Pergamon 0094-5765(94)00103-0

Acta Astronautica Vol. 33, pp. 137-141, 1994 Elsevier Science Ltd. Printed in Great Britain

THE ANEMIA OF MICROGRAVITY AND RECUMBENCY: ROLE OF SYMPATHETIC NEURAL CONTROL OF ERYTHROPOIETIN PRODUCTION

David Robertson, M.D., Sanford B. Krantz, M.D., and Italo Biaggioni, M.D.

Center for Space Physiology and Medicine, Departments of Medicine and Pharmacology Vanderbilt University, Nashville, Tennessee 37232-2195

Abstract We hypothesize that reduced sympathetic stimulation of erythropoietin production may maintain

the anemia which develops in virtually all space travellers. We tested this hypothesis in a human model of reduced sympathetic activity. Thirty-three patients with the Bradbury-Eggleston syndrome were divided into three groups according to their hemoglobin (Hgb) level. Patients with low Hgb had lower upright norepinephrine and lower upright renin. Patients with anemia also had inappropriately low plasma erythropoietin levels. We administered recombinant erythropoietin (Epogen) 25-50 units/kg s.c. 3 times per week and found that the anemia seen in autonomic failure could be reversed by this treatment. These results support the hypothesis that erythropoiesis is modulated by the sympathetic nervous system and that such mechanisms may also operate in the microgravity environment where sympathetic activity is reduced.

Introduction Development of mild anemia has been noted in crewmembers during both American and Soviet

space flights. In the mid 1960's, it was observed that a fall in red blood cell mass of approximately 15% occurred during space travel (Fischer et al, 1967). In general, reticulocyte counts have been congruent with the red blood cell mass measurements (Kimzey 1977, Johnson 1973, Leach et al. 1985).

Taken together, the fall in red cell mass and the reduced reticulocyte count suggest a reduction in red blood cell production (for review, see Kalandarova, 1986). The prevailing view is that there is both a decrease in red blood cell mass induced in man by space flight and also a failure of appropriate red blood cell production to compensate for this loss (Johnson et al., 1985; Nicogossian et al., 1989). For this reason, there has been great interest in erythropoietin levels in space. Erythropoietin was measured on the Spacelab I flight and it appeared that within 24 hours, there was a 50% absolute reduction in serum erythropoietin levels, although it was noted that preflight levels were relatively high. Given the small study population, statistical significance of the above changes was not achieved (Leach et al., 1985). Increases in erythropoietin levels following flights have been reported by Soviet investigators (Legen'kov et al., 1977), suggesting active compensation post-flight. Data emerging from the SLS-I experiments of Drs. Alfrey, Lange, and Huntoon seem to support and provide a more quantifiable basis for these observations (Alfrey, 1992).

There has been relatively little interest in recent years in the role of the nervous system and its relevant neurotransmitters in the control of red blood cell production and, in particular, erythropoietin (for review, see Halvorsen, 1966). It is noteworthy that some of the earliest investigations of erythropoiesis focused on such a role for the nervous system (Hollan, 1962, Seip et al., 1961, Miran et al., 1964, Evans et al., 1961). Furthermore, an important role for splanchnic nerves, which innervate both the kidney and adrenal gland, has been recognized and confirmed (Takaru et al., 1961; Beynon, 1977; Finne and Skoglund, 1970).

Results from various studies point to the importance of circulating catecholamines in erythropoietin production and function. Clinical reports of polycythemia of presumed central origin have appeared (Gilbert and Silverstein, 1965), and polycythemia associated with the catecholamine-producing tumor pheochromocytoma is by no means uncommon (Robertson and Biaggioni, 1990). In mice, rabbits, and dogs, administration of [32 adrenoreceptor agonists has been shown to cause an increase in erythropoiesis (Fink and Fisher 1977a, Fink and Fisher 1977b, Radtke et al 1980, Jelkman and Bauer

137

138 lOth IAA Man in Space Symposium

1980). It has also been shown that 132 receptor antagonists cause decreased erythrocyte production (Fink and Fisher 1977a, Zivny et al 1983). Other investigations have shown a circadian rhythm in erythropoietin levels which is congruent with the known rhythm of posture-induced alterations in plasma norepinephrine levels in persons duing normal activity (Wide et al, 1989).

