bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of perfusate glucose concentration on rat lung glycolysis.
Authors: Kerr J S , Baker N J , Bassett D J , Fisher A B
Published: December 2017

We investigated the relationship between perfusate concentration of glucose and its utilization and lactate production derived from exogenous glucose and from metabolism of endogenous substrates. Isolated rat lungs were ventilated with 5% CO2 in air and perfused for 100 min with Krebs-Ringer bicarbonate buffer containing 3% bovine serum albumin, 10(-2) U/ml insulin, [U-14C]glucose and [5-3H]glucose. Glucose utilization, total lactate production, [14C]lactate production, and 3H2O production were measured. The apparent Km and Vmax for glucose utilization were 3.4 mM and 72.5 mumol/g dry wt per h, respectively. Lactate production from endogenous substrates, calculated as the difference between total and [14C]lactate, was 37.6 +/- 2.2 mumol/g dry wt (n = 36); it was unaffected by perfusate glucose concentration and by omission of insulin, but increased threefold with anoxia. Lactate production from 1.5 mM glucose was significantly less (P less than 0.02) with insulin omitted. Glycogen content was unchanged during perfusion without glucose. These results suggest that: 1) protein catabolism contributes to lung lactate production; 2) glucose utilization by lung is not maximal at resting physiological glucose concentrations; and 3) insulin is required at low glucose concentrations for maximal glycolytic rates.
Effects of glutamine deprivation on glucose and amino acid metabolism in tissue culture.
Authors: Pardridge W M , Casanello-Ertl D
Published: December 2017

The effects of glutamine deprivation on cultured skeletal muscle cells were analyzed by incubating 10-day-old myotube preparations in glutamine free Dulbecco's modified Eagle medium containing 10% fetal calf serum for up to 48 h. Under these conditions net glutamine production was not observed, but active ammonia production (average rate = 1.0 nmol/min . mg protein) continued despite glutamine withdrawal. Glutamine deprivation was associated with a progressive depletion of intracellular aspartate and glutamate. Maximal aspartate depletion correlated with a 15-fold increase in the intracellular lactate:pyruvate ratio and a 3-fold decrease in the estimated intracellular glutamate:(alpha-ketoglutarate) (ammonia) ratio. Despite wide shifts in cell metabolite concentrations, the mass action ratios of alanine and aspartate aminotransferase approximated the expected equilibria constants. These results suggest that 1) glutamine deprivation is associated with a marked reduction of aspartate, and the maintenance of aspartate depletion is due in part to the tendency of aspartate aminotransferase to maintain the metabolites of this reaction at a near equilibrium level; 2) the transport of reducing equivalents from the cytosolic to the mitochondrial compartments via the malate-aspartate shuttle may be limited under conditions of aspartate depletion.
Effects of selective insulin or glucagon deficiency on glucose turnover.
Authors: Lickley H L , Ross G G , Vranic M
Published: December 2017

To study the importance of glucagon and insulin in diabetes, somatostatin (ST) was infused, alone or with insulin or glucagon, in 11 conscious dogs. Plasma immunoreactive insulin (IRI) and glucagon (IRG) levels fell 65 +/- 4% and 33 +/- 3%, respectively, with somatostatin infusion. Glucose production (Ra) assessed by [3-3H]glucose, [2-3H]glucose, or [1-14C]glucose decreased transiently. This is in contrast to the rise in Ra seen after insulin withdrawal in depancreatized dogs, which have normal levels of IRG. Thus, suppression of IRG with somatostatin prevented an increase in Ra in spite of suppression of IRI. When near basal IRG levels were provided during ST infusion in normal dogs, Ra increased, indicating that glucagon contributes to the acute development of diabetes. When basal IRI levels were provided with ST, suppression of Ra was maintained, suggesting that the transience of the metabolic effects of ST-induced glucagon suppression requires concomitant insulin suppression. A comparison of glucose turnover measured using different tracers showed that ST-related hormonal changes did not alter the rate of futile cycling in the liver. ST induced a rise in plasma free fatty acid (FFA) levels, attributed solely to insulin deficiency, as glucagon suppression did not significantly alter FFA concentrations when normal insulin levels were maintained.
Normophosphatemic phosphate depletion in growing rat.
Authors: Brautbar N , Lee D N , Coburn J W , Kleeman C R
Published: December 2017

To study the influence of phosphate depletion (PD) on the serum, urinary, bone, and soft tissue phosphorus, we studied growing rats given a high-phosphorus (HP), normal-phosphorus (NP), or low-phosphorus (LP) diet. We obtained the following results. a) With an LP diet, animals did not grow but developed the characteristic biochemical changes of PD. b) The NP rats had an unexplained accelerated rate of growth, and developed all the biochemical changes of PD, although they were normophosphatemic. c) Bone P and Ca were significantly lower in the LP and NP rats compared to the HP rats, suggesting that minerals were mobilized from bone to support soft tissue P needs. d) Soft tissue P was not different in HP, NP, and LP rats, confirming previous observations that soft tissue P is maintained even in PD. We conclude that 1) the physiologic adaptation to PD may occur in growing rats on an apparently normal phosphorus diet when the metabolic demand is unusually high, e.g. accelerated growth; 2) the evolution of the biochemical parameters of PD in the face of normophosphatemia suggest a sensor mechanism sensitive to change in dietary P concentration.
Frequency content of esophageal peristaltic pressure.
Authors: Ask P , Oberq P A , Tibbling L
Published: December 2017

