Humoral Control of Erythropoietic Activity in Man During and After Altitude Exposure.

Reynafarje, C; Ramos, J.; Faura, J; Villavicencio, D

doi:10.3181/00379727-116-29331

Cited by 63 publications

(27 citation statements)

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“…A rapid drop consistently starts as early as 2 to 4 days after the phlebotomy, in spite of a continued very low Hb at that time (ϳ3.4 -5.5 g/dl). The same phenomena have been observed in several animals, including humans (Reynafarje et al, 1964;Abbrecht and Littell, 1972;Miller and Howard, 1979). The EPO plasma level is affected by both by EPO production and elimination.…”

Section: Discussionsupporting

confidence: 50%

Pharmacokinetic/Pharmacodynamic Analysis of Paradoxal Regulation of Erythropoietin Production in Acute Anemia

Al‐Huniti¹,

Widness²,

Schmidt³

et al. 2004

J Pharmacol Exp Ther

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The regulatory mechanism responsible for a paradoxal, rapid drop in the erythropoietin (EPO) plasma level seen 2 to 4 days after acute, phlebotomy-induced anemia was investigated in seven adult sheep. To introduce acute anemia, each sheep underwent two phlebotomies where the hemoglobin (Hb) was reduced to 3 or 4 g/dl over 4 to 5 h. The phlebotomies were spaced 4 to 6 weeks apart in three animals, and 8 days apart in four other animals. EPO plasma levels, reticulocyte count, Hb, and p50 for oxygen-Hb dissociation were determined from frequent blood samplings throughout the study period. EPO's disposition pharmacokinetic (PK) and plasma clearance were determined from i.v. bolus injections of tracer amounts of a recombinant human EPO tracer. The controlled drop in Hb resulted in a rapid increase in plasma EPO to 836 Ϯ 52 mU/ml (mean Ϯ coefficient of variation percentage) that was followed by a paradoxical rapid drop 2 to 4 days after the phlebotomy while the animals were still very anemic (Hb ϭ 4.3 Ϯ 15 g/dl). The rapid drop in plasma EPO level could not be explained by the up-regulated clearance (clearance increased by a factor of less than 2.5) or by physiological adaptation (no change in p50, p Ͼ 0.05, second phlebotomy to Hb ϭ 3g/dl inadequately stimulated the EPO production). The PK/pharmacodynamic (PD) analysis supports the hypothesis of a limited sustained high EPO production rate in acute anemia, which indicates an apparent deficiency in the regulation of EPO production in acute anemia. The hypothesis was supported by a PK/PD feedback inhibition model that showed good agreement with the data (r ϭ 0.973 Ϯ 1.57).Erythropoietin (EPO) is a 34-kDa glycoprotein that is the primary hormone regulator of erythrocyte production. The main objectives of the present study are to elucidate quantitatively the kinetic regulatory mechanisms responsible for the rapid drop in EPO plasma level seen 2 to 4 days after phlebotomy-induced acute anemia while the Hb is still very low and to identify kinetic parameters of importance in EPO's production to provide a scientific basis for optimal use of EPO. Addressing these two objectives will provide a better understanding of the many factors affecting the erythropoiesis that should lead to more effective clinical use of EPO. Previously, we published a PK/PD analysis that simultaneously linked EPO plasma level, reticulocyte, and Hb responses (Veng-Pedersen et al., 2002). However, a PK/PD analysis of the physiology of EPO production under induced phlebotomy anemia has not been reported. Therefore, this work extends our previous work by kinetically analyzing the next step in the erythropoiesis, namely, EPO production and its regulation.This physiology-oriented analysis is done through a comprehensive, integrated PK/PD analysis, which simultaneously quantitatively links the Hb concentration, EPO production, and plasma level responses. Of particular interest of the proposed kinetic model is its ability to estimate a number of physiologically important parameters and to provide a k...

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Section: Discussionsupporting

confidence: 50%

Pharmacokinetic/Pharmacodynamic Analysis of Paradoxal Regulation of Erythropoietin Production in Acute Anemia

Al‐Huniti¹,

Widness²,

Schmidt³

et al. 2004

J Pharmacol Exp Ther

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“…These experiments, however, were performed using excessively large amounts of these substances; and it is not known whether the amounts present during hemolytic episodes are sufficient to stimulate EP production. Still other feedback mechanisms include suppression of erythropoiesis and EP production in polycythemic and de hydrated animals [93,125], presumably by the increase in blood viscosity; and the presence of inhibitors of erythropoiesis which have been reported to occur in the plasma of plethoric animals and humans [138,168]. The physiologic role of these various feedback phenomena remains to be ascer tained.…”

Section: Factors Which Affect Erythropoietin Production In Renal and mentioning

confidence: 99%

Erythropoietm and the Kidney

Fried¹

1975

Nephron

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Erythropoietin is a polypeptide hormone, which is produced in response to a deficit in the delivery of oxygen to the tissues relative to their oxygen needs; although other feedback mechanisms also modulate its production. The kidneys play a major role in the elaboration of this hormone. However, the precise action of the kidney is not yet known. Diseases of the kidneys cause profound alteration in the normal regulation of erythropoiesis. Some of these are reviewed here.

