Hypoxia

Depletion of high-energy compounds

Anaerobic metabolism produces only one-nineteenth of the yield of the high-energy phosphate molecule adenosine triphosphate (ATP) per mole of glucose, compared with aerobic metabolism (page 153). In organs with a high metabolic rate such as the brain, it is impossible to increase glucose transport sufficiently to maintain the normal level of ATP production. Therefore, during hypoxia, the ATP/adenosine diphosphate (ADP) ratio falls, and there is a rapid decline in the level of all high-energy compounds ( Fig. 23.1 ). Similar changes occur in response to arterial hypotension. These changes will rapidly block cerebral function, but organs with a lower energy requirement will continue to function for a longer time and are thus more resistant to hypoxia (see later).

Under hypoxic conditions, there are two ways in which reductions in ATP levels may be minimized, both of which are effective for only a short time. First, the high-energy phosphate bond in phosphocreatine may be used to create ATP, and initially this slows the rate of reduction of ATP ( Fig. 23.1 ). Second, two molecules of ADP may combine to form one of ATP and one of adenosine monophosphate (AMP; the adenylate kinase reaction). This reaction is driven forward by the removal of AMP, which is converted to adenosine (a potent vasodilator) and thence to inosine, hypoxanthine, xanthine and uric acid, with irreversible loss of adenine nucleotides. The implications for production of reactive oxygen species by this pathway are discussed on page 288.

End products of metabolism

The end products of aerobic metabolism are carbon dioxide and water, both of which are easily diffusible and lost from the body. The main anaerobic pathway produces hydrogen and lactate ions which, from most of the body, escape into the circulation, where they may be measured or quantified in terms of the base deficit. However, the blood–brain barrier is relatively impermeable to charged ions, therefore hydrogen and lactate ions are retained within the neurones of the hypoxic brain. Lactacidosis can only occur when circulation is maintained to provide the large quantities of glucose required for conversion to lactic acid.

In severe cerebral hypoxia, a major part of the dysfunction and damage is because of intracellular acidosis rather than simply depletion of high-energy compounds (see later). Gross hypoperfusion is more damaging than total ischaemia, because the latter limits glucose supply and therefore the formation of lactic acid. Similarly, patients who have an episode of cerebral ischaemia whilst hyperglycaemic (e.g., a stroke) have been found to have more severe brain injury than those with normal or low blood glucose levels at the time of the hypoxic event.

Initiation of glycolysis

The enzyme 6-phosphofructokinase (PFK) is the rate-limiting element of the glycolytic pathway (see Fig. 10.12 ). Activity of PFK is enhanced by the presence of ADP, AMP and phosphate, which will rapidly accumulate during hypoxia, thus accelerating glycolysis. PFK is, however, inhibited by acidosis, which will quickly limit the formation of ATP from glucose. The intracellular production of phosphate from ATP breakdown also promotes the activity of glycogen phosphorylase, which cleaves glycogen molecules to produce fructose-1,6-diphosphate. This enters the glycolytic pathway below the rate-limiting PFK reaction, avoiding the expenditure of two molecules of ATP in its derivation from glucose. Therefore four molecules of ATP are produced from one of fructose-1,6-diphosphate in comparison with two from one molecule of glucose. There is no subsequent stage in the glycolytic pathway that is significantly rate limited by acidosis. Provided glycogen is available within the cell, this second pathway therefore provides a valuable reserve for the production of ATP.

Immediate cellular responses to hypoxia

Because of the dramatic clinical consequences of nervous system damage, neuronal cells are the most widely studied, and therefore form the basis for the mechanisms described in this section. Changes in the transmembrane potential of a hypoxic neurone are shown in Figure 23.2 , along with the major physiological changes that occur. At the onset of anoxia, central nervous system cells immediately become either slightly hyperpolarized (as shown in Fig. 23.2 ) or depolarized, depending on the cell type. This is followed by a gradual reduction in membrane potential until a ‘threshold’ value is reached, when a spontaneous rapid depolarization occurs. At this stage there are gross abnormalities in ion channel function, and the normal intracellular and extracellular ionic gradients are abolished, leading to cell death.