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.
Rat livers perfused at constant flow via the portal vein with dibutyryl cyclic AMP produced glucose equivalents at a steady maximal rate (6 mumol/min per g of liver). Addition of adenosine (150 microM) caused a biphasic effect. (i) First, the glycogenolytic rate rose transiently, to a mean peak of 150% of control levels after 2 min. This glycogenolytic burst was reproduced by two P1-receptor agonists, but not by ATP, and was blocked by a P1-antagonist (8-phenyltheophylline), as well as by inhibitors of eicosanoid synthesis (indomethacin, ibuprofen or aspirin). It did not occur in phosphorylase-kinase-deficient livers. The adenosine-induced glycogenolytic burst coincided with moderate and transient changes in portal pressure (+6 cmH2O) and O2 consumption (-20%), but it could not be explained by an increase in cytosolic Pi, since the n.m.r. signal fell precipitously. (ii) Subsequently, the rate of glycogenolysis decreased to one-third of the preadenosine value, in spite of persistent maximal activation of phosphorylase. The decrease could be linked to the decline in cytosolic Pi: both changes were prevented by the adenosine kinase inhibitor 5-iodotubercidin, whereas they were not affected by ibuprofen or 8-phenyltheophylline, and were not reproduced by non-metabolized adenosine analogues. In comparison with adenosine, ATP caused a slower decrease of Pi and of glycogenolysis. The fate of the cytosolic Pi was unclear, especially with administered ATP, which did not increase the n.m.r.-detectable intracellular ATP.
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