bluuebunny/crossref_metadata_2025 huggingface dataset:
Adrenergic modulation of potassium metabolism during exercise in normal and diabetic humans
Authors: Castellino P. , Simonson D. C. , DeFronzo R. A.
Published: December 2017

The effect of acute and chronic beta- and alpha-adrenergic blockade on potassium homeostasis during moderate intensity exercise (40% VO2max) was investigated in control and insulin-dependent diabetic subjects. In protocol I, subjects were studied during exercise alone, exercise plus intravenous propranolol, and exercise plus intravenous phentolamine. In both the control and diabetic groups, exercise alone produced a modest increase in the plasma potassium concentration (0.31 +/- 0.06 meq/l), while propranolol exacerbated this hyperkalemic response. In contrast, the increment in plasma potassium during phentolamine was similar to exercise alone in normals but was 26% (P less than 0.05) lower in the diabetic group. In protocol II, the effect of chronic (5 days) beta-adrenergic blockade on potassium homeostasis was examined. Subjects participated in three studies: exercise alone, exercise plus propranolol (beta 1/beta 2-antagonist), and exercise plus metoprolol (beta 1 antagonist). In the nondiabetic group, both propranolol and metoprolol were associated with a 40% greater increase in potassium compared with exercise alone. In the diabetic group, propranolol, but not metoprolol, was associated with a deterioration in potassium tolerance. In no study could the alterations in potassium homeostasis be explained by a change in urinary potassium excretion. In summary, alpha-adrenergic blockade ameliorates exercise-induced hyperkalemia in diabetic but not in control subjects, nonspecific beta-adrenergic blockade causes a greater increment in potassium when compared with exercise alone, and specific beta 1-adrenergic blockade exacerbates exercise-induced hyperkalemia in control, but not in diabetic subjects. These results indicate that both alpha- and beta-adrenergic regulation of extrarenal potassium metabolism is altered in insulin-dependent diabetes mellitus.
Insulin receptor binding and protein kinase activity in muscles of trained rats
Authors: Dohm G. L. , Sinha M. K. , Caro J. F.
Published: December 2017

Exercise has been shown to increase insulin sensitivity, and muscle is quantitatively the most important tissue of insulin action. Since the first step in insulin action is the binding to a membrane receptor, we postulated that exercise training would change insulin receptors in muscle and in this study we have investigated this hypothesis. Female rats initially weighing approximately 100 g were trained by treadmill running for 2 h/day, 6 days/wk for 4 wk at 25 m/min (0 grade). Insulin receptors from vastus intermedius muscles were solubilized by homogenizing in a buffer containing 1% Triton X-100 and then partially purified by passing the soluble extract over a wheat germ agglutinin column. The 4 wk training regimen resulted in a 65% increase in citrate synthase activity in red vastus lateralis muscle, indicating an adaptation to exercise. Insulin binding by the partially purified receptor preparation s was approximately doubled in muscle of trained rats at all insulin concentrations, suggesting an increase in the number of receptors. Training did not alter insulin receptor structure as evidenced by electrophoretic mobility under reducing and nonreducing conditions. Basal insulin receptor protein kinase activity was higher in trained than untrained animals and this was likely due to the greater number of receptors. However, insulin stimulation of the protein kinase activity was depressed by training. These results demonstrate that endurance training does alter receptor number and function in muscle and these changes may be important in increasing insulin sensitivity after exercise training.
Selective suppression of hepatic glucose output by human proinsulin in the dog
Authors: Lavelle-Jones M. , Scott M. H. , Kolterman O. , Rubenstein A. H. , Olefsky J. M. , Moossa A. R.
Published: December 2017

By using the euglycemic glucose-clamp technique we have observed the effects of comparable low dose proinsulin and insulin infusions on isotopically determined glucose turnover in 20 anesthetized dogs. In each animal somatostatin (SRIF) infusion was used to suppress endogenous pancreatic hormone secretion and basal glucagon was replaced. Peripheral proinsulin (0.083 micrograms X kg-1 X min-1) and insulin (350 microU X kg-1 X min-1) levels 15- to 20-fold higher than insulin on a molar basis, based on previous observations that proinsulin has only 5-10% the biologic potency of insulin. Three groups of infusion studies were performed: SRIF and glucagon (n = 5); SRIF, glucagon, and proinsulin (n = 10); and SRIF, glucagon, and insulin (n = 5). The mean serum proinsulin level of 2.43 +/- 0.36 pmol/ml achieved represented a 17-fold excess compared with the mean serum insulin level of 0.14 +/- 0.03 pmol (20 +/- 4 microU/ml). At these concentrations, both hormones reduced hepatic glucose production rates by approximately 50% to 2.0 +/- 0.2 mg X kg-1 X min-1 and 1.8 +/- 0.5 mg X kg-1 X min-1, respectively. In contrast, proinsulin failed to stimulate peripheral glucose utilization, whereas insulin led to a 2.0 +/- 0.3 mg X kg-1 X min-1 increment (approximately 50% increase) in glucose uptake (P less than 0.05). Thus at low infusion rates proinsulin exerts its effect predominantly by suppressing hepatic glucose production without measurable stimulation of peripheral glucose disposal. In contrast, for a comparable degree of hepatic glucose output suppression, insulin also significantly stimulates glucose disposal.
Effects of insulin on hexose transport across blood-brain barrier in normoglycemia
Authors: Namba H. , Lucignani G. , Nehlig A. , Patlak C. , Pettigrew K. , Kennedy C. , Sokoloff L.
Published: December 2017

