Factors Contributing to Detrusor Overactivity - Obstruction, Hypertrophy and Afferent Nerve Stimulation

Sammanfattning: The consequences of bladder outlet obstruction (BOO) with respect to detrusor hypertrophy, structural and functional changes, and obstruction-induced detrusor overactivity were investigated in vivo and in vitro utilizing various animal models. Possible pathophysiological pathways and therapeutic approaches were tested by drug treatment and the use of knockout models. Furthermore the role of estrogen receptor (ER) subtypes in normal micturition and afferent signaling was tested in estrogen receptor knockout-mice, as well as the response of bladder strips to in-vitro stimulation. In rabbits it was found that 2 weeks of BOO caused significant changes in bladders shape, and regional differences occurred in response to different in-vitro stimuli. It was concluded that the bladder is an inhomogeneous organ with significant differences in both its mechanical and pharmacological properties. The effect of an orally administered Endothelin-converting-enzyme (ECE) inhibitor was investigated in rats undergoing 2 weeks of BOO. ECE-inhibition did not prevent the increase of bladder weight after BOO, but seemed to preserve contractile function in vivo. Detrusor overactivity did not occur, in contrast to the untreated obstructed animals. In mice it was found that early BOO-induced overactivity may develop without bladder hypertrophy, and marked differences in voiding pattern can correlate to bladder weight. It was concluded that changes in the afferent function may play a greater role than changes in smooth muscle or efferent neurotransmission, as changes in vitro were subtle. In EP1 receptor knockout mice it was found that the EP1 receptor does not seem to be important in normal micturition, but seems to play a role in the development of detrusor overactivity following BOO, presumably by an effect on the afferent arm of the signaling pathway. PGE2 induced detrusor overactivity appears to be mediated solely by the EP1 receptor. Lack of ERalpha, ERbeta, or both had little or no effect on in-vitro contractility or on continuous cystometry in conscious animals under normal conditions. However, afferent signaling involving capsaicin-sensitive fibers appears to be partly linked to ER subtype-distribution.