Effects of changes in excitability and intercellular coupling on synchronization in the rabbit sino-atrial node.

The mechanisms of synchronization between sino-atrial pace-maker cells were studied in biological preparations from rabbit hearts, and in computer simulations of the Hodgkin & Huxley type. For biological experiments, thin strips of sino-atrial node were placed in a three-compartment bath. The electrical properties of the tissue in the middle segment (the 'gap') were manipulated pharmacologically to alter electrical coupling and/or excitability of cells in that segment, and to study the patterns of interaction between two pace-maker centres in the external segments. Superfusion of the gap segment with either verapamil (2 microM) or acetylcholine (10 microM) produced a loss of 1:1 synchrony (entrainment) of spontaneous discharges generated by the external pace-makers but subharmonic (i.e. 3:2; 5:4; 9:8; etc.) entrainment was always maintained. When the gap segment was superfused with heptanol (3.5 mM), which is known to increase intercellular resistance, the pace-maker centres in the external chambers beat independently of one another. Progressive loss of synchrony paralleled reductions in amplitude of electrotonic responses to current pulses applied across the gap. Gap superfusion with hypertonic Tyrode solution (600 mosM) produced a major reduction in the degree of synchronization between the external pace-makers, even though the cells in the central compartment maintained their excitability. Under these conditions, as many as three independent pace-maker centres, one in each chamber, coexisted in a given preparation. Using computerized simulations based on equations of time- and voltage-dependent membrane currents, three 'cells', each capable of maintaining spontaneous activity, were connected in a linear array through ohmic resistances. When selective parameters (e.g. membrane conductances, coupling resistance) were modified appropriately, the mathematical simulations reproduced very closely the interaction patterns observed in the experimental preparations. Our results show that synchronization in the sinus node results from mutual interactions and entrainment between all the cells in this region. These interactions are of the kind expected for a population of coupled, self-sustained oscillators, and are mediated through electrotonic propagation of current across low-resistance junctions.