bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional adrenal blood flow responses to adrenocorticotropic hormone in fetal sheep
Authors: Carter A. M. , Richardson B. S. , Homan J. , Towstoless M. , Challis J. R.
Published: December 2017

To determine whether adrenocorticotropic hormone (ACTH) at plasma concentrations measured during mild hypoxemia and at term affects adrenal blood flow, we measured regional blood flows in five unanesthetized normoxemic fetuses (125–130 days gestation) during a 24-h intravenous infusion of ACTH-(1–24) in isotonic saline solution. Another five fetuses received an infusion of vehicle. Blood flows were determined before the infusion, at 2 and 24 h from its onset, and 24 h afterward using radionuclide-labeled microspheres. Blood flow to the adrenal medulla was fivefold greater than that to the adrenal cortex. Adrenal blood flow rose 99% at 24 h of the ACTH infusion. There was a large increase in adrenal cortical blood flow of 272% at this time but medullary blood flow did not change significantly during ACTH infusion. The rise in cortical blood flow was attributable to decreased vascular resistance. No significant alterations occurred in fetal arterial blood pressure and heart rate, or in blood flow to other lower body organs of the fetus or to the placental cotyledons. These findings are consistent with the hypothesis that the increase in adrenal blood flow observed during fetal hypoxia is associated with changes in plasma ACTH concentration. They are also indicative of selective regulation of cortical and medullary blood flows in the sheep fetus at this stage of gestation.
Thyroidal vascular responsiveness to parasympathetic stimulation is increased in hyperthyroidism
Authors: Dey M. , Michalkiewicz M. , Huffman L. J. , Hedge G. A.
Published: December 2017

It has been suggested that thyroid blood flow (TBF) is regulated by both parasympathetic and sympathetic nerves. Because thyroxine (T4) pretreatment increases the sensitivity of the thyroid to the effects of thyrotropin, the present study was conducted to determine whether T4 pretreatment can also sensitize the thyroid to the effect of parasympathetic stimulation on TBF. Untreated or T4-pretreated rats were anesthetized, and both superior laryngeal nerves (SLN) were transected. TBF was continuously monitored by laser Doppler flowmetry (LDF), and thyroid vascular conductance (TVC) was also determined by the microsphere technique. Stimulation of the SLN had no effect on TBF or TVC in untreated rats when measured by LDF or microspheres. In contrast, stimulation of the SLN after T4 pretreatment increased TBF by 65 +/- 21% over prestimulus levels as measured by LDF. TVC was also increased significantly (P < 0.05) in these rats compared with TVC in a nonstimulated T4-pretreated group. To examine the role of muscarinic receptor activation in the mediation of these increases in TVC, T4 pretreated rats were given saline or atropine prior to SLN transection. Stimulation of the SLN in T4-pretreated rats given saline increased TVC significantly (P < 0.05) compared with TVC in the nonstimulated saline-treated or atropine-treated group. In contrast, TVC in the stimulated group given saline was not significantly different from the group that was stimulated after atropine injection. Our results suggest that the thyroidal vascular responsiveness to parasympathetic stimulation is increased in the hyperthyroid condition.
Metabolic effects and fate of succinate esters in pancreatic islets
Authors: Malaisse W. J. , Sener A.
Published: December 2017

The metabolic effects and the catabolism of succinate methyl esters were examined in rat pancreatic islets. The esters augmented 14CO2 production from islets prelabeled with L-[U-14C]-glutamine but inhibited NH4+ output, suggesting that they do not activate glutamate dehydrogenase. They decreased 14CO2 output from islets prelabeled with [U-14C]palmitate. They had little effect on the oxidation of exogenous D-[3,4-14C]glucose, D-[2-14C]glucose, D-[6-14C]glucose, or D-[1-14C]glucose, suggesting unaltered ratio between the input of acetyl residues and four- or five-carbon metabolites, such as succinate, into the Krebs cycle. By following the fate of both [1,4-14C]succinate dimethyl ester and [2,3-14C]succinate dimethyl ester, data were obtained to indicate that succinate is efficiently formed from the ester and further metabolized, leading to the generation of 14C-labeled acidic metabolites including pyruvate and L-lactic acid, CO2, and amino acids. It is proposed that a concerted increase of both succinate and acetyl residue influx into the Krebs cycle accounts for the increase in O2 uptake caused by the succinate methyl esters and, hence, for stimulation of both pro-insulin biosynthesis and insulin release.
Myofibrillar protein synthesis in young and old men
Authors: Welle S. , Thornton C. , Jozefowicz R. , Statt M.
Published: December 2017

