A comparison between environmental hypoxia and anemia, The

optimal oxygen equilibrium curve: A comparison between environmental hypoxia and anemia, The

Colin John Brauner

SYNOPSIS. Internal hypoxia in vertebrates occurs during anemia, when blood oxygen (O ^ sub 2^ ) carrying capacity is reduced, or during exposure to environmental hypoxia. In non-altitude adapted vertebrates, exposure to environmental hypoxia results in a change in blood O ^ sub 2^ affinity which, in some cases is beneficial to tissue O ^ sub 2^ delivery. In contrast, the elevation in blood O ^ sub 2^ carrying capacity observed in almost all vertebrates is always beneficial to tissue O ^ sub 2^ delivery (assuming no large changes in blood viscosity) and may be more important than changes in blood O ^ sub 2^ affinity in maintaining tissue O ^ sub 2^ delivery.

Experimental anemia in vertebrates results in a decrease in blood O ^ sub 2^ affinity which is always beneficial to tissue O ^ sub 2^ delivery. The reduction in affinity is brought about by an increase in the organic phosphate to hemoglobin ratio (NTP:Hb) within the red cell. In fish NTP:Hb decreases during environmental hypoxia but increases during anemia indicating that NTP regulation is quite different between these treatments despite the similarity of these treatments at the tissue level.

The Optimal Oxygen Equilibrium Curve: A Comparison Between Environmental Hypoxia and Anemia 1



^ SUB 2^ deprivation induced either externally by exposure to reduced atmospheric O ^ sub 2^ tension or internally by experimental anemia.


***formula text omitted***

***formula text omitted***


Blood oxygen affinity is conventionally expressed as the Po ^ sub 2^ at which 50% of the Hb in the blood is saturated (P ^ sub 50^ ). Assuming saturation of arterial blood is complete and arterial-venous oxygen extraction remains constant, an increase in P ^ sub 50^ of the blood results in an increase in the diffusion gradient for O ^ sub 2^ and an increase in venous





The analysis in Figure 2 neglects the effect of polycythemia on blood viscosity and the increase in metabolic work required to overcome the increased resistance to blood flow. The degree to which this effect will influence the model is unknown but the changes in Hb concentration modelled above are moderate and would not be expected to impart large metabolic costs through viscosity effects. At some point polycythemia will obviously become maladaptive. An extreme pathological condition is observed in “Monges disease” or “chronic mountain sickness” where the hematocrit (Hct) in Andean natives living at altitude may reach 83% (cf. Bouverot, 1985)! The model also assumes no change in blood volume associated with an increase in Hct while often blood volume increases with an increase in Hct. Assuming a constant metabolic rate, an increase in blood volume in conjunction with an increase in Hct will result in an underestimate of the changes in PVO2 due to an increase in carrying capacity reported in Figure 2.

The polycythemic response in vertebrates exposed to hypoxia is not always considered to be adaptive because animals genotypically adapted to altitude do not exhibit an elevation in Hct (see reviews by Bouverot, 1985; Monge and Leon-Velarde, 1991). Altitude adapted animals often possess low P ^ sub 50^ values and consequently low P ^ sub v^ O ^ sub 2^ levels indicating that adaptation has occurred at the tissue level eliminating additional metabolic costs associated with an elevated Hct (Tenney, 1995). However, in animals not genotypically adapted to altitude, the polycythemic response during exposure to hypoxia may be equally or more important than changes in P ^ sub 50^ in maintaining O ^ sub 02^ delivery to the tissues (Fig. 2).




Several studies on humans (Eaton and Brewer, 1968; Woodson et al., 1978), domestic mammals (Dhindsa et al., 1971), and fish (Lane et al., 1981; Val et al., 1994) demonstrate that P ^ SUB 50^ is indeed increased during anemia. In mammals, the increase in P ^ SUB 50^ is due to increased levels of red cell 2,3DPG, whereas the response in fish can be ascribed to increases in red cell triphosphates such as ATP and GTP (collectively referred to as NTP; Val et al., 1994). Recently, we have shown that amphibians also increase the NTP: Hb ratio during isovolemic anemia (where red cell numbers are reduced but total blood volume is maintained constant; Fig. 4), indicating that an increase in P ^ sub 50^ appears to constitute a universal response among vertebrates to anemic hypoxia.

