The heart responds to an increase in sino-atrial node wall stress with an augmentation in rate of contraction. It has been suggested that swelling-activated ion channels may play a key role in that response. This paper investigates directly the effects of cell swelling on spontaneous activity of rabbit isolated sino-atrial node pacemaker cells. The main finding is that sino-atrial node cells, studied in current clamp mode using amphotericin-permeabilized patches, decrease their spontaneous pacemaker rate by 24.2 +/- 7.8% (P < 0.01, n = 9) during 75% hyposmotic swelling. This response is opposite to the predicted impact of volume-activation of sarcolemmal ion conductances. Computer modelling (OXSOFT Heart v4.8) suggests that swelling-induced dilution of the cytosol, reduction in intracellular potassium concentration, and decrease in the delayed rectifier potassium current, IK, are leading mechanisms in the response. This is supported by voltage-clamp data that show a swelling-induced positive shift in the reversal potential of IK by between 5 and 10 mV (n = 7) and a reduction in amplitude of its rapidly activating component, IKr, (n = 6). Thus, spontaneously active sino-atrial node cells reduce pacemaking rate during swelling. This response cannot be explained by the known volume-activated sarcolemmal ion conductances, but appears to be dictated by other mechanisms including dilution of the cytosol and reduction in IK. The results re-enforce the view that cardiac responses to cell volume changes may be quite different from those to longitudinal stretch.