We tested the hypothesis that healthy older men (> 60 yr old) have a slower rate of myofibrillar protein synthesis than young men (< 35 yr old). Myofibrillar protein synthesis was determined by the in vivo incorporation of L-[1-13C]leucine into myofibrillar proteins obtained by muscle biopsy. Subjects were eight young (21-31 yr) and eight older (62-81 yr) men, all healthy and moderately active. There was no significant difference in the mean height and weight of the two age groups, but the older group had 12% less lean body mass (determined by 40K counting) and 21% less muscle mass (estimated by urinary creatinine excretion). Upper leg strength was approximately one-third lower in the older subjects according to isokinetic dynamometry. The fractional rate of myofibrillar protein synthesis was 28% slower in the older group (0.039 +/- 0.009 vs. 0.054 +/- 0.010 %/h, mean +/- SD, P < 0.01). Total myofibrillar protein synthesis, estimated as total myofibrillar mass (from creatinine excretion) times the fractional synthesis rate, was 44% slower in the older group (1.4 vs. 2.5 g/h, P < 0.001). Whole body protein synthesis, assessed as the difference between leucine disappearance rate and leucine oxidation, was marginally slower (8%, P = 0.10) in the older group, but not when the data were adjusted for lean body mass. Myofibrillar protein synthesis was a smaller fraction of whole body protein synthesis in the older group (12 vs. 19%). Reduced myofibrillar protein synthesis may be an important mechanism of the muscle atrophy associated with aging.
Endogenous neuropeptide Y regulates thyroid blood flow
Authors: Michalkiewicz M. , Huffman L. J. , Dey M. , Hedge G. A.
Published: December 2017

Neuropeptide Y (NPY) is present in thyroid sympathetic nerve fibers. To assess the involvement of endogenous NPY in the regulation of thyroid function, a NPY antiserum was produced in a rabbit, characterized, and used for immunization of normal and hyperthyroid rats. Plasma thyroxine, thyroid-stimulating hormone (TSH), thyroidal, and other organ blood flows (BF) were measured in anesthetized (ketamine and pentobarbital sodium) male Sprague-Dawley rats at 1 h after intravenous administration of 1 ml of the antiserum, normal rabbit serum, or saline. Immunization against NPY had no effect on the plasma levels of thyroxine, TSH, or arterial blood pressure, but it significantly increased thyroidal BF in normal rats. In the hyperthyroid rats (treated with 5 micrograms.100 g body wt-.day-1 thyroxine for 6 days), the NPY antiserum reversed the hyperthyroidism-induced decrease in thyroid BF and significantly increased duodenal and testicular BF values, but it did not alter BF values in four other organs. These results indicate that endogenous NPY regulates thyroid BF in normal rats. They also provide an example of NPY involvement in the pathophysiological adjustment of some organs to hyperthyroidism.
Total energy expenditure in 4- to 6-yr-old children
Authors: Goran M. I. , Carpenter W. H. , Poehlman E. T.
Published: December 2017

There is a sparsity of data on energy expenditure in young children. We therefore examined the components of daily energy expenditure in a group of 30 children (16 boys, 14 girls; age 4–6 yr) characterized for body weight, height, heart rate, and body composition from bioelectrical resistance. Total energy expenditure (TEE) was measured over 14 days under free living conditions by doubly labeled water, resting energy expenditure (REE) from indirect calorimetry, and activity energy expenditure was estimated from the difference between TEE and REE. Mean TEE was 1,379 +/- 290 kcal/day, which was 475 +/- 202 kcal/day lower than energy intake recommendations for this age group. Activity-related energy expenditure was estimated to be 267 +/- 203 kcal/day. TEE was most significantly related to fat-free mass (FFM; r = 0.86; P < 0.001), body weight (r = 0.83; P < 0.001), and REE (r = 0.80; P < 0.001). When TEE was adjusted for FFM, a significant correlation with heart rate was observed (partial r = 0.54; P = 0.002). Collectively, 86% of interindividual variation in TEE was accounted for by FFM, heart rate, and REE. We conclude that, in young 4- to 6-yr-old children, 1) TEE is approximately 25% lower than current recommendations for energy intake and 2) combined measurement of FFM, heart rate, and REE explain 86% of interindividual variation in TEE, thus providing a possible alternative method to estimate TEE in young children.
Changes in ovine fetal adrenocortical responsiveness after long-term hypoxemia
Authors: Harvey L. M. , Gilbert R. D. , Longo L. D. , Ducsay C. A.
Published: December 2017

