PDE4B and PDE4D differentially regulate cardiac pacemaker activity

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During sympathetic stimulation, the activation of β-adrenergic receptors (βAR) increases cAMP levels, leading to positive chronotropic effect. Among the 6 cardiac cAMP-PDE families, PDE4 is critical for controlling excitation-contraction coupling (ECC) during β-stimulation in atrial and ventricular myocytes. PDE4 may also be important for automaticity. Three genes encode for PDE4 in the heart (pde4a, 4b, 4d). To investigate the respective contribution of PDE4 isoforms to the regulation of pacemaker activity. Total PDE activity in mouse SAN was determined as the cAMP-hydrolytic activity measured in the absence of PDE inhibitor and the fraction corresponding to PDE4 activity was assessed by including the PDE4 inhibitor Ro-20-1724. The in vitro pacemaker activity was assessed by measuring spontaneous Ca 2+ transients in Fluo4-loaded-SAN tissue from Wild-type (WT) and PDE4KO using confocal microscopy. Telemetry EKG was recorded in conscious mice in control (CTRL) conditions, after pharmacological denervation (atropine + propranolol) and after isoproterenol (ISO). PDE4 activity represents 60% of total cAMP-PDE activity in SAN. PDE4A, 4B and 4D isoforms are expressed in mouse SAN. In PDE4BKO, the effect of ISO on SAN beating rate was higher than in WT. Ablation of PDE4D induced decreased beating rate in CTRL and ISO conditions and increased Ca 2+ spark frequency compared to WT. In vivo, PDE4BKO and PDE4DKO mice displayed increased resting HR during day and night. After pharmacological denervation, the rhythmic phenotype was only maintained in PDE4BKO but not in PDE4DKO. The response to ISO was higher in PDE4BKO than in PDE4DKO. In addition, ISO provoked more premature beats and atrioventricular blocks in PDE4DKO than in PDE4BKO mice. PDE4B controls intrinsic SAN automaticity and PDE4D might be important for autonomic nervous system-mediated regulation of HR and conduction.