In view of the considerable literature on the role of g2-adrenoreceptors in stimulation of erythropoietin production, we hypothesized that patients deficient in norepinephrine and epinephrine might have reduced erythropoietin and a correspondingly reduced red blood cell mass. We tested this hypothesis in a human model of reduced sympathetic activity, the Bradbury-Eggleston syndrome, also known as pure autonomic failure or idiopathic orthostatic hypotension.

Materials and Methods We studied 33 patients with the Bradbury-Eggleston syndrome. They were admitted to the

Clinical Research Center at Vanderbiit University and put on a diet containing 150 mEq of sodium and 6 mEq of potassium per day. Routine hematologic and serum erythropoietin values were determined for each patient. Blood samples for catecholamines and plasma renin activity were taken after the patients had been supine overnight and after 30 minutes of standing upright. Patients were divided according to their hemoglobin (Hgb) level into 3 groups (<12, 12-13, and >13 g/d0.

To confirm that the anemia in these patients was sensitive to erythropoietin, we attempted to reverse it by treatment with recombinant erythropoietin (Epogen). Five patients with significant anemia received Epogen 25-50 units/kg s.c. 3 times per week until the hematocrit normalized.

Results Patients with low Hgb (Group l) had lower upright norepinephrine (hiE, pg/ml) table, r=0.9,

p<0.05) and lower upright renin (PRA, ng/ml/hr, r=0.9) than the other two groups. Data are shown in Table 1.

Table 1

Group (n) Hbg NE PRA I (7) 11.14-0.2 1154.36 0.3+0.04

II (15) 12.6±0.1 1594.21 0.44-0.1 III (1 l) 14.14-0.1 2104-37 0.6±0.2

Patients with anemia (Hgb=l 1.64-0.5 g/dl) also had inappropriately low plasma erythropoietin levels (10.5+1.2 Mu/ml, n=4; predicted erythropoietin for degree of anemia = 20-50 Mu/ml).

Epogen therapy reversed the anemia in all five patients treated. Hemoglobin levels increased significantly from a pretreatment mean of 10.82 to a posttreatment mean of 13.32 (p=0.01). Supine blood pressures increased, although the increase was statistically insignificant. There was a significant increase in upright blood pressures, from a mean of 72.4 to a mean of 104.8 (p=0.01).

Discussion We have based our hypothesis about the anemia of space travel on the assumption that there is

reduced sympathetic stimulation in microgravity. Data from both American and Soviet space flights and from bedrest simulations of microgravity show decreased levels of urinary and plasma cateeholamines (Convertino 1993, Leach et al 1973, Maass et al 1992, Kvetnansky et al 1991, Leach 1983). Heart rate, blood volume, and blood pressure are known to be under the control of the sympathetic nervous system. Disturbances in these functions during spaceflight and upon return to microgravity have been documented (Smith et al 1975, Michel et al, Leach et al 1977, Johnson et al 1977, Vernikos 1993) and we believe they can be explained by reduced sympathetic stimulation (Robertson et al, submitted). Given this evidence, it was logical to explore the causes of the anemia of space travel in the same light.

The Bradbury-Eggleston syndrome has proved to be very useful in elucidating the causes, consequences, and possible remedies for reduced sympathetic activity in humans. As we expected, some patients with this syndrome were found to be anemic and to have an inappropriately low erythropoietin response. Table 1 demonstrates that the anemia of autonomic failure is not accompanied by the expected increase in level oferythropoietin. Instead, the erythropoietin level is actually low, whether one compares the data to age-matched controls or to rheumatoid arthritis patients with a comparable degree of anemia

10th IAA Man in Space Symposium 139

(Baor ot al., 1987). The etiology of the Bradbury-Eggloston syndrome is unknown, but does not appear to be associated with an inflammatory reaction or effects on the homatopoietic system other than those described herein.

It is noteworthy that although the anemia of autonomic failure has been mentioned from time to time in case reports in the autonomic literature, this observation has not permeated the hematology literature and has not been a focus of research among investigators primarily interested in hematology. The anemia has probably been significantly underestimated because Bradbury-Eggloston patients have low plasma volumes, rendering their hematocrits unreliable in assessing red blood cell mass. If the anemia of autonomic failure were due to inadequate beta-adrenoreceptor stimulation of erythropoietin producing cells, one would expect an increase in hematocrit when an adrenorecoptor agonist was administered to the patient. Indeed, in preliminary studies, in a patient with the Bradbury-Eggloston syndrome, the chronic administration of an adrenoreceptor agonist resulted in a restoration of the homatocrit toward normal.