The effects of insulin on 3-O-[14C]methylglucose transport across the blood-brain barrier (BBB) were studied in conscious rats under steady-state normoglycemic conditions. The [14C]methylglucose was infused intravenously at a constant rate, and animals were killed at various times between 5 and 30 min after the initiation of the infusion. The time course of the arterial plasma concentration of [14C]methylglucose was determined in timed arterial blood samples taken during the infusion. Local cerebral tissue concentrations of [14C]methylglucose at the time of killing were determined by quantitative autoradiography of brain sections. The rate constants for inward and outward transport of [14C]methylglucose across the BBB, K1, and k2, respectively, were estimated by a least-squares, best-fit of a kinetic equation to the measured time courses of plasma and tissue concentrations. K1 and k2 were reduced by an average of 24 and 31%, respectively, in gray matter and 7 and 16% in white matter from values estimated similarly in normal insulinemic control rats. The equilibrium distribution ratio, K1/k2, for [14C]methylglucose in brain increased by approximately 10–11% in the hyperinsulinemic animals. Because 3-O-[14C]methylglucose shares the same carrier that transports glucose and other hexoses across the BBB, these results suggest that hyperinsulinemia decreases the rate constants for transport but increases the distribution space for hexoses in brain. These effects are, however, quite small and are probably minor or negligible when compared with the major effects of insulin in other tissues.
Portal copper transport in rats by albumin
Authors: Gordon D. T. , Leinart A. S. , Cousins R. J.
Published: December 2017

The distribution of newly absorbed copper among serum proteins obtained from the portal circulation of rats was examined by conventional and high-performance gel filtration chromatography, affinity chromatography, and Western blotting. Within 10–30 min after being administered by gavage or directly into the intestine, 67Cu and 64Cu, respectively, were recovered in the albumin fraction. By 8 h after administration of the radionuclides, virtually all of the radioactivity was found with ceruloplasmin. Affigel blue fractionation and subsequent Superose-6 chromatography further demonstrated that all of the copper in the albumin-containing fractions was in fact bound to this protein rather than high molecular weight moieties. Vascular perfusion of the isolated rat intestine, where 64Cu was infused into the lumen, showed that newly absorbed 64Cu in the vascular perfusate collected from the cannulated portal vein was associated with albumin. Uptake of radioactivity by isolated rat liver parenchymal cells from medium containing rat serum with 67Cu bound to albumin was demonstrated. In vitro binding of 64Cu to serum proteins that were transferred to nitrocellulose by Western blotting techniques showed that albumin is essentially the only protein that binds appreciable amounts of copper. The data suggest that albumin is the plasma protein that is responsible for the initial transport of copper after absorption.
Secretion from corticotropes after avidin-fluorescein stains for biotinylated ligands (CRF or AVP)
Authors: Childs G. V. , Unabia G. , Burke J. A. , Marchetti C.
Published: December 2017

Viable pituitary target cells were identified with biotin-labeled corticotropin-releasing factor (1-Bio-CRF) or arginine vasopressin (Bio-AVP) and avidin-fluorescein (cell sorter grade). Stain was reduced from 8–10% of pituitary cells to less than 3% if nonbiotinylated ligands were added to compete with their respective biotinylated ligand for specific binding sites. However, AVP did not decrease the stain for 1-Bio-CRF nor did CRF decrease the Bio-AVP stain. Media adrenocorticotropin (ACTH) levels increased 4–18 times when 1-Bio-CRF or Bio-AVP were added during the staining process. One hour after staining, the cells secreted ACTH at levels identical to prestain basal levels. When challenged with CRF or AVP after this hour, the cells responded again with increases not different from those seen during staining. Tests of stained cell populations also showed that the cells were fully responsive 24 h after staining. The reverse hemolytic plaque assay for ACTH, which was used to study secretion from individual stained cells, showed that approximately 80% of plaques contained a stained cell and that plaque numbers and areas were like those of unstained populations. These data show that corticotropes are not chronically desensitized during exposure to low doses of biotinylated ligands (50–500 pM).
Regression of brown adipose tissue mitochondrial function and structure in neonatal goats
Authors: Vatnick I. , Tyzbir R. S. , Welch J. G. , Hooper A. P.
Published: December 2017

Rapidly regressing perirenal brown adipose tissue (BAT) of neonatal goats was studied to correlate changes in mitochondrial metabolism and thermogenic capacity with changes in mitochondrial structure. The alpha-glycerophosphate shuttle activity of perirenal BAT mitochondria declined 60% from birth to 6 days of age. Oxygen consumption and thermogenic capacity measured by ion conductance peaked at birth and declined to low levels at 6 days. Sample electron micrographs of perirenal BAT showed intact electron-dense mitochondria with many cristae and little matrix area at 2 days. However, by 6 days the mitochondria were very relaxed with large matrix area, few cristae, and observable degradation. These results indicate that the morphological changes exhibited by rapidly regressing goat's perirenal BAT in the 1st wk postpartum are accompanied by dramatic alterations in BAT mitochondrial function.
Glucocorticoid-mediated activation of muscle branched-chain alpha-keto acid dehydrogenase in vivo
Authors: Block K. P. , Richmond W. B. , Mehard W. B. , Buse M. G.
Published: December 2017

