A high basal phosphodiesterase (PDE) activity in sinoatrial node cells (SANC) regulates cAMP and modulates cAMP-mediated PKA-dependent phosphorylation of Ca
2+
cycling proteins that determines the characteristics of local subsarcolemmal Ca
2+
releases (LCR). LCRs occur during the terminal diastolic depolarization and activate the inward Na
+
-Ca
2+
exchange current, thus, regulating the SANC basal spontaneous beating rate. Though both PDE3 and PDE4 are present in rabbit SANC, a role of PDE4 or its interaction with PDE3 is not clear. To determine to what extent PDE4 controls LCRs and the SANC spontaneous beating rate, we used perforated patch to record spontaneous action potentials (APs) in conjunction with confocal linescan images or whole-cell patch clamp to measure L-type Ca
2+
current (I
Ca,L
) at 35
o
C. A specific PDE3 inhibitor, cilostamide (Cil, 0.3 μmol/L), increased the spontaneous beating rate by 28% (from 154 ± 21 to 191 ± 17 beat/min); in contrast a specific PDE4 inhibitor, rolipram (Rol, 2 μmol/L), had no effect on the firing rate. The substantial role of PDE4 in the control of basal spontaneous SANC firing was unmasked when PDE3 and PDE4 were simultaneously inhibited: the combination of Rol and Cil produced ~57% acceleration of the beating rate (from129 ± 10 to 200 ± 10 beat/min) equivalent to that produced by the broad-spectrum PDE inhibitor, IBMX (100μM), i.e. ~55% (from 145 ± 8 to 221 ± 6 beat/min). The combination of Cil and Rol increased LCR amplitude, size and decreased the LCR period similar to IBMX. Both IBMX and the combination of Cil and Rol produced a substantial increase in I
Ca,L
~135% (from 10 ± 2 to 22 ± 3 pA/pF) and ~125% (from 6 ± 1 to 13 ± 3 pA/pF) respectively. The efficiency of PDE3 inhibition alone on spontaneous beating rate might be ascribed to its lower K
m
for cAMP, than that of PDE4. When PDE3 is suppressed level of cAMP is sufficiently elevated to activate PDE4. Therefore, in the presence of PDE3 inhibition, PDE4 inhibition contributes to the increase in the spontaneous beating rate. Thus, an interaction of basal PDE3 and PDE4 activities in SANC modulates cAMP level and I
Ca,L
which controls Ca
2+
influx, cell Ca
2+
load, determining LCR characteristics. When both PDE3 and PDE4 are inhibited the maximum spontaneous beating rate of SANC is achieved.
Heterogeneous expression of the delayed‐rectifier K
+
currents
i
K,r
and
i
K,s
in rabbit sinoatrial node cells
