Adaptation to Hypoxia: A Chimera?

"The Chimera was, according to Greek mythology, a monstrous fire-breathing hybrid creature of Lycia in Asia Minor, composed of the parts of more than one animal [...]

Comparative response of brain to chronic hypoxia and hyperoxia

Two antithetic terms, hypoxia and hyperoxia, i.e., insufficient and excess oxygen availability with respect to needs, are thought to trigger opposite responses in cells and tissues. This review aims at summarizing the molecular and cellular mechanisms underlying hypoxia and hyperoxia in brain and cerebral tissue, a context that may prove to be useful for characterizing not only several clinically relevant aspects, but also aspects related to the evolution of oxygen transport and use by the tissues. While the response to acute hypoxia/hyperoxia presumably recruits only a minor portion of the potentially involved cell machinery, focusing into chronic conditions, instead, enables to take into consideration a wider range of potential responses to oxygen-linked stress, spanning from metabolic to genic. We will examine how various brain subsystems, including energetic metabolism, oxygen sensing, recruitment of pro-survival pathways as protein kinase B (Akt), mitogen-activated protein kinases (MAPK), neurotrophins (BDNF), erythropoietin (Epo) and its receptors (EpoR), neuroglobin (Ngb), nitric oxide (NO), carbon monoxide (CO), deal with chronic hypoxia and hyperoxia to end-up with the final outcomes, oxidative stress and brain damage. A more complex than expected pattern results, which emphasizes the delicate balance between the severity of the stress imposed by hypoxia and hyperoxia and the recruitment of molecular and cellular defense patterns. While for certain functions the expectation that hypoxia and hyperoxia should cause opposite responses is actually met, for others it is not, and both emerge as dangerous treatments

The dissociation of carbon monoxide from hemoglobin intermediate.

To investigate the mechanism of allosteric switching in human hemoglobin, we have studied the dissociation of the ligand (CO) from several intermediate ligation states by a stopped-flow kinetic technique that utilizes competitive binding of CO by microperoxidase. The hemoglobin species investigated include Hb(CO)4, the diliganded symmetrical species (alpha beta-CO)2 and (alpha-CO beta)2, and the di- and monoliganded asymmetrical species (alpha-CO beta-CO)(alpha beta), (alpha-CO beta)(alpha beta-CO), (alpha beta-CO) (alpha beta), and (alpha-CO beta)(alpha beta). They were obtained by rapid reduction with dithionite of the corresponding valence intermediates that in turn were obtained by chromatography or by hybridization. The nature and concentration of the intermediates were determined by isoelectric focusing at −25 degrees C. The study was performed at varying hemoglobin concentrations (0.1, 0.02, and 0.001 mM [heme]), pH (6.0, 7.0, 8.0), with and without inositol hexaphosphate. The results indicate that: (a) hemoglobin concentration in the 0.1-0.02 mM range does not significantly affect the kinetic rates; (b) the alpha chains dissociate CO faster than the beta chains; (c) the symmetrical diliganded intermediates show cooperativity with respect to ligand dissociation that disappears in the presence of inositol hexaphosphate; (d) the monoliganded intermediates dissociate CO faster than the diliganded intermediates; (e) the asymmetrical diliganded intermediates are functionally different from the symmetrical species

Effects of PDE-5 Inhibition on the Cardiopulmonary System After 2 or 4 Weeks of Chronic Hypoxia.

In pulmonary hypertension (PH), hypoxia represents both an outcome and a cause of exacerbation. We addressed the question whether hypoxia adaptation might affect the mechanisms underlying PH alleviation through phosphodiesterase-5 (PDE5) inhibition. Eight-week-old male Sprague-Dawley rats were divided into two groups depending on treatment (placebo or sildenafil, a drug inhibiting PDE5) and were exposed to hypoxia (10% O <sub>2</sub> ) for 0 (t0, n = 9/10), 2 (t2, n = 5/5) or 4 (t4, n = 5/5) weeks. The rats were treated (0.3 mL i.p.) with either saline or sildenafil (1.4 mg/Kg per day). Two-week hypoxia changed the body weight (- 31% vs. - 27%, respectively, P = NS), blood hemoglobin (+ 25% vs. + 27%, P = NS) and nitrates+nitrites (+ 175% vs. + 261%, P = 0.007), right ventricle fibrosis (+ 814% vs. + 317%, P < 0.0001), right ventricle hypertrophy (+ 84% vs. + 49%, P = 0.007) and systolic pressure (+ 108% vs. + 41%, P = 0.001), pulmonary vessel density (+ 61% vs. + 46%, P = NS), and the frequency of small (< 50 µm wall thickness) vessels (+ 35% vs. + 13%, P = 0.0001). Most of these changes were maintained for 4-week hypoxia, except blood hemoglobin and right ventricle hypertrophy that continued increasing (+ 52% vs. + 42%, P = NS; and + 104% vs. + 83%, P = 0.04). To further assess these observations, small vessel frequency was found to be linearly related with the right ventricle-developed pressure independent of hypoxia duration. Thus, although hypoxia adaptation is not yet accomplished after 4 weeks, PH alleviation by PDE5 inhibition might nevertheless provide an efficient strategy for the management of this disease

