1. A scheme is presented which summarizes the activation and deactivation of the membrane currents which underlie pacemaking in the natural pacemaker of the heart. 2. Experimental evidence (mostly obtained using the voltage-clamp technique) for the properties of the time-dependent membrane currents in pacemaking tissue of the frog and the rabbit is discussed. 3. The mode of the inhibitory action of acetylcholine on pacemaker cells is considered. In the amphibian pacemaker cell, acetylcholine probably reduces slow inward current (as it certainly does in amphibian atrium) but in mammalian sino-atrial node it seems that such action, if present at all, is much less marked. In the pacemakers of both amphibian and mammal, acetylcholine greatly increases outward potassium current and there is recent evidence that it may do so by opening up a special acetylcholine-activated potassium channel. 4. Adrenaline greatly increases the slow inward current in pacemaker as in other cardiac tissues. This increase, together with (in mammal at least) an increased change of an additional pacemaking current, overrides an adrenaline-induced increase in outward current and leads to acceleration of the pacemaking rate. 5. The Appendix contains a brief consideration of the experimental and theoretical basis for the method of exponential separation of outward current components in the presence of the extracellular potassium accumulation that inevitably accompanies the flow of outward membrane current.

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