Lower urinary tract symptoms (LUTS) are a family of bladder symptoms that are a major negative driver of the quality of life of men and women who suffer from them. The pathophysiology is largely unknown; however, mechanisms are proposed to originate from neurogenic and myogenic changes. The neurogenic and myogenic origins of urinary bladder dysfunction are often characterized by lower urinary tract symptoms associated with inflammation, specifically resulting from mast cell degranulation, that are proposed to alter sensory nerves and urothelial cells within the urinary bladder. Interestingly, these same inflammatory mediators released from mast cells cause both short-and long-lasting contractions of urinary bladder smooth muscle (UBSM). These contractions could be viewed as initial disruptors of normal bladder function and can lead to dysregulation of bladder smooth muscle contractility. Thus, this dissertation seeks to address the following hypothesis: histamine released after mast cell activation directly increases urinary bladder smooth muscle contractility independent of nerves. We discovered that histamine-mediated contractions rapidly desensitize, whereas the mast cell activator compound 48/80 caused both a long-lasting increase in the amplitude and frequency of spontaneous phasic contractions as well as a transient increase in baseline tension in UBSM strips. Compound 48/80 also significantly augmented nerve-evoked contractions in UBSM strips, whereas histamine did not alter these contractions. Surprisingly, none of these effects were dependent on mast cells. Mast cell-deficient mice responded identically to compound 48/80, as compared to the mast cell-sufficient controls. Instead, the effects of compound 48/80 were dependent upon the release of prostaglandins from the urothelium. Together, these findings suggest that mast cells alone are not responsible for driving myogenic changes to urinary bladder contractility. Rather, the urothelium itself responds to pseudoinflammatory insults by releasing prostaglandins that alter UBSM responses to normal neuronal input. This mast cell-independent mechanism may be useful for identifying urothelium-specific targets for the treatment of LUTS.
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