Figure 11.

Hypothetical regulation of cAMP levels by activated PDE3 (3) and PDE4 (4) in compartments at different distances from activated β₁- and β₂-adrenoceptors in rat ventricle. (A) Physiological situation. (B) Inhibition of PDE3. (C) Inhibition of PDE4. (D) Inhibition of both PDE3 and PDE4. Black dots represent steady state concentrations of cAMP in each domain. (−)-Noradrenaline (NA) and (−)-adrenaline (Adr) stimulate β₁- and β₂-adrenoceptors, respectively, thereby increasing the production of cAMP and activating PDE3 and PDE4. Two sequential barriers, formed by activated PDEs, break down cAMP. The composition of PDEs in both barriers is different for β₁- and β₂-adrenoceptors. L-type Ca²⁺ channel function is enhanced by cAMP and only reduced by PDE activity of the first barrier (smaller half-circle), whereas inotropically relevant cAMP has to pass through the more distal second barrier (larger half-circle) to reach the SR. The first barrier corresponds to PDE3 and PDE4 bound to the sarcolemma. The second barrier is produced by PDE3 and PDE in the cytoplasm and at the SR. Arrows represent Ca²⁺ current through L-type channels and Ca²⁺ release from RyR2 channels (RyR). Arrow thickness is proportional to I_Ca-L and Ca²⁺ release. The inotropic responses are assumed to be proportional to Ca²⁺ released from the SR through RyR2 channels. The cAMP-dependent activation of PKA and subsequent PKA-catalysed phosphorylation of Ca²⁺ channels, phospholamban (PLB), PDE4 and RyR2 is not represented to avoid overcrowding. Both PDE3 and PDE4 blunt the I_Ca-L response to (−)-noradrenaline (NA) mediated through β₁-adrenoceptors but only PDE3 blunts the I_Ca-L response to (−)-adrenaline mediated through β₂-adrenoceptors. Positive inotropic responses to both (−)-noradrenaline (β₁-adrenoceptors) and (−)-adrenaline (β₂-adrenoceptors) are assumed to occur at least in part through PKA-catalysed phosphorylation of Ca²⁺ channels, RyR2 channels and phospholamban (PLB). The positive inotropic effects of catecholamines are controlled by PDE4 through β₁-adrenoceptors but by PDE3 through β₂-adrenoceptors.