In fish, the process of NTP regulation is especially interesting. Despite the fact that tissue hypoxemia occurs during exposure to environmental hypoxia and during experimental anemia, the NTP:Hb ratio is regulated in opposite directions in these two conditions. That is, environmental hypoxia induces a reduction in the NTP:Hb ratio (Wood and Johansen, 1972; Tetens and Lykkeboe, 1981) while experimental anemia induces an increase in the NTP: Hb ratio (Lane et al., 1981; Val et al., 1994). The means through which NTP is regulated under these conditions is largely unresolved, but appears to be correlated with changes in blood pH (Jensen et al., 1990).

Although an increase in P ^ sub 50^ has been demonstrated to be beneficial in maintaining oxygen delivery to the tissues, the change in blood O ^ sub 2^ affinity comprises only part of the compensatory response to anemia. A large increase in cardiac output during experimental anemia has been observed in the absence of a change in metabolic rate in mammals, reptiles, amphibians, and fish (Woodson et al., 1978; Wood et al., 1979; Wang et al., 1997). An increase in cardiac output is the most rapid and possibly most important response to anemia. In fish an increase in ventilation volume has also been observed (Wood et al., 1979).





CJB was supported by an NSERC Postdoctoral Fellowship and TW was supported by an NSERC International Postdoctoral Fellowship. We thank the two anonymous referees for their valuable comments.

1 From the Symposium Control of Arterial Blood Gases: Cardiovascular and Ventilatory Perspectives presented at the Annual Meeting of the Society for Integrative and Comparative Biology, 26-30 December 1995, at Washington, D.C.


Bauer, C. 1974. On the respiratory function of haemoglobin. Rev. Physiol. Biochem. Pharmacol. 70:1-31.

Bouverot, P. 1985. Adaptation to altitude-hypoxia in

vertebrates. Springer-verlag, Berlin. pp. 176. Dhindsa, D. S., A. S. Hoversland, W. A. Neill, and J. Metcalfe. 1971. Changes in blood oxygen affinity and hemodynamics in anemic dogs. Respir. Physiol. 11:346-353.

Eaton, J. W. and G. J. Brewer. 1968. The relationship between red cell 2,3-Diphosphoglycerate and levels of hemoglobin in the human. Proc. Natl. Acad. of Sci. U.S.A. 61:756-760.

Eaton, J. W., T. D. Skelton, and E. Berger. 1974. Survival at extreme altitude: Protective effect of increased hemoglobin oxygen affinity. Science 183:743-744.

Hebbel, R. P., J. W. Eaton, R. S. Kronenberg, E. D. Zanjani, L. G. Moore, and E. M. Berger. 1978. Human llamas: Adaptation to altitude in subjects with high hemoglobin oxygen affinity. J. Clin. Invest. 62:593-600.

Hillyard, S. D. 1981. Respiratory and cardiovascular adaptations of amphibians and reptiles to altitude. In S. M. Horvath and M. K. Yousef (eds.), Environmental physiology: Aging, heat and altitude. pp. 362-377. Elsevier, New York. Hutchison, V. H., H. B. Haines, and G. Engbretson. 1976. Aquatic life at high altitude: Respiratory adaptations in the lake Titicaca frog, Telmatobius culeus. Respir. Physiol. 27:115-129. Jensen, F B., N. A. Andersen, and N. Heisler. 1990. Interrelationships between red cell nucleoside triphosphate content and blood pH, Oz tension and haemoglobin concentration in the carp, Cyprinus carpio.

Lane, H. C., A E. Rolfe and J. R. Nelson. 1981. Changes in the nucleotide triphosphate/haemoglobin and nucleotide triphosphate/red cell ratios of rainbow trout, Salmo gairdneri Richardson, subjected to prolonged starvation and bleeding. J. Fish Biol. 18:661668.

Lenfant, C., J. D. Torrance, and C. Reynafarje. 1971. Shift of the OZ-Hb dissociation curve at altitude: Mechanism and effect. J. Appl. Physiol. 30:625631.

Mairbaurl, H. 1994. Red blood cell function in hypoxia at altitude and exercise. Int. J. Sports Med. 15(2):51-63.

McGrath, J. J. 1971. Acclimation response of pigeons to simulated high altitude. J. Appl. Physiol. 31 (2):274-276.

