstructed rabbits. In addition, EM examination of mildly obstructed bladders revealed focal damage to nerve and muscle cellular and subcellular membranes, i.e., damage was localized only to specific cells within the fields evaluated. From these studies, we have developed the following hypothesis: Ischemia / reperfusion (I/R) - induced membrane damage originates in areas of transient focal hypoxia that first occur in specific regions of the bladder wall during the organs initial response to partial outlet obstruction and are present during compensated function. In the muscle compartment these hypoxic foci are the initiation sites for the contractile and biochemical dysfunctions and smooth muscle collagen synthesis that continue during progressive decompensation. Progression from compensated function to end-stage decompensation occurs as a result of a graduated change from a focal to global response to focal hypoxia; the shift from compensated to decompensated function occurs as membrane damage and collagen synthesis originating in hypoxic foci spreads into normoxic tissue. A corollary of this hypothesis states that aging is accompanied by a loss of antioxidant potential in the bladder resulting in increased sensitivity to I/R damage and increased rate of progression of obstructive bladder dysfunction. The following are our specific aims: Specific Aim 1: To show that I / R - induced focal hypoxic damage begins during the initial response to partial outlet obstruction and continues into and during compensated function. Specific Aim 2" To show that the shift from compensation to decompensation occurs when membrane damage originating in the hypoxic foci spreads into normoxic areas of the bladder wall and that progression to end-stage decompensation occurs as a result of a shift from a focal to a global organ response to focal hypoxia. Specific aim 3: To show that aging results in decreased antioxidant potential of the bladder and an increase in the progression of obstructive bladder dysfunction.