The present experiments were undertaken to assess the influence of preischemic hypo- or hyperglycemia on the coupling among changes in extracellular K+ concentration (K+e) and in cellular energy state, as the latter is reflected in the tissue concentrations of phosphocreatine (PCr), Cr, ATP, ADP, and AMP, and in the calculated free ADP (ADPf) concentrations. The questions posed were whether the final release of K+ was delayed because the extra glucose accumulated by hyperglycemic animals produced enough ATP to continue supporting Na+–K+-driven ATPase activity, and whether the additional acidosis altered the ionic transients. As expected, preischemic hypoglycemia shortened and hyperglycemia prolonged the phase before K+e rapidly increased. This was reflected in corresponding changes in tissue ATP content. Thus, hypoglycemia shortened and hyperglycemia prolonged the time before the fall in ATP concentration accelerated. When tissue was frozen at the moment of depolarization, the tissue contents of ATP were similar in hypo-, normo-, and hyperglycemic groups, ∼ 30% of control. This suggests that hyperglycemia retards loss of ion homeostasis by leading to production of additional ATP. However, hyperglycemia did not reduce the rate at which the PCr concentration fell, and the ATP/ADPf ratio decreased. There were marked differences in the amount of lactate accumulated between the groups. Thus, massive depolarization in hypoglycemic groups occurred at a tissue lactate content of ∼4 m M kg−1. This corresponds to a decrease in intracellular pH (pHi) from ∼7.0 to ∼6.9. In the hyperglycemic groups, depolarization occurred at a lactate content of about 12 mm kg−1, corresponding to a pHi of ∼6.4. This fall in pHi, or the accompanying fall in extracellular pH (pHe), did not affect the maximal rate of efflux of K+. Measurements of ischemic depolarization at constant tissue temperature (37°C) suggest that the influence of the plasma glucose concentration on the terminal depolarization time is restricted. Thus, the time to depolarization varied between 30 s (hypoglycemia) and 90 s (moderate to severe hyperglycemia). Previous results obtained without temperature control may well have reflected a combination between hyperglycemia and a fall in tissue temperature.
Functional modulation of PTH1R activation and signalling by RAMP2
