Bladder voiding dysfunction is closely related to local oxidation,
inflammation, and enhanced channel activities. Given that the
AMP-activated protein kinase (AMPK) has anti-oxidative, anti-inflammatory and channel-inhibiting properties, we examined whether and how AMPK affected bladder activity. AMPK activation in rat bladder smooth muscle cells (BSMCs) using three different AMPK agonists resulted in a decrease in
connexin43 (
Cx43) expression and function, which was associated with reduced CREB phosphorylation,
Cx43 promoter activity and
mRNA expression, but not
Cx43 degradation. Downregulation of CREB with
siRNA increased
Cx43 expression. A functional analysis revealed that AMPK weakened BSMC contraction and bladder capacity. AMPK also counteracted the IL-1β- and TNFα-induced increase in
Cx43 in BSMCs. In vivo administration of the AMPK agonist
AICAR attenuated
cyclophosphamide-initiated bladder oxidation,
inflammation,
Cx43 expression and voiding dysfunction. Further analysis comparing the responses of the wild-type (
Cx43(+/+)) and heterozygous (
Cx43(+/-))
Cx43 mice to
cyclophosphamide revealed that the
Cx43(+/-) mice retained a relatively normal micturition pattern compared to the
Cx43(+/+) mice. Taken together, our results indicate that AMPK inhibits
Cx43 in BSMCs and improves bladder activity under pathological conditions. We propose that strategies that target AMPK can be developed as novel therapeutic approaches for treating bladder dysfunction.