Stability of Brain Intracellular Lactate and ³P-Metabolite Levels at Reduced Intracellular pH during Prolonged Hypercapnia in Rats

Abstract

The tolerance of low intracellular pH (pHi) was examined in vivo in rats by imposing severe, prolonged respiratory acidosis. Rats were intubated and ventilated for 10 min with 20% CO2, for 75 min with 50% CO2, and for 10 min with 20% CO2. The maximum PaCO2 was 320 mm Hg. Cerebral intracellular lactate, pHi, and high-energy phosphate metabolites were monitored in vivo with 31P and 1H nuclear magnetic resonance (NMR) spectroscopy, using a 4.7-T horizontal instrument. Within 6 min after the administration of 50% CO2, pHi fell by 0.57 +/- 0.03 unit, phosphocreatine decreased by approximately 20%, and Pi increased by approximately 100%. These values were stable throughout the remainder of the hypercapnic period. Cerebral intracellular lactate, visible with 1H NMR spectroscopy in the hyperoxic state, decreased during hypercapnia, suggesting either a favorable change in oxygen availability (decreased lactate production) or an increase in lactate clearance or both. All hypercapnic animals awakened and behaved normally after CO2 was discontinued. Histological examination of cortical and hippocampal areas, prepared using a hematoxylin and eosin stain, showed no areas of necrosis and no glial infiltrates. However, isolated, scattered, dark-staining, shrunken neurons were detected both in control animals (no exposure to hypercapnia) and in animals that had been hypercapnic. This subtle histological change could represent an artifact resulting from imperfect perfusion-fixation, or it could represent subtle neurologic injury during the hypercapnia protocol. In summary, extreme hypercapnia and low pHi (approximately 6.5) are well tolerated in rats for periods up to 75 min if adequate oxygenation is maintained.(ABSTRACT TRUNCATED AT 250 WORDS)

Permissive hypercapnia. How permissive should we be?

“…It consists of a reduced glycolytic flux mainly related to inhibition of phosphofructokinase, resulting in a decreased supply of two-carbon skeletons to the Krebs cycle. A compensatory increase in oxidative deamination follows, leading to partial depletion of the intracellular amino-acid pool and to accumulation of glutamine and NH 3 • Energy state is remarkably preserved, even with severe intracellular acidosis (20,25,31,32). For instance, maintained levels of ATP (as measured by NMR) were reported in the brains of rats exposed to CO 2 tensions of 750 mm Hg (pHi 6.2) in a hyperbaric environment ( Figure 1) (30).…”

L’hypercapnie augmente la tension en oxygène du tissu cérébral chez des rats anesthésiés

“…Compensation for this inhibition of glycolysis include a concurrent increase in oxidative deamination, with subsequent depletion of intracellular amino acids, which are utilized to generate ATP by oxidative processes. 25,33 Thus, anaerobic generation of ATP is inhibited and cells become more dependent on aerobic metabolism. Under these circumstances the brain may be relatively protected from injury as long as adequate O 2 is available.…”

“…Under these circumstances the brain may be relatively protected from injury as long as adequate O 2 is available. 33 Therefore, the mechanisms by which cerebral tissue oxygenation is augmented during hypercapnia may have evolved teleologically as a defence against respiratory acidosis. These observations may help to explain why hypercapnia reduces tissue injury secondary to ischemia and reperfusion [11][12][13] possibly contributing to the observed increase in survival of critically ill patients treated with permissive hypercapnia.…”

Tolerance of low cerebral intracellular pH in rats during hyperbaric hypercapnia.

“…5 We previously described recovery, normal behavior, and no histological injury in well-oxygenated rats exposed to 75 minutes of PCO2 of approximately 350 mm Hg (pli of about 6.60) 6 and 15 minutes of PcOj of approximately 500 mm Hg (pH| of about 6.45). 7 Because of the rightward shift of the hemoglobin dissociation curve, decreases in P02 that are required to reach higher PCO2 values result in hypoxemia (i.e., oxyhemoglobin saturation of <80%) at ambient pressure.…”