How “Funny” is the Cardiac Pacemaking? a Quantitative Analysis Based on Dynamic Clamp Recordings

A typical feature of sinoatrial (SA) node pacemaker cells is the presence of an ionic current that activates upon hyperpolarization. The quantitative role of this hyperpolarization-activated current known as the 'funny current', If, in the spontaneous pacemaker activity of SA nodal cells remains a matter of intense debate.We aimed to characterize the impact of If as implemented in recent conflicting mathematical models of rabbit SA node pacemaker cells by using the Dynamic Clamp technique.Experiments were performed using the Real-Time eXperiment Interface (RTXI) which is a real-time biological experimentation system based on Real-Time Linux. The time course of If was dynamically reconstructed from the experimentally recorded action potentials of a single isolated rabbit SA nodal pacemaker cell according to the mathematical models of Maltsev and Lakatta(2009) and Severi et al.(2012). Two different protocols were implemented: i) selective If block by Ivabradine (3μM) and substitution with the "syntethic" If ii) comparison of the effects of a virtual Isoprenaline(ISO)-induced shift (7.5 mV) of If activation with the real effects of 1μM ISO.In relation to the substitution of the Ivabradine-sensitive current, the model of Severi et al. (Sev) allowed to restore the control pacemaking rate (Ctrl [Hz]: 2.77±0.13 Vs Sev: 2.70±0.09, N.S.), whereas Maltsev and Lakatta's (ML) induced only a smaller recovery from current-blocking conditions (Control [Hz]: 2.77±0.13 vs ML: 2.39±0.10, p<0.05). Preliminary results on the virtual ISO-induced shift produced a rate increase comparable to the real drug effect (+42±9 % vs +58±15 %, N.S.), suggesting that If accounts for most of the ISO-induced rate increase.Dynamic Clamp results are in agreement with the quantitative description of the If impact on the modulation of cardiac pacemaking provided by our recent computational sinoatrial model (Severi et al. 2012).