The effect of combined chronic hypoxia and N-ethyl-N-nitrosourea on the carotid bodies of rats

Summary We measured the carotid body volume of rats treated with chronic hypoxia alone and chronic hypoxia together with a single neonatal injection of N-ethyl-N-nitrosourea (10 mg/kg). All the animals so treated showed enlargement of their carotid bodies, but no carotid body chemodectomas occurred.This work was supported by a grant from the North West Cancer Research Fund.     

Mast cell stabilizing compound FPL 55618 reduces right ventricular hypertrophy and lung mast cell hyperplasia in chronically hypoxic rats

Rats treated with chronic hypobaric hypoxia (21 days, 380 Torr) and mast cell stabilizing compound FPL 55618 had significantly less right ventricular hypertrophy and lung mast cell hyperplasia than rats subjected to chronic hypoxia alone. Right ventricular blood pressure was not reduced.     

Mast cell stabilizing compound FPL 55618 reduces right ventricular hypertrophy and lung mast cell hyperplasia in chronically hypoxic rats

Summary Rats treated with chronic hypobaric hypoxia (21 days, 380 Torr) and mast cell stabilizing compund FPL 55618 had significantly less right ventricular hypertrophy and lung mast cell hyperplasia than rats subjected to chronic hypoxia alone. Right ventricular blood pressure was not reduced.Compound FPL 55618 was kindly donated by Mr P. Sheard of Fisons Ltd Pharmaceutical Division, Loughborough, Leicestershire, LE11 OQY England.This study was supported by grants from the Medical Research Council of Canada and St. Joseph's Hospital Foundation.     

The exercising heart at altitude

Maximal cardiac output is reduced in severe acute hypoxia but also in chronic hypoxia by mechanisms that remain poorly understood. In theory, the reduction of maximal cardiac output could result from: (1) a regulatory response from the central nervous system, (2) reduction of maximal pumping capacity of the heart due to insufficient coronary oxygen delivery prior to the achievement of the normoxic maximal cardiac output, or (3) reduced central command. In this review, we focus on the effects that acute and chronic hypoxia have on the pumping capacity of the heart, particularly on myocardial contractility and the molecular responses elicited by acute and chronic hypoxia in the cardiac myocytes. Special emphasis is put on the cardioprotective effects of chronic hypoxia. (Part of a multi-author review.)     

A transbasisphenoidal approach for selective occlusion of the middle cerebral artery in rats

Summary The authors report a new model of focal cerebral ischemia following a selective occlusion of the middle cerebral artery in rats, without additional insults of hypoxia, hypotension and handling of carotid and vertebral arteries, as required in previously described models.     

Degradation of the mitochondrial complex I assembly factor TMEM126B under chronic hypoxia

Cell stress such as hypoxia elicits adaptive responses, also on the level of mitochondria, and in part is mediated by the hypoxia-inducible factor (HIF) 1α. Adaptation of mitochondria towards acute hypoxic conditions is reasonably well understood, while regulatory mechanisms, especially of respiratory chain assembly factors, under chronic hypoxia remains elusive. One of these assembly factors is transmembrane protein 126B (TMEM126B). This protein is part of the mitochondrial complex I assembly machinery. We identified changes in complex I abundance under chronic hypoxia, in association with impaired substrate-specific mitochondrial respiration. Complexome profiling of isolated mitochondria of the human leukemia monocytic cell line THP-1 revealed HIF-1α-dependent deficits in complex I assembly and mitochondrial complex I assembly complex (MCIA) abundance. Of all mitochondrial MCIA members, we proved a selective HIF-1-dependent decrease of TMEM126B under chronic hypoxia. Mechanistically, HIF-1α induces the E3-ubiquitin ligase F-box/WD repeat-containing protein 1A (β-TrCP1), which in turn facilitates the proteolytic degradation of TMEM126B. Attenuating a functional complex I assembly appears critical for cellular adaptation towards chronic hypoxia and is linked to destruction of the mitochondrial assembly factor TMEM126B.     

