Sinus node (SN) dysfunction (SND) is caused by failure to generate a normal SN action potential. SND patients are identified clinically as having sinus bradycardia, generally defined as a heart rate below 50 bpm. The commonest form of SND is related to ageing of the cardiac tissue. Only a few pharmacologic options are currently available to treat transient SND. However, most patients present with chronic symptomatic SND that can be treated only by pacemaker implantation as definitive therapy. In Europe and the U.S., SND now accounts for nearly half a million-pacemaker device implantations per year and this is predicted to double over the next half century. Considering this global burden of SND, innovative pharmacologic and molecular strategies based on novel insights into disease mechanisms are needed for SND treatment. Recently, it has been demonstrated that the ‘funny’-current (If) and heart rate are positively regulated by phosphoinositide 3-kinase (PI3K), by a mechanism which is independent of the autonomic nervous system input. Although it is known that heart rate, expression of SN ion channels and PI3K activity all decrease with age, the role of PI3K in age-related SN bradycardia remains unexplored.

To determine which SN ionic currents are regulated by PI3K in age-related SND focusing on the discrimination between Cav1.3 and Cav1.2–mediated L-type Ca2+ currents (ICaL).

WT young (2 months old) and aged (24 months old) mice were used to isolate SN cells. 1μM Calciseptine (Cas) – a selective Cav1.2 channel blocker – was used to distinguish between regulation by PI3K of Cav1.3 and Cav1.2 isoform. Upon perfusion of Cas, the Cas-sensitive current is attributed to Cav1.2, while the resistant component is attributed to Cav1.3. SN cells were incubated for 2h with 1μM PI-103 to inhibit PI3K before patch experiments.

We tested the effect of PI-103 on If in SN myocytes from aged mice. PI-103 had no effect on If in terms of current density and shift in activation curve. Aging had no effect on ICav1.2 but ICav1.3 was reduced in old mice. PI-103 reduced only ICav1.3 amplitude without changing ICav1.2 in young mice. PI-103 had no effects on both Cav1.3 and Cav1.2–mediated L-type Ca2+ currents in old mice.

Dissection of PI3K regulation of Cav1.3 and Cav1.2 channels provides new knowledge on the ionic mechanisms of regulation of intrinsic SN rate by PI3K and L-type Ca2+ channels in adult and aged SN.