Constitutively active phosphodiesterase type 4 controls large conductance Ca2+‐activated K+ channel activity in guinea pig urinary bladder smooth muscle

Abstract

Nonselective pharmacological inhibition of phosphodiesterases (PDE) elevates cellular cAMP levels, leading to activation of the large conductance Ca2+‐activated K+ (BK) channels and attenuation of guinea pig urinary bladder smooth muscle (UBSM) excitability and contractility. Here, we investigated the mechanism of selective inhibition of cAMP‐specific PDE4 on UBSM excitability and contractility using the perforated patch‐clamp technique on isolated UBSM cells and isometric tension recordings of UBSM isolated strips. Our data showed that selective PDE4‐inhibition with rolipram increased the spontaneous transient BK currents frequency and hyperpolarized the cell resting membrane potential (RMP). Blocking BK channels with paxilline reversed the hyperpolarization effect of rolipram and depolarized the RMP back to the control levels. PDE4‐inhibition did not cause RMP hyperpolarization in the presence of cAMP‐dependent protein kinase (PKA) inhibitor, H‐89. PDE4 inhibition reduced the UBSM spontaneous phasic and carbachol‐induced contraction frequency and amplitude, as well as the electrical‐field‐stimulation‐induced contraction amplitude. In conclusion, selective inhibition of the constitutively active PDE4 suppressed the guinea pig UBSM excitability and contractility via a BK channel‐dependent mechanism involving the PKA signaling pathway. Supported by NIH DK08424 to GVP.