Joseph F. Garcia

Increased erythropoiesis and elevated erythropoietin in infants born to diabetic mothers and in hyperinsulinemic rhesus fetuses.

The pathogenesis of the increased erythrocytosis and extramedullary erythropoiesis observed in infants of diabetic mothers (IDM) has been obscure. In the present studies, IDM were found to have elevated umbilical plasma erythropoietin (Ep) concentrations by radioimmunoassay. 22 of 61 IDM (36%) had levels above the range of 28 nonasphyxiated, appropriately grown normal infants. In 16 controls and 20 IDM, plasma Ep correlated directly with plasma insulin (P less than 0.001, r = 0.73). To investigate this relationship further, a chronic rhesus model was studied with continuous fetal hyperinsulinemia for 21 d in utero in the last third of pregnancy. In five experimental fetuses, plasma insulin levels averaged 4,210 microU/ml at delivery, whereas plasma Ep was above the range of six controls. In addition, the experimental fetuses had elevated reticulocyte counts in umbilical cord blood. The mechanism for the increased plasma Ep associated with hyperinsulinemia in the fetus is unexplained but may be mediated by fetal hypoxia.

Diurnal Levels of Immunoreactive Erythropoietin in Normal Subjects and Subjects with Chronic Lung Disease

Summary. Serum levels of immunoreactive erythropoietin (Ep) were measured in 48 normal male and female volunteers, ages 20‐60 years, to establish a control value for Ep of 18·5±5·0 (x̄ SD) mU/ml. Levels of the hormone were also measured sequentially over a 24 h period of time in an additional 17‘normal’volunteers with no diurnal variation. Diurnal levels of immunoreactive Ep were also measured in 30 subjects with chronic lung disease. These patients, in contrast to normal subjects, exhibited a diurnal variation in the level of immunoreactive Ep with peak levels occurring at midnight. The only variable measured which correlated with the serum immunoreactive Ep level in subjects with chronic lung disease was the level of carboxyhaemoglobin (P <0·02).

Serum immunoreactive erythropoietin levels in patients with polycystic kidney disease as compared with other hemodialysis patients.

Serum erythropoietin levels were randomly collected and measured by a sensitive radioimmunoassay in a hemodialysis population. For analysis, the patients were divided into two groups: those with polycystic kidney disease and those with other kidney diseases. In 12 polycystic kidney disease patients, serum erythropoietin was 22.6 +/- 2.4 mU/ml, hematocrit 29.7 +/- 1.0%, and absolute reticulocyte count 17.0 +/- 4.1 X 10(4)/microliters. In 24 other kidney disease patients, serum erythropoietin was 12.4 +/- 0.7 mU/ml, hematocrit 21.2 +/- 0.8%, and reticulocyte count 7.5 +/- 1.5 X 10(4)/microliters. Serum erythropoietin was 18.5 +/- 0.7 mU/ml in normal controls. Polycystic kidney disease patients manifested higher hematocrit, reticulocyte counts, and serum erythropoietin levels when compared to other kidney disease patients (p less than 0.01). The data suggest (1) an inappropriately low serum erythropoietin level for the severity of anemia in uremic hemodialysis patients and (2) that greater availability of erythropoietin results in more effective erythropoiesis, even in the uremic environment.

Effects of Acute and Chronic Administration of Narcotic Analgesics on Growth Hormone and Corticotrophin (ACTH) Secretion in Rats

Publisher Summary This chapter focuses on the experiments that are designed (1) to compare the acute effects of various narcotic analgesics on growth hormone (GH) and corticotrophin (ACTH)-secretion, and (2) to examine endocrine aspects of tolerance in rats treated chronically with morphine or methadone. The effects of narcotic analgesics on ACTH-secretion and on hypothalamo-pituitary systems have been reviewed recently. The effects of narcotic analgesics on GH and ACTH secretion in rats appear to be dose-related. The lower doses of morphine, methadone and codeine employed in this study mainly caused a rise of plasma GH and had little or no effect on plasma corticosterone. Higher doses of morphine and methadone produced increases of both plasma corticosterone and GH. Acute abstinence produced by naloxone resulted in a marked increase of plasma corticosterone and a diminution of plasma GH. Dose-response studies with narcotic antagonists showed that nalorphine produced simultaneous increases of plasma corticosterone and GH, while naloxone had no consistent effects on GH or ACTH secretion.

Erythropoietin elevation in the chronically hyperglycemic fetal lamb.

