Impact of manipulation of energy substrates on sinus nodal rhythm

Background: The high energy demand of the heart is supported by metabolic flexibility in the utilization of energy substrates for adenosine triphosphate (ATP) synthesis. To investigate the roles of glucose and long-chain fatty acids (FA) as energy substrates in sinus nodal rhythm, we developed an isolated mouse atrial preparation and studied the effects of manipulating these energy substrates on atrial beating rate. Methods: The spontaneous beating rate of isolated atria from mouse was measured at resting tension in a modified Tyrode solution that was gassed with 100% O₂ at 37°C and contained 1 of the following sets of energy substrates: 10 mM glucose plus 0.4 mM palmitate (control), 5 mM glucose plus 0.4 mM palmitate (low glucose), or 10 mM glucose without palmitate (FA (-)). Atria were subjected to hypoxic conditions for 10 min followed by re-oxygenation. Results: The spontaneous beating rate measured under low glucose conditions was significantly lower than that measured under control conditions, which was associated with concomitant reductions in ATP level and glucose consumption. In contrast, in FA (-) conditions, beating rate was significantly lower than that under control conditions, but the reduction in beating rate was not accompanied by significant changes in ATP level or glucose consumption. To investigate change in energy substrate preference under hypoxic conditions, atria were subjected to hypoxia in 3 modified Tyrode solutions. Under low glucose conditions, beating rate during hypoxia decreased to almost the same level as that of control, while recovery of beating rate during re-oxygenation was compromised. Under FA (-) conditions, exposure to hypoxia revealed a shift of energy substrate to glucose. Conclusions: ATP produced by glucose metabolism is required in order to maintain sinus nodal rhythm. FA may be involved in regulating beating rate not only as an energy substrate but also through a novel mechanism.