Effects of single-channel noise on spontaneous beating and the phase-resetting response of cardiac oscillators

Abstract

From our everyday life, we know that our hearts beat with a rhythm which is not perfectly periodic. Even an isolated spontaneously beating cardiac cell, devoid of neural, hormonal, and intracardiac regulatory input, does not beat perfectly regularly. I investigate the hypothesis that the beat-to-beat fluctuations in transmembrane potential of spontaneously beating cardiac cells are due to stochastic gating of the ionic channels in the cell membrane.Recordings of transmembrane potential from small clusters of spontaneously beating 7-day-old embryonic chick ventricular cells were analyzed to characterize the voltage waveform and the regularity of beating. I constructed a deterministic Hodgkin-Huxley-type ionic model which reproduces spontaneous activity in our experimental recordings, as well as the experimental results of applying various ion channel blockers (D-600, almokalant, and Ba2+). The model consists of six currents: a calcium current (ICa), three potassium currents (IKs, I Kr, IK1), a background current ( Ib), and a seal-leak current (I seal).The deterministic Hodgkin-Huxley-type model was then reformulated into a stochastic single-channel model. The single-channel model reproduces the irregularity of beating seen experimentally: e.g. the coefficient of variation of interbeat interval was 4.4% vs. 3.9% in the clusters. In the model, IKs is the current giving the major contributions to fluctuations in interbeat interval.Phase resetting of the spontaneous activity of cardiac pacemaker cells by a brief stimulus pulse was simulated in Hodgkin-Huxley-type models and single-channel models of slow-upstroke (central) and fast-upstroke (peripheral) rabbit sinoatrial node cells. In the Hodgkin-Huxley-type models the phase-resetting response is continuous, but can be extremely delicate in the fast-upstroke model, in that a tiny difference in the stimulus timing can change the stimulus response from a delayed action potential to an advanced one. Therefore, the noise in the fast-upstroke single-channel model can cause a stimulus with fixed amplitude and fixed timing to have widely different effects: sometimes it will induce an action potential but in other cases it will delay an action potential, as seen previously in experiments on cardiac preparations