Abstract
The cardiac hyperpolarization-activated “funny” current (If), which contributes to sinoatrial node (SAN) pacemaking, has a more negative half-maximal activation voltage and smaller fully-activated macroscopic conductance in human than in rabbit SAN cells. The consequences of these differences for the relative roles of If in the two species, and for their responses to the specific bradycardic agent ivabradine at clinical doses have not been systematically explored. This study aims to address these issues, through incorporating rabbit and human If formulations developed by Fabbri et al. into the Severi et al. model of rabbit SAN cells. A theory was developed to correlate the effect of If reduction with the total inward depolarising current (Itotal) during diastolic depolarization. Replacing the rabbit If formulation with the human one increased the pacemaking cycle length (CL) from 355 to 1,139 ms. With up to 20% If reduction (a level close to the inhibition of If by ivabradine at clinical concentrations), a modest increase (~5%) in the pacemaking CL was observed with the rabbit If formulation; however, the effect was doubled (~12.4%) for the human If formulation, even though the latter has smaller If density. When the action of acetylcholine (ACh, 0.1 nM) was considered, a 20% If reduction markedly increased the pacemaking CL by 37.5% (~27.3% reduction in the pacing rate), which is similar to the ivabradine effect at clinical concentrations. Theoretical analysis showed that the resultant increase of the pacemaking CL is inversely proportional to the magnitude of Itotal during diastolic depolarization phase: a smaller If in the model resulted in a smaller Itotal amplitude, resulting in a slower pacemaking rate; and the same reduction in If resulted in a more significant change of CL in the cell model with a smaller Itotal. This explained the mechanism by which a low dose of ivabradine slows pacemaking rate more in humans than in the rabbit. Similar results were seen in the Fabbri et al. model of human SAN cells, suggesting our observations are model-independent. Collectively, the results of study explain why low dose ivabradine at clinically relevant concentrations acts as an effective bradycardic agent in modulating human SAN pacemaking.
Highlights
The pacemaker activity of sinoatrial node (SAN) cells in the mammalian heart arises from the integrated action of multiple sarcolemmal ionic channel currents and the interaction between the intracellular calcium handling and sarcolemmal electrogenic processes (Irisawa et al, 1993; Mangoni and Nargeot, 2008; Lakatta et al, 2010)
By replacing the rabbit If formulation with the human If formulation, the pacemaking activity was slowed down, with a pacemaking cycle length (CL) that increased from 355 ms to 1,139 ms, which was associated with a slight increase in INa and ICaT at the late period of the diastolic depolarization phase (DDP), and a slight decrease in IKr, IKs, Ito, and INaK during the DDP
20% reduction in the channel conductance produced a similar decrease in the avarage If in the rabbit-like and the human-like model, but the relative change was greater in the latter model because of its smaller If in the control condition
Summary
The pacemaker activity of sinoatrial node (SAN) cells in the mammalian heart arises from the integrated action of multiple sarcolemmal ionic channel currents and the interaction between the intracellular calcium handling and sarcolemmal electrogenic processes (Irisawa et al, 1993; Mangoni and Nargeot, 2008; Lakatta et al, 2010). HCN channels generate an inward current over the pacemaking potential range which, together with the current generated by other electrogenic processes of the intracellular calcium handling (i.e., the Ca2+ clock), contributes to the genesis of intrinsic pacemaker activity of the SAN (Lakatta and Difrancesco, 2009). HCN channels are modulated by adrenergic agonists via cAMP (Bucchi et al, 2003; Craven and Zagotta, 2006)
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