Amplified NO/cGMP‐mediated relaxation and ryanodine receptor‐to‐BK Ca channel signalling in corpus cavernosum smooth muscle from phospholamban knockout mice

BACKGROUND AND PURPOSE Relaxation of corpus cavernosum smooth muscle (CCSM) is induced by NO. NO promotes the formation of cGMP, which activates cGMP‐dependent protein kinase I (PKGI). The large conductance calcium‐activated potassium (BK Ca ) channel is regarded as a major target of NO/cGMP signalling; however, the mechanism of BK Ca activation remains unclear. The aim of the present study was to determine whether sarcoplasmic reticulum (SR) Ca 2+ load and Ca 2+ release from the SR via ryanodine receptors (RyRs) is important for BK Ca channel activation in response to NO/cGMP. EXPERIMENTAL APPROACH In vitro myography was performed on CCSM strips from wild‐type and PLB knockout (PLB −/− ) mice to evaluate contraction and relaxation in response to pharmacological agents and electrical field stimulation (EFS). KEY RESULTS In CCSM strips from PLB −/− mice, a model of increased SR Ca 2+ load, contractile force in response to EFS or phenylephrine (PE) was increased by nearly 100%. EFS of strips precontracted with PE induced transient relaxation in CCSM, an effect that was significantly larger in PLB −/− strips. Likewise, the relaxation of PE‐induced contraction in response to SNP and cGMP was greater in PLB −/− , as demonstrated by a shift in the concentration–response curve towards lower concentrations. Blocking RyRs and BK Ca channels diminished the induced relaxations and eliminated the difference between wild‐type and PLB −/− . CONCLUSIONS AND IMPLICATIONS NO/cGMP activates BK Ca channels through RyR‐mediated Ca 2+ release. This signalling pathway is responsible for approximately 40% of the NO/cGMP effects and is amplified by increased SR Ca 2+ concentrations.