Acute Oxygen Sensing Mechanisms

Abstract

oseph priestley, one of the three scientists credited with the discovery of oxygen, described the death of mice that were deprived of oxygen. However, he was also well aware of the toxicity of too much oxygen, stating, "For as a candle burns much faster in dephlogisticated [oxygen-enriched] than in common air, so we might live out too fast, and the animal powers be too soon exhausted in this pure kind of air. A moralist, at least, may say, that the air which nature has provided for us is as good as we deserve." 1In this review we examine the remarkable mechanisms by which different organs detect and respond to acute changes in oxygen tension. Specialized tissues that sense the local oxygen tension include glomus cells of the carotid body, neuroepithelial bodies in the lungs, chromaffin cells of the fetal adrenal medulla, and smooth-muscle cells of the resistance pulmonary arteries, fetoplacental arteries, systemic arteries, and the ductus arteriosus. Together, they constitute a specialized homeostatic oxygen-sensing system. Although all tissues are sensitive to severe hypoxia, these specialized tissues respond rapidly to moderate changes in oxygen tension within the physiologic range (roughly 40 to 100 mm Hg in an adult and 20 to 40 mm Hg in a fetus) (Fig. 1).In fetal life, the pulmonary vascular bed has a high resistance to blood flow. Consequently, oxygenated blood returning from the placenta is diverted from the unventilated lungs and across the foramen ovale and ductus arteriosus. At birth, when air breathing begins, the lungs expand and oxygen levels rise. With reversal of fetal hypoxic pulmonary vasoconstriction, the pulmonary vessels dilate and the ductus arteriosus constricts, thereby establishing the transition from the fetal to the neonatal circulation.After birth, hypoxic pulmonary vasoconstriction remains important, because it reduces perfusion of poorly ventilated areas of lung, and in so doing it decreases the shunting of desaturated, mixed venous blood to the systemic circulation. Inhibition of hypoxic pulmonary vasoconstriction reduces the systemic arterial oxygen tension, particularly in small-airway disease. 2 Moreover, as was first demonstrated in humans in 1947, 3 the intensity of hypoxic pulmonary vasoconstriction depends on the severity and duration of alveolar hypoxia. 4,5 The endothelium produces vasodilators, such as nitric oxide and prostacyclin, and vasoconstrictors, such as endothelin and thromboxane A 2 ; these molecules from endothelial cells modulate hypoxic pulmonary vasoconstriction, but the ability of small pulmonary vessels to contract in response to hypoxia resides in their smooth-muscle cells. 6 Three sites in these cells are involved in the mechanism of hypoxic pulmonary vasoconstriction: the membrane, the sarcoplasmic reticulum, and the contractile apparatus.

Cellular and Molecular Basis of Pulmonary Arterial Hypertension

“…” Both are characterized by mitochondrial hyperpolarization, depressed pyruvate dehydrogenase complex activity, and depressed H 2 O 2 production (53). In both there is also an O 2 -independent perpetuation of the rapid, reversible metabolic/redox shifts that normally occur in response to hypoxia and initiate hypoxic pulmonary vasoconstriction (54,55). This metabolic shift creates a “pseudohypoxic environment” with glycolytic predominance and normoxic hypoxia-inducible factor (HIF)-1α activation.…”

Basic Science of Pulmonary Arterial Hypertension for Clinicians

“…PDK activation thus impairs the Krebs' cycle and creates a glycolytic shift in glucose metabolism. Subversion of the mitochondrial O 2 -sensing mechanism, normally used to sense and respond to decreases in PO 2 65, appears to cause the sensor to signal hypoxia despite adequate PO 2 . These acquired (and reversible) mitochondrial abnormalities of fusion/fission and metabolism61 are postulated to cause the observed normoxic activation of HIF-1∝ in PAH14, 66 and cancer 63.…”

“…Several channels are germane to PAH, most notably Kv1.5. Acute inhibition of Kv1.5 by hypoxia initiates hypoxic pulmonary vasoconstriction65. Interestingly anorexigens such as dexfenfluramine, which promote PAH, also acutely inhibit PASMC K+ current and block Kv1.5.…”

Mitochondrial reactive oxygen species regulate hypoxic signaling

“…The importance of oxygen as the terminal electron acceptor of the electron transport chain has led to the evolution of multiple mechanisms by which cells and organisms maintain an adequate supply of oxygen. Acute exposure of mammals to hypoxic environments results in the calcium-dependent constriction of pulmonary arteries, allowing for increased blood oxygen perfusion [1]. Prolonged hypoxia stimulates multiple cell types and induces the Hypoxia Inducible Factors (HIFs) which mediate transcription of a large number of hypoxia-sensitive genes, including the production of erythropoietin in the kidney [2].…”