Biomedical subjects

D H Polk

Publications and source records attributed to D H Polk.

At least 55 records · Page 3Linked to original sources

PubMed1990

Distribution of thyrotropin-releasing hormone (TRH) and precursor peptide (TRH-Gly) in adult rat tissues.

TRH (pGlu-His-Pro-NH2) arises from the post-translational processing of a larger precursor peptide containing multiple copies of the TRH progenitor sequence, Gln-His-Pro-Gly. Concentrations of TRH and its precursor peptide (TRH-Gly) were determined in serum and a variety of tissues of the rat using specific RIA systems. TRH and TRH-Gly immunoreactivities were detectable in almost all tissues studied. TRH was distributed mainly in neural tissues, with the highest mean concentration (126 pg/mg tissue) in hypothalamus. In extra-neural tissues, mean TRH levels ranged from 0.6-4.8 pg/mg tissue; the mean serum concentration was 12.4 pg/ml. In contrast to the distribution of TRH, relatively higher mean TRH-Gly concentrations were observed in serum (76.5 pg/ml) and in extraneural tissues, including prostate (83.3 pg/mg tissue), spleen (19.0 pg/mg), adrenal (16.2 pg/mg), kidney (13.3 pg/mg), and gastrointestinal tract (6.3-19.8 pg/mg). Among brain tissues, the TRH-Gly concentration was highest in pituitary gland (13.1 pg/mg). The mean ratio of TRH-Gly/TRH concentrations was less than 1 in neural tissues and pancreas. The lowest ratio (0.04) was observed in hypothalamus, and the highest ratio (66) in prostate gland. Assuming that tissue TRH-Gly levels reflect TRH synthesis, these results suggest that 1) the processing of TRH-Gly to TRH varies among tissues, 2) TRH-Gly to TRH conversion occurs most efficiently in neural tissues, and 3) TRH-Gly to TRH conversion may be a rate-limiting step in TRH biosynthesis.

Animals↗

PubMed1989

Development of the thyroid.

The fetal hypothalamic-pituitary-thyroid axis develops autonomously of maternal influence. System ontogenesis begins with the appearance and histological development of the thyroid and pituitary glands followed by development of the hypothalamus and the pituitary portal vascular system. Hypothalamic-pituitary control of thyroid function matures during the last half of human fetal development. Thyroid hormones undergo several types of biochemical transformations in tissues, including deiodination, side-chain metabolism, and conjugation with sulphate or glucuronide. Enzyme-mediated monodeiodination is the most important pathway. The first step in T4 metabolism is either outer-ring monodeiodination to active T3 or innerring monodeiodination to inactive rT3. Most T4 is metabolized to rT3 in fetal tissues and/or placenta and rT3 is the major circulating T4 metabolite in the fetus. Selective tissues, such as brain, can monodeiodinate T4 to T3, and this T3 is available for local action. Nuclear thyroid hormone receptors mature at different times in different tissues. Receptors appear earlier in brain than in liver and local T3 production and action may be important in fetal brain development. Most thyroid hormone actions, however, appear in the perinatal period, and infants with thyroid agenesis appear normal at birth and develop normally with prompt neonatal diagnosis and treatment. Premature infants, particularly those less than 30-32 weeks' gestational age, have an immature thyroid system and manifest a state of transient hypothalamic-pituitary TSH deficiency. This does not require treatment. Infants with primary hypothyroidism, either due to thyroid dysgenesis or to thyroid dyshormonogenesis, by contrast, require prompt diagnosis and treatment. Rarely an infant is born with permanent TSH deficiency with or without other pituitary hormone deficiencies. These infants also require prompt treatment. Mothers with thyroid disease or a history of thyroid disease and with IgG autoantibodies to thyroid gland TSH receptors may deliver infants with hypothyroidism or hyperthyroidism due to transplacental passage of the receptor-blocking or receptor-stimulating autoantibodies. These infants also require careful evaluation and management.

Animals↗

PubMed1988

Ontogeny of thyroid hormone effect on tissue 5'-monodeiodinase activity in fetal sheep.