Fourier analysis of esophageal peristaltic pressure waves was performed by computer fast Fourier transform. The highest power spectral density was obtained in the frequency range below 1 Hz. The Fourier analysis showed spectral components up to about 12 Hz in the upper esophageal sphincter (UES). The significance of different frequency components was investigated by low-pass filtering at different cut-off frequencies. A reduction in the amplitude of UES contractions was obtained at a cut-off frequency of 4 Hz, whereas the cut-off frequency of 8 Hz did not show any distortion. For perfused manometry systems, only a low-compliance perfusion pump will have sufficient bandwidth for accurate recording of esophageal peristaltic pressures.
Effect of estrogen on rate of 59Fe uptake by hemopoietic tissue in Japanese quail.
Authors: Clermont C P , Schraer H
Published: December 2017

Injection of 2 mg estradiol valerate into male Japanese quail caused the rate of 59Fe uptake by the skeleton to drop 70% within 48 h. This phenomenon was due to an increase in the iron-binding capacity of the plasma induced by estrogen that caused a substantial decline in the availability of the label for hematopoiesis and to partial inhibition of hematopoiesis by estrogen directly. The changes in 59Fe uptake induced by estrogen were accompanied by a significant drop in circulating red blood cell concentration and a substantial rise in plasma volume. These altered physiological conditions were similar to those normally found in the laying hen.
Fructose-6-phosphate substrate cycling and glucose and insulin regulation of gluconeogenesis in vivo.
Authors: Dunn A , Chenoweth M
Published: December 2017

The question whether glucose or insulin regulates gluconeogenesis by effecting changes in the fructose-6-phosphate (F-6-P) substrate cycle (phosphofructokinase (PFK), fructose-1,6-diphosphatase (FDPase)) was investigated in vivo in fasted normal rats using [3-3H,U-14C]- or [3-3H,6-14C]glucose. The plasma glucose 3H/14C ratio was used as an index of substrate cycling because 3H loss from the liver hexose phosphate pool is limited by the activities of PFK and FDPase during gluconeogenesis and glycolysis, respectively. The 3H/14C ratio was corrected where necessary for glucose or insulin-induced changes in reincorporation of 14C from C-6 to C-1-3 of plasma glucose. A glucose infusion producing hyperglycemia and insulinemia was accompanied by decreased hepatic glucose production and diminished F-6-P substrate cycling, i.e., decreased FDPase activity. When insulin was infused along with glucose to produce high plasma insulin levels and avoid hypo- or hyperglycemia, the 3H/14C decay rate did not change, suggesting that the hormone does not influence basal rates of gluconeogenesis or PFK or FDPase activities. These in vivo results suggest that increased blood glucose levels inhibit gluconeogenesis and depress F-6-P substrate cycling. Whether these cycle changes constitute primary regulatory actions of glucose or occur secondarily to other metabolic events resulting from excess hexose (e.g., increased glycogen synthetase activity) cannot now be concluded.
Development of secretory mechanisms in rat pancreas.
Authors: Werlin S L , Grand R J
Published: December 2017

Mechanisms and development of secretory function were studied in rat pancreas in vitro. Amylase release from term fetal pancreas was refractory to stimulation by carbamylcholine chloride (carbachol) and cholecystokinin-octapeptide (CCK-OP), but was significantly augmented by calcium ionophore (A23187), DBcAMP, 8-Br-cGMP, and theophylline. The latter agent when combined with either cyclic nucleotide analogue further increased secretory responses. At 1 day and 8 days postnatally, responsiveness to carbachol and CCK-OP had been acquired because amylase secretion stimulated by these agents was brisk and at a level comparable to that found in mature tissue. Increasing extracellular calcium concentrations from 1.23 to 5.28 mM had no effect on basal amylase release in either the fetal or 8-day pancreas. No changes in intracellular cAMP concentrations were found at any age under experimental conditions used. Similarily, in fetal tissue, no changes in cGMP concentrations were found in response to carbachol or A23187. However, at 8 days of age, both agents produced two- to four-fold increases in tissue cGMP levels at 1, 2, and 5 min of incubation. These studies confirm that responsiveness to carbachol and CCK-OP is a maturational process in the pancreas that lags behind the development of intracellular processes involved in stimulus-secretion coupling.
Nutritional and hormonal regulation of pyruvate metabolism in the liver.
Authors: McDaniel H G
Published: December 2017

The effect of fasting, glucose, and glucagon injection on pyruvate metabolism of rat liver mitochondria was studied. Fasting for 24 h caused a) a twofold increase in mitochondrial pyruvate uptake, b) fivefold increase in CO2 fixation, and c) no change in pyruvate decarboxylation. Injection of glucose to fasted rats 2 h prior to preparation suppressed by one-half the increase in mitochondrial pyruvate uptake and CO2 fixation and increased hepatic pyruvate content. Injection of glucagon together with glucose abolished the depression of pyruvate uptake by glucose but did not prevent the decrease in mitochondrial CO2 fixation or hepatic ketone content caused by glucose alone. The effects of insulin injection resembled that of glucose in decreasing hepatic ketone content, but differed by increasing pyruvate uptake without much change in CO2 fixation. It is concluded that the increase in gluconeogenesis induced by fasting is due to an increase in pyruvate uptake and carboxylation by hepatic mitochondria. The latter is due to the increased mobilization and oxidation of fatty acids induced by reciprocal changes in insulin and glucagon.
Developmental changes in thymidine kinase, DNA, and fat cellularity in Zucker rats.
Authors: Cleary M P , Brasel J A , Greenwood M R
Published: December 2017