Muscle branched-chain alpha-keto acid dehydrogenase, the rate-limiting enzyme for branched-chain amino acid oxidation in skeletal muscle, was measured after treatment of rats with glucocorticoids. Cortisone treatment (10 mg X 100 g body wt-1 X day-1 for 2–5 days) resulted in an approximate doubling of the percentage of active enzyme. To further characterize this effect, the enzyme complex was measured 4 h after the intraperitoneal injection of 6 alpha-methylprednisolone, a water-soluble glucocorticoid with rapid onset effects. The percentage of active enzyme increased linearly as the dose of methylprednisolone was increased from 0.125 to 12.5 mg/100 g body wt, while total enzyme activity was unchanged. Administration of insulin with glucose had no significant effect on the activity of the enzyme. However, treatment of rats with insulin and glucose after methylprednisolone administration partially blocked branched-chain alpha-keto acid dehydrogenase activation. The activity of the enzyme complex was correlated with the concentration of leucine in plasma and muscle. Activation of skeletal muscle branched-chain alpha-keto acid dehydrogenase by increased glucocorticoids may play a role in the acceleration of branched-chain amino acid oxidation observed during severe stress.
Alanine uptake by liver at midpregnancy in rats
Authors: Pastor-Anglada M. , Remesar X. , Bourdel G.
Published: December 2017

The participation of the liver to the increase in alanine utilization seen at midpregnancy was studied in 9- and 12-day pregnant rats. Liver fractional extraction of alanine was assessed in vivo from the changes in concentration in afferent and efferent vessels. Hepatic active transport of alanine was determined in vitro using isolated plasma-membrane vesicles. Compared with nonpregnant controls, alanine fractional extraction was significantly increased on day 12 but not on day 9 of pregnancy. Vesicles isolated from 9- and 12-day pregnant animals had a greater capacity for Na+-dependent transport than those from controls. Eadie-Hofstee plotting showed that this increase was due to an increase in Vmax with no change in Km. Both A and ASC systems contributed to the Vmax increase. These results indicate that, although by day 9 the liver has developed an increased capacity for alanine uptake, the actual extraction is seen only by day 12 of pregnancy. At this stage the liver participates actively in the turnover of alanine and the development of hypoalaninemia.
Reassessment of primed constant-infusion tracer method to measure urea kinetics
Authors: Jahoor F. , Wolfe R. R.
Published: December 2017

The validity of the primed constant-infusion tracer technique to make short-term measurements of urea production rates (Ra) in humans in a physiological steady state and during disruption of steady state was evaluated. Four subjects received a primed constant infusion (P/I = 560 min) of [13C]urea for 8 h. A plateau in urea enrichment was reached after 2 h and maintained throughout. When [13C]- and [18O]urea were simultaneously infused into four subjects at P/I ratios of 560:1 and 360:1, respectively, both tracers reached plateau enrichment at the same time (2-4 h). The enrichment at plateau was a function of the infusion rate rather than the priming dose, and calculated urea Ra was the same with either prime. In five additional experiments the technique responded acutely to a physiological perturbation (alanine infusion) in a dose-dependent manner. The results confirm that this technique is appropriate for short-term measurements of urea Ra, and the requirement for accuracy in estimating the priming dose is not impractically stringent.
Role of pancreatic somatostatin in determining glucagon response to arginine and morphine
Authors: Klaff L. J. , Taborsky G. J.
Published: December 2017

It has been proposed that pancreatic somatostatin (SS) tonically inhibits pancreatic glucagon secretion. In keeping with this hypothesis, we have previously shown that infusion of a nonimmunoreactive analogue of SS, [D-Ala5,D-Trp8]somatostatin (SSa), which in low doses inhibits SS secretion without inhibiting glucagon or insulin secretion, is associated with a large increase in glucagon and small increase in insulin secretion. Although direct stimulation of the alpha- and beta-cells by the analogue could not be excluded, high doses of the analogue appeared to inhibit insulin and glucagon secretion. These data therefore suggested that the effect of the analogue on insulin and glucagon secretion was indirect and due to reduction of tonic inhibition on the alpha- and beta-cells by SS. If pancreatic SS is an important regulator of glucagon secretion, then alterations in pancreatic SS should influence the glucagon response to secretagogues. Therefore, in the present study, we have examined the glucagon response to two different stimuli, arginine and morphine, either before or during suppression of pancreatic SS secretion. Intravenous injection of arginine produced a rapid increase of pancreatic glucagon output from the in vivo dog pancreas. When basal pancreatic SS output was suppressed by infusion of SSa, arginine injection produced a twofold larger glucagon response. Infusion of morphine directly into the pancreatic artery of the dog decreased pancreatic SS output and increased pancreatic glucagon output. When SS was suppressed by SSa infusion, morphine did not further suppress pancreatic SS secretion and the glucagon response to morphine was abolished.(ABSTRACT TRUNCATED AT 250 WORDS)
Melatonin rhythms in fetal and maternal circulation during pregnancy in sheep
Authors: Yellon S. M. , Longo L. D.
Published: December 2017

In many seasonally breeding species, the nocturnal melatonin rhythm is part of an endogenous biological clock mediating information about day length to time the onset of puberty and the annual adult reproductive cycle. To determine whether timekeeping persists during pregnancy, we studied the pattern of melatonin in circulation in sheep during the last trimester of gestation. We measured plasma melatonin concentrations in the chronically catheterized ewe and fetus (n = 6) over a 48-h period (every 1-4 h) at approximately 120 days gestation. A typical rhythm was present in the pregnant ewes; plasma melatonin was low during the day and remained increased throughout the night. In the fetus, a modest 24-h pattern was detected, which lagged 0.5-1.5 h behind that of the maternal circulation. In combination with findings later in gestation (126 and 135 days) or even during parturition, it is clear that melatonin rhythms were sustained in all pregnant ewes and a 24-h pattern was present in the fetus. In those sheep that went to full term, births occurred during the night at 0130 +/- 2.6 h (mean +/- SE, n = 3). These findings suggest that measurement of day length is maintained in female sheep during the last trimester of pregnancy. Moreover, information about day length and/or time of day may be transferred across the placenta, because the pattern of melatonin in fetal circulation follows the maternal circadian melatonin rhythm.
Kinetics of glucose transport in rat muscle: effects of insulin and contractions
Authors: Ploug T. , Galbo H. , Vinten J. , Jorgensen M. , Richter E. A.
Published: December 2017

