Hypoxic Hypometabolism Research Articles

Implications of hypoxic hypometabolism during mammalian ontogenesis.

During hypoxia, many newborn mammals, including the human infant, decrease metabolic rate, therefore adopting a strategy common to many living creatures of all classes, but usually not adopted by adult humans and other large mammals. In acute hypoxic conditions, hypometabolism largely consists in actively dropping mechanisms of thermoregulation. One implication is a decrease in body temperature. This is a safety mechanism, which favours hypoxic survival. Indeed, artificial warming during hypoxia can be counterproductive. Because carbon dioxide is an important stimulus for pulmonary ventilation, the drop in its metabolic production may tilt the balance of ventilatory control in favor of respiratory inhibition. Some experimental data support this view. In conditions of sustained hypoxia, the newborn's hypometabolism also results from a depression of tissue growth and differentiation. Some organs are affected more than others. To what extent the blunted organ growth will be compatible with survival depends not only on the severity and duration of hypoxia, but also on the timing of its occurrence during development. Upon termination of hypoxia, the newborn's metabolic rate recovers and growth resumes at higher rate. Even if body weight may be completely regained, alterations in the respiratory mechanical properties and in aspects of ventilatory control can persist into adulthood, a phenomenon not seen when the hypoxia was experienced at later stages of development. Some of the long-term respiratory effects of neonatal hypoxia are reminiscent of those observed in adult animals and humans native and living in high altitude regions.

Metabolic depression and enhanced O(2) affinity of mitochondria in hypoxic hypometabolism.

This study examined whether the steady-state hypometabolism seen in overwintering frogs (Rana temporaria) is reflected at the mitochondrial level either by a reduction in their resting (state 4) and active (state 3) respiration rates and/or by increases in O(2) affinity. We isolated mitochondria from the skeletal muscle of cold-submerged frogs at different stages during their hibernation in normoxic and hypoxic water. A modest metabolic depression at the whole animal level (normoxic submergence) was not associated with a reduction in mitochondrial state 4 and state 3 respiration rates. However, mitochondria isolated from frogs that were submerged for 1 mo manifested an increase in their O(2) affinity compared with controls and with animals submerged for 4 mo. Hypometabolism was more pronounced at the whole animal level during hypoxic submergence and was accompanied by 1) a reduction in mitochondrial state 4 and state 3 rates and 2) an increase in the O(2) affinity of mitochondria. These findings demonstrate that metabolic depression can be reflected at all levels of biological organization in hypoxia-tolerant animals.

Hypoxic hypometabolism in the anesthetized turtle, Trachemys scripta.

A hypometabolic response during acute exposure to hypoxia has been measured in both endothermic and ectothermic vertebrates. In the turtle, we determined the metabolic response to normocapnic hypoxia and hypercapnic hypoxia. In addition, we tested the hypothesis that hypoxic hypometabolism was a regulated response that did not depend on O(2) availability. Metabolic, cardiovascular, and blood gas measurements were collected in anesthetized turtles under two conditions: during normocapnic hypoxia [fractional inspired O(2) FI(O(2)) = 0.1 and 0.05] and during hypercapnic hypoxia [FI(O(2)) = 0.1 and 0.05 plus fractional inspired CO(2) (FI(CO(2))) = 0.05]. During normoxia, rate of O(2) consumption (VO(2)) was 0.82 ml. min(-1). kg(-1) and was reduced by nearly 30% at the lowest FI(O(2)). Normocapnic hypoxia of FI(O(2)) = 0.1 had no significant effect on VO(2). The addition of 5% CO(2) to the inspired air did not enhance the effects of hypoxia. Injections of 2,4-dinitrophenol increased VO(2) during hypercapnic hypoxia in some animals to levels greater than those measured during normoxia. We conclude that hypoxia produces a hypometabolic state in anesthetized turtles, and the pharmacological stimulation of VO(2) counteracts the effects of hypoxia on metabolism. The hypoxic hypometabolism in turtles most likely represents a regulated response and does not reflect limited O(2) availability at the cellular level. Finally, we hypothesize that hypoxemia induced by the right-to-left cardiac shunt often associated with diving may trigger the development of a hypometabolic state and therefore contribute to the prolongation of aerobic dive times.

