The large‐conductance, voltage‐dependent and Ca2+‐dependent K+(BK) channel links membrane depolarization and local increases in cytosolic free Ca2+to hyperpolarizing K+outward currents, thereby controlling smooth muscle contractility. Constitutive deletion of the BK channel in mice (BK−/−) leads to an overactive bladder associated with increased intravesical pressure and frequent micturition, which has been revealed to be a result of detrusor muscle hyperexcitability. Interestingly, time‐dependent and smooth muscle‐specific deletion of the BK channel (SM‐BK−/−) caused a more severe phenotype than displayed by constitutive BK−/−mice, suggesting that compensatory pathways are active in the latter. In detrusor muscle of BK−/−but not SM‐BK−/−mice, we found reduced L‐type Ca2+current density and increased expression of cAMP kinase (protein kinase A; PKA), as compared with control mice. Increased expression of PKA in BK−/−mice was accompanied by enhanced β‐adrenoceptor/cAMP‐mediated suppression of contractions by isoproterenol. This effect was attenuated by about 60–70% in SM‐BK−/−mice. However, the Rp isomer of adenosine‐3′,5′‐cyclic monophosphorothioate, a blocker of PKA, only partially inhibited enhanced cAMP signaling in BK−/−detrusor muscle, suggesting the existence of additional compensatory pathways. To this end, proteome analysis of BK−/−urinary bladder tissue was performed, and revealed additional compensatory regulated proteins. Thus, constitutive and inducible deletion of BK channel activity unmasks compensatory mechanisms that are relevant for urinary bladder relaxation.