Rapid changes in the average water diffusion constant, Dav = 1/3[Dxx+Dyy+Dzz], and in the concentrations of lactate and purine nucleotides and nucleosides were measured upon global ischemia (cardiac arrest) in cat brain, at a combined time resolution of 36 s (n = 7). At this time resolution, the normalized time curves of 1 - Dav and the increase in ATP breakdown product did not coincide, with the changes in Dav being most rapid. The normalized curves of 1 - Dav and the lactate increase coincided for the first 2-2.5 min after which the change in Dav was more rapid. After this time point, an excellent correlation was found between the drop in Dav and the decrease in energy utilization rate, which was calculated from the measured time curves of lactate formation and ATP breakdown, and from the time curve for phosphocreatine use reported in the literature. These results are in agreement with the expected biphasic changes in ion and water homeostasis during ischemia and with the model of diffusional changes being a consequence of a water shift from interstitial to intracellular space.