Abstract The effects of chronic fetal glucose infusion upon fetal oxygenation and endogenous erythropoietin (Ep) production were studied using the chronically catheterized fetal lamb. Fetal glucose infusion at rates between 5 and 20 mg/kg/min resulted in sustained fetal hyperglycemia. During glucose infusion (maximal glucose concentration achieved = 55.4 ± 3.7 mg/dl) fetal arterial oxygen contents fell from 5.8 ± 0.9 to 4.2 ± 1.0 ml/dl while no changes were observed in simultaneously sampled, noninfused twins. Although plasma insulin concentration rose in the infused fetuses, the elevations were inconstant and no relationship between fetal plasma insulin concentration and decrement in fetal oxygen content was evident. Fetal plasma arterial Ep concentrations in the control state were 13.2 ± 2.8 mU/ml. In infused fetuses, plasma Ep concentrations rose to 150.7 ± 35.9 mU/ml when the fetal arterial oxygen contents fell below 60% of their basal values. A reciprocal relationship was demonstrated between fetal arterial oxygen content and fetal plasma arterial Ep concentration (P < 0.001) in the pooled data of infused fetuses. The changes in plasma Ep concentration were noted prior to any significant fetal metabolic acidosis (as evidence of tissue hypoxia) and no changes in plasma Ep concentration were observed in simultaneously sampled noninfused twins. No relationship was apparent between fetal arterial plasma insulin and Ep concentrations. Since neither fetal anemia nor hemodilution occurred in these preparations, glucose-induced fetal hypoxemia is the likely mechanism behind elevated fetal Ep concentrations in these experiments. Similarities between this animal model and human fetuses and infants of diabetic mothers suggest that chronic in utero hypoxemia may be a common feature responsible for such diverse abnormalities as polycythemia, hyperbilirubinemia, and late fetal demise. The mechanism behind the glucose-induced fetal hypoxemia is not known.

Effects of Δ9 - THC on growth hormone and ACTH secretion in rats

Abstract Δ 9 - THC in doses of 5 – 20 mg/kg caused inhibition of GH secretion and stimulation of ACTH secretion. A rise in plasma corticosterone concentration following injection of Δ 9 - THC was used as an index of increased ACTH secretion. Daily administration of 20 mg/kg of Δ 9 - THC for 20 days did not result in significant tolerance to its neuroendocrine effects. Dexamethasone blocked the acute stimulant ffect of Δ 9 - THC on ACTH secretion but did not alter its inhibitory effects on GH secretion. Pentobarbital also suppressed pituitary-adrenal activation by Δ 9 - THC but was less effective than dexamethasone; the pentobarbital-induced rise of plasma GH, however, was suppressed by Δ 9 - THC. These results show that Δ 9 - THC acts as a pharmacological stressor of hypothalamo-pituitary function in rats since the same changes in plasma corticosterone and GH concentrations are elicited in response to many stimuli that are commonly of a stressful nature.

Plasma levels of immunoreactive erythropoietin after acute blood loss in man.

Summary. Plasma levels of immunoreactive erythropoietin (Ep) were measured after acute blood loss (50,75,200 and 450 ml) in man in order to determine the volume of blood loss required to trigger an Ep response as well as to define the reticulocyte response. There was a highly significant (P <0.01) linear increase in reticulocyte count after 200 and 450 ml of blood loss. Analysis of trends also showed a highly significant (P < 0.01) linear response of haematocrit and Ep after a 450 ml blood loss. The reticulocyte count increases were not dependent on a prior increase in Ep level indicating that at least two mechanisms are operative in restoring the red cell mass to normal after blood loss.

Chronic morphine effects on regional brain amines, growth hormone and corticosterone

This study was designed to examine the relationship between regional levels of brain amines (norepinephrine, NE; dopamine, DA; serotonin, 5-HT) and plasma hormone levels (corticosterone, CS; growth hormone, GH) in rats following chronic morphine administration (40 mg/kg twice daily). Rats were sacrificed at 4:00 pm (and the final injection was made at 9:00 am). Amine and hormone levels were determined after 1, 2 and 6 weeks of daily injections of morphine. Increased plasma CS was found after 1 and 2 weeks of injections and decreased GH levels were present after 2 and 6 weeks. In another 2 week study when morphine was administered 1 hr before sacrifice, plasma levels of CS were decreased and GH increased. Serotonin levels were decreased in all brain regions after 2 and 6 weeks of morphine administration and DA was decreased in the amygdala after 6 weeks. In 2 weeks treated rats injected 1 hr before sacrifice 5-HT levels had returned to control levels and DA was decreased. Inverse correlations were found to relate with 5-HT and CS levels, CS with GH levels and GH with brain DA. A direct correlation was present in GH and 5-HT levels.

Concentration of Highly Potent Erythropoietic Activity from Urine of Anemic Patients.

Summary 1) Some patients with aplastic anemia had exceptionally high levels of erythropoietic activity in plasma. The urine of these patients was assayed, and in some it was equally as potent as the plasma. As little as 1 ml daily for 14 days of untreated urine from such a patient produced a significant polycythemia in normal adult rats. When a concentrate of such urine, prepared by ultrafiltration, was injected at a dose equivalent to 30 ml daily for 14 days into normal adult rats, a polycythemia was produced which exceeded that resulting from exposure to a simulated altitude of 15.000 feet for the same period of time. 2) The high potency of such urine has allowed its assay in normal rats. This finding, together with the easy availability of urine and the efficiency of ultrafiltration as a method for preparing concentrates of urinary erythropoietic activity, should allow for a more rapid investigation of the chemistry and biology of this factor.

The Effect of Plethora on Erythropoietin Levels

Summary The mechanism by which plethora suppresses erythropoiesis in experimental animals has been assumed to be related to a decrease in erythropoietin (Ep) levels. Prior to the advent of a radioimmunoassay (RIA) for Ep this theory could not be confirmed because of the insensitivity of the bioassay for Ep. In the present study hypertransfusion induced plethora was associated with approximately a 50% reduction in plasma Ep levels in CF1 mice. The technical assistance of Ms. Greta Duke and Mr. David Wei is gratefully acknowledged.