Thymidine kinase activity and the pattern of DNA accretion in the genetically obese Zucker rat (fafa) were shown to develop in a manner fundamentally different from that of the lean rat. In normal lean Zucker rats, fat cell size and number, thymidine kinase activity, total DNA, and DNA in lipid-filled and nonlipid-filled tissue changed as previously reported for the normally growing lean Sprague-Dawley rat. In the epididymal depot of the developing obese rat, the progressive obesity is characterized by marked early enlargement of fat cell size, elevated thymidine kinase activity until 273 days of age, increased rate of total tissue DNA accretion until 182 days of age, and fat cell hyperplasia that becomes manifest after an apparent "peak" cell size is reached at 98 days of age.
alpha-Ketoisocaproate stimulates branched-chain amino acid transaminase in kidney and muscle.
Authors: Mitch W E , Chan W
Published: December 2017

We have reported that branched-chain amino acid transaminase (BATase) activity of isolated rat kidney is stimulated by perfusion with alpha-ketoisocaproate (KL). This study examines the mechanism of this effect in kidney and documents that stimulation occurs in intact skeletal muscle. Increased activity was not attributable to synthesis of enzyme because it occurred in the presence of cycloheximide. The in vivo degradation rate of BATase estimated from sequential measurements of activity following intravenous cycloheximide was longer than 90 min, whereas during in vitro perfusion stimulation could be detected within 5 min. Incubation of supernatant from kidney homogenate with KL stimulated BATase; incubation with alpha-keto-beta-methylvalerate (KI), alpha-ketoisovalerate (KV), leucine (leu), or isovaleryl CoA did not. Perfusion of rat hindquarter with KL increased muscle BATase activity; perfusion with acetoacetate, KI, KV, or leu did not. Again, cycloheximide studies indicated a direct effect of KL on muscle BATase. These findings suggest that alpha-ketoisocaproate can increase BATase activity and thus may be involved in regulation of its activity.
Insulin sensitivity of rat skeletal muscle: effects of starvation and aging.
Authors: Goodman M N , Ruderman N B
Published: December 2017

The effects of starvation and of aging on the sensitivity of skeletal muscle to insulin were studied in the isolated perfused rat hindquarter preparation. As we have shown previously, starvation for 48 h had no effect on glucose uptake in hindquarters perfused with high levels of insulin (5 and 20 mU/ml). On the other hand, in the presence of physiological concentrations of insulin (50--200 muU/ml), glucose utilization was substantially greater in starved rats. Low concentrations of insulin had a greater effect on glucose uptake in fed young (100-g) than in fed older (350-g) rats. Starvation for 48 h enhanced glucose uptake in both young and older rats; however, the relative differences persisted. Starvation had similar effects on glucose utilization by the incubated soleus and extensor digitorum longus muscle. In addition, it augmented the stimulation by insulin of alpha-aminoisobutyric acid transport into the incubated extensor digitorum longus muscle. These results suggest that the in vitro sensitivity of skeletal muscle to physiological concentrations of insulin is enhanced during starvation. The basis for these findings and their physiological implications remain to be determined.
Evidence that dog kidney is an endogenous source of histidine.
Authors: Fukuda S , Kopple J D
Published: December 2017

Net production or utilization (Qmet) of histidine by the kidney was evaluation or utilization (Qmet) of histidine by the kidney was evaluated in 11 normal and 8 chronically uremic female dogs during intravenous infusion, first of half-normal saline and then an amino acid solution containing L-histidine. Also, Qmet for histidine, alanine, beta-alanine, and carnosine (beta-alanyl-L-histidine) was determined during infusion of half-normal saline and then carnosine into the renal artery in seven normal dogs. During infusion of half-normal saline, Qmet histidine, calculated from the plasma data, was significantly positive in normal but not uremic dogs. Qmet histidine correlated with creatinine clearance. In uremic dogs, plasma histidine was decreased possibly due to decreased renal production and increased urinary excretion. Qmet histidine, calculated from the whole blood data during infusion of half-normal saline, was positive but not significantly so. During carnosine infusion, there was significant utilization of carnosine, and histidine production increased. Thus during fasting, the dog kidney appears to produce histidine, and histidine production increases with carnosine infusion. Hydrolysis of carnosine, possibly by carnosinase, may be a source of histidine released by the dog kidney.
Effect of angiotensin II on parotid saliva secretion in conscious sheep.
Authors: McKinley M J , Denton D A , Hatzikostas S , Weisinger R S
Published: December 2017

Intravenous infusion of angiotensin II over the dose range 3-20 microgram/h for 15 min caused a dose-dependent reduction in parotid saliva secretion and increase in arterial blood pressure in conscious sheep. The blood levels of angiotensin II contrived by these infusions were probably within the physiological range for sheep. Infusion of angiotensin II (3 microgram/h) into the carotid artery ipsilateral to the parotid gland under study caused greater reduction in saliva secretion rate than an equivalent infusion of angiotensin II into the contralateral carotid artery. This result suggests a direct effect of angiotensin II at the parotid, possibly by a constrictor action on its vasculature or by altering water and electrolyte transport by the gland. In sodium-deplete sheep, intravenous infusion of the angiotensin antagonist saralasin (1 mg/h for 1 h) caused transient increase of saliva flow for 20-30 min. It is suggested that angiotensin II may have a physiological role in regulating parotid saliva secretion during sodium depletion.
Endocrine regulation of thymic biosynthetic polyamine decarboxylases in adult rat.
Authors: Scalabrino G , Ferioli M E , Basagni M , Nebuloni R , Fraschini F
Published: December 2017