This study tested the hypothesis that in the fetus long-term hypoxemia induces premature adrenocortical maturation and augments adrenal responsiveness to adrenocorticotropin hormone (ACTH). Pregnant ewes were exposed to high altitude (3,820 m) from 30 to 120 days gestation, when surgery was performed. Maternal arterial pressure of O2 (PaO2) was maintained at approximately 60 Torr by N2 infusion through a tracheal catheter. Fetal PaO2 was significantly lower in the hypoxemic (21 +/- 0.2 Torr) vs. normoxic (26 +/- 0.4 Torr) fetuses (P < 0.01). Between 125 and 140 days, basal ACTH and cortisol concentrations were similar in both groups. To assess changes in adrenal responsiveness, we challenged the fetuses with ACTH (100 ng/kg body wt, iv bolus) at 126 and 136 days. At 126 days, after ACTH challenge, fetal plasma ACTH peaked at similar values (275 +/- 43 and 250 +/- 26 pg/ml) in normoxic and hypoxemic fetuses, respectively. Plasma cortisol subsequently increased to 84 +/- 8 and 44 +/- 6 ng/ml in these groups. At 136 days, after ACTH challenge, plasma ACTH peaked at 379 +/- 57 and 336 +/- 21 pg/ml in normoxic and hypoxemic fetuses, respectively. Although plasma cortisol concentration in normoxic fetuses increased to 180 +/- 21 ng/ml, levels in hypoxemic fetuses only reached 62 +/- 12 ng/ml (P < 0.05 compared with normoxic). Catecholamine concentrations were not significantly different between the two groups. These data do not support the hypothesis that adrenocortical maturation occurs prematurely, augmenting adrenal responsiveness to ACTH after exposure to long-term hypoxemia. Rather, the ability of the fetus to respond to an ACTH challenge is blunted.
In vitro and in vivo evidence that dopamine exerts growth hormone-releasing activity in goldfish
Authors: Wong A. O. , Chang J. P. , Peter R. E.
Published: December 2017

We have previously demonstrated that dopamine (DA) and the DA D1 agonist SKF 38393 stimulate growth hormone (GH) release from perifused pituitary fragments of the goldfish, suggesting an involvement of DA D1 receptors in GH regulation. In the present study, the role of DA on GH release and body growth of the goldfish was further investigated both in vivo and in vitro. DA consistently stimulated GH release in a dose-dependent manner from perifused goldfish pituitary fragments. The GH-releasing action of DA was seasonal, being the highest in sexually regressed fish, intermediate in recrudescent fish, and the lowest in sexually mature (prespawning) fish. Somatostatin, a known GH-release inhibitor in the goldfish, suppressed basal GH release and abolished the GH response to DA in perifused pituitary fragments as well as pituitary cells under static incubation. Intraperitoneal administration of the nonselective DA agonist apomorphine and the D1 agonist SKF 82958 increased the plasma GH levels in the goldfish. These GH responses were blocked by simultaneous treatment with the D1 antagonist Sch 23390 but not the D2 antagonist pimozide. Apomorphine administered orally also induced a similar elevation in plasma GH levels. Long-term feeding with apomorphine was found to be stimulatory to the body growth of goldfish. These results provide evidence that the neurotransmitter DA, by acting through DA D1 receptors in the pituitary, also functions as a GH-releasing factor in the goldfish.
Regulation of maternal IGF-I by placental GH in normal and abnormal human pregnancies
Authors: Caufriez A. , Frankenne F. , Hennen G. , Copinschi G.
Published: December 2017

