Frank L. Powell

Epidermal Sensing of Oxygen Is Essential for Systemic Hypoxic Response

Skin plays an essential role, mediated in part by its remarkable vascular plasticity, in adaptation to environmental stimuli. Certain vertebrates, such as amphibians, respond to hypoxia in part through the skin; but it is unknown whether this tissue can influence mammalian systemic adaptation to low oxygen levels. We have found that epidermal deletion of the hypoxia-responsive transcription factor HIF-1alpha inhibits renal erythropoietin (EPO) synthesis in response to hypoxia. Conversely, mice with an epidermal deletion of the von Hippel-Lindau (VHL) factor, a negative regulator of HIF, have increased EPO synthesis and polycythemia. We show that nitric oxide release induced by the HIF pathway acts on cutaneous vascular flow to increase systemic erythropoietin expression. These results demonstrate that in mice the skin is a critical mediator of systemic responses to environmental oxygen.

The asparaginyl hydroxylase factor inhibiting HIF-1α is an essential regulator of metabolism

Factor inhibiting HIF-1alpha (FIH) is an asparaginyl hydroxylase. Hydroxylation of HIF-alpha proteins by FIH blocks association of HIFs with the transcriptional coactivators CBP/p300, thus inhibiting transcriptional activation. We have created mice with a null mutation in the FIH gene and found that it has little or no discernable role in mice in altering classical aspects of HIF function, e.g., angiogenesis, erythropoiesis, or development. Rather, it is an essential regulator of metabolism: mice lacking FIH exhibit reduced body weight, elevated metabolic rate, hyperventilation, and improved glucose and lipid homeostasis and are resistant to high-fat-diet-induced weight gain and hepatic steatosis. Neuron-specific loss of FIH phenocopied some of the major metabolic phenotypes of the global null animals: those mice have reduced body weight, increased metabolic rate, and enhanced insulin sensitivity and are also protected against high-fat-diet-induced weight gain. These results demonstrate that FIH acts to a significant degree through the nervous system to regulate metabolism.

The influence of chronic hypoxia upon chemoreception

Carotid body chemoreceptors are essential for time-dependent changes in ventilatory control during chronic hypoxia. Early theories of ventilatory acclimatization to hypoxia focused on time-dependent changes in known ventilatory stimuli, such as small changes in arterial pH that may play a significant role in some species. However, plasticity in the cellular and molecular mechanisms of carotid body chemoreception play a major role in ventilatory acclimatization to hypoxia in all species studied. Chronic hypoxia causes changes in (a) ion channels (potassium, sodium, calcium) to increase glomus cell excitability, and (b) neurotransmitters (dopamine, acetylcholine, ATP) and neuromodulators (endothelin-1) to increase carotid body afferent activity for a given PO(2) and optimize O(2)-sensitivity. O(2)-sensing heme-containing molecules in the carotid body have not been studied in chronic hypoxia. Plasticity in medullary respiratory centers processing carotid body afferent input also contributes to ventilatory acclimatization to hypoxia. It is not known if the same mechanisms occur in patients with chronic hypoxemia from lung disease or high altitude natives.

Effects of intermittent hypoxia on the isocapnic hypoxic ventilatory response and erythropoiesis in humans

Isocapnic hypoxic ventilatory response (HVR) and hematological variables were measured in nine adult males (age: 29.3+/-3.4) exposed to normobaric intermittent hypoxia (IH, 2 h daily at FI(O(2))=0.13, equivalent to 3800 m altitude) for 12 days. Mean HVR significantly increased during IH, however, after reaching a peak on Day 5 (0.79+/-0.12 vs. 0.27+/-0.11 L.min(-1).%(-1) on Day 1, P<0.05), it progressively decreased toward a lower value (0.46+/-0.16 L min(-1) x %(-1) on Day 12). In contrast, the subjects showed no changes in the ventilatory data and arterial O(2)-saturation in normoxia or poikilocapnic hypoxia (PET(CO(2)) uncontrolled). Hematocrit and hemoglobin concentration did not change, but the reticulocyte count increased by Day 5 (P<0.01). Our results suggest that moderate intermittent hypoxia induces changes in ventilatory O(2)-sensitivity and triggers the hematological acclimatization by increasing the percentage of reticulocytes in the blood. Normal ventilatory acclimatization to hypoxia was, however, not observed and the mechanisms involved in the biphasic changes in HVR we observed remain to be determined.

Central nervous system mechanisms of ventilatory acclimatization to hypoxia

Ventilatory acclimatization to hypoxia is the time-dependent increase in ventilation that occurs with chronic exposure to hypoxia. Despite decades of research, the physiological mechanisms that increase the hypoxic ventilatory response during chronic hypoxia are not well understood. This review focuses on adaptations within the central nervous system (CNS) that increase the hypoxic ventilatory response. Although an increase in CNS responsiveness had been proposed many years ago, only recently has strong experimental evidence been provided for an increase in the CNS gain in the rat, which has proved to be a good model of VAH in humans. Within the CNS, several neuroanatomical sites could be involved as well as changes in various neurotransmitters, neuromodulators or signalling mechanisms within any of those sites. Lastly, adaptations within the CNS could involve both direct effects of decreased P(O(2)) and indirect effects of increased afferent nerve activity due to chronic stimulation of the peripheral arterial chemoreceptors.