Most of the thyroxine (T4) in fetal mammals is deiodinated to the inactive metabolite, reverse triiodothyronine (rT3), via an iodothyronine 5-monodeiodinase in fetal tissues. Maturation of the tissue 5'-monodeiodinase (MDI) enzymes required for conversion of T4 to active triiodothyronine (T3) in the rat, an altricial species, occurs in the postnatal period. To characterize fetal maturation of the enzymes for active T3 production in a precocial species, 5'-MDI activities were measured in liver, kidney, and brain tissue homogenates of ovine fetuses 13 days after total thyroidectomy (Tx) conducted at gestational ages of 99-107 or 129-132 days. Sham-operated twin fetuses served as controls. Hepatic type I 5'-MDI activity was not significantly lowered by Tx in group I but was significantly lower after Tx in group II fetuses. Renal type I 5'-MDI was not affected by Tx in either group. Type II 5'-MDI activity in cerebral cortex was significantly elevated after Tx in both groups I and II fetuses. Tissue sulfhydryl contents were similar in liver, kidney, and cerebral cortex from control and Tx fetuses in group I. These data indicate that hypothyroidism induced early in the third trimester is associated with increased brain type II 5'-MDI activity without significant change in liver or kidney type I 5'-MDI. Late third trimester hypothyroidism is associated with decreased type I 5'-MDI activity in liver homogenates as well as increased type II 5'-MDI activity in brain tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain↗

PubMed1988

Catecholamine and endorphin responses to delivery in term and preterm lambs.

A marked increase in catecholamines and endorphins at birth has been described in animals and man. Because the factors which regulate catecholamine secretion are incompletely understood and because it has been suggested that endogenous opiates are important in the regulation of catecholamine secretion, we designed studies to compare changes in plasma catecholamines at birth with simultaneously measured endorphins. Catecholamines and beta-endorphin-like immunoreactivity (beta-ELI) were measured at birth in term (145 days) and preterm (130 days) lambs. Preterm lambs were given natural sheep surfactant intratracheally to prevent respiration failure. Following umbilical cord cutting, there was a marked increase in circulating norepinephrine (NE) and epinephrine (E) levels. The peak preterm NE (2.2 +/- 0.3 ng/ml at 1 h) was greater than the peak term NE (1.0 +/- 0.2 ng/ml at 5 min). The peak preterm E occurred later and also was greater than the peak term E (4.0 +/- 0.5 ng/ml at 1 h vs. 1.3 +/- 0.4 ng/ml at 15 min, respectively, p less than 0.01). Baseline beta-ELI in term animals (767 +/- 15 pg/ml) was greater than preterm (456 +/- 12 pg/ml). Following cord cutting peak beta-ELI in term animals rose to 867 +/- 201 pg/ml compared to a peak beta-ELI in preterm animals of 1,866 +/- 450 pg/ml. These results and their significance for neonatal adaptation to extrauterine life are discussed.

Animals↗

PubMed1988

Thyroid hormone effects on neonatal thermogenesis.

It is clear that thyroid hormones modulate non-shivering heat production of the newborn mammal. While some obvious thyroid hormone effects on thermogenesis can be demonstrated in adult, cold-acclimated or hibernating animals, these findings cannot be directly applied to the newborn, in which changes in amount and composition of brown adipose tissue, as well as sympathetic and thyroid system maturational events, are occurring. Thyroid hormones do influence the prenatal development and subsequent responses of brown adipose tissue in neonates through primary actions on brown adipose tissue iodothyronine 5'monodeiodinase and mitochondrial uncoupling protein. Secondary effects involving brown adipocyte growth, lipid composition, oxidation proteins, and sympathoadrenal activity are of lesser importance in thyroid hormone modulation of newborn thermogenesis. The acute surge in thyroid hormones that occurs at birth seems of limited significance with regard to neonatal thermogenesis. The stimulation of sympathoadrenal activity at the time of birth, as well as continued in situ conversion of T4 to T3 in the brown adipocyte, are of critical importance in stimulating and modulating heat production in the newborn.

Adipose Tissue↗

PubMed1987

Dopamine pharmacokinetics in critically ill newborn infants.

