MP8-08 PROLONGED ISCHEMIA MEDIATES OVERACTIVE BLADDER TRANSITION TO UNDERACTIVE BLADDER

Abstract

INTRODUCTION AND OBJECTIVES: Underactive bladder (UB) is a clinical challenge both in terms of accurate diagnosis and effective treatment. The etiology of UB remains unknown. Growing evidence suggests that chronic ischemia may contribute to bladder structural damage and dysfunction. We examined voiding behavior, cystometrograms (CMG), and tissue samples after short-term (8 weeks) and long-term (16 weeks) bladder ischemia. METHODS: Male Sprague-Dawley rats were assigned to treatment, sham,andage-matchedcontrol groups. In the treatedgroup, vascular lesions were introduced to create bilateral iliac artery atherosclerosis and chronic bladder ischemia. Subgroups underwent metabolic cage studies, hemodynamicmeasurements, andCMGat 8weeks and 16weeks after the induction of bladder ischemia. Tissues were processed for analysis. RESULTS: Iliac artery and bladder blood flow decreased in the treated group. At 8 weeks, 60% of treated group developed moderate bladder ischemia (MBI) and 40%had severe bladder ischemia (SBI). At 16 weeks, 30% of treated group had MBI and 70% had SBI. Metabolic cage studies showed increased micturition frequency (MF) and decreased voided volume (VV) in short-term MBI and SBI and long-term MBI. Longterm SBI decreased MF but did not alter VV. CMG showed marked fluctuations in intravesical pressure in MBI and decreased contractile activity in SBI. With filling, pre-micturition pressure increased and bladder compliance decreased in short-termMBI and SBI and in long-termMBI. In long-term SBI, pre-micturition pressure and bladder compliance decreased and residual volume increased. Markers of free radical injury and oxidative stress were present in MBI and SBI. Organ bath showed hypersensitivity to contractile stimuli in MBI and impaired contractile reactivity in SBI. Western blot showed significant upregulation of muscarinic M2 receptor in both short-term and long-term MBI and upreguation of M1 and downregulation of M3 in long-term SBI. TEM showed mitochondrial structural damage in MBI and decrease mitochondrial density in SBI. CONCLUSIONS: Structural and functional consequences of bladder ischemia depend on the severity and duration of arterial insufficiency. Short-term ischemia induced overactivity regardless of severity, while the effects of long-term ischemia are severity-dependent. Prolonged severe ischemia leads to changes consistent with UB. Longterm SBI appears to mediate the transition to underactivity via mechanisms involving oxidative stress, muscarinic receptors, mitochondrial energy production, and loss of contractile activity.