The activities of ornithine and S-adenosyl-L-methionine decarboxylase were assayed in the thymuses of adult rats killed at 7-day intervals up to 6 wk after either pinealectomy or sham pinealectomy. The absence of the pineal gland markedly influenced the ornithine decarboxylase activity in the thymus, in which the level of the enzyme was decreased permanently by the 4th wk after the operation (P less than 0.05). The time course of the changes in S-adenosyl-L-methionine decarboxylase activity in the thymus during the entire period investigated was also significantly (P less than 0.05) modified by pinealectomy but did not show any stable trend. Adrenalectomy significantly raised (P less than 0.001) for ornithine decarboxylase; P less than 0.01 for S-adenosyl-L-methionine decarboxylase) the basal levels of the thymic biosynthetic polyamine decarboxylases. A pharmacological dose of corticosterone or cortisol produced a rapid and significant decrease in ornithine and S-adenosyl-L-methionine decarboxylase activities (P less than 0.02) in the thymus, whereas the injection of either D-aldosterone or ACTH was ineffective. Therefore, the thymic biosynthetic polyamine decarboxylases that in this organ are known to be located only in the lymphocytes appear to be regulated in opposing ways by the pineal gland and by the adrenal cortex.
Perinatal development of intestinal myoelectrical activity in dogs and sheep.
Authors: Bueno L , Ruckebusch Y
Published: December 2017

Both slow waves and bursts of spike potentials were recorded prior to birth in dogs and sheep. At 0l7-0.8 of term the slow-wave frequency of the jejunum did not exceed 12/min. It increased in a similar way during the last stage of fetal life in sheep and after birth in dogs. Adult values were attained 10-15 days after birth in the lamb but only by 40 days of age in the puppy. In both species, three stages of development of the spiking activity were identified. Stage 1, termed unorganized spiking activity, was converted in the fetal lamb at 0.8 of term to a fetal pattern (stage 2) characterized by cyclic 3- to 4-min periods of regular spiking occurring at 10- to 20-min intervals and propagated along a short intestinal segment. Stage 3, which corresponds to myoelectric complexes, occurred during the last 10 days of fetal life. In dogs, the fetal pattern (stage 2) was recorded from 5 days before to 15 days after birth. Stage 3 was seen in the 15-day-old neonate. The results suggest that the patterns of electrical activity seen in the last third of fetal life can be related to their function of mixing and absorbing but not expelling intestinal contents. They indicate that the electrical phenomena of the gastrointestinal tract are in accord with the overall greater maturity and independence of the newborn sheep compared to the dog.
Na+,K+-ATPase enzyme units in lean and obese (ob/ob) thyroxine-injected mice.
Authors: Lin M H , Vander Tuig J G , Romsos D R , Akera T , Leveille G A
Published: December 2017

The possible involvement of Na+,K+-ATPase in the etiology of obesity in the obese (ob/ob) mouse was explored. The number of Na+,K+-ATPase enzyme units in skeletal muscle, liver, and kidneys from 4- and 8-wk-old obese and lean mice was estimated from saturable [3H]ouabain binding to particulate fractions. Neither phenotype nor age altered the Kd value for ouabain binding in these three tissue preparations. The total number of [3H]ouabain binding sites in hindlimb muscles was 35--55% lower in 4- and 8-wk-old obese mice than in their lean counterparts. However, the total number of [3H]ouabain binding sites in liver and kidneys of obese mice was similar to values observed in their lean counterparts. Because it has been suggested that ob/ob mice are hypothyroid, we investigated the response of Na+,K+-ATPase in these mice to thyroid hormone treatment (approximately 5 microgram thyroxine/day for 2 wk). The number of [3H]ouabain binding sites in the three tissues increased in both obese and lean mice injected with this relatively large dose of thyroxine, but the obese mice were 2--3 times more responsive than lean mice.
Maternal starvation and progesterone secretion, litter size, and growth in the pig.
Authors: Hard D L , Anderson L L
Published: December 2017

The relationships of maternal nutrition and progesterone secretion to prenatal fetal loss and neonatal survival and growth were investigated in domesticated pigs that normally experience 40% fetal loss. Yorkshire pigs were subjected to prolonged starvation (40 days; 0 kcal/day; water only) in either the middle third or last third of pregnancy and then gradually realimented to a full diet and allowed to advance to parturition; controls received a full diet (7,028 kcal/day) throughout gestation. Pregnancies were maintained in 74% of the pigs starved during either middle or late gestation compared to 100% in controls. In dams starved from days 30--70, progesterone levels remained similar to controls, but were maintained at lower levels during realimentation between days 72 and 99. Progesterone levels in dams starved days 50--90 and controls were similar from days 50 to 130. At parturition, litter size in starved dams (9.4) was similar to full-diet controls (8.0) although birth weight and neonatal growth of piglets were reduced markedly from dams starved in middle or late pregnancy. These results indicate that severe maternal nutrient deprivation during the middle or last third of gestation has little effect on ovarian progesterone secretion and is not a major limitation to fetal survival in this litter-bearing species. Maternal nutrient deprivation imposes a significant detrimental effect, however, on birth weight and neonatal growth to 80 days of age.
Effect of fasting on insulin removal by liver of perfused liver-pancreas.
Authors: Striffler J S , Curry D L
Published: December 2017