Taken together, these data strongly suggest that circulating catecholamines or direct sympathetic stimulation within the kidney may be an important ancillary determinant of erythropoietin production (in addition to the well-established determinant, hypoxia) and that a relative lack of sympathetic activation and a relatively low norepinephrine or epinephrine level can contribute to the production of an erythropoietin suppression dependent anemia.

Thus, the anemia seen in autonomic failure is associated with inappropriately low erythropoietin response, and can be reversed by treatment with recombinant erythropoietin. These results support the hypothesis that erythropoiesis is modulated by the sympathetic nervous system and that such mechanisms may also operate in the microgravity environment.

LITERATURE CITED

1. Alfrey CP, Leach CS, Udden MM. Influence of space flight on ertyrokinetics in man in Spacelab. Life Scienees-I 180-Day Preliminary Results, 1992.

2. Baer AN, Dessypris EN, Goldwasser E, Krantz SB. Blunted erythropoietin response to anaemia in rheumatoid arthritis. Brit J Haemotol 1987; 66:559-564.

3. Beynon G. The influence of the autonomic nervous system in the control of crythropoetin secretion in the hypoxic rat. J Physiol 1977; 266:347-360.

. Convertino VA. Exercise and adaptation to microgravity. Handbook of Physiology: Adaptation to the Environment. Bethesda, MD: American Physiological Society, 1993: in press.

5. Evans ES, Rosonberg LL, Simpson ME. Erythropoietic response to calorigenic hormones. Endocrinology 1961; 68:517-532.

6. Fink GD, Fisher JW. Stimulation of erythropoiesis by beta adrenergic agonist. I. Characterization of activity in polycythemic mice. J Pharmacol Exp Thor 1977a; 202:192-200.

7. Fink GD, Fisher JW. Stimulation of erythropoiesis by beta adrenergic agonist. II. Mechanism of action. J Pharmacol Exp Ther 1977b; 202:199-208

8. Finne PH, Skoglund RW. Erythropoietin production in the rat following splanchnic neurectomy. J Lab Clin Med 1970; 76:103-106.

9. Fischer CL, Johnson PC, Berry CA. Red blood cell mass and plasma volume changes in manned space flight. JAMA 1967; 20.0:99-102.

10. Gilbert HS, Silverstein A. Neurogenic polycythemia. Report of a patient with transient erythrocytosis associated with occlusion of a middle cerebral artery and review of the literature. Am J Med 1965; 38:807-813.

140

11. Halvorsen S. 3_55 :65-79.

lOth IAA Man in Space Symposium

The central nervous system in regulation of erythropoiesis. Aeta Haemat 1966;

12. Hollan SR. Uber die neurale Regulation der Blutzellen. Folia Haemat (Leipzig) 1963; 8._0:138- 152.

13. Jelkman W, Bauer C. 82-Adrenergic stimulation of erythropoiesis in busulfan treated mice. ExD Hemato11980; 8:742-748.

14. Johnson PC. Hematology/immunology (MI 110 series). Part C: Blood volume and red cell life span (M113). In: Skvlab Medical ExPeriments Altitude Test (SMEAT) (NASA TM X-58115: Johnson Space Center, Houston, Texas) 1973.

15. Johnson PC, Driscoll TB, LeBlanc AD. Blood volume. In: Johnston RS, Deitlein LF, eds. Biom~i0al Results from Skylab. Washington, D.C.: NASA, 1977:235-241.

16. Johnson PC, Driscoll TB, Huntoon CL. Iron kinetics during exposure to microgravity. Aviat Space Environ Med 1985; 56:482-489.

17. Kalandarova MP. [Effect of spaceflight factors on hemopoiesis]. Kosmich Biol Aviak Med 1986; 20:7-17.

18. Kimzey SL. Hematology and immunology studies. In: Johnston RS, Dietlein LF (eds). Biomedical Results from Skylab (NASA SP-377) (Washington, D.C.: U.S. Government Printing Office) 1977.