To compare clinical responses with plasma concentrations of dopamine and to compare dopamine pharmacokinetics in infants of different gestational age or clinical condition, dopamine was administered under carefully controlled conditions of dose and rate of infusion. The dose was increased stepwise from 1 to 2, to 2 to 4, and 4 to 8 micrograms/kg/min. Plasma concentrations of catecholamines, including dopamine, were compared with blood pressure, heart rate, and Doppler cardiac output. The data were analyzed to determine the threshold or minimal plasma concentration of dopamine necessary to produce discernible effects. Plasma clearance rate was calculated from steady-state plasma concentrations. The average threshold for increases in mean arterial pressure was 50% below that for increases in heart rate. Improvements in arterial pressure were noted before and at lower thresholds than for increases in heart rate. Serial echocardiographic data showed dose-dependent increases in cardiac output and stroke volume without significant change in heart rate or systemic vascular resistance. Thresholds and plasma clearance values were similar in infants of gestational age 27 to 42 weeks and birth weights 900 to 4300 g. Administration of dopamine at initial dosages lower than commonly recommended, followed by incremental increase in dose, may be associated with improved left ventricular performance with avoidance of undesirable tachycardia and arrhythmias.

Dopamine↗

PubMed1987

Epidermal growth factor acts as a corticotropin-releasing factor in chronically catheterized fetal lambs.

Epidermal growth factor (EGF) has been reported to stimulate adrenocorticotropin hormone (ACTH), growth hormone and prolactin secretion from pituitary tissue in vitro, and in large doses evokes ACTH secretion in adult sheep in vivo. In order to assess a possible role for EGF in the pituitary hyperfunction characteristic of the in utero fetus, we measured changes in plasma immunoreactive ACTH concentrations after acute administration of saline, purified mouse EGF or synthetic ovine corticotropin releasing factor (CRF) to chronically catheterized fetal sheep. Both CRF and EGF were associated with increases in plasma immunoreactive ACTH concentrations. Peak values 60 min after 10-micrograms injections of either EGF or CRF increased from baseline ACTH values of 61 +/- 11 pg/ml to 191 +/- 37 and 178 +/- 25 pg/ml, respectively. Dose-response studies indicate that at low doses (less than 20 micrograms) EGF is as potent a stimulus for ACTH release as CRF. EGF infusion was not associated with detectable changes in circulating CRF, catecholamines, arginine vasopressin levels, or plasma growth hormone concentrations. We speculate that EGF may be important in the regulation of pituitary function in the developing mammalian fetus.

Adrenocorticotropic Hormone↗

PubMed1987

Effect of fetal thyroidectomy on newborn thermogenesis in lambs.

We investigated the effect of the transient neonatal hyperthyroid state on thermogenesis at birth by measuring rectal temperature, plasma free fatty acids, plasma catecholamines, and in vitro brown adipose tissue respiration in thyroidectomized (n = 6) and sham operated (n = 5) fetal sheep. Surgery was performed at an average of 133 days of gestation followed by cesarean delivery at 146 days. Fetuses were delivered into a constant room temperature of 25 degrees C. Serial measurements were made in utero before delivery and at timed intervals after birth. Serum 3,3',5 triiodothyronine and thyroxine concentrations in the neonatal period were normal in sham operated and nondetectable in thyroidectomized fetuses. Rectal temperatures and serum free fatty acid levels were reduced in thyroidectomized newborns. Plasma epinephrine concentrations were increased and the hypothyroid neonates were acidotic when compared to control animals. In vitro basal and norepinephrine stimulated brown adipose tissue respiration were reduced in thyroidectomized compared to control animals. These results indicate that thyroid hormone deficiency impairs nonshivering thermogenesis in brown adipose tissue and leads to hypothermia despite augmented plasma epinephrine values.

Adipose Tissue, Brown↗

PubMed1987

Neonatal adaptation: naloxone increases the catecholamine surge at birth.