Using in situ perfused rat liver-pancreas preparations, the hepatic clearance of biphasically released endogenous insulin was studied using livers of fed and fasted rats. Hepatic insulin extraction was determined by subtracting the mean endogenous insulin output found in the posthepatic vena cava effluent of liver pancreas preparations from the amount of insulin found in the prehepatic portal effluent of perfused pancreas preparations. All pancreas perfusions and liver-pancreas perfusions were subjected to the same plasma glucose stimulus (250 mg/dl) for 40 min. In the fed state, no significant hepatic extraction of insulin occurred. The biphasic pattern of insulin appearance in the posthepatic vena cava effluent, which ranged from less than 1 to 21 ng/ml, was unaffected by passage through the liver. In contrast, when rats were fasted for 24 h, approximately 50% of the insulin released into the portal vein was removed by their livers during one transhepatic passage. After a 48-h fast, insulin extraction capacity decreased relative to the capacity observed for livers of 24-h fasted rats.
Differential effects of epinephrine on glucose production and disposal in man.
Authors: Rizza R , Haymond M , Cryer P , Gerich J
Published: December 2017

Normal subjects were infused 1) with epinephrine (50 ng/(kg.min)) for 180 min followed by epinephrine plus glucagon (3 ng/(kg.min)) for 60 min after which the epinephrine infusion rate was increased (125 ng/(kg.min)) or 2) with epinephrine plus somatostatin (500 microgram/h) for 180 min. Epinephrine increased glucose production and plasma glucagon transiently but caused persistent suppression of glucose clearance and sustained hyperglycemia (despite increased plasma insulin and gluconeogenic substrates); glucose production increased again on addition of glucagon and on increasing the epinephrine infusion rate. During epinephrine plus somatostatin, glucose production still increased transiently, but further suppression of glucose clearance caused more marked hyperglycemia. In conclusion, 1) in man hyperepinephrinemia within the physiological range caused sustained suppression of glucose clearance but only a transient increase in glucose production; 2) this transient hepatic response a) was not due to glycogen or substrate depletion, b) occurred without changes in plasma glucagon or insulin, c) was specific for epinephrine but permitted subsequent responses to changes in plasma epinephrine; 3) epinephrine can serve as a physiological regulator of glucose homeostasis in man both by increasing glucose production and by decreasing glucose clearance.
1,25(OH)2D response to combined zinc and phosphorus depletion in rats.
Authors: Kimmel P L , Watkins D W , Slatopolsky E , Langman C B
Published: December 2017

To investigate the role of zinc depletion in the response of calcitriol to a single provocative stimulus, we studied vitamin D metabolites, parathyroid hormone (PTH), and mineral balance during phosphorus depletion in animals with different zinc nutritional status. Male Lewis rats (66) were pair fed normal phosphorus (NP), zinc-replete (+) or -deplete (-) diets for 2 wk. Thereafter, one-half of each paired group underwent 1 wk of phosphorus depletion (LP). Zinc-deplete animals had lower plasma zinc, and phosphorus-deplete animals had lower plasma phosphorus concentrations than respective nutritionally replete controls. Plasma calcium, PTH, and 25-hydroxycholecalciferol concentrations were similar in all four groups at end of experiment. Mean plasma 1,25(OH)2D concentration increased 80% from 35 +/- 3 to 63 +/- 9 pg/ml (P less than 0.007) when values were compared before and after phosphorus restriction in zinc-replete animals (LP + group). The 7.9% increase from 35 +/- 4 to 38 +/- 4 pg/ml in 1,25(OH)2D concentration in animals with combined zinc and phosphorus depletion (LP-) was not significant. External calcium balance, however, was maintained in the combined zinc and phosphorus-deplete group. We conclude that zinc depletion limits the increase in plasma 1,25(OH)2D concentration associated with phosphorus depletion. The mechanism is unknown but may involve an effect of zinc on renal 25(OH)D 1-alpha-hydroxylase synthetic activity.
Operating behavior of dual or multiple endocrine pulse generators.
Authors: Veldhuis J D , Lassiter A E , Johnson M L
Published: December 2017

We describe an endocrine model of dual or multiple stochastic generators of episodic pulse signals, provide a sensitivity analysis of output responses, and illustrate the statistical effects of a plurality of independent pulse generators on peak detector performance (sensitivity, specificity, positive accuracy, and negative accuracy). We define the probability distribution of random summation or interference events and evaluate physiological implications of two or more interacting pulse-generator systems. Such observations offer a basis for quantitative examination of the operating characteristics of two or more interacting endocrine pulse generators in specified physiological contexts.
Regulation of plasma calcium and phosphate in calcitonin-infused rats.
Authors: Lausson S , Tracqui P , Toubiana L , Milhaud G , Perault-Staub A M , Staub J F
Published: December 2017

The effects of long-term constant infusion of moderate doses (2-32 ng/h) of salmon calcitonin (sCT) on plasma Ca (and its radionuclide 45Ca), Pi, Mg, and on endogenous rat CT (rCT) metabolism were investigated in the rat. Daily variations were included. 1) The plasma concentrations of Ca and Pi fell and that of Mg increased transiently during infusion, with the duration of responses (1-3 days) depending on the sCT dose. Rats infused with 8 ng/h sCT remained sensitive to CT after 7 and 14 days, as indicated by the effects of minipump removal and of a bolus injection of exogenous sCT on plasma mineral concentrations. 2) In contrast to control rats, the well-established daily variations in plasma Ca and Pi levels were no longer observed after 7 and 14 days of sCT infusion (8 ng/h), but normal variations persisted for plasma Mg, circulating rCT, rCT mRNA, and rCT thyroid content. 3) Statistical analysis of plasma mineral data, collected at five sequential times during days 7 and 14, showed that the means were not significantly different and that the daily variations were essentially identical on days 7 and 14 in control rats. In contrast, the variability of measurements for plasma Ca and Pi, but not for Mg, increased significantly between days 7 and 14 in infused rats, and the mean differences were significantly lower in infused rats on day 7 than in control rats. These results are consistent with a transitory loss of the daily variations for Ca and Pi (day 7) and the later (day 14) spontaneous recovery of some variations in these parameters, although the individuals remain unsynchronized.(ABSTRACT TRUNCATED AT 250 WORDS)
Entrainment of circadian phase in developing gray short-tailed opossums: mother vs. environment.
Authors: Rivkees S A , Reppert S M
Published: December 2017