The effects of insulin and prior muscle contractions, respectively, on 3-O-methylglucose (3-O-MG) transport in skeletal muscle were studied in the perfused rat hindquarter. Initial rates of entry of 3-O-MG in red gastrocnemius, soleus, and white gastrocnemius muscles as a function of perfusate 3-O-MG concentration exhibited Michaelis-Menten kinetics. Uptake by simple diffusion could not be detected. The maximum 3-O-MG transport velocity (Vmax) was increased more by maximum isometric contractions (10- to 40-fold, depending on fiber type) than by insulin (20,000 microU/ml; 3- to 20-fold) in both red and white muscles. The effects of both contractions and insulin were greater in red than in white muscles. In red but not in white muscles, maximum increases in Vmax elicited by contractions and by insulin were additive. Both insulin and contractions decreased the half-saturating substrate concentration for glucose transport (apparent Km) in all three muscles, in fast-twitch fibers from 70 to approximately 7 mM and in slow-twitch fibers from 12 to 7 mM. After contractions, reversal of contraction-induced glucose transport was monoexponential in red fibers, with a half-time of 7 and 15 min in slow- and fast-twitch fibers, respectively. In white muscle, Vmax continued to increase after contractions, reached a plateau after 10 min, and had only decreased 45% after 70 min. In contrast to the prevailing opinion, in all fiber types, reversal of contraction-induced glucose transport took place in the absence of muscle glycogen repletion.
Hormonal control of postprandial thermogenesis in dogs
Authors: Diamond P. , LeBlanc J.
Published: December 2017

The role of catecholamines, insulin, and thyroid hormones on postprandial thermogenesis was determined in dogs. O2 consumption (VO2) and respiratory quotient (RQ) were continuously monitored 1 h before and 2 h after a 1,016-kcal meal under the three following experimental conditions corresponding to 1) normal feeding, 2) sham feeding (with food deflected into an esophageal pouch), and 3) tube feeding intragastrically. A first phase (cephalic phase), lasting at least 45 min, was observed during both normal and sham feeding, whereas a second phase (digestive phase), occurred in both normal and tube feeding. Increases of 260% for norepinephrine (NE) were found during the cephalic phase in both normal and sham feeding. Epinephrine (E) increased by 425 and 600% during this early phase in normal and sham feeding, respectively. No change in plasma catecholamines was found in the tube-feeding experiment. Large increases of 75 and 39 microU/ml of insulin occurred early after the meal in both normal and sham feeding, whereas insulin increased only after 30 min in tube feeding. Thyroxine and triiodothyronine were not changed with any feeding experiment. Insulin change was positively correlated with NE and E changes rather than with glucose change during the cephalic phase after feeding. The results suggest an important role of catecholamines in the increased postprandial thermogenesis during the cephalic phase with a possible modulating effect of insulin.
Hyperglycemia and hyperinsulinemia increase glucose utilization in fetal rat tissues
Authors: Leturque A. , Revelli J. P. , Hauguel S. , Kande J. , Girard J.
Published: December 2017

In vivo measurement of glucose utilization by individual tissues of 19-day rat fetuses have been performed using radioactive 2-deoxy-D-glucose technique. In the basal state, glucose metabolic index was 13.6 +/- 0.5 ng.min-1.mg-1 for the whole fetus, 21 +/- 1 in the hindlimb muscles, 13 +/- 2 in the liver, and 16 +/- 2 in the brain, whereas the fetal heart had the highest value: 62 +/- 5 ng.min-1.mg-1. To raise the fetal glycemia, the basal maternal blood glucose concentration of 0.78 +/- 0.02 g/l was elevated to 1.04 +/- 0.02 g/l by mean of hyperglycemic clamps. The fetal hyperglycemia increased glucose metabolic index by 30-100% over basal values in all the tissues tested except in the brain. To raise fetal insulinemia, maternal euglycemic clamp with supraphysiological insulin concentrations were performed, then a fraction (1%) of exogenous insulin crossed the placenta. Fetal plasma insulin concentrations were thus elevated to 180 +/- 32 and 255 +/- 23 microU/ml. The fetal heart increased significantly its glucose metabolic index in response to the lower insulin level. Glucose metabolic index in hindlimb muscles and liver was increased by 50-100% for the highest insulin level, whereas the brain was unaffected by exogenous insulin. We conclude that glucose metabolic index is stimulated by physiological hyperglycemia in individual fetal tissues and that fetal tissues (heart, liver, and muscle) are sensitive to exogenous insulin.
Bradykinin-induced vasoconstriction and thromboxane release in perfused human placenta
Authors: Wilkes B. M. , Mento P. F.
Published: December 2017