Throughout gestation, maternal insulin-like growth factor I (IGF-I) increases progressively despite suppressed pituitary growth hormone (GH) secretion. We have previously shown that in normal pregnancy, a specific placental GH variant, rather than human placental lactogen (hPL), substitutes for pituitary GH in the regulation of maternal IGF-I. We studied the maternal IGF-I secretion in a cohort of 286 normal and abnormal pregnancies (617 blood samples). Regardless of pathology and gestational age, IGF-I values correlated with corresponding placental GH but not with hPL values. Similar correlations were evidenced for each 2-wk gestational period between 32 and 39 wk. In pathological pregnancies, when only those hormonal results that are obtained before any treatment are considered and diabetes is excluded, IGF-I levels were closely related to corresponding placental GH, but not to hPL. In women with a fetoplacental unit disorder, low placental GH levels resulted in low IGF-I and in a secondary pituitary GH increase, whereas in patients without detectable impairment of the fetoplacental unit normal placental GH corresponded to normal IGF-I. These results suggest that in pathological as well as in normal pregnancy, placental GH, and not hPL, substitutes for pituitary GH to regulate the maternal IGF-I secretion.
Ontogenetic regulation of mouse Ren-2d renin gene in transgenic hypertensive rats, TGR(mREN2)27
Authors: Zhao Y. , Bader M. , Kreutz R. , Fernandez-Alfonso M. , Zimmermann F. , Ganten U. , Metzger R. , Ganten D. , Mullins J. J. , Peters J.
Published: December 2017

TGR(mREN2)27 is a new monogenetic rat model with fulminant hypertension, low kidney renin, and high extrarenal renin gene expression. This study characterizes and compares expression of the Ren-2 gene in TGR(mREN2)27 with that in DBA/2 mice and with renin gene expression in rats. Except in the submandibular gland, the tissue-specific expression of Ren-2 is similar in TGR(mREN2)27 and DBA/2. This demonstrates maintenance of tissue specificity. Organs that are involved in cardiovascular regulation, such as the adrenal gland, kidney, and brain, express the Ren-2 gene before hypertension has developed, consistent with the possibility of a causal relationship between transgene expression in these tissues and hypertension. Because these tissues express the renin gene in nontransgenic rats as well, we suggest that this model can be used to study the regulation of renin gene expression and its role in hypertension at these sites. In addition, as an indication that interactions may exist between blood pressure and renin gene expression, we describe reciprocal changes in blood pressure and Ren-2 mRNA levels in the kidney and brain.
High Km of GLUT-2 glucose transporter does not explain its role in insulin secretion
Authors: Lachaal M. , Spangler R. A. , Jung C. Y.
Published: December 2017

Evidence indicates that the high-Km GLUT-2 function of the islet cells is essential for insulin secretion in response to glucose. To examine possible significance of the high-Km transport function of GLUT-2 in this secretory response, we have studied by computer simulation the effects of high- and low-Km glucose uptake on the steady-state intracellular glucose concentration and glucose phosphorylation in beta-cells. Our computations reveal that both the intracellular glucose concentration and the glucose phosphorylation catalyzed by glucokinase increase significantly as the extracellular glucose concentration increases from 5 to 20 mM, even with a transport Km as low as 1.5 mM, the lowest value known for GLUT-1. Our results indicate that the apparent requirement of GLUT-2 for glucose-sensitive insulin secretion cannot be explained simply by its high-Km transport function alone and suggest that an isoform-specific, direct coupling of GLUT-2 with a certain glycolytic enzyme, such as glucokinase, is essential for the secretory response.
Prefeeding increase in paraventricular NE release is regulated by a feeding-associated rhythm in rats
Authors: Mitome M. , Honma S. , Yoshihara T. , Honma K.
Published: December 2017