In a marsupial species, the gray short-tailed opossum (Monodelphis domestica), the suprachiasmatic nuclei (SCN), the site of a circadian clock, are formed postnatally and begin oscillating as a circadian clock on day 20. In this study, we examined how the timing (phase) of the SCN clock in the developing opossum is coordinated to the environmental light-dark cycle. When pups were reared from birth in darkness by intact dams, the circadian phases in SCN metabolic activity (monitored by 2-deoxy-D-[14C]glucose autoradiography) in 27-day-old pups were desynchronized. When pups were reared in a light-dark cycle that was 12 h out of phase with the circadian time of blinded dams, the pattern of SCN metabolic activity on day 20 was rhythmic and in phase with the light-dark cycle but out of phase with the circadian time of the dam. On day 20, retina-mediated light activation of SCN metabolic activity was also demonstrated, and anterograde tract-tracing studies revealed the presence of the retinohypothalamic tract within the SCN. These results show there is no influence of the opossum dam on the timing of the pup's biological clock. Instead, from the inception of the daily rhythm in SCN metabolic activity, its timing is regulated by retina-mediated light-dark entrainment.
Disuse osteopenia is accompanied by downregulation of gene expression for bone proteins in growing rats
Authors: Wakley G. K. , Portwood J. S. , Turner R. T.
Published: December 2017

Unilateral sciatic neurectomy (USN) resulted in cortical osteopenia in tibiae from the sciatic nerve-sectioned limb of growing rats. The bone deficit resulted from decreased periosteal addition; there were no changes in the indexes of bone resorption. The periosteal bone formation rate was reduced in the nerve-sectioned limb within 7 days of sciatic neurectomy, and this decrease persisted for at least 56 days. Steady-state mRNA levels for bone proteins were determined in periosteum isolated from tibiae and femurs 7 and 14 days after sciatic nerve section. Nerve section resulted in decreased levels of mRNA for osteocalcin, alkaline phosphatase, and possibly the prepro-alpha (I)-subunit of type I collagen (collagen). The effects were more pronounced in tibiae than femurs, corresponding to the greater degree of immobility induced by USN in the former bone. The results demonstrate that decreased bone formation precedes establishment of disuse cortical osteopenia in growing rats with no evidence for a change in bone resorption. Furthermore, the decreased bone formation is associated with, and may be due to, reduced mRNA levels for matrix proteins and other important bone proteins.
Upregulation of V1a vasopressin receptors by glucocorticoids
Authors: Colson P. , Ibarondo J. , Devilliers G. , Balestre M. N. , Duvoid A. , Guillon G.
Published: December 2017

WRK1 cells (a rat mammary tumor cell line) exhibit a vasopressinergic receptor of V1a subtype tightly coupled to phospholipase C. Addition of dexamethasone to the culture medium principally potentiated the vasopressin-sensitive accumulation of inositol phosphates and to a lesser extent the NaF-sensitive phospholipase C activity. On the opposite, such treatment was without effect on the basal level of intracellular inositol phosphates or on bradykinin- or serotonin-sensitive phosphoinositide metabolisms. Glucocorticoid receptors were probably involved in these actions since dexamethasone was found to be more potent than aldosterone or corticosterone. Dexamethasone treatment also increased the number of vasopressin binding sites without affecting its affinity for vasopressin or other specific vasopressin analogues. These results strongly suggest that dexamethasone principally acts at the vasopressin receptor level by affecting its synthesis and/or the translation of its mRNA and also affects the G protein that couples the V1a receptor to the phospholipase C. These results explain how glucocorticoids may regulate the transduction mechanisms involved in vasopressin actions on WRK1 cells. They provide explanations for understanding the cross talk between adrenal steroids and hormones, which mobilize intracellular calcium.
Regulation of free fatty acid metabolism by insulin in humans: role of lipolysis and reesterification
Authors: Campbell P. J. , Carlson M. G. , Hill J. O. , Nurjhan N.
Published: December 2017

The regulation of lipolysis, free fatty acid appearance into plasma (FFA R(a)), an FFA reesterification and oxidation were examined in seven healthy humans infused intravenously with insulin at rates of 4, 8, 25, and 400 mU.m-2.min-1. Glycerol and FFA R(a) were determined by isotope dilution methods, and FFA oxidation was calculated by indirect calorimetry or by measurement of expired 14CO2 from infused [1-14C]palmitate. These measurements were used to calculate total FFA reesterification, primary FFA reesterification occurring within the adipocyte, and secondary reesterification of circulating FFA molecules. Lipolysis, FFA R(a), and secondary FFA reesterification were exquisitely insulin sensitive [the insulin concentrations that produced half-maximal suppression (EC50), 106 +/- 26, 91 +/- 20 vs. 80 +/- 16 pM, P = not significant] in contrast to insulin suppression of FFA oxidation (EC50, 324 +/- 60, all P < 0.01). The absolute rate of primary FFA reesterification was not affected by the increase in insulin concentration, but the proportion of FFA molecules undergoing primary reesterification doubled over the physiological portion of the insulin dose-response curve (from 0.23 +/- 0.06 to 0.44 +/- 0.07, P < 0.05). This served to magnify insulin suppression of FFA R(a) twofold. In conclusion, insulin regulates FFA R(a) by inhibition of lipolysis while maintaining a constant rate of primary FFA reesterification.
Effect of training on insulin-mediated glucose uptake in human muscle
Authors: Dela F. , Mikines K. J. , von Linstow M. , Secher N. H. , Galbo H.
Published: December 2017

