P542Contribution of the hyperpolarization-activated 'funny' current, If, to the intrinsic pacemaker activity of rabbit and mouse sinoatrial node cells

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Abstract

Purpose

The hyperpolarization-activated ‘funny’ current, If, is present in pacemaker cells isolated from rabbit and mouse sinoatrial node (SAN) cells, with HCN4 as the predominant isoform of the HCN gene family in both rabbit and mouse. However, it remains a matter of debate to which extent If contributes to murine SAN pacemaker activity, in particular because If seems to activate at more negative membrane potentials in mouse than in rabbit. To assess the role of If in SAN pacemaker activity, we studied If under identical experimental conditions in rabbit and mouse SAN cells.

Methods

Action potentials and If were recorded from single cells isolated from rabbit or mouse SAN at 37°C using the perforated patch-clamp technique. If characteristics were determined in voltage clamp mode in presence of blockers to minimize contamination by K+ and Ca2+ currents. The current profile of If during the acquired action potentials was reconstructed in computer simulations using a first-order Hodgkin and Huxley-type kinetic scheme based on the acquired voltage clamp data.

Results

Fully-activated current density, reversal potential and time constants of (de)activation of If did not differ between rabbit and mouse SAN cells. However, with a value of –83.5 ± 2.2 (mean ± SEM, n=9) vs. –73.5 ± 2.9 mV in rabbit (n=9), the half-activation voltage of the If activation curve was ≈10 mV more negative in mouse, whereas the slope of this curve was similar. In rabbit SAN cells, block of If with 2 µmol/L Cs + resulted in a decrease in diastolic depolarization rate and an increase in cycle length (318 ± 15 vs. 254 ± 13 ms, n=5). In mouse cells, Cs + block of If resulted in a noticeable hyperpolarizing shift in the maximum diastolic potential and a substantial increase in maximum upstroke velocity without affecting diastolic depolarization rate or cycle length (217 ± 14 vs. 212 ± 15 ms, n=5). Reconstruction of the current profile of If revealed that the amplitude of If during diastolic depolarization is approximately two-fold larger in rabbit than in mouse. However, in both rabbit and mouse, the amplitude of If during diastolic depolarization is similar to that of the net membrane current, as derived from the time derivative of the action potential traces.

Conclusions

If is functionally present in mouse SAN cells. If blockade in mouse SAN cells does not affect the intrinsic cycle length, most likely because a reduction in If is counteracted by the activation of additional Na+ current in response to the hyperpolarizing shift in the maximum diastolic potential induced by the If reduction.

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