The respiratory gases, oxygen and carbon dioxide, play a vital role in the regulation of the respiratory and cardiovascular systems.  They are major players in determining how vigorously we breathe, in regulating the heart, and in setting the tone of blood vessels.  The two main circulations of the body, the pulmonary and systemic, respond in diametrically opposite ways to changes in concentrations of the gases.  The effects of the gases dominate homeostasis in everyday life, account for important perturbations in such situations as high altitude exposure, exercise and anaesthesia, and contribute substantially to the way disease presents in such conditions as chronic bronchitis, hypertension, and autonomic failure.

The effects of brief exposures (~15 min) to hypoxia or hypercapnia have been well studied.  In the mid-1990s we discovered large gradual effects of hypoxia on the pulmonary circulation of the rabbit in experiments lasting ~6 hours and went on to discover large delayed and gradual effects of sustained hypoxia on the human pulmonary and systemic circulations.  We are currently using pharmacological interventions in humans with endothelin, corticosteroids, iron chelation and autonomic blockers to understand something of the mechanisms that underlie the profound effects that these gases have on breathing and on the circulation. 

Current Research Programme

We are seeking answers to the following questions:

Are the slow ventilatory and circulatory responses to hypoxia related to the activity of the Hypoxia-Inducible Factor (HIF) system of regulation of gene expression? 

This system has been found by others (including Prof. Peter Ratcliffe in Oxford) to be the means by which erythropoietin production is regulated.  It is possible to modify the HIF pathway in humans using iron chelation, vitamin C administration, and corticosteroid medication.  Evidence so far suggests that the pulmonary vascular responses to hypoxia that commence after 40 min of hypoxic exposure and develop over ~6 hours may well be in part under HIF control.

Do oxygen and carbon dioxide interact additively or multiplicatively in regulation of the pulmonary vascular tone, in the way they do to regulate breathing?

The dogma in the field is that matching of ventilation and perfusion in the lungs is achieved by the constriction of pulmonary arteries in response to hypoxia in the alveoli.  Our experiments have discovered that these vessels respond more vigorously to changing levels of carbon dioxide.  We hypothesize that ventilation-perfusion matching in health is largely under control of carbon dioxide, and are working to examine this hypothesis from several angles.  It is of particular interest to find out to what extent the two gases act synergistically in regulating the pulmonary circulation.

What is the role of the autonomic nervous system in controlling ventilatory and circulatory responses to hypoxia and hypercapnia?

The autonomic nervous system is hugely important in permitting us to get out of bed in the morning and cycle to work.  The extent to which the large effects of oxygen and carbon dioxide on the circulation are mediated via the autonomic nervous system remains unclear.  Using both healthy volunteers and patients with autonomic failure, we hope to shed light on this relationship.

Further information can be found at www.physiol.ox.ac.uk/~kld

Keith Dorrington