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The function of the bladder is twofold: 1) to store urine at low pressure, and 2) under control of the nervous system, to generate a contractile force coordinated with a lowered urethral resistance that allows for emptying.20 Clinically, this system is most commonly affected by bladder outlet obstruction, and the response of the detrusor is remarkable in its variability. Experimentally, most investigators agree that after outlet obstruction, there is an increase in bladder mass seen irrespective of the model used. Within most experimental models of partial obstruction (as with humans), there exists a degree of variability in terms of detrusor response. Some bladders enter a state of compensation and are able to sustain elevated voiding pressures and empty satisfactorily. Others enter a state of decompensation and lose their ability to empty effectively.15 The molecular mechanisms for such decompensations are under current investigation, and may involve alterations in cytosolic calcium handling,19,21 disruptions in mitochondrial function,4 and changes in the expression of contractile filaments.1 In the late stages, as the bladder slides into the decompensated state, major depositions of extracellular matrix are seen in a variety of species.3,9,11

Force production by the bladder body smooth muscle and relaxation of the bladder outlet, required for bladder emptying, are regulated by Ca2+ via myosin light chain (MLC) phosphorylation by a Ca2+-calmodulin-dependent MLC kinase (for review, 1–3). Besides this mode of regulation, evidence from most laboratories, including ours, supports the existence of a thin-filament-mediated regulation due to protein-protein interaction by actin-binding proteins acting in concert with tropomyosin and a calcium-binding protein, most likely, calmodulin. Caldesmon (CaD), a thin-filament-associated protein, inhibits the ac-tin-myosin interaction and actomyosin ATPase, and this inhibition is reversed by calmodulin in the presence of Ca2+.3–5 Urinary bladder outlet obstruction interferes with the ability of the bladder to empty its contents, thereby inducing changes in the bladder wall smooth muscle cells which enable the bladder to produce the increased contractile force required to expel urine through the obstructed urethra. In the initial phases of outlet obstruction, there is transient decompensation of the bladder smooth muscle, which initiates the molecular events that lead to hypertrophy of the detrusor smooth muscle cells enabling it to generate and maintain force. However, continuation of the outlet obstruction induces molecular, cellular, and structural alterations in the muscle cells of the bladder wall, leading ultimately to decreased compliance and impaired emptying. The ability of smooth muscles to compensate for increased functional demand is associated with alterations in the expression of proteins in the thick- and thin-filaments.

The purpose of the urinary bladder is to store urine at low pressures, and allow for effective evacuation at an appropriate time, location and social situation. For this complex set of requirements to be carried out, it is essential that the major components of the lower urinary tract interact in a unified fashion.1 The basic elements of the bladder which contribute to the active (contractile) and passive properties (resistance to deformation) are listed in Table 1. It is important to note that even the passive properties of the urinary bladder are in part determined by actin myosin interactions that are calcium mediated and energy dependent. Failure of any one (usually several) of these components will contribute to a failure to empty or to store, or some combination thereof. Although each component within this table makes an important contribution to shaping the bladder’s biologic properties, the purpose of this review will be to focus on the role of cell calcium regulation in which the sarcoplasmic reticulum (SR) plays a major role.

Urinary outlet obstruction causes rapid increases in bladder mass; the extent of the increase in mass is directly proportional to the severity of the obstruction1–3. Although there may be some species differences, in general, the changes in bladder contractility associated with outlet obstruction are also dependent upon the degree of increase in bladder mass. Bladder strips from animals with “mild” obstruction (less than 3-fold increase in bladder mass) respond to electrical field stimulation or contractile agents with no change or increases in contractile response compared to controls1–5. In contrast, bladder strips from animals with “severe” obstruction, where the bladder mass increases more than 6-fold, respond to contractile stimuli with decreases in contractile responses and an impaired ability of the bladder to empty2,3,6–10. Depending on the duration and severity of obstruction, removal of the obstruction generally causes reversal of the contractile dysfunction11,12. The mechanisms responsible for the changes in bladder contractility associated with bladder outlet obstruction are still unclear, but as described in other chapters in this book, may include alterations in glucose metabolism13–19, in bladder innervation and/or action potential properties20–25, or alterations in the contractile proteins responsible for smooth muscle contraction26–31. The latter mechanism will be discussed in this chapter.