Role of nitric oxide in hypoxic hypometabolism in rats.

Because it has been recently suggested that nitric oxide (NO) may mediate the effects of hypoxia on body temperature and ventilation, the present study was designed to assess more completely the effects of a neuronal NO synthase inhibitor (7-nitroindazole, 25 mg/kg ip), at ambient temperature of 26 and 15 degrees C, on the ventilatory (V), metabolic (O(2) consumption), and thermal changes (colonic and tail temperatures) induced by ambient hypoxia (fractional inspired O(2) of 11%) or CO hypoxia (fractional inspired CO of 0.07%) in intact, unanesthetized adult rats. At both ambient temperatures, 7-nitroindazole decreased oxygen consumption, colonic temperature, and V in normoxia. The drug reduced ambient or CO hypoxia-induced hypometabolism and ventilatory response, but the hypothermia persisted. It is concluded that NO arising from neural NO synthase plays an important role in the control of metabolism and V in normoxia. As well, it mediates, in part, the hypometabolic and the ventilatory response to hypoxia. The results are consistent with the notion that central nervous system hypoxia resets the thermoregulatory set point by decreasing brain NO.

Neuromodulators and hypoxic hypothermia in the rat

This study was designed to assess if opioids or adenosine are involved in the hypometabolism induced by hypoxia in the rat. Accordingly, antagonists such as naloxone (NLX) for opioids or theophylline (THEO) for adenosine were injected into conscious adult rats acutely exposed to either ambient hypoxia (AHx, F iO 2: 12%) at ambient temperatures of 26 or 9°C, or to CO hypoxia (COHx, F iCO=0.05%) at an ambient temperature (Ta) of 9°C. Oxygen consumption, ventilation, colonic temperature and shivering were recorded. The results show that with NLX, the degree of hypoxic hypometabolism was reduced with AHx at 26°C and slightly decreased with COHx at 9°C. With THEO, hypoxic hypometabolism was slightly reduced with AHx and COHx at 9°C. The ventilatory response to AHx and COHx was not consistently affected by either NLX or THEO. It is concluded that adenosine and opioids play a minor role, in mediating AHx or COHx hypothermia, especially during cold exposure.

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Oxygen transport in conscious newborn dogs during hypoxic hypometabolism.

We questioned whether the decrease in O2 consumption (VO2) during hypoxia in newborns is a regulated response or reflects a limitation in O2 availability. Experiments were conducted on previously instrumented conscious newborn dogs. VO2 was measured at a warm ambient temperature (30 degrees C, n = 7) or in the cold (20 degrees C, n = 6), while the animals breathed air or were sequentially exposed to 15 min of fractional inspired O2 (FIO2): 21, 18, 15, 12, 10, 8, and 6%. In normoxia, VO2 averaged 15 +/- 1 (SE) and 25 +/- 1 ml . kg-1 . min-1 in warm and cold conditions, respectively. In the warm condition, hypometabolism (i.e., hypoxic VO2 < normoxic VO2) occurred at FIO2 </=10%, whereas in the cold condition, hypometabolism occurred at FIO2 </=12%. The same results were obtained in a separate group (n = 14) of noninstrumented puppies. For all levels of FIO2 with hypometabolism, the relationships between measures of O2 availability (arterial O2 saturation or content, venous PO2 or saturation, x-axis) vs. VO2 (y-axis) had lower slopes in warm than in cold conditions. Hence, VO2 during hypometabolism in the warm condition was not the maximal attainable for the level of oxygenation. The results do not support the possibility that the hypoxic drop in VO2 in the newborn reflects a limitation in O2 availability. The results are compatible with the idea that the phenomenon is one of "regulated conformism" to hypoxia.

Effect of 2,4-dinitrophenol on the hypometabolic response to hypoxia of conscious adult rats.

