Tissue oxygen tension and brain sensitivity to hypoxia

Abstract

Mammalian brain is a highly oxidative organ and although it constitutes only a small fraction of total body weight it accounts for a disproportionately large percentage of bodily oxygen consumption (in humans about 2 and 20%, respectively). Yet, the partial pressure and concentration of oxygen in the brain are low and non-uniform. There is a large number of enzymes that use O₂ as a substrate, the most important of which is cytochrome c oxidase, the key to mitochondrial ATP production. The affinity of cytochrome c oxidase for oxygen is very high, which under normal conditions ensures undiminished activity of oxidative phosphorylation down to very low P_O2. By contrast, many other relevant enzymes have K_m values for oxygen within, or above, the ambient cerebral gas tension, thus making their operations very dependent on oxygen level in the physiological range. Among its multiple, versatile functions, oxygen partial pressure and concentration control production of reactive oxygen species, expression of genes and functions of ion channels. Limitation of oxygen supply to the brain below a ‘critical’ level reduces, and eventually blocks oxidative phosphorylation, drastically decreases cellular (ATP) and leads to a collapse of ion gradients. Neuronal activity ceases and if oxygen is not re-introduced quickly, cells die. The object of this review is to discuss briefly the central oxygen-dependent processes in mammalian brain and the short-term consequences of O₂ deprivation, but not the mechanisms of long-term adaptation to chronic hypoxia. Particular emphasis is placed on issues which have been the focus of recent attention and/or controversy.

Introduction

It is not widely recognised that there are over 100 known enzymatic reactions which utilise oxygen as a substrate and that a majority of them are also present in mammalian tissues (Vanderkooi et al., 1991). The explosion in appearance on Earth of multicellular, complex organisms has been greatly facilitated by transition from a relatively inefficient anaerobic means of producing energy to the highly effective aerobic process of oxidative phosphorylation. The dependence of mammalian cells on a constant and abundant supply of ATP means a dependence on an adequate provision of oxygen. However, the gas itself and in particular some products of its metabolism, the reactive oxygen species (ROS), can be highly toxic. These facts make the ambient partial pressure of oxygen and its concentration one of the key elements which control living processes on earth.