The response of human skeletal muscle tissue to hypoxia

Hypoxia refers to environmental or clinical settings that potentially threaten tissue oxygen homeostasis. One unique aspect of skeletal muscle is that, in addition to hypoxia, oxygen balance in this tissue may be further compromised when exercise is superimposed on hypoxia. This review focuses on the cellular and molecular responses of human skeletal muscle to acute and chronic hypoxia, with emphasis on physical exercise and training. Based on published work, it is suggested that hypoxia does not appear to promote angiogenesis or to greatly alter oxidative enzymes in skeletal muscle at rest. Although the HIF-1 pathway in skeletal muscle is still poorly documented, emerging evidence suggests that muscle HIF-1 signaling is only activated to a minor degree by hypoxia. On the other hand, combining hypoxia with exercise appears to improve some aspects of muscle O₂ transport and/or metabolism.     

Serotonin in the human infant carotid body

By immunocytochemistry serotonin was localized in the chief cells of the carotid body in human infants. Radioenzymatic measurement of the serotonin concentration revealed that it represents a significant proportion of the total amine content of the carotid body.     

On maximal oxygen consumption in hypoxic humans

The present paper discusses the factors affecting maximal O2 consumption (VO2max) in hypoxia (4300 m above sea level) along the following lines: 1) In acute hypoxia, the fractional limitation to VO2max imposed by circulatory O2 transport (FQ') is 50%, instead of 70% as in normoxia. This is due to the increase in the blood O2 transport coefficient (beta b) as PO2 decreases, as a consequence of the sigmoidal shape of the O2 dissociation curve of hemoglobin. The remaining 50% is assumed to be equally partitioned between tissue O2 transfer (Ft') and mitochondria O2 utilization (Fm'). 2) In chronic hypoxia, FQ' = 0.45, Ft' = 0.20 and Fm' = 0.35, as a consequence of reduced muscle fiber size and muscle mitochondrial density following acclimatization. 3) The relationship between VO2max and PIO2 in both acute and chronic hypoxia reflects the O2 dissociation curve. 4) Acclimatization to chronic hypoxia does not have the function of preserving VO2max.     

Serotonin in the human infant carotid body

Summary By immunocytochemistry serotonin was localized in the chief cells of the carotid body in human infants. Radioenzymatic measurement of the serotonin concentration revealed that it represents a significant proportion of the total amine content of the carotid body.     

Meclofenamate does not reduce chronic hypoxic pulmonary vasoconstriction.

There was no reduction in the pulmonary pressor response to hypoxia following inhibition of prostaglandin synthesis in rats exposed to chronic hypoxia. A fall in left ventricular weight suggested that systemic pressure may have been reduced after inhibition of prostaglandin synthesis in normoxic rats.     

Effects of 6-hydroxydopamine on rat carotid body chief cells

Summary Administration of 6-hydroxydopamine (6-OHDA) in concentrations high enough to cause degeneration of perivascular adrenergic nerve terminals has no morphological effect on the catecholamine-storing cells of the rat carotid body. Uptake of 6-OHDA by carotid body chief cells may be more selective than that exhibited by small-intenselyfluorescent cells and other catecholamine-storing cells which are affected by 6-OHDA. Alternatively, the sustentacular cells which envelope the chief cells may provide an effective barrier against the uptake of 6-OHDA.Supported by a Grant-in-Aid from the American Heart Association (77 630) and with funds contributed in part by the Texas Affiliate.     

Meclofenamate does not reduce chronic hypoxic pulmonary vasoconstriction

Summary There was no reduction in the pulmonary pressor response to hypoxia following inhibition of prostaglandin synthesis in rats exposed to chronic hypoxia. A fall in left ventricular weight suggested that systemic pressure may have been reduced after inhibition of prostaglandin synthesis in normoxic rats.This work was supported by NIH grant No. HL14985.     

Effect of hypoxia on human adipose-derived mesenchymal stem cells and its potential clinical applications

Human adipose-derived mesenchymal stem cells (hASCs) are an ideal cell source for regenerative medicine due to their capabilities of multipotency and the readily accessibility of adipose tissue. They have been found residing in a relatively low oxygen tension microenvironment in the body, but the physiological condition has been overlooked in most studies. In light of the escalating need for culturing hASCs under their physiological condition, this review summarizes the most recent advances in the hypoxia effect on hASCs. We first highlight the advantages of using hASCs in regenerative medicine and discuss the influence of hypoxia on the phenotype and functionality of hASCs in terms of viability, stemness, proliferation, differentiation, soluble factor secretion, and biosafety. We provide a glimpse of the possible cellular mechanism that involved under hypoxia and discuss the potential clinical applications. We then highlight the existing challenges and discuss the future perspective on the use of hypoxic-treated hASCs.     