A marked increase in plasma catecholamines at birth has been described in animals and man. Because the factors that regulate catecholamine secretion are incompletely understood and because it has recently been suggested that endogenous opiates are important in the regulation of catecholamine secretion, we designed studies to determine the influence of opiate receptor blockade prior to delivery on the increase in plasma catecholamines at birth. Term fetal sheep were delivered by cesarean section and randomly assigned to receive naloxone or vehicle. Naloxone was given just prior to umbilical cord cutting as a 2 mg/kg bolus followed by 2 mg/kg/h. Naloxone administration resulted in significantly greater peak levels of plasma norepinephrine (peak levels of 1.5 +/- 0.4 versus 0.9 +/- 0.1 ng/ml) and epinephrine (peak levels of 1.4 +/- 0.7 versus 0.9 +/- 0.3 ng/ml) and higher norepinephrine values throughout the study period. Naloxone administration was associated with significantly elevated heart rate (peak 184 +/- 12 versus 207 +/- 13 beats per min) and blood pressure (peak 95 +/- 6 versus 88 +/- 2 mm Hg). These studies demonstrate that opiate receptor blockade from birth markedly augments the neonatal sympathoadrenal response in the term newborn lamb.

Animals↗

PubMed1986

Blunted response of maternal ovine placental lactogen levels to arginine stimulation after single umbilical artery ligation in pregnant sheep.

Ovine placental lactogen levels in the maternal circulation are significantly reduced after single umbilical artery ligation in pregnant sheep. We report the ovine placental lactogen response to high-dose amino acid stimulation in four ewes with fetuses that underwent single umbilical artery ligation and six control ewes with fetuses that underwent sham operation. After maternal infusion with 50 gm of arginine in 350 ml of distilled water, mean ovine placental lactogen levels in ewes with fetuses that underwent single umbilical artery ligation increased by 170%, while mean levels in control ewes increased by 294%. Maternal infusions with hypertonic saline solution of osmolality and volume equal to those of the arginine solutions failed to increase maternal ovine placental lactogen levels. Fetal well-being, both during and after the maternal arginine infusions, was confirmed by unchanged fetal arterial blood gases and catecholamines. The ovine placental lactogen levels in the fetal circulation were not altered by maternal arginine infusion. These data suggest that the correlation between maternal ovine placental lactogen levels and functioning placental mass may be enhanced by arginine stimulation. The possible use of this provocation of placental lactogen levels as a test of placental function in clinical practice is discussed.

Animals↗

PubMed1986

Serum thyroid hormones and tissue 5'-monodeiodinase activity in acutely thyroidectomized newborn lambs.

After either total thyroidectomy or sham operation in full-term fetal sheep, fetuses were delivered and serial blood samples were obtained for measurements of thyroxine (T4), triiodothyronine (T3), and catecholamines. Despite comparable serum T4 values (T4 means +/- SE, sham 7.1 +/- 0.6 micrograms/dl, thyroidectomized 6.8 +/- 0.7 micrograms/dl at 60 min after birth), serum T3 values were lower in the thyroidectomized animals (T3 means +/- SE, thyroidectomized 39 +/- 4.8 ng/dl, sham 153 +/- 20.1 ng/dl at 60 min after birth). Four hours after birth, the animals were killed with an intravenous overdose of barbiturate. Brain, thyroid, liver, kidney, and brown adipose tissues were dissected and analyzed for thyroxine 5'-monodeiodinase (5'-MDI) activity in vitro. 5'-MDI activity was comparable in all tissues from sham-operated and thyroidectomized lambs. Plasma epinephrine and norepinephrine concentrations, mean arterial pressure, mean pulse, rectal temperature, and arterial blood gas values were similar in the two groups of animals. These data support the hypothesis that the thyroid gland is the major source of T3 for the T3 surge in the immediate newborn period. They also indicate that the neonatal T3 surge has limited immediate metabolic significance in euthyroid newborns.

Adipose Tissue, Brown↗

PubMed1986

Effect of thyroid status on lung and heart beta-adrenergic receptors in fetal and newborn sheep.

The effect of altered thyroid status on the development of beta-adrenergic receptor (BAR) density and affinity was investigated in ovine fetal and newborn heart and lung. Fetal (119-121 days gestation) and newborn (2-3 days of age) sheep underwent either thyroidectomy alone, thyroidectomy plus infusion of a large dose of T3 or sham operation. Eight days later BAR were measured in heart and lung using the tritiated radioligand dihydroalprenolol. There was no apparent effect of altered thyroid status on fetal heart or lung BAR density or affinity. In contrast, the newborns thyroidectomized and infused with T3 had a 96% increase in heart BAR density and an 83% increase in lung BAR compared to the thyroidectomized only or sham-operated newborns which were similar. These results suggest that in the near term ovine fetus heart and lung tissue BAR are neither dependent on nor responsive to thyroid hormones, whereas in the newborn period heart and lung BAR are highly responsive to thyroid hormones.