Detection of haemoglobins with abnormal oxygen affinity by single blood gas analysis and 2,3-diphosphoglycerate measurement

The aim is to determine if a single measurement of blood 2,3-diphosphoglycerate combined with gas analysis (pH, PCO2, PO2 and saturation) can identify the cause of an altered blood-oxygen affinity: the presence of an abnormal haemoglobin or a red cell disorder. The population (n=94) was divided into healthy controls (A, n=14), carriers of red cell disorders (B, n=72) and carriers of high oxygen affinity haemoglobins (C, n=8). Those variables were measured both in samples equilibrated at selected PCO2 and PO2 and in venous blood. In the univariable approach applied to equilibrated samples, we correctly identified C subjects in 93.6% or 96.8% of the cases depending on the selected variable, the standard P50 (PO2 at which 50% of haemoglobin is oxygenated) or a composite variable calculated from the above measurements. After introducing the haemoglobin concentration as a further discriminating variable, the A and B subjects were correctly identified in 91.9% or 94.2% of the cases, respectively. These figures become 93.0% or 86.1%, and 93.7% or 94.9% of the cases when using direct readings from venous blood, thereby avoiding the blood equilibration step. This test is feasible also in blood samples stored at 4\ub0C for 48 h, or at room temperature for 8 h

Red cell function at extreme altitudes on Mount Everest

As part of the American Medical Research Expedition to Everest in 1981, we measured hemoglobin concentration, red cell 2,3-diphosphoglycerate (2,3-DPG), Po2 at which hemoglobin is 50% saturated (P50), and acid-base status in expedition members at various altitudes. All measurements were made in expedition laboratories and, with the exception of samples from the South Col of Mt. Everest (8,050 m), within 2 h of blood collection. In vivo conditions were estimated from direct measurements of arterial blood gases and pH or inferred from base excess and alveolar PCO2. As expected, increased 2,3-DPG was associated with slightly increased P50, when expressed at pH 7.4. Because of respiratory alkalosis, however, the subjects' in vivo P50 at 6,300 m (27.6 Torr) was slightly less than at sea level (28.1 Torr). The estimated in vivo P50 was progressively lower at 8,050 m (24.9 Torr) and on the summit at 8,848 m (19.4 Torr in one subject). Our data suggest that, at extreme altitude, the blood O2 equilibrium curve shifts progressively leftward because of respiratory alkalosis. This left shift protects arterial O2 saturation at extreme altitude

Oxygen affinity of blood in altitude Sherpas

Oxygen equilibrium curves on blood within 6 h from sampling have been estimated from polarographic measurements of oxyhemoglobin concentration, in 13 male 14- to 50-yr old Sherpas residing at 3,850 m above sea level (Kumjung, Nepal). In samples with red blood cell counts = 4.7 +/- 0.8 (SD) x 10(6)/mm3, total hemoglobin concentration [Hb] = 17.0 +/- 1.9 g/dl, and hematocrit = 53.3 +/- 5.0, the mean oxygen half-saturation of hemoglobin (P50) (pH = 7.4 and PCO2 = 40 Torr) was 27.3 +/- 1.8 Torr. The P50 of altitude Sherpas was not significantly different from that of acclimatized lowlanders (28.2 +/- 1.3; n = 7), sea-level Caucasian residents (26.5 +/- 1.0; n = 17), and Sherpas at sea level (27.1; n = 3). The 2,3-diphosphoglyceric acid-to-hemoglobin concentration ratio ([2,3-DPG]/[Hb]) in altitude Sherpas was 1.22 +/- 0.03, the same as that of acclimatized Caucasians (1.22 +/- 0.10). The Bohr effect measured for the blood of one altitude Sherpas by the ratio deltalog P50/deltapH was -0.32 and -0.45 at PCO2 levels of 40 and 20 Torr, respectively. These values are not significantly different from those found in Caucasians at sea level where deltalog P50/deltalpH was -0.35 and -0.42, respectively. It is concluded that the P50 in native highlanders is not significantly different from that observed in sea-level dwellers. [2,3-DPG]/[Hb] at altitude, both in natives and in newcomers, is 20% higher than in sea-level residents