During insulin stimulation whole body glucose uptake is increased in trained compared with untrained humans. However, it is not known which tissue is responsible. Seven young male subjects bicycle trained one leg for 10 wk at 70% of maximal O2 consumption (VO2max). Sixteen hours after last exercise bout, a three-step euglycemic hyperinsulinemic clamp (clamp 1) was performed (insulin levels, means +/- SE: 9 +/- 1, 53 +/- 3, 174 +/- 5, and 2,323 +/- 80 was microU/ml), with measurement of arteriovenous differences and blood flow in both legs. After 6 days of detraining subjects were restudied, having exercised the untrained leg 16 h before. VO2max for trained (T) and untrained (UT) legs was 52 +/- 2 vs. 44 +/- 2 ml.min-1.kg-1 (P < 0.05). In clamp 1 glucose uptake in T and UT legs was 1.0 +/- 0.2 vs. 0.5 +/- 0.1 mg.min-1.kg-1 (basal), 9.7 +/- 2.3 vs. 6.7 +/- 1.7 (P < 0.05) (step I), 19.2 +/- 2.8 vs. 14.3 +/- 2.0 (P < 0.05) (step II), and 22.8 +/- 2.3 vs. 18.6 +/- 2.2 (P < 0.05) (step III). During insulin infusion lactate release (P < 0.05) [8.9 +/- 1.8 vs. 2.9 +/- 0.9 mumol.min-1.kg-1 (step I), 24.6 +/- 3.1 vs. 12.5 +/- 2.6 (step III)] and glycogen storage (P < 0.1) calculated by indirect calorimetry [6.7 +/- 2.3 vs. 5.0 +/- 1.7 mg.min-1.kg-1 (step I), 16.8 +/- 2.1 vs. 14.1 +/- 1.8 (step III)] were always higher in T than in UT legs. Release of glycerol, free fatty acids, and tyrosine and clearance of insulin were not influenced by training. Insulin-mediated glucose uptake was not increased after detraining or a single bout of exercise. In conclusion, training increases sensitivity and responsiveness of insulin-mediated glucose uptake in human muscle by local mechanisms. Glycolysis and glycogen storage are equally enhanced. The training effect represents a genuine adaptation to repeated exercise but is short lived. Insulin clearance in muscle is not influenced by training.
A reexamination of the effect of exercise on rate of muscle protein degradation
Authors: Kasperek G. J. , Conway G. R. , Krayeski D. S. , Lohne J. J.
Published: December 2017

The purpose of this study was to examine the effect of exercise on the rate of protein degradation in rat skeletal muscle. The rates of total and myofibrillar protein degradation were determined by the measurement of the rates of release of tyrosine and 3-methylhistidine, respectively, from the perfused single rat leg. This method measures the rate of protein degradation in the entire lower leg and does not suffer from the limitations inherent in methods that rely on urinary excretion. The rate of total protein degradation was increased by exercise and involved increased flux through the lysosomal pathway, while the breakdown of myofibrillar protein was unchanged. The changes in the rates of protein degradation during the recovery period were greatly influenced by energy intake. Again the rate of myofibrillar protein degradation was unchanged or slightly increased during the recovery period, after either level or downgrade running. Exercise did prevent the increase in the rate of total protein degradation caused by food restriction, which may have important implications in weight reduction diets.
Vitamin D and regulation of vascular cell function
Authors: Jamali Nasim , Sorenson Christine M. , Sheibani Nader
Published: December 2017

Vitamin D deficiency is linked to pathogenesis of many diseases including cardiovascular, cancer, and various eye diseases. In recent years, important roles for vitamin D in regulation of immune function, inflammation, angiogenesis, and aging have been demonstrated. Thus, vitamin D and its analogs have been evaluated for the treatment of various types of cancer and chronic diseases. We have previously shown that the active form of vitamin D [1,25(OH)2D3] is a potent inhibitor of angiogenesis. This activity is consistent with the important role proposed for vitamin D and its analogs in the mitigation of tumor growth through inhibition of angiogenesis. Here, we review the important nutritional value of vitamin D and the abnormalities linked to its deficiency. We will explore its potential role as a regulator of angiogenesis and vascular cell function and the role vitamin D receptor (VDR) expression plays in these activities during vascular development and neovascularization. Our studies have established an important role for 1,25(OH)2D3and VDR in the regulation of perivascular supporting cell function. In addition, the interaction of 1,25(OH)2D3and VDR is essential for these activities and inhibition of neovascularization. Delineating the signaling pathways involved and identification of genes that are the target of 1,25(OH)2D3regulation in vascular cells will allow us to identify novel pathways that are targets for regulation of vascular function and angiogenesis.
Increased (pro)renin receptor expression in the subfornical organ of hypertensive humans
Authors: Cooper Silvana G. , Trivedi Darshan P. , Yamamoto Rieko , Worker Caleb J. , Feng Cheng-Yuan , Sorensen Jacob T. , Yang Wei , Xiong Zhenggang , Feng Yumei
Published: December 2017