19. Kimzey SL, Johnston PC. Hematological and immunological studies. In: Nicogossian AE (ed) The Apo!!o-Soyuz Test P.roie0t Medical Report (NASA SP-411) (Washington: U.S. Government Printing Office) 1977.

20. Kvetnansky R, Noskov VB, Blazicek P, Gharib C, Popova IA, Gauquelin G, Macho L, Gueil A, and Grigoriev AI. Activity of the sympathoadrenal system in cosmonauts during 25-day space flight on station Mir. Acta Astronautica. 1991; 23:109-116.

21. Leach CS, Hulley SB, Rambaut PC, Dietlein LF. SDace Life Sciences. 1973; 4:415-423.

The effect of bedrest on adrenal function.

22. Leach CS, Rambaut PC. Biochemical responses of the Skylab crewmen: An overview. In: Johnston RS, Dietlein LF, eds. Biomedical results from Skylab. Washington, D.C.: NASA, 1977:204-215.

23. Leach CS, Altchuler SI, Cintron-Trevino NM. The endocrine and metabolic response to space flight. Med. Sci. SPorts Exercise. 1983; 15:432-440.

24. Leaoh CS, Chen JP, Crosby W, Dunn CDR, Johnson PC, Lange RD, Larkin E, Tavassoli M. Spacelab 1 hematology experiment (INS103): Influence of space flight on erythokinetics in man. NASA TM-58263 (Houston: Johnson Space Center) 1985.

25. Legen~ov VI, Kiselev RK, Gudim VI, Moskaleva GP. [Changes in peripheral blood of crewmembers of the Salyut-4 orbital station]. Kosmich Biol Aviak Med 1977; 1_!1:1-12.

26. Maass H, Transmontano J, Baisch F, Response of adrenergic receptors to 10 days head-down tilt bedrest. A eta Physiol. Stand. 1992; 144(supp1604):61-68.

27. Michel EL, Rummel JA, Sawin CG, Buderer MC, Lem JD. Results from Skylab medical experiment M 171-metabolic activity. In: Johnston RS, Dietlein LF, eds._Biomedical Results

10th IAA Man in Space Symposium

From $kylab. Washington, DC: NASA, 1977:284-312.

14t

28. Miran EA, Grace Yl", Johnston GS, Murphy GP. Effects of hypothalamic stimulation on the erythropoietic response in the Rhesus monkey. Nature 1964; 204:1163-1169.

29. Nicogossian AE, Huntoon CL, Pool SL (eds). Space Physiology and Medicine Second Edition (Philadelphia: Lea and Febiger) 1989:222-239.

30. Radtke HW, Jubiz W, Smith JB, Fisher JW. Albuterol-induced erythropoietin production and prostaglandin release in the isolated perfused dog kidney. J Pharmaeol Exp Ther 1980; 214:467-471.

31 Robertson D, Biaggioni I (eds). Disorders of the Autonomic Nervous System (London: Harwood) In press, 1993.

32. Robertson D, Convertino V, Vernikos J. The Sympathetic Nervous System and the Physiological Consequences of Spaceflight. Submitted.

33. Seip M, Halvorsen S, Andersen P, Kaada BR. Effects of hypothalamic stimulation on erythropoiesis in rabbits. Scandinav J Clin & Lab Investigation 1961; 13:553-563.

34. Smith RF, Stanton K, Stoop D, Brown D, King PH. Quantitative electrocardiography during extended space flight. Acta Astronautica. 1975; 2:89-102.

35. Takaru F, Hirashima K, Okinaka S. Effect of the bilateral section of the splanchnic nerve on erythropoiesis. Nature 1961; 191:500-501.

36. Vernikos J. The role of plasma volume in orthostatic hypotension. Boccalon H, ed. Vascular Medicine. Amsterdam: Elsevier, 1993:569-572

37. Wide L, Bengtsson C, Birgegard G. Circadian rhythm of erythropoietin in human serum. Brit J Haematol 1989; 72:85-90.

38. Zivny J, Ostadal B, Neuwirt J, Prochazka J, Pelouch V. Effect of beta adrenergic blocking agents on erythropoiesis in rats. J Pharmacol Exp Ther 1983; 22_6:222-226.