Monge, C. and F. Leon-Velarde. 1991. Physiological adaptation to high altitude: Oxygen transport in mammals and birds. Physiol. Rev. 71:1135-1172. Penney, D. and M. Thomas. 1975. Hematological alterations and response to acute hypobaric stress. J. Appl. Physiol. 39:1034-1037. Pinder, A. and W. Burggren. 1983. Respiration during chronic hypoxia and hyperoxia in larval and adult bullfrogs (Rana catesbeiana). J. Exp. Biol. 105:205-213.

Pough, F H. 1980. Blood oxygen transport and de

livery in reptiles. Amer. Zool. 20:173-185. Tenney, S. M. 1995. Functional significance of differences in mammalian hemoglobin affinity for oxygen. In J. R. Sutton, C. S. Houston, and G. Coates (eds.), Hypoxia and the brain, pp. 57-68. Queen City Printers, Burlington Vt. Tetens, V. and G. Lykkeboe. 1981. Blood respiratory properties of rainbow trout, Salmo gairdneri: Responses to hypoxia acclimation and anoxic incubation of blood in vitro. J. Comp. Physiol. 134:117-125.

Turek, Z., F. Kreuzer, and L. C. J. Hoofd. 1973. Advantage or disadvantage of a decrease of blood oxygen affinity for tissue oxygen supply at hypoxia: A theoretical study comparing man and rat. Pflugers Arch. 342:185-197.

Turek, Z., F Kreuzer and B. E. M. Ringnalda. 1978. Blood gases at several levels of oxygenation in rats with a left-shifted blood oxygen dissociation curve. Pflugers Arch. 376:7-13. Val, A. L., C. F. Mazur, R. H. S. Souza, and G. K. Iwama. 1994. Effects of experimental anaemia on intra-erythrocytic phosphate levels in rainbow trout, Oncorhynchus mykiss. J. Fish Biol. 45:269277.

Wang, T., E. Krosniunas, and J. W. Hicks. 1997. Regulation of central, vascular blood flows in turtles. Amer. Zool. 37:00000. Ward, M. P., J. S. Milledge, and J. B. West. (1989). High altitude medicine and physiology. University of Pennsylvania Press, Philadelphia. Weiskopf, R. B. and J. W. Severinghaus. 1972. Lack of effect of high altitude on hemoglobin oxygen affinity. J. Appl. Physiol. 33(2):276-277. Wells, R. M. G., B. J. Trevenen, and T. Brittain. 1989. Organic phosphate-hemoglobin interactions appear non-adaptive in the hypoxic toad, Buffo marinus. Comp. Biochem. Physiol. 92B(3):587-593. West, J. B. 1982. Respiratory and circulatory control

at high altitudes. J. exp. Biol. 100:147-157. Winslow, R. M. 1984. Red cell function at extreme altitude. In J. B. West and S. Lahiri (eds.), High altitude and man, pp. 59-72. American Physiological Society. Bethesda, Maryland. Willford D. C., E. P. Hill, and M. Y. Moores. 1982. Theoretical analysis of optimal PSo- J. Appl. Physiol. 52(4):1043-1048.

Wood, C. M., B. R. McMahon and D. G. McDonald. 1979. Respiratory, ventilatory, and cardiovascular responses to experimental anaemia in the starry flounder, Platichthys stellatus. J. exp. Biol. 82:139-162.

Wood, S. C. and K. Johansen. 1972. Adaptation to hypoxia by increased HbO2 affinity and decreased red cell ATP concentration. Nature 237:278-279. Wood, S. C. and C. J. M. Lenfant. 1976. Respiration: Mechanics, control and gas exchange. In C. Gans (ed.) Biology of the Reptilia, Vol. V, pp. 225-274. Academic Press, London, New York. Wood, S. C., R. W. Hoyt, and W. W. Burggren. 1982. Control of hemoglobin function in the salamander, Ambystoma tigrinum. Mol. Physiol. 2:263-272. Woodson, R. D., R. E. Wills, and C. Lenfant. 1978. Effect of acute and established anemia on Oz transport at rest, submaximal and maximal work. J. Appl. Physiol. 44(1):36-43.


*Department of Zoophysiology, Aarhus University

8000 Aarhus C. Denmark

(t) lnstitute of Biology, University of Odense

DK-5230 Odense M. Denmark

Copyright Society for Integrative and Comparative Biology Feb 1997

Provided by ProQuest Information and Learning Company. All rights Reserved