The central nervous system plays an important role in essential hypertension in humans and in animal models of hypertension through modulation of sympathetic activity and Na+and body fluid homeostasis. Data from animal models of hypertension suggest that the renin-angiotensin system in the subfornical organ (SFO) of the brain is critical for hypertension development. We recently reported that the brain (pro)renin receptor (PRR) is a novel component of the brain renin-angiotensin system and could be a key initiator of the pathogenesis of hypertension. Here, we examined the expression level and cellular distribution of PRR in the SFO of postmortem human brains to assess its association with the pathogenesis of human hypertension. Postmortem SFO tissues were collected from hypertensive and normotensive human subjects. Immunolabeling for the PRR and a retrospective analysis of clinical data were performed. We found that human PRR was prominently expressed in most neurons and microglia, but not in astrocytes, in the SFO. Importantly, PRR levels in the SFO were elevated in hypertensive subjects. Moreover, PRR immunoreactivity was significantly correlated with systolic blood pressure but not body weight, age, or diastolic blood pressure. Interestingly, this correlation was independent of antihypertensive drug therapy. Our data indicate that PRR in the SFO may be a key molecular player in the pathogenesis of human hypertension and, as such, could be an important focus of efforts to understand the neurogenic origin of hypertension.

NEW & NOTEWORTHY This study provides evidence that, in the subfornical organ of the human brain, the (pro)renin receptor is expressed in neurons and microglia cells but not in astrocytes. More importantly, (pro)renin receptor immunoreactivity in the subfornical organ is increased in hypertensive humans and is significantly correlated with systolic blood pressure.
Responses of cerebral arteries and arterioles to acute hypotension and hypertension
Authors: Kontos H. A. , Wei E. P. , Navari R. M. , Levasseur J. E. , Rosenblum W. I. , Patterson J. L.
Published: December 2017

The responses of cerebral precapillary vessels to changes in arterial blood pressure were studied in anesthetized cats equipped with cranial windows for the direct observation of the pial microcirculation of the parietal cortex. Vessel responses were found to be size dependent. Between mean arterial pressures of 110 and 160 mmHg autoregulatory adjustments in caliber, e.g., constriction when the pressure rose and dilation when the pressure decreased, occurred only in vessels larger than 200 micron in diameter. Small arterioles, less than 100 micron in diameter, dilated only at pressures equal to or less than 90 mmHg; below 70 mmHg their dilation exceeded that of the larger vessels. When pressure rose to 170- 200 mmHg, small vessels dilated while the larger vessels remained constricted. At very high pressures (greater than 200 mmHg) forced dilation was frequently irreversible and was accompanied by loss of responsiveness to hypocapnia. Measurement of the pressure differences across various segments of the cerebral vascular bed showed that the larger surface cerebral vessels, extending from the circle of Willis to pial arteries 200 micron in diameter, were primarily responsible for the adjustments in flow over most of the pressure range.
Increased contractile potential of papillary muscles from exercise-trained rat hearts
Authors: Mole P. A.
Published: December 2017

Female rats (n = 24) swam 6 h/day, 5 days/wk, for over 6 wk. Training increased both wet and dry weight of ventricles 15% above control. The active length-tension curve for trained left ventricular papillary muscles (LVPM) was elevated, with maximum tension (Tmax) at optimal length 37% higher than that of untrained LVPM. Training did not alter passive length-tension, time-to-peak tension (TPT), or half-relaxation time (1/2RT). The maximum rate of tension development (dT/dt), however, was increased 22% by training. The force-velocity curve of trained LVPM was shifted upward; both estimated Vmax and the minimum isometric load where shortening equals zero were greater than control. Exogenous isoproterenol (5.8 nM) did not affect Tmax but significantly decreased TPT and 1/2RT to the same extent for both groups of muscles. Maximum dT/dt was increased to a greater extent by isoproterenol for trained LVPM. These findings indicate hearts hypertrophied by exercise have an increased contractile potential per unit of myocardial mass.
Prostaglandins: renal vascular responses to bradykinin, histamine, and nitroglycerine
Authors: Feigen L. P. , Chapnick B. M. , Flemming J. E. , Kadowitz P. J.
Published: December 2017

A study was undertaken to evaluate the effects of inhibitors of prostaglandin (PG) synthesis on renal vascular responses to several renal vasodilators in anesthetized dogs. Indomethacin (IND) and meclofenamate (MEC), two dissimilar cyclooxygenase inhibitors were used. An electromagnetic flow probe was placed on the renal artery and a needle was inserted proximal to the probe. Injections of bradykinin, histamine, nitroglycerine, and arachidonic acid (AA) were given before and after administration of IND or MEC, 2.5 mg/kg body wt. In each experiment, inhibition of PG synthesis was estimated by reduction of vasodilator activity following AA injection. Although renal vascular resistance increased slightly after IND or MEC, elevations of renal blood flow in response to injections of bradykinin and nitroglycerine were not affected by PG synthesis inhibitors, whereas percent responses to histamine were enhanced by IND but not MEC. In addition, the action of 5 mg/kg IND on responses to injections and infusions of bradykinin was evaluated. No decrease in vasodilator activity following the kinin was detected in these studies. These results demonstrate that renal vascular responses to bradykinin, histamine, and nitroglycerine were not dependent on endogenously produced products of cyclooxygenase (e.g., prostaglandins) in the kidney of the anesthetized dog.