Erythropoietin formation during hypoxia in mice with impaired responsiveness to erythropoietin induced by irradiation or 5-fluorouracil injection

Summary Plasma erythropoietin levels during continuous exposure to hypobaric hypoxia in mice with marrow aplasia induced by whole body X-irradiation or 5-fluorouracil injection were higher than in control mice similarly exposed. These findings give support to the hypothesis that a relationship exists between erythropoietin production rate and erythroid responsiveness to the hormone.Supported by Conicet and Subcyt grants. Request for reprints should be addressed to C. E. B.     

Breathing at high altitude

Acclimatization to long-term hypoxia takes place at high altitude and allows gradual improvement of the ability to tolerate the hypoxic environment. An important component of this process is the hypoxic ventilatory acclimatization (HVA) that develops over several days. HVA reveals profound cellular and neurochemical re-organization occurring both in the peripheral chemoreceptors and in the central nervous system (in brainstem respiratory groups). These changes lead to an enhanced activity of peripheral chemoreceptor and re-inforce the central translation of peripheral inputs to efficient respiratory motor activity under the steady low O₂ pressure. We will review the cellular processes underlying these changes with a particular emphasis on changes of neurotransmitter function and ion channel properties in peripheral chemoreceptors, and present evidence that low O₂ level acts directly on brainstem nuclei to induce cellular changes contributing to maintain a high tonic respiratory drive under chronic hypoxia. (This study is part of a multi-author review.)     

The acetylcholinesterase reaction and catecholamine fluorescence in the glomus cells of rat carotid body

Summary The presence of both acetylcholinesterase reaction and glyoxylic acid-induced fluorescence of catecholamines in the same glomus cells of rat carotid body was demonstrated using combined histochemical methods. A suggestion is made that the glomus cells have both excitatory and inhibitory effects on the chemosensory nerve via acetylcholine and catecholamines, respectively.Acknowledgments. The present study was supported by grants from the Emil Aaltonen Foundation and the Finnish Cancer Foundation to Timo Waris.     

Brain ischemia hypertension

Summary Hypertension was produced in anesthetized and conscious dogs when cerebral perfusion was reduced. It lasted up to 19 days in chronic studies, was not abolished by carotid sinus denervation nor with beta receptor blockade, but was absent after removal of brachiocephalic artery constriction (BCAC). The cardiovascular features of this neurogenic hypertension are presented.     

Role of hepcidin in murine brain iron metabolism

Brain iron homeostasis is maintained by a balance of both iron uptake and release, and accumulating evidence has revealed that brain iron concentrations increase with aging. Hepcidin, an iron regulatory hormone produced by hepatocytes in response to inflammatory stimuli, iron, and hypoxia, has been shown to be the long-sought hormone responsible for the regulation of body iron balance and recycling in mammals. In this study, we report that hepcidin is widely expressed in the murine brain. In cerebral cortex, hippocampus and striatum, hepcidin mRNA levels increased with aging. Injection of hepcidin into the lateral cerebral ventricle resulted in decreased Fpn1 protein levels in cerebral cortex, hippocampus, and striatum. Additionally, treatment of primary cultured neurons with hepcidin caused decreased neuronal iron release and Fpn1 protein levels. Together, our data provide further evidence that hepcidin may be involved in the regulation of brain iron metabolism.     

Effect of various stressors on the levels of lipid peroxide,antioxidants and Na+, K+-ATPase actrivity in rat brain

The level of malondialdehyde (MDA), an index of lipid peroxidation, and the antioxidants superoxide dismutase (SOD) and glutathione (GSH), as well as the activity of Na⁺, K⁺-ATPase, were assessed in whole rat brain after immobilization, anemic hypoxia (NaNO₂) and 72 h starvation. The effect of these stressors on plasma glucose and corticosterone levels was also observed. Hypoxia and starvation stimulated the lipidj peroxide formation in braini as indicated by an increase in the level of MDA, being higher after starvation than hypoxia. Brain SOD activity was also increased in response to hypoxia and starvation while GSH content was only diminished ini hypoxia. However, neither MDA nor antioxidants were affected by immobilization. On the other hand, the activity of brain Na⁺, K⁺-ATPase was significantly increased by immobilization and hypoxia but decreased in starvation. A similar pattern of change was also observed in plasma glucose and corticosterone levels in response to these stressors. These results elucidate differences in the biochemical response of animals towards various types of stress, with increased lipid peroxide formation in hypoxia and starvation.