A RAPID REDISTRIBUTION OF HYDROGEN-IONS IS ASSOCIATED WITH DEPOLARIZATION AND REPOLARIZATION SUBSEQUENT TO CEREBRAL-ISCHEMIA REPERFUSION

1. The aim of this study was to examine the rapid changes in extracellular hydrogen ion activity ([H+](o) or pH(o)) which are associated with depolarization and repolarization subsequent to cerebral ischemia reperfusion. Two parallel studies were performed with different rat models of ischemia: repetitive severe ischemia produced in anesthetized animals by occlusion of the vertebral and carotid arteries and temporary interruption of blood flow in isolated brain. [H+](o) and direct current potential (DC potential) were recorded simultaneously in all experiments. Examination of these two parameters was supplemented by recording tissue concentration of carbon dioxide (PtCO2) in the four-vessel occlusion model and assaying major metabolites involved in energy production in experiments with isolated brains. 2. Measurements of [H+](o) during ischemia consistently revealed a steady increase of [H+](o) on which was superimposed an abrupt and transient fall in [H+](o) closely related to the occurrence of the fast negative shift of DC potential characterizing brain-cell depolarization. Analysis of the relationship between the magnitude of the transient fall in H+ and the level of [H+](o) at which this occurred showed that the amplitude of the transient fall in H+ increased with tissue acidosis. 3. We propose that this phenomenon is indirect evidence that rapid transfer of acid equivalents occurs across the plasmalemma, concomitantly to its depolarization. Both events probably result from a common cause, i.e., nonspecific increase of the cell-membrane permeability to ions subsequent to opening of membrane channels. 4. Early on during recirculation, an acidotic [H+](o) shift associated with membrane repolarization was clearly visible whenever the ionic gradients recovered rapidly. We propose that this event reflected active recovery of [H+](i) regulation with normalization of cellular-membrane permeability and vigorous extrusion of H+ and/or HCO3- influx. 5. In several cases the rate of ischemia-induced PtCO2 increase was steeper after anoxic depolarization. This may reflect a sudden transmembrane redistribution in H+ and HCO3- or an increased production of H+ subsequent to increased ATP hydrolysis because of activation of the ionic pumps attempting to restore transmembrane ionic grandient. Na+-K+-ATPase is strongly activated by high extracellular [K+] and intracellular [Na+], and assays of high-energy phosphates in cerebral cortex samples rapidly frozen when anoxic depolarization occurred showed that tissue ATP levels were still one-third of control at that time. 6. The opening of membrane channels, which is suspected to occur during ischemia and to cause both membrane depolarization and rapid transfer of acid equivalents from the interstitial to the intracellular space, may also render ineffective the ionic exchanges responsible for intracellular pH regulation (Na+/H+ and Cl-/HCO3-). If this hypothesis is confirmed, it will reinforce the concept that anoxic depolarization is a critical event for cell survival.