The slow inward current, i si , in the rabbit sino-atrial node investigated by voltage clamp and computer simulation

Abstract

The properties of the slow inward current, i si in the sino-atrial (s.a.) node of the rabbit have been investigated using two microelectrodes to apply voltage clamp to small, spontaneously beating, preparations. Many of the experimental results can be closely simulated using the computer model of s.a. node electrical activity (Noble & Noble 1984) which has been developed from models of Purkinje fibre activity (Noble 1962; DiFrancesco & Noble 1984). Comparison of the computed reconstructions with experimental results provides a test of the validity of the modelling. Experiments using paired depolarizing clamp pulses show that inactivation of i si is calcium -entry dependent although, unlike the inactivation of Ca 2+ currents in some other systems, it also shows some voltagedependence. Re-availability (recovery from inactivation) of i si in s.a. node is much slower than inactivation at the same potential, showing that isi is not controlled by a single first order process. This very slow recovery from inactivation of i si in the s.a. node and the slow time course of its activation and inactivation a t voltages near threshold ( — 40 to —50 mV) can be closely modelled by assuming that there are two components of ‘total i si ’: a fast inward current, i Ca f , representing the ‘gated’ fraction and a second, slower, inward current component, i NaCa which, we propose, is caused by the sodium -calcium exchange that ensues when the initial Ca 2+ -entry triggers the release of stored intracellular Ca 2+ . When repetitive trains of clamp pulses are given, a ‘staircase’ of i si magnitude is seen which can be increasing (‘positive’) or decreasing (‘negative’) according to the potential level and frequency of the pulse train given. W hen computer reconstructions of such staircases are made, it is found that the positive staircases (which, in contrast to negative staircases, imply that more complex processes than simple inactivation are present) can be closely simulated by a model which incorporates slower processes (suggested Na-Ca exchange current) in the total i si in addition to the gated current component. Further evidence for such additional components of i si is provided firstly by its slow time course (ca. 75 ms to peak) near threshold; second, by a change in time course of the i si recorded after progressively more negative conditioning hyperpolarizations (a result which is hard to account for using equations for a single gated channel) and, third, by the occasional appearance of a double-peaked i si record, both when i si is recorded after hyperpolarizations and in ‘ staircases ’ during trains of repetitive clamp pulses. In this latter case, the two components of i si show a different pattern of change one from another as the staircase progresses.