This investigation was performed to study the effects of bradykinin on the human fetoplacental circulation. The artery to a single placental cotyledon was perfused with RPMI medium (0.764 ml/min). Bradykinin caused a dose-related increase in vascular resistance. Because bradykinin is generally a vasodilator, we investigated the possibility that bradykinin-induced vasoconstriction was due to interactions with other pressor systems. Bradykinin and 9,11-dideoxy-9 alpha, 11 alpha-epoxymethanoprostaglandin F2 alpha (a stable thromboxane agonist) caused a dose-related increase in perfusion pressure. The bradykinin response was not mediated by angiotensin II, because bradykinin-induced vasoconstriction was not inhibited by saralasin, a competitive angiotensin antagonist. Bradykinin increased thromboxane B2 production by 62.0%. Prostaglandin E2 levels were increased by 86.7%, but prostaglandin E2 did not affect fetoplacental vascular resistance. Angiotensin II did not stimulate thromboxane B2 production and caused only a slight increase in prostaglandin E2. Indomethacin decreased the pressor response to angiotensin II. SQ29548, a specific thromboxane antagonist, caused a 61.6% inhibition of the bradykinin pressor response but did not change angiotensin II responsiveness. The data demonstrate that thromboxane is an important mediator of bradykinin-induced vasoconstriction in the isolated perfused human placenta.
Response to deep hypoglycemia does not involve glucoreceptors in carotid perfused tissue
Authors: Cane P. , Haun C. K. , Evered J. , Youn J. H. , Bergman R. N.
Published: December 2017

In the present study we examined whether the magnified hormonal counter-regulatory response seen during deep hypoglycemia (40 mg/dl) could be attenuated by supplying the forebrain with glucose furnished through carotid infusion. Two protocols were performed in conscious dogs. In the first protocol we infused glucose bilaterally into the carotid circulation to produce a forebrain glycemia of 55 +/- 1 mg/dl (as reflected in the jugular vein), whereas systemic glycemia declined to 39 +/- 2 mg/dl. In the second protocol as a control we infused glucose into the systemic circulation at a rate matched to protocol 1 so that both systemic and jugular plasma glucose concentrations were equivalent to the systemic glucose concentrations in protocol 1 (jugular, 41 +/- 3 mg/dl; systemic, 40 +/- 2 mg/dl; P greater than 0.9). In spite of a substantial difference in forebrain glycemia (55 mg/dl compared with 41 mg/dl) there were no differences in the counter-regulatory responses of catecholamines or glucagon. In addition, through the use of radiolabeled microspheres, we defined the precise regions of the forebrain irrigated during bilateral intracarotid glucose infusions. The concentration of microspheres was high in the forebrain but very low in the hindbrain. Our results indicate that glucoreceptor cells in tissues perfused by carotid arteries may play a tautological role in the sympathetic response to hypoglycemia and imply that glucose-sensitive receptors must also be located elsewhere in the central nervous system or in the periphery.
Androgenic influences on body size and composition of adult rhesus monkeys
Authors: Kemnitz J. W. , Sladky K. K. , Flitsch T. J. , Pomerantz S. M. , Goy R. W.
Published: December 2017

The effects of daily treatment with testosterone propionate (TP, 2 mg/kg) and dihydrotestosterone propionate (DHTP, 2 mg/kg) were examined in rhesus monkeys in three experiments. In experiments 1 and 2, males and females gonadectomized in infancy, and female pseudohermaphrodites produced by prenatal exposure to TP or DHTP and gonadectomized postpubertally, were studied in conjunction with intact males (IM). The IM group was heavier in adulthood than the three gonadectomized groups, which did not differ in body weight from each other. Genetic males had greater crown-rump length than genetic females. Treatment of the gonadectomized groups with TP produced large increases in body mass (averaging approximately 50%) that were attributable to accretion of lean tissue. This effect did not differ significantly between males and females. In experiment 3, additional groups of males that had been castrated as infants were given daily injections with DHTP or oil. The DHTP treatment resulted in increases in body size that were not different from those seen following TP treatment. When TP and DHPT treatments were discontinued, body weights and dimensions reverted to base-line values. Increased body size induced by TP and DHTP was accomplished without reliable increases in food intake. Because testosterone (T) is metabolized to dihydrotestosterone (DHT), while DHT cannot be converted to T, these results show that both T and DHT are effective anabolic hormones in rhesus.
Structure and function changes in rat adrenal glands during aging
Authors: Reaven E. , Kostrna M. , Ramachandran J. , Azhar S.
Published: December 2017

The current study examines corticosterone production in young and old rats with a view to understanding how hormone production is related to aging changes in the adrenal gland. For this purpose, we compared total (plasma volume-corrected) values for adrenocorticotropic hormone (ACTH)-induced maximal corticosterone production in young, mature (5-mo-old), and aging (18-mo-old) rats. These values were subsequently corrected for measured age-related differences in adrenal weight, adrenal cortex volume, specific adrenal zone volumes, and total number of corticosterone-producing cells in the adrenals of the differently aged rats. In addition, corticosterone disposal rates were measured in the two groups of rats, and adrenal cortical ACTH binding sites were identified by autoradiography after perfusion with 125I-labeled ACTH analogue. The results show that maximal serum ACTH-induced corticosterone concentrations (per ml serum) in the 18-mo-old rats are somewhat less than those seen in the younger animals. However, because the plasma volume is greater in the older animals (and corticosterone disposal rates do not vary), total circulating corticosterone production is, in fact, equivalent in the two groups of animals. When these total values for corticosterone are corrected for various structural changes in the adrenal gland with age, corticosterone production was found to be lower in the older group of rats: i.e., one sees an approximately 50% decline when corticosterone is expressed per adrenal weight or zonal volume and an approximately 20% decline when expressed per number of endocrine cells per adrenal.(ABSTRACT TRUNCATED AT 250 WORDS)
Influence of verapamil on some subcellular defects in diabetic cardiomyopathy
Authors: Afzal N. , Pierce G. N. , Elimban V. , Beamish R. E. , Dhalla N. S.
Published: December 2017