During acute hypoxia, a hypometabolic response is commonly observed in many newborn and adult mammalian species. We hypothesized that, if hypoxic hypometabolism were entirely a regulated response with no limitation in O2 availability, pharmacological uncoupling of the oxidative phosphorylation should raise O2 consumption (VO2) by similar amounts in hypoxia and normoxia. Metabolic, ventilatory, and cardiovascular measurements were collected from conscious rats in air and in hypoxia, both before and after intravenous injection of the mitochondrial uncoupler 2,4-dinitrophenol (DNP). In hypoxia (10% O2 breathing, 60% arterial O2 saturation), VO2, as measured by an open-flow technique, was less than in normoxia (approximately 80%). Successive DNP injections (6 mg/kg, 4 times) progressively increased VO2 in both normoxia and hypoxia by similar amounts. Body temperature slightly increased in normoxia, whereas it did not change in hypoxia. The DNP-stimulated VO2 during hypoxia could even exceed the control normoxic value. A single DNP injection (17 mg/kg iv) had a similar metabolic effect; it also resulted in hypotension and a drop in systemic vascular resistance. We conclude that pharmacological stimulation of VO2 counteracts the VO2 drop determined by hypoxia and stimulates VO2 not dissimilarly from normoxia. Hypoxic hypometabolism is likely to reflect a regulated process of depression of thermogenesis, with no limitation in cellular O2 availability.

Ventilatory and metabolic responses of a bat, Phyllostomus discolor, to hypoxia and CO2: implications for the allometry of respiratory control.

The ventilatory and metabolic responses of lesser spear-nosed bats to hypoxia and hypercapnia were measured to determine whether these corresponded to preliminary allometries and a positive relationship between hypoxic ventilatory threshold and P50. Ventilatory responses of lesser spear-nosed bats to 3, 5 and 7% CO2 differed significantly from ventilation on air and each other. The magnitude of their ventilatory response to CO2 is consistent with the prediction of a smaller ventilatory response to hypercapnia in small compared to large mammals [% delta V varies MB0.130; Williams et al. (1994)]. Among 12, 10 and 8% O2 treatments only the ventilatory response to 8% O2 differed significantly from ventilation on air or the other treatments. Metabolic rate was significantly reduced at both 10 and 8% O2. The hypoxic ventilatory response of these bats does not support the prediction of a greater response in small compared to large mammals [% delta V veries MB0.273; Boggs and Tenney (1984)]. Their metabolic response is consistent with the hypoxic hypometabolism typical of small mammals, though not of comparable magnitude. The response, expressed as percent change in convection requirement (V/VO2), is also less than that observed in other small mammals. This relative insensitivity to hypoxia may be associated with this bat's unusually high affinity hemoglobin (P50 = 27.5 torr).

Interactions among metabolic rate, hypoxia, and control of breathing

This review attempts to emphasize the fact that the interpretation of the ventilatory response to hypoxia may be complicated by the reduction in metabolic rate that is often associated with hypoxia. The hypoxic hypometabolism is more apparent when oxygen consumption is relatively high, either in small or young mammals at subnormal ambient temperatures or in larger mammals exposed to cold. This hypometabolism is not mediated by an activation of the arterial chemoreceptors and, furthermore, may result from a decrease in arterial oxygen content independent of the arterial PO2. Substantial experimental evidence supports the hypothesis of a lowering of the thermoregulatory set point during hypoxia through a direct action on central neural structures. The ventilatory response to hypoxia, which may appear blunted or depressed, especially in small animals exposed to cold, should in fact be reevaluated by taking into account the hypometabolism and hypothermia associated with hypoxia. Finally, it is emphasized that the mechanisms involved in control of body temperature and those that account for the interactions with hypoxia are located in the hypothalamus. This suggests that common integrative structures are probably involved in the metabolic and ventilatory responses to hypoxia.

Metabolic-ventilatory interaction in conscious rats: effect of hypoxia and ambient temperature.