Extracellular norepinephrine (NE) in the vicinity of the paraventricular nucleus was continuously measured over 24 h by means of in vivo microdialysis in rats under restricted daily feeding and ad libitum feeding. A 24-h rhythm in plasma corticosterone was monitored in separate rats under identical conditions. Under ad libitum feeding, the paraventricular NE showed a 24-h rhythm with lower levels in the light period and higher levels in the dark period. The temporal pattern was not affected by food deprivation for 3 days. The circadian peak of paraventricular NE lagged slightly behind that of plasma corticosterone under ad libitum feeding. On the other hand, when rats were fed for 2 h at a fixed time of day for 3 wk, the NE rhythm was changed and showed a major peak just before daily meals. To examine the nature of the prefeeding NE peak, a 24-hour variation of paraventricular NE was measured in rats under food deprivation that had been subjected to restricted daily feeding for 3 wk and subsequently to ad libitum feeding for 7 days. The paraventricular NE was high around the time when meal had been supplied under restricted daily feeding and low in the dark period. Similar changes were observed in plasma corticosterone. The findings indicate that the prefeeding increase in the paraventricular NE release is regulated by a feeding-associated circadian rhythm manifest in rats under restricted daily feeding.
Changes in serum triiodothyronine kinetics and hepatic type I 5'-deiodinase activity of cold-exposed swine
Authors: Reed H. L. , Quesada M. , Hesslink R. L. , D'Alesandro M. M. , Hays M. T. , Christopherson R. J. , Turner B. V. , Young B. A.
Published: December 2017

Swine exposed to cold air have elevated serum values of total triiodothyronine (TT3) and free T3 (FT3). To characterize the mechanism of these increases, we measured in vivo kinetic parameters after a bolus intravenous injection of 125I-labeled T3 by use of both multicompartmental (MC) and noncompartmental (NC) methods and in vitro hepatic type I iodothyronine 5'-deiodinase (5'D-I) activity. Ten ad libitum-fed 5-mo-old boars were divided into two groups, living for 25 days in either control (22 degrees C) or cold (4 degrees C) conditions. Cold-exposed animals consumed 50% more calories than control animals but showed no difference in total body weight, percent body fat, or plasma volume. Thyroid gland weight was increased 86% (P < 0.004), as was serum total thyroxine (TT4) (48%), free T4 (FT4) (61%), TT3 (103%), and FT3 (107%), whereas serum thyrotropin (TSH) was not different in cold-exposed compared with control animals. The T3 plasma clearance rate was similar between groups when both MC and NC techniques were used. However, T3 plasma appearance rate (PAR) was elevated in cold-treated animals 110% over controls by MC (P < 0.001) and 83% by NC methods (P < 0.001). The animal total hormone pool of T3 was increased 76% (MC) and 53% (NC) compared with control (P < 0.01). The Michaelis constant of hepatic 5'D-I was not different between groups, but the maximum enzyme velocity increased (106%; P < 0.02). Therefore cold exposure for 25 days is associated with increased energy intake, thyroid size, T3 PAR, and hepatic 5'D-I activity with little change in serum TSH.
Effect of tumor necrosis factor on substrate and amino acid kinetics in conscious dogs
Authors: Sakurai Y. , Zhang X. J. , Wolfe R. R.
Published: December 2017

Two groups of conscious dogs were studied using isotopic tracer techniques to test the hypothesis that tumor necrosis factor (TNF) affects glucose production, lipolysis, amino acid, and protein kinetics. [1-13C]leucine, [15N2]urea, [6,6-2H2]glucose, and [2H5]glycerol were infused to determine the leucine, urea, glucose, and lipid kinetics, and NaH14CO3 was infused to determine the rate of CO2 production. In one group, after a 2-h basal period (period 1), recombinant human TNF was infused (prime, 2.5 micrograms/kg; constant, 62.5 ng.kg-1.min-1) for 2 h (period 2; group 1, n = 15). Group 2 received saline rather than TNF in period 2 (n = 3). TNF infusion caused a significant increase in endogenous glucose production, a significant increase in glucose clearance rate, and a decrease in glycerol flux. Although TNF infusion did not change leucine flux, leucine oxidation increased by 49% (P < 0.0001), and nonoxidative leucine disappearance decreased during TNF infusion by 13% (P < 0.0001). TNF infusion also caused a significant increase (18%) in endogenous urea production. TNF significantly increased plasma glucagon concentration. We conclude that TNF causes a shift toward carbohydrate metabolism and stimulates the oxidation of amino acids. Whereas whole body protein breakdown is not affected by TNF, protein synthesis is impaired, leading to an increase in net protein breakdown.
Effects of flow and contraction on lactate transport in the perfused rat hindlimb
Authors: Watt P. W. , Gladden L. B. , Hundal H. S. , Crawford R. E.
Published: December 2017