The effects of verapamil on cardiac myofibrillar adenosinetriphosphatase (ATPase) activity, myosin ATPase, and myosin isoenzyme profile as well as sarcoplasmic reticular Ca2+ uptake and ATPase activities were examined in Sprague-Dawley rats made diabetic with a single injection of streptozotocin (65 mg/kg). Myofibrillar ATPase activity and myosin Ca2+ ATPase activity as well as Ca2+ uptake and Ca2+-stimulated ATPase activities of the sarcoplasmic reticulum were significantly decreased in diabetic hearts in comparison to the control values. The myosin isoenzyme component V3 was prominent in diabetic hearts, whereas V1 isoenzyme was the major myosin component in control hearts. Chronic treatment of diabetic rats with verapamil (8 mg/kg daily for 4-8 wk) resulted in an improvement of the altered myofibrillar ATPase activity, myosin ATPase, myosin isoenzyme distribution, and sarcoplasmic reticular Ca2+-pump activities in ventricular tissue. The ability of verapamil to normalize the observed defects in the subcellular organelles in diabetic cardiomyopathy may be related to its effects in controlling the entry of Ca2+ into the cardiac cell.
Responses of vasopressin, atrial natriuretic peptide, and blood pressure to central osmotic stimulation
Authors: Iitake K. , Kimura T. , Ota K. , Shoji M. , Inoue M. , Ohta M. , Sato K. , Yamamoto T. , Yasujima M. , Abe K. , et al.
Published: December 2017

To assess whether intracerebroventricular osmoreceptors are involved in vasopressin (AVP) and atrial natriuretic peptide (ANP) release and in the pressor response to centrally administered hypertonic NaCl, artificial cerebrospinal fluid (ACSF) or ACSF made hypertonic by adding 0.2 M NaCl, 0.4 M mannitol, and 0.4 M glucose in isotonic ACSF or 0.4 M urea was infused into the 3rd ventricle of conscious rats. In addition, intravenous infusion of [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),2-(O-methyl)tyrosine]AVP (TMeAVP), a V1-AVP antagonist, was given in rats receiving intracerebroventricular infusion of 0.2 M NaCl in isotonic ACSF. Intracerebroventricular 0.2 M NaCl, 0.4 M mannitol, and 0.4 M glucose in isotonic ACSF increased plasma AVP and mean arterial pressure (MAP) without changing heart rate (HR) or plasma ANP. Urea at 0.4 M decreased plasma AVP and ANP with a slight rise in MAP but no change in HR. ACSF alone did not affect plasma AVP, ANP, MAP, or HR. Intravenous TMeAVP attenuated the pressor response to infusion of 0.2 M NaCl in isotonic ACSF, decreased plasma ANP, but did not affect HR. These results indicate that central osmoreceptors are involved in the release of AVP and in the pressor response to centrally administered hypertonic NaCl.
Involvement of vitamin D3 with cardiovascular function. III. Effects on physical and morphological properties
Authors: Weishaar R. E. , Kim S. N. , Saunders D. E. , Simpson R. U.
Published: December 2017

We have previously shown that depletion of vitamin D3 in rats results in a large increase in the contractile function of isolated hearts (R. E. Weishaar, J. Clin. Invest. 79: 1706-1712, 1987). To characterize the mechanism responsible for this increase, the effect of vitamin D3 depletion on key physical and morphological properties of cardiac muscle was examined. Depletion of vitamin D3 increased the heart weight/body weight ratio. This increase could neither be blocked by limiting hypocalcemia nor reversed by restoring increasing serum calcium levels. The cardiomegaly observed 9 wk after vitamin D3 depletion was not accompanied by an increase in myocardial water content or leakage of myocardial creatine phosphokinase and was not caused by myocardial cell hypertrophy. Histological examination of ventricular muscle from vitamin D3-deficient rats revealed a significant decrease in myofibrillar area and a significant increase in extracellular space. The increase in extracellular space was accompanied by a significant increase in myocardial collagen. Prevention of hypocalcemia in the vitamin D3-deficient rats did not prevent the increase in myocardial collagen. Such alterations in the physical and morphological properties of myocardial tissue might represent the basis for the change in myocardial contractile function that accompanies lengthy periods of vitamin D3 deficiency.
Amino acid metabolism after intense exercise
Authors: Devlin J. T. , Brodsky I. , Scrimgeour A. , Fuller S. , Bier D. M.
Published: December 2017

We studied postexercise amino acid metabolism, in the whole body and across the forearm. Seven volunteers were infused with L-[alpha-15N]lysine and L-[1-13C]-leucine twice [one time during 3 h after cycle exercise (75% VO2max), and one time in the resting state]. Whole body protein breakdown was estimated from dilution of L-[alpha-15N]lysine and L-[1-13C]ketoisocaproic acid (KIC) enrichments in plasma. Leucine oxidation was calculated from 13CO2 enrichments in expired air. Whole body protein breakdown was not increased above resting levels during the recovery period. Leucine oxidation was decreased after exercise (postexercise 13 +/- 2.3 vs. resting 19 +/- 3.2 mumol.kg-1.h-1; P less than 0.02), while nonoxidative leucine disposal was increased (115 +/- 6.1 vs. 103 +/- 5.6 micrograms.kg-1.min-1; P less than 0.02). After exercise, forearm net lysine balance was unchanged (87 +/- 25 vs. 93 +/- 28 nmol.100 ml-1.min-1), but there were decreases in forearm muscle protein degradation (219 +/- 51 vs. 356 +/- 85 nmol.100 ml-1.min-1; P less than 0.05) and synthesis (132 +/- 41 vs. 255 +/- 69 nmol.100 ml-1.min-1; P less than 0.01). In conclusion, after exercise 1) whole body protein degradation is not increased, 2) leucine disposal is directed away from oxidative and toward nonoxidative pathways, 3) forearm protein synthesis is decreased. Postexercise increases in whole body protein synthesis occur in tissues other than nonexercised muscle.
Intracerebroventricular infusion of RU28318 blocks aldosterone-salt hypertension
Authors: Gomez-Sanchez E. P. , Fort C. M. , Gomez-Sanchez C. E.
Published: December 2017

