The ionic currents underlying pacemaker activity in rabbit sino-atrial node: experimental results and computer simulations

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Abstract
The membrane currents underlying the pacemaker depolarization have been investigated in rabbit s.a. node preparations using the two-microelectrode voltage clamp technique. Many of the experimental results have been simulated using a computer model of s.a. node electrical activity. Changes of three time-dependent membrane currents which could contribute to pacemaker depolarization are found to occur in the relevant potential range: decay of the potassium current, i$_{\text{K}}$, and activation of the inward current, i$_{\text{f}}$, and of the slow inward current, i$_{\text{si}}$. The contribution of i$_{\text{f}}$ activation to the pacemaker depolarization ranges from nil to an appreciable part depending on the preparation; when Cs (1 mM) blocks i$_{\text{f}}$, it nevertheless does not prevent pacemaking. In the model, holding the i$_{\text{f}}$ activation variable at zero slows but does not stop pacemaking; doubling i$_{\text{f}}$ conductance and shifting its activation curve by 15 mV in the positive direction causes a 15% faster rate of pacemaking. The slow time course of re-availability of i$_{\text{si}}$ must be allowed for when determining the i$_{\text{si}}$ threshold. A voltage clamp protocol designed to mimic as closely as possible an action potential followed by a pacemaker depolarization gives an estimate of i$_{\text{si}}$ threshold at the potential level of the last third of the pacemaker depolarization. This has been confirmed in experiments in which the voltage clamp was switched on at different points in the pacemaker depolarization. In the computer simulation, `blocking' i$_{\text{si}}$ depolarizes the membrane to the zero current level (close to the potential reached at the end of a pacemaker depolarization) and stops the generation of action potentials. The decay of i$_{\text{K}}$ contributes to the pacemaker depolarization; with both our own model and that of K. Yanagihara, A. Noma and H. Irisawa, Jap. J. Physiol. 30, 841-857 (1980) `blocking' i$_{\text{K}}$ decay abolishes pacemaker activity. Computations of extracellular K$^{+}$ concentration changes compared with i$_{\text{k}}$ decay in a cylindrical model allow re-assessment of the interpretation of K$^{+}$ concentration measurements during pacemaking made by J. Maylie, M. Morad and J. Weiss, J. Physiol., Lond. 311, 167-178 (1981). The experimental results together with the computer simulations support the view that i$_{\text{K}}$ decay and i$_{\text{si}}$ activation are essential for s.a. node pacemaking, i$_{\text{si}}$ contributing only to the last third of the pacemaker depolarization and to the upstroke. Differing amounts of i$_{\text{f}}$ activation can modulate the pacemaker rate.