Animals↗

PubMed1986

The effect of chemical sympathectomy on catecholamine release at birth.

The precise source of circulating catecholamine (CA) at birth and their role in circulatory adaptation is unclear. In order to determine the contribution of increased postganglionic sympathetic nerve activity to the CA surge at birth, we induced complete sympathectomy in near term fetal lambs prior to delivery by giving 6-hydroxydopamine. Chronically catheterized fetal sheep received either 6-hydroxydopamine (n = 5) or control infusion (n = 6). Chemical sympathectomy was verified by tyramine infusion. Lambs were delivered at 142 +/- 1 days of gestation and serial plasma CA, heart rate, blood pressure, cardiac output, blood gases, blood glucose, and free fatty acids, were measured before and for 4 h after delivery. Myocardial beta-adrenergic receptors and tissue CA concentration were determined following sacrifice. Baseline circulating norepinephrine (NE) values were lower in sympathectomized animals (183 +/- 45 versus 373 +/- 125 pg/ml, p less than 0.05) and epinephrine values were slightly higher (118 +/- 89 versus 48 +/- 1 pg/ml, NS). There was only a 2-fold increase in NE after cord cutting in sympathectomized animals while control animals had a 4-fold increase (peak NE values 354 +/- 121 versus 1305 +/- 363 pg/ml respectively, p less than 0.001). Epinephrine increased significantly in both groups and there were no significant differences between sympathectomized and control animals. Heart rate and blood pressure rose abruptly in both groups after cord cutting and there were no significant differences.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Biochemical and ontogenic characterization of thyroxine 5'-monodeiodinase in brown adipose tissue from fetal and newborn lambs.

We characterized T4 5'-monodeiodinase (5'-MDI) and its ontogenic changes in brown adipose tissue (BAT) of fetal lambs from a gestational age of 99 days to the newborn period. BAT 5'-MDI activity in fetal or newborn lamb was markedly enhanced by dithiothreitol (DTT); a near-maximum stimulation was reached at a DTT concentration of 1 mM. The enzyme is heat-labile (inactivated when heated to 56 C for 5 min) and has a pH optimum at 6.5. In the presence of 1 mM DTT, BAT 5'-MDI was extremely sensitive to propylthiouracil (PTU): 0.04 mM PTU resulted in 94% inhibition of the T4 to T3-converting activity. An increase of DTT concentration to 20 mM in the incubation media reduced the inhibition by 0.04 mM PTU to 59%. Kinetic analysis, in the presence of 4 mM DTT, revealed a Michaelis-Menten constant (Km) of 1.43 microM for T4 and an inhibitory constant (Ki) of 22 microM for PTU. A marked and progressive rise of BAT 5'-MDI was noted from the 99-day fetus to the newborn period [6.0 vs. 94 +/- (SE) 12 pmol T3/mg protein X h]. The total sulfhydryl content in BAT varied from 3.8 to 5.4 mmol/kg wet weight equivalent, whereas nonprotein sulfhydryl content varied from 0.5 to 0.9 mmol/kg in groups of lambs between 99 days and the newborn period, without a significant change with age. These results indicate that 5'-MDI in fetal lamb BAT increases progressively between 99 days gestation and the neonatal period. Ovine fetal BAT 5'-MDI is highly sensitive to the inhibitory effect of PTU at low DTT concentration (1 mM) and is relatively insensitive to PTU only at high DTT concentration (20 mM). Finally, 5'-MDI in BAT from the fetal lamb reaches maximal activity near term and seems similar in its biochemical characteristics to the 5'-MDI of liver, kidney, or thyroid.

Adipose Tissue, Brown↗

PubMed1986

Autoimmune sympathectomy in fetal rabbits.