The chronic intracerebroventricular (icv) infusion of aldosterone in rats and dogs elevates the blood pressure within 10-14 days at doses far below those that produce hypertension systemically. The effect in rats is dose dependent and blocked by the concomitant icv infusion of the antimineralocorticoid, prorenone. The effect of the icv infusion of RU28318, another specific spironolactone mineralocorticoid antagonist, on the hypertension produced by chronic subcutaneous (sc) administration of aldosterone in sensitized rats was reported. Miniosmotic pumps were used to deliver 1 micrograms/h aldosterone sc and 1.1 micrograms/h RU8318 icv. Over a 24-day period the indirect systolic blood pressure of the control, RU28318 icv, and aldosterone sc plus RU28318 icv groups increased from 105 to 123 mmHg and were not significantly different from each other, whereas the aldosterone sc group increased to 156 mmHg. RU28318, icv or sc, did not alter the increase in urine volume produced by aldosterone sc, and there was no significant differences in weight between the groups. This study provides evidence of the importance of the central nervous system in the pathogenesis of hypertension produced by systemic mineralocorticoid excess.
Myocardial metabolism in insulin-deficient diabetic humans without coronary artery disease
Authors: Avogaro A. , Nosadini R. , Doria A. , Fioretto P. , Velussi M. , Vigorito C. , Sacca L. , Toffolo G. , Cobelli C. , Trevisan R. , et al.
Published: December 2017

Eleven insulin-dependent diabetes mellitus (IDDM) patients with angiographically normal coronary arteries and a normal hemodynamic response to an echocardiographic-dipyridamole test and 12 normal controls were studied at rest and after atrial pacing simultaneously sampling arterial and coronary sinus blood. In IDDM patients, despite hyperglycemia [10.0 +/- 2.0 (SE) mmol/l], myocardial glucose uptake was slightly lower than in controls. This process was significantly activated in both groups during atrial pacing. The isotopically calculated net flux of lactate across myocardium, in agreement with the net balance value based on unlabeled lactate-pyruvate arteriovenous differences, showed a net uptake in controls (3.5 +/- 0.6 mumol.min-1.1.73 m-2) and a net release in IDDM (12.4 +/- 2.6; P less than 0.01). Atrial pacing stimulated lactate uptake in both groups. Myocardial uptake of ketone bodies was significantly higher in IDDM (37.0 +/- 6.3 mumol.min-1.1.73 m-2) than in controls (10.1 +/- 3.4 mumol.min-1.1.73 m-2; P less than 0.01). Free fatty acid uptake was also significantly greater in IDDM than in controls (44.1 +/- 7.0 vs. 24.1 +/- 5.1 mumol.min-1.1.73 m-2; P less than 0.01). Alanine and branched amino acids were released by diabetic but not by control hearts at rest. The normalization of blood glucose concentrations restored normal patterns of lactate and ketone body kinetics across diabetic myocardium. In conclusion, 1) at rest, myocardial lactate and amino acid uptake is markedly impaired in IDDM without coronary artery disease, and 2) the metabolic abnormalities of the diabetic myocardium are not a primary phenomenon but rather a consequence of hypoinsulinemia and hyperglycemia because insulin administration, resulting in euglycemia, restored normal patterns of cardiac metabolism.
Dehydroepiandrosterone reduces cancellous bone osteopenia in ovariectomized rats
Authors: Turner R. T. , Lifrak E. T. , Beckner M. , Wakley G. K. , Hannon K. S. , Parker L. N.
Published: December 2017

The effects of dehydroepiandrosterone (DHA) on cortical bone at the tibial diaphysis and cancellous bone at the tibial metaphysis were determined in intact and ovariectomized rats. Total plasma DHA was reduced at 10 and 16 wk after ovariectomy. Intact and ovariectomized rats were implanted monthly with controlled-release subcutaneous pellets containing 2.5 mg of DHA or placebo. Plasma DHA was elevated in DHA-treated intact rats and was near normal in hormone-treated ovariectomized rats. Ovariectomy resulted in severe cancellous bone osteopenia, which was reduced in DHA-treated animals. Cross-sectional and cortical areas were increased at the diaphysis in ovariectomized rats, and this was not altered by DHA treatment. Bone formation at the endosteal and periosteal surfaces of the tibial diaphysis was decreased 16 wk after ovariectomy, and DHA treatment appeared to antagonize these changes. We interpret these results as evidence that decreased peripheral DHA levels contribute to the skeletal changes in ovariectomized rats.
Interactive effect of body posture on exercise-induced atrial natriuretic peptide release
Authors: Ray C. A. , Delp M. D. , Hartle D. K.
Published: December 2017