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“…The O 2 gradient between atmospheric air and cells decreases from 105 mmHg at sea level to 49 mmHg at high altitude (20). There are a number of adaptive responses that are triggered by this situation, such as increased ventilation (28), pulmonary hypertension (40), erythropoiesis (39), and heart work load. The adaptation to high altitude constitutes a situation that has both advantageous and disadvantageous consequences for human health.…”

mentioning

confidence: 99%

Mitochondrial nitric oxide metabolism during rat heart adaptation to high altitude: effect of sildenafil,l-NAME, andl-arginine treatments

Zaobornyj¹,

Valdez²,

Iglesias³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Zaobornyj T, Valdez LB, Iglesias DE, Gasco M, Gonzales GF, Boveris A. Mitochondrial nitric oxide metabolism during rat heart adaptation to high altitude: effect of sildenafil, L-NAME, and L-arginine treatments. Am J Physiol Heart Circ Physiol 296: H1741-H1747, 2009. First published April 3, 2009 doi:10.1152/ajpheart.00422.2008.-Rats submitted to high altitude (Cerro de Pasco, Perú, 4,340 m, PO2 ϭ 12.2 kPa) for up to 84 days showed a physiological adaptive response with decreased body weight gain (15%), increased right ventricle weight (100%), and increased hematocrit (40%) compared with sea level animals. These classical parameters of adaptation to high altitude were accompanied by an increase in heart mitochondrial enzymes: complexes I-III activity by 34% and mitochondrial nitric oxide synthase (mtNOS) activity and expression by Ͼ75%. The hyperbolic increase for mtNOS activity during adaptation to high altitude was similar to the observed pattern for hematocrit. Hematocrit and mtNOS activity mean values correlated linearly (r 2 ϭ 0.75, P Յ 0.05). Chronic treatment for 28 days with sildenafil (50 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) decreased the response of mtNOS to high altitude by 25%. Conversely, N Gnitro-L-arginine methyl ester treatment (8.3 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) increased such response by 40%, whereas L-arginine treatment (106 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) had no effect. Nitric oxide (NO) production by mtNOS accounts for ϳ49% of total cellular NO production in sea level rats and for ϳ54% in rats exposed to high altitude for 84 days. It is concluded that mtNOS is a substantial source of cardiac NO, a factor in the adaptive response to sustained heart hypoxia that is susceptible to be modified by pharmacological treatments. mitochondrial nitric oxide synthase activity; mitochondrial nitric oxide synthase expression; mitochondrial respiratory complexes; hematocrit; nitro-L-arginine methyl ester HIGH ALTITUDE IS A MULTIFACTORIAL source of stress in which hypobaric hypoxia is the most important component. The O 2 gradient between atmospheric air and cells decreases from 105 mmHg at sea level to 49 mmHg at high altitude (20). There are a number of adaptive responses that are triggered by this situation, such as increased ventilation (28), pulmonary hypertension (40), erythropoiesis (39), and heart work load. The adaptation to high altitude constitutes a situation that has both advantageous and disadvantageous consequences for human health. The main long term effects are decreased physical activity and life span. Among the beneficial effects, there is a recognized cardioprotection with improvement of the myocardial tolerance to ischemic episodes. A number of studies involving exposure to natural (22) or simulated (29) hypobaric hypoxia reported that this adaptation is associated to lower incidence and smaller size of myocardial infarction (30).Although the mechanism by which adaptation to hypoxia has cardioprotective effects remains not elucidated, nitric oxide (NO) has been extensively proposed as one of the molecular messengers inv...

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Humoral Control of Erythropoietic Activity in Man During and After Altitude Exposure.

Cited by 63 publications

References 0 publications

Pharmacokinetic/Pharmacodynamic Analysis of Paradoxal Regulation of Erythropoietin Production in Acute Anemia

Pharmacokinetic/Pharmacodynamic Analysis of Paradoxal Regulation of Erythropoietin Production in Acute Anemia

Erythropoietm and the Kidney

Mitochondrial nitric oxide metabolism during rat heart adaptation to high altitude: effect of sildenafil,l-NAME, andl-arginine treatments

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