This review is divided into three parts: (a) The primary site of oxygen sensing is the carotid body which instantaneously respond to hypoxia without involving new protein synthesis, and is historically known as the first oxygen sensor and is therefore placed in the first section (Lahiri, Roy, Baby and Hoshi). The carotid body senses oxygen in acute hypoxia, and produces appropriate responses such as increases in breathing, replenishing oxygen from air. How this oxygen is sensed at a relatively high level (arterial PO2 approximately 50 Torr) which would not be perceptible by other cells in the body, is a mystery. This response is seen in afferent nerves which are connected synaptically to type I or glomus cells of the carotid body. The major effect of oxygen sensing is the increase in cytosolic calcium, ultimately by influx from extracellular calcium whose concentration is 2 x 10(4) times greater. There are several contesting hypotheses for this response: one, the mitochondrial hypothesis which states that the electron transport from the substrate to oxygen through the respiratory chain is retarded as the oxygen pressure falls, and the mitochondrial membrane is depolarized leading to the calcium release from the complex of mitochondria-endoplasmic reticulum. This is followed by influx of calcium. Also, the inhibitors of the respiratory chain result in mitochondrial depolarization and calcium release. The other hypothesis (membrane model) states that K(+) channels are suppressed by hypoxia which depolarizes the membrane leading to calcium influx and cytosolic calcium increase. Evidence supports both the hypotheses. Hypoxia also inhibits prolyl hydroxylases which are present in all the cells. This inhibition results in membrane K(+) current suppression which is followed by cell depolarization. The theme of this section covers first what and where the oxygen sensors are; second, what are the effectors; third, what couples oxygen sensors and the effectors. (b) All oxygen consuming cells have a built-in mechanism, the transcription factor HIF-1, the discovery of which has led to the delineation of oxygen-regulated gene expression. This response to chronic hypoxia needs new protein synthesis, and the proteins of these genes mediate the adaptive physiological responses. HIF-1alpha, which is a part of HIF-1, has come to be known as master regulator for oxygen homeostasis, and is precisely regulated by the cellular oxygen concentration. Thus, the HIF-1 encompasses the chronic responses (gene expression in all cells of the body). The molecular biology of oxygen sensing is reviewed in this section (Semenza). (c) Once oxygen is sensed and Ca(2+) is released, the neurotransmittesr will be elaborated from the glomus cells of the carotid body. Currently it is believed that hypoxia facilitates release of one or more excitatory transmitters from glomus cells, which by depolarizing the nearby afferent terminals, leads to increases in the sensory discharge. The transmitters expressed in the carotid body can be classified into two ma...

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Oxygen intake, ventilation and heart rate were measured in six subjects performing ergometer exercise at various altitudes from sea level to 7,440 m (24,400 ft) (Bar. 300 mm Hg) during a Himalayan expedition lasting 8 months. Oxygen intake for a given work rate was constant and independent of altitude, up to the maximum work rate that could be maintained for 5 min. Maximum oxygen intake declined with increase of altitude, reaching 1.46 liters/min at 7,440 m (24,400 ft) in the best subject. Ventilation (STPD) for a given work rate was independent of altitude in light and moderate exercise but increased at each altitude as maximum oxygen intake was approached. Ventilation values of 140–200 liters (BTPS)/min were observed at altitudes above 4,650 m (15,300 ft). Heart rates at altitude were higher at low and moderate work intensities, but the same as or lower than the corresponding sea-level value for the same work load, as maximum oxygen intake was approached. Breathing oxygen at sea-level pressure at 5,800 m (19,000 ft) reduced ventilation and heart rate for a given work rate, restored work capacity almost to sea-level values and increased maximum heart rate. With the aid of data on blood, lung diffusion, and cardiac output from companion studies, the oxygen transport system was analyzed in three subjects, including a high-altitude Sherpa; and evidence is put forward that lung diffusion, cardiac output, and the high oxygen cost of extreme ventilation all contributed to the limitation of exercise at 5,800 m (19,000 ft). respiration, work and altitude; ventilation, work and altitude; heart rate, work and altitude; O2 transport system at high altitudes; altitude acclimatization Submitted on July 29, 1963

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A~traet Carbon monoxide was shown to be competitive with 02 in oxygen sensing by perfused carotid bodies isolated from cats, afferent electrical activity increasing with either decreasing Oz or increasing CO. The CO-induced increase in afferent activity was fully reversed by bright light. At submaximal light intensities the extent of reversal, after correcting to equal light intensity of light quanta at each wavelength, was maximal for light of 432 + 2 and 590 + 2 nm, with a ratio (432/590) of approximately 6. This spectrum is characteristic of the CO compound of mitochondrial cytochrome a 3. The photo-reversible inhibition of oxygen sensing activity by CO accounts for at least 80% of the oxygen chemosensory activity of the carotid body.

The time-dependent effects of hypoxia on the discharge rate carotid chemoreceptors were measured in anesthetized cats. Hypoxic exposure of two different durations were used: a short-term exposure (2-3 h) was used to measure the response of the same carotid chemoreceptors; and a long-term exposure (28 days at inspired PO2 of 70 Torr) to study carotid chemoreceptor properties in one group of cats relative to those of a control group. In the chronically hypoxic and control groups, determinations were made of the 1) steady-state responses to four levels of arterial PO2 (PaO2) at constant levels of arterial PCO2; 2) steady-state responses to acute hypercapnia during hyperoxia; and 3) maximal discharge rates during anoxia. We found that the acute responses of carotid chemoreceptor afferents to a given level of hypoxia (PaO2 = 30-40 Torr) did not significantly change within 2-3 h. After long-term exposure the carotid chemoreceptor responses to hypoxia significantly increased, with no significant changes in the hypercapnic response and in the maximal discharge rate during anoxia. We conclude that isocapnic hypoxia may not elicit a sufficient cellular response within 2-3 h in the cat carotid body to sensitize the O2 responsive mechanism, but hypoxia of longer duration will sensitize such a mechanism, thereby augmenting the chemosensory activity.

At very high altitude, exercise performance in the human sojourner may depend on a sufficient hypoxic ventilatory response (HVR). To study the relationship of HVR to exercise performance at high altitude, we studied HVR at sea level and 5,400 m and exercise ventilation at sea level, 5,400 m, and 6,300 m in nine members of the American Medical Research Expedition to Everest. The relationship of HVR between individuals was maintained when HVR was repeated after acclimatization to 5,400 m (P less than 0.05). There was a significant correlation in all subjects between HVR and ventilatory equivalent during exercise at sea level (r = 0.704, P less than 0.05). Subjects were then grouped into high (H) and low (L) HVR responders (ventilation increase to end-tidal PO2 of 40 Torr = 21.2 +/- 5.4 and 5.6 +/- 0.9 1 X min-1, respectively. At low and moderate levels of exercise, ventilation at sea level and after acclimatization to 6,300 m was higher in the high HVR group. At 6,300 m blood O2 saturation (Sao2%) decreased from rest to maximum exercise: H = 8.3 +/- 1.8%, L = 20.0 +/- 2.5% (P less than 0.01). HVR correlated inversely in all subjects with the decrease in Sao2 from rest to maximum exercise (P less than 0.05). Climbers with the highest HVR values reached and slept at higher altitudes. We conclude that the relative value of HVR in our group of climbers was not significantly altered after acclimatization; HVR predicts exercise ventilation at sea level and high altitude; the drop in Sao2% that occurs with exercise is inversely related to HVR; and sojourners with high HVR may perform better at extreme altitude.