Physiological hypoxia is a hypoxic hypoxia produced by a decrease in ambient PO₂ as it happens naturally at high altitude due to a decrease in the barometric pressure. It is physiological because it proceeds without any pathology for the entire life span of individuals and from generation to generation. The upper limit to physiological hypoxia can be set at an altitude of ~4000 m above sea level, equivalent to a barometric pressure of ~465 mmHg, an inspired P_O2 of ~88 mmHg and, before compensatory hyperventilation, an alveolar P_O2 of ~40 mmHg. Nearly 15 million people live at an altitude close to 4000 m, and after corrections for racial and nutritional factors, no differences from sea level inhabitants in reproduction, growth or physical performance are found.

The normal functioning of the organisms in physiological hypoxia is possible because three cell systems, the chemoreceptor cells of the carotid body (CB), the erythropoietin-producing cells of the kidney and the pulmonary artery smooth muscle cells, are endowed with the ability to detect and to respond to physiological hypoxia. These three cell systems share several properties: they respond to hypoxia with a low threshold (i.e. mild hypoxia), their responses increase with the intensity of hypoxia, are sustained and reversible, and they are at the origin of regulation loops, aimed to restore O₂ availability to cells, i.e. the responses of these cells to hypoxia trigger local or reflex responses aimed to protect the entire organism from hypoxia. These cells are ‘true’ oxygen sensors. In adult mammals, the hypoxic threshold for the CB is an arterial P_O2 of ~70-75 mmHg (arterial oxygen content > 94 %), it responds with progressive higher intensity if the intensity of hypoxia increases, and the CB response to hypoxia does not adapt. The release of neurotransmitters in the CB chemoreceptor cells initiate a reflex hyperventilation aimed to restore O₂ availability for the entire organism. Contrary to this situation, most stirps of mammalian cells, including the neurons of the central nervous system, only respond to hypoxia if it is intense, and the responses generated are transient and reflect pathogenic mechanisms of the hypoxic damage or cellular protective mechanisms against hypoxia. Since the terms ‘mild’ and ‘severe’ might pose uncertainties due to the diversity of preparations, of methods of measurement or simply due to the lack of data on the thresholds of the hypoxic responses for most cell systems, it might suffice to state that cells endowed with sensitivity to physiological hypoxia respond to levels of hypoxia not threatening survival while the appearance of responses to hypoxia in other cell types, as for example in brain neurons, start only at much lower arterial P_O2, which might represent a menace for the life of the animals.

These considerations, directed to distinguish physiological from pathological responses to hypoxia, are not intended to rest interest from the definition and characterization of the pathological responses to hypoxia and their mechanisms. On the contrary, their characterization would allow medical interventions to disrupt the pathogenic mechanism of the hypoxic damage or to potentiate the protective mechanisms of the cells. Even further, it is now clear that physiological and pathological responses share mechanisms. For example, the transcription factor HIF-1α controls the production of erythropoietin and via vascular endothelial growth factor directs normal vasculogonesis, yet, at the same time, it increases the expression of vascular growth factor and glycolytic enzymes in tumoural cells securing tumour survival, growth and progression. Similarly, the inhibition of potassium channels is an early step in the activation of chemoreceptor cells and in the physiological pulmonary hypoxic vasoconstriction; the inhibition of the same channels in some brain areas might underlie their great susceptibility to hypoxic damage.

Aside from these general considerations on hypoxia, I shall present the most recent data of our laboratory dealing with the mechanisms of detection of hypoxia in the chemoreceptor cells of CB, including the significance of oxygen reactive species and of a putative plasma membrane-linked hemoprotein. I shall also present data supporting a role for regulatory β subunits of the potassium channels as coupling elements between the oxygen sensing element and the conducting unit of the potassium channels. Finally, I shall discuss the molecular identity of oxygen sensitive potassium channel in the rabbit CB chemoreceptor cells.

This work was supported by Spanish DGICYT grant BFI2001-1713.