The purpose of this investigation was to test the hypothesis that supine exercise elicits a greater atrial natriuretic peptide (ANP) response than upright exercise because of higher atrial filling pressure attained in the supine posture. Plasma ANP concentration ([ANP]) was measured during continuous graded supine and upright exercise in eight healthy men at rest after 4 min of cycling exercise at 31, 51, and 79% of posture-specific peak oxygen uptake (VO2 peak), after 2 min of cycling at posture-specific VO2 peak, and 5 and 15 min postexercise. [ANP] was significantly increased (P less than 0.05) above rest by 64, 140, and 228% during supine cycling at 51 and 79% and VO2 peak, respectively. During upright cycling, [ANP] was significantly increased (P less than 0.05) at 79% (60%) and VO2 peak (125%). After 15 min of postexercise rest, [ANP] remained elevated (P less than 0.05) only in the supine subjects. [ANP] was 63, 79, and 75% higher (P less than 0.05) in the supine than in the upright position during cycling at 51 and 79% and VO2 peak. Systolic, diastolic, and mean blood pressures were not significantly (P greater than 0.05) different between positions in all measurement periods. Heart rates were lower (P less than 0.05) in the supine position compared with the upright position. In conclusion, these results suggest that supine exercise elicits greater ANP release independent of blood pressure and heart rate but presumably caused by greater venous return, central blood volume, and concomitant atrial filling pressure and stretch.
In vivo effects of flavonoid EMD 21388 on thyroid hormone secretion and metabolism in rats
Authors: Schroder-van der Elst J. P. , van der Heide D. , Kohrle J.
Published: December 2017

In vitro, the synthetic flavonoid EMD 21388 appears to be a potent inhibitor of thyroxine (T4) 5'-deiodinase and diminishes binding of T4 to transthyretin. In this study, in vivo effects of long-term administration of EMD 21388 on thyroid hormone production and metabolism were investigated. Intact male rats received EMD 21388 (20 mumol.kg body wt-1.rat-1.day-1) for 14 days. [125I]T4 and 3,5,3'-[131I]triiodotyronine (T3) were infused continuously and intravenously in a double-isotope protocol for the last 10 and 7 days, respectively. EMD 21388 decreased plasma thyroid hormone concentrations, but thyrotropin levels in plasma and pituitary did not change. Plasma clearance rates for T4 and T3 increased. Thyroidal T4 secretion was diminished, but T3 secretion was elevated. Extrathyroidal T3 production by 5'-deiodination was lower. T4 concentrations were markedly lower in all tissues investigated. Total tissue T3 was lower in brown adipose tissue, brain, cerebellum, and pituitary, tissues that express the type II 5'-deiodinase isozyme due to decreased local T3 production. Most tissues showed increased tissue/plasma ratios for T4 and T3. These results indicate that this flavonoid diminished T4 and increased T3 secretion by the thyroid, probably in analogy with other natural flavonoids, by interference with one or several steps between iodide uptake, organification, and hormone synthesis.
Glucocorticoid upregulation of interleukin 1 receptor expression in a glioblastoma cell line
Authors: Gottschall P. E. , Koves K. , Mizuno K. , Tatsuno I. , Arimura A.
Published: December 2017

Interleukin 1 (IL-1) is a multifunctional cytokine produced by numerous cell types, including cells of the central nervous system (CNS). In the CNS, IL-1 produced by glia is thought to support trophic functions after brain injury. However, little is known about whether the IL-1 receptor (IL-1R) is expressed in brain cells and how these receptors might be regulated. Analysis of IL-1R expression in the human glioblastoma cell line U-87 MG indicated the presence of a specific, saturable, and high-affinity (dissociation constant = 104 +/- 14 pM) binding site, which was of moderately high density (1,228 +/- 156 sites/cell). Incubation of U-87 MG cells with cortisol or dexamethasone for as little as 6 h resulted in an upregulation of IL-1R expression, which could be blocked by coincubation with cycloheximide or actinomycin D. IL-1 beta downregulated the expression of its own binding site. Upregulation of the IL-1R by glucocorticoids (GCs) appeared to be coupled to the release of interleukin 6 (IL-6), since IL-1 was significantly more potent in inducing IL-6 release in U-87 cells that were preincubated in the presence of GCs compared with cells incubated in the absence of GCs. These results suggest that IL-1 acts on glial cells via a high-affinity receptor and indicate that GCs may amplify or prolong the actions of IL-1 in the CNS.
Compartmental model of leucine kinetics in humans
Authors: Cobelli C. , Saccomani M. P. , Tessari P. , Biolo G. , Luzi L. , Matthews D. E.
Published: December 2017

The complexity of amino acid and protein metabolism has limited the development of comprehensive, accurate whole body kinetic models. For leucine, simplified approaches are in use to measure in vivo leucine fluxes, but their domain of validity is uncertain. We propose here a comprehensive compartmental model of the kinetics of leucine and alpha-ketoisocaproate (KIC) in humans. Data from a multiple-tracer administration were generated with a two-stage (I and II) experiment. Six normal subjects were studied. In experiment I, labeled leucine and KIC were simultaneously injected into plasma. Four plasma leucine and KIC tracer concentration curves and label in the expired CO2 were measured. In experiment II, labeled bicarbonate was injected into plasma, and labeled CO2 in the expired air was measured. Radioactive (L-[1-14C]leucine, [4,5-3H]KIC, [14C]bicarbonate) and stable isotope (L-[1-13C]leucine, [5,5,5-2H3]KIC, [13C]bicarbonate) tracers were employed. The input format was a bolus (impulse) dose in the radioactive case and a constant infusion in the stable isotope case. A number of physiologically based, linear time-invariant compartmental models were proposed and tested against the data. The model finally chosen for leucine-KIC kinetics has 10 compartments: 4 for leucine, 3 for KIC, and 3 for bicarbonate. The model is a priori uniquely identifiable, and its parameters were estimated with precision from the five curves of experiment I. The separate assessment of bicarbonate kinetics (experiment II) was shown to be unnecessary. The model defines masses and fluxes of leucine in the organism, in particular its intracellular appearance from protein breakdown, its oxidation, and its incorporation into proteins. An important feature of the model is its ability to estimate leucine oxidation by resolving the bicarbonate model in each individual subject. Finally, the model allows the assessment of the domain of validity of the simpler commonly used models.