Previous studies have indicated that the hypometabolic response to hypoxia depends on ambient temperature (Ta), being more pronounced in the cold. If metabolic rate were an important contributor to the level of ventilation (VE), the magnitude of the hyperpneic response to hypoxia should also depend on Ta. We tested this hypothesis on adult conscious male rats. In normoxia, a drop in Ta from 25 to 10 degrees C increased O2 consumption and CO2 production (VO2 and VCO2, respectively, measured by an open-flow technique) and VE (measured with the barometric method) by 80 and 60%, respectively, with no changes in blood gases. At both Ta, hypoxia (10% inspired O2, 33-35 Torr arterial PO2) induced the same degree of hyperventilation, i.e., the same drop in arterial PCO2 (about -13 Torr). The hyperventilation at 25 degrees C Ta was achieved exclusively by an increase in VE, whereas at 10 degrees C Ta the hyperpnea was minimal (+15%) and accompanied by a drop (-30%) in VO2 and VCO2. Diaphragmatic electromyograms confirmed the VE results. Changes in blood pressure were similar at both Ta. Addition of 3% CO2 to the inspired air further increased VE, indicating that the hypoxic rat was not breathing at its maximal VE at either Ta. We conclude that, in the rat, changes in metabolic rate play an important role in the VE response to hypoxia and that Ta influences the response because of its effect on the degree of hypoxic hypometabolism.

Regulation of Oxygen Delivery and Consumption in Anesthetized Rats during Acute Hypoxia.

Physiological roles of ventilatory responses to acute hypoxia in the regulation of O2 transport and consumption were evaluated quantitatively in halothane anesthetized and spontaneously breathing rats with or without peripheral chemoreceptor afferents. Ventilation (VE), blood gas values, cardiac output (Q), and whole-body O2 consumption (VO2) were measured at various levels of inspired O2 concentration (FIO2) before and after denervation of carotid chemoreceptor afferents. In the carotid sinus nerve (CSN)-intact rat, the reduction in FIO2 from > 0.27 (hyperoxia) to about 0.10 (mild-moderate hypoxia) elicited an augmentation of VE which was accompanied by a well maintained total amount of O2 delivered to tissue (Q x O2 content of arterial blood, DO2) and VO2. The increase in VE was, however, turned off and the VE value did not differ from that in hyperoxia at FIO2 lower than 0.10 (moderate-severe hypoxia) (hypoxic ventilatory depression, HVD). Significant decreases in Q, DO2, and VO2 were also seen at FIO2 < 0.10. After CSN section, VE, Q, DO2, and VO2 values decreased progressively with the reduction in FIO2 from hyperoxia to mild hypoxia (FIO2 = 0.20-0.15). These findings indicate that the normal DO2 and VO2 are preserved in the presence of carotid chemoreceptor afferents in the FIO2 range > 0.10 and that HVD is accompanied by the decrease in VO2. Summarizing all results, VO2 decreased linearly with the reduction in PaO2 lower than about 60 mmHg or DO2 lower than 4 ml/min/100 g bw (critical PaO2 or DO2 for metabolic suppression), above which VO2 remained unchanged. The decrease in VO2 in lower PaO2 or DO2 levels (hypoxic hypometabolism) ensues perhaps from "adaptive" mechanisms reducing O2 demand when adequate O2 supply to tissue is limited.

Lung growth induced by hypoxia.

Lung growth induced by hypoxia.

Effect of hypoxia on shivering.

ARTICLESEffect of Hypoxia on ShiveringAllan Hemingway, and Lucy BirzisAllan Hemingway, and Lucy BirzisPublished Online:01 May 1956https://doi.org/10.1152/jappl.1956.8.6.577MoreSectionsPDF (491 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Back to Top Next Download PDF FiguresReferencesRelatedInformationCited ByIn Shackleton's trails: Central and local thermoadaptive modifications to cold and hypoxia after a man-hauling expedition on the Antarctic PlateauJournal of Thermal Biology, Vol. 73Invited Editorial on “Oxygen transport in conscious newborn dogs during hypoxic hypometabolism”Henry Gautier1 March 1998 | Journal of Applied Physiology, Vol. 84, No. 3 More from this issue > Volume 8Issue 6May 1956Pages 577-579 Copyright & PermissionsCopyright © 1956 the American Physiological Societyhttps://doi.org/10.1152/jappl.1956.8.6.577PubMed13331838History Published online 1 May 1956 Published in print 1 May 1956 Metrics