EXTRACELLULAR VOLUME FRACTION AND DIFFUSION CHARACTERISTICS DURING PROGRESSIVE ISCHEMIA AND TERMINAL ANOXIA IN THE SPINAL-CORD OF THE RAT

Extracellular space (ECS) volume fraction (alpha), ECS tortuosity (lam bda), and nonspecific uptake (k'), three parameters affecting the diff usion of substances in nervous tissue, were studied during ischemisa a nd anoxia in the rat spinal cord gray matter in vivo. Progressive isch emia evoked by exsanguination, as well as anoxia evoked by respiratory or cardiac arrest, produced prominent extracellular K+ and pH changes closely related to a decrease in blood pressure and amplitude of fiel d potentials. With use of ion-selective microelectrodes, the changes i n the diffusion parameters were measured by quantitative analysis of c oncentration-time profiles of tetramethylammonium (TMA(+)) applied by iontophoresis concomitantly with ionic shifts. Under normoxic conditio ns (in rats with blood pressure of 80-110 mm Hg) diffusion parameters in the dorsal horn gray matter at depth 500-900 mu m were as follows: alpha = 0.20 +/- 0.019, lambda = 1.62 +/- 0.12, k' = 4.6 +/- s(-1) (me an +/- SD, n = 39). Extracellular K+ 2.5 x 10(-3) s(-1) (mean +/- SD, n = 39). Extracellular K+, pH, and diffusion properties gradually chan ged during progressive ischemia. As the blood pressure fell to 50-60 m m Hg and field potential amplitude to 20-60%, K+ rose to 6-12 mM, pH(e ) fell by similar to 0.05-0.1 pH unit, and volume fraction of the ECS significantly decreased, to alpha = 0.16 +/- 0.019 (n = 22). Even thou gh the tortuosity remained virtually constant, the nonspecific uptake significantly decreased to k' = 3.4 +/- 1.8 x 10(-3) s(-1). As the blo od pressure fell to 20-30 mm Hg and field potential amplitude to 0-6%, K+ rose to 60-70 mM, pH(e) fell by similar to 0.6-0.8 pH unit, and al l three diffusion parameters significantly changed. The ECS volume fra ction decreased to alpha = 0.05 +/- 0.021, tortuosity increased to lam bda = 2.00 +/- 0.24, and TMA(+) uptake decreased to k' = 1.5 +/- 1.6 x 10(-3) s(-1) (n = 12). No further increase in extracellular K+ or cha nges in the alpha were found during and up to 120 min after the death of the animal. However, there was a further significant increase in la mbda = 2.20 +/- 0.14 and decrease in k' = 0.4 +/- 0.3 x 10(-3) s(-1) ( n = 24). The acid shift reached its maximum level at similar to 5-10 m in after respiratory arrest and then the pH(e) gradually increased by similar to 0.2 unit. Full recovery to ''normoxic'' diffusion parameter s was achieved after reinjection of the blood or after an injection of noradrenaline during severe ischemia, if this resulted in a rise in b lood pressure above 80 mm Hg and a decrease in extracellular K+ below 12 mM. At similar to 10 and 30 min after this recovery, the ECS volume fraction significantly increased above ''normoxic'' values, to alpha = 0.25 +/- 0.016 (n = 7) and alpha = 0.30 +/- 0.021 (n = 6), respectiv ely. The lambda and k' were not significantly different from the value s found under normoxic conditions. Our data represent the first detail ed in vivo measurements of diffusion parameters alpha, lambda, and k' during and after progressive ischemia and anoxia. The observed substan tial changes in the diffusion parameters could affect the diffusion an d aggravate the accumulation of ions, neurotransmitters, metabolic sub stances, and drugs used in therapy of nervous diseases and thus contri bute to ischemic CNS damage.