An autoimmune model for in utero immunosympathectomy of fetal rabbits was developed. Non-pregnant, female rabbits were injected with purified nerve growth factor and then bred after confirmation of high titers of anti-nerve growth factor antiserum. Fetuses were delivered and sacrificed at 27 and 31 days gestation and tissue norepinephrine concentration was used as an index of sympathetic innervation. There were significant reductions in tissue norepinephrine at both gestational ages. At 31 days there was a 32% reduction in lung norepinephrine concentration, 46% in the heart and 60% in brown adipose tissue. Corresponding reductions at 27 days were 68% for lung, 44% for heart and 49% for brown adipose tissue. Adrenal catecholamine content was unaffected but para-aortic gland catecholamines were slightly increased. Pulmonary beta adrenergic receptors showed a 30% up regulation in response to dennervation. Carcass weight was reduced 15% to 11% in the dennervated animals. These results demonstrate that dependence of organ sympathetic innervation on nerve growth factor can be demonstrated as early as 27 days gestation. This is a useful model to study the timing and dependence of organ sympathetic innervation on nerve growth factor and the factors which regulate this dependence.

Animals↗

PubMed1986

The mechanism of low serum T3 in the fetus: hepatic T4-5'-monodeiodinase versus tissue sulfhydryl content--a clarification.

Using optimal tissue concentration, supplemented with a thiol-protecting agent, the fetal liver has lower T4 5'-monodeiodinating activity than maternal or neonatal tissue. This is a true deficiency and is not due to deficiency of sulfhydryl groups in fetal tissue as previously suggested. Evidence indicates a dissociation of the neonatal surge of serum T3 and the increase in hepatic T4 to T3 conversion activity, suggesting that the neonatal T3 surge is related more to thyroid gland stimulation than to T4 to T3 conversion in non-thyroid tissues.

Animals↗

PubMed1985

Neonatal adaptation: greater sympathoadrenal response in preterm than full-term fetal sheep at birth.

A marked increase in sympathoadrenal activity at birth has been described in animals and humans. Studies to determine whether the magnitude and duration of the catecholamine surge at birth in preterm lambs is similar to full-term lambs were undertaken using an acutely exteriorized fetal lamb. To maintain a physiologically stable preparation, all preterm lambs were given natural sheep surfactant intratracheally before the first breath. Base-line catecholamine values were similar in the full-term and preterm lambs. After umbilical cord cutting there was a marked increase in circulating norepinephrine (NE) and epinephrine (E) in both full-term and preterm animals. The preterm animals exhibited a delayed but exaggerated elevation of both NE and E relative to term animals. The peak preterm value for NE (3.8 +/- 1.2 ng/ml) occurred at 60 min and exceeded the peak NE value 1.2 ng/ml observed at 15 min in full-term animals. The peak E concentration in preterm animals was over 9 ng/ml between 2 and 3 h of age, whereas full-term animals reached a peak value of 1.1 ng/ml at 5 min. Heart rate and blood pressure rose abruptly to peak values by 5-15 min in full-term animals. Changes in heart rate and mean arterial pressure were less profound and more gradual in preterm animals. Full-term animals also demonstrated a five-to sevenfold increase in plasma free fatty acids, whereas concentrations in preterm animals increased only two- to threefold. There was a similarly blunted response in blood glucose in preterm animals. The catecholamine surge at birth may be an important adaptive phenomenon with physiological implications.

Adaptation, Physiological↗

PubMed1985

Ovine fetal-maternal water transfer is independent of fetal prolactin levels.

To examine the effect of prolactin (PRL) on transplacental water flow, we infused mannitol (500 ml; 20% solution) over 10 min into five chronically catheterized ewes (121-134 days' gestation), producing a peak maternal plasma osmolality by 10 min and fetal osmolality by 20 min. One day before or after, an identical amount of mannitol was infused into the same ewe during the 2nd h of a 2-h infusion of PRL (40 +/- 2.2 micrograms/h) into a fetal leg vein. Mean (+/- SE) fetal plasma PRL levels were 6.9 +/- 3.2 ng/ml at baseline. Steady state fetal PRL levels were 17.7 +/- 7.4 ng/ml during PRL infusion. Maternal mannitol infused without administration of PRL to the fetus evoked a rise in fetal plasma osmolality similar to that following maternal mannitol during PRL administration to the fetus. Thus, as shown previously, PRL affects water permeability across the membranous chorioamnion, whereas results of the present study indicate that the hormone does not affect water transfer across the ovine chorionic villi (placenta).

Animals↗