Physiological Effects of Intermittent Hypoxia

Intermittent hypoxia (IH), or periodic exposure to hypoxia interrupted by return to normoxia or less hypoxic conditions, occurs in many circumstances. In high altitude mountaineering, IH is used to optimize acclimatization although laboratory studies have not generally revealed physiologically significant benefits. IH enhances athletic performance at sea level if blood oxygen capacity increases and the usual level of training is not decreased significantly. IH for high altitude workers who commute from low altitude homes is of considerable practical interest and the ideal commuting schedule for physical and mental performance is being studied. The effect of oxygen enrichment at altitude (i.e., intermittent normoxia on a background of chronic hypoxia) on human performance is under study also. Physiological mechanisms of IH, and specifically the differences between effects of IH and acute or chronic continuous hypoxia remains to be determined. Biomedical researchers are defining the molecular and cellular mechanisms for effects of hypoxia on the body in health and disease. A comparative approach may provide additional insight about the biological significance of these effects.

Time domains of the hypoxic ventilatory response in awake ducks: episodic and continuous hypoxia.

Time-dependent ventilatory responses to episodic and continuous isocapnic hypoxia were measured in unidirectionally ventilated, awake ducks. Three protocols were used: (1) ten 3-min episodes of moderate hypoxia (10% O(2)) with 5-min normoxic intervals; (2) three 3-min episodes of severe hypoxia (8% O(2)) with 5-min normoxic intervals; and (3) 30-min of continuous moderate hypoxia. Ventilation (V(I)) increased immediately within a hypoxic episode (acute response), followed by a further slow rise in V(I) (short-term potentiation). The peak V(T) response increased from the first to second moderate hypoxic episode (progressive augmentation), but was unchanged thereafter. During normoxic intervals, V(I) increased progressively (56% following the tenth episode; long term facilitation). Time-dependent changes were not observed during or following 30-min of continuous hypoxia. Although several time-dependent ventilatory responses to episodic hypoxia are observed in awake ducks, they are relatively small and biased towards facilitation versus inhibitory mechanisms.

Ventilatory response to CO2 in birds. I. Measurements in the unanesthetized duck.

Ventilation and blood gases were measured in unanesthetized ducks at various levels of inspired CO2 partial pressure (PICO2). Ventilation was markedly augmented with increasing PICO2, whereas arterial and mixed venous PCO2 stayed essentially constant up to a PICO2 of about 20 torr and changed only slightly between that and the highest level tested (34 torr). After carbonic anhydrase had been blocked, blood PCO2 was elevated at all levels of PICO2 but the ventilatory response to increases in PICO2 were attenuated. The response to CO2 in the normal bird (before administration of acetazolamide) shows similarities to that in mammals. Qualitative differences between both classes of vertebrates after blockade of carbonic anhydrase may, however, suggest differences in their systems that control ventilation.

Room oxygen enrichment improves sleep and subsequent day-time performance at high altitude

We carried out a randomized, double-blind trial at 3800 m altitude to test whether a small degree of room oxygen enrichment at night improves sleep quality, and performance and well-being the following day. Eighteen sea-level residents drove from sea level to 3800 m in one day, and then slept one night in ambient air, and another night in 24% oxygen, the order being randomized. With oxygen enrichment the subjects had fewer apneas (P < 0.01) and spent less time in periodic breathing with apneas (P < 0.01) than when they slept in ambient air. Subjective assessments of sleep quality were also significantly improved. There was a lower acute mountain sickness score during the morning after oxygen-enriched sleep (P < 0.01) and a greater increase in arterial oxygen saturation from evening to morning (P < 0.05). The larger increases in arterial oxygen saturation from evening to morning suggest that the control of breathing may have been altered. Installing an oxygen-enriched room at high altitude is relatively simple and inexpensive, and shows promise for improving well-being of both commuters and residents.

Changes in dopamine D2-receptor modulation of the hypoxic ventilatory response with chronic hypoxia

Modulation of the hypoxic ventilatory response (HVR) by dopamine D(2)-receptors (D(2)-R) in the carotid body (CB) and central nervous system (CNS) are hypothesized to contribute to ventilatory acclimatization to hypoxia. We tested this with blockade of D(2)-R in the CB or CNS in conscious rats after 0, 2 and 8 days of hypoxia. On day 0, CB D(2)-R blockade significantly increased VI and frequency (fR) in hyperoxia (FI(O(2))=0.30), but not hypoxia (FI(O(2))=0.10). CNS D(2)-R blockade significantly decreased fR in hypoxia only. On day 2, neither CB nor CNS D(2)-R blockade affected VI or fR. On day 8, CB D(2)-R blockade significantly increased hypoxic VI and fR. CNS D(2)-R blockade significantly decreased hypoxic VI and fR. CB and CNS D(2)-R modulation of the HVR decreased after 2 days of hypoxia, but reappeared after 8 days. Changes in the opposing effects of CB and CNS D(2)-R on the HVR during chronic hypoxia cannot completely explain ventilatory acclimatization in rats.