A perfused rat hindlimb preparation was used to assess the effects of perfusate flow and electrical stimulation to mimic exercise on the rates of lactate influx (measured by a dual tracer technique with [3H]mannitol as the extracellular marker) and net lactate production. The same perfused muscle system was also used for assessing the effects of alpha-cyano-4-hydroxycinnamate (CIN, 15 mM), phloretin (0.6 mM), and pyruvate on tracer lactate influx. Unidirectional lactate influx, oxygen uptake (VO2), and net lactate flux were all significantly dependent on perfusate flow rate (all P < 0.05). The hindlimb was in net lactate production at all flow rates studied. Electrical stimulation (60 Hz, 100 ms, 20 V trains at 0.6 min-1) at perfusate lactate concentration of 1 mM significantly increased the hindlimb VO2 from 8.0 +/- 1.1 to 16.0 +/- 2.2 ml.kg-1.min-1 and production of lactate from -69 +/- 31 to -823 +/- 77 nmol.min-1.g-1 (both P < 0.001) but did not affect tracer-measured unidirectional lactate influx (nonstimulated: 235.4 +/- 78.1; stimulated: 235.0 +/- 31.0 nmol.min-1.g-1). At a perfusate flow of 0.55 ml.g-1.min-1 the unidirectional influx of 1 mM lactate was markedly inhibited (90 +/- 5%) by 15 mM CIN. CIN also significantly reduced VO2 from 6.2 +/- 0.16 to 4.45 +/- 0.57 ml.kg-1.min-1 (P < 0.05, n = 5). Phloretin (0.6 mM, n = 3) had no significant effect on lactate influx.(ABSTRACT TRUNCATED AT 250 WORDS)
beta-Adrenergic stimulation of skeletal muscle metabolism in relation to weight reduction in obese men
Authors: Blaak E. E. , Van Baak M. A. , Kemerink G. J. , Pakbiers M. T. , Heidendal G. A. , Saris W. H.
Published: December 2017

In a companion study [Blaak, E.E., M.A. van Baak, G.J. Kemerink, M.T.W. Pakbiers, G.A.K. Heidendal, and W.H.M. Saris. Am. J. Physiol. 267 (Endocrinol. Metab. 30): E306-E315, 1994.], we found that during infusion of the nonselective beta-agonist isoprenaline (Iso), obese males had a lowered Iso-induced rise in arterial glycerol and nonesterified fatty acids (NEFA) and a lowered muscle NEFA oxidation. The present study was intended to investigate whether a period of weight reduction would alter this impaired fat utilization in obese males. Before and after a 5-wk diet intervention (very low calorie diet) whole body energy expenditure was determined during rest and during intravenous infusion of increasing doses of Iso. In addition, forearm muscle metabolism was investigated with Iso infusion with and without simultaneous infusion of the beta 1-blocker atenolol (AT) by measuring skeletal muscle blood flow and arteriovenous concentration differences of various metabolites across muscle. The Iso-induced whole body thermogenesis tended to increase as a result of weight loss when this response was related to the plasma Iso concentration (P = 0.09), whereas both before and after diet there were no changes in the respiratory exchange ratio during Iso infusion. The increases in arterial NEFA and glycerol concentrations as a result of Iso infusion were not significantly different before and after weight reduction. In addition, muscle NEFA uptake did not change as a result of Iso or Iso plus AT infusion both before and after diet, whereas muscle glucose uptake and lactate release tended to be more pronounced after weight reduction.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of physiological hyperinsulinemia on counterregulatory response to prolonged hypoglycemia in normal humans
Authors: Davis S. N. , Shavers C. , Collins L. , Cherrington A. D. , Price L. , Hedstrom C.
Published: December 2017

To test the hypothesis that differing physiological insulin levels can modify the counter-regulatory response to prolonged hypoglycemia, experiments were carried out in 10 healthy male subjects. Insulin was infused subcutaneously for 8 h in two separate randomized protocols, so that steady-state levels of 132 +/- 6 pM (low) and 402 +/- 18 pM (high) were obtained. The fall in plasma glucose was controlled by the glucose-clamp technique. Plasma glucose fell slowly and similarly in both groups, reaching an identical steady-state (final 120 min of each study) level of 3.4 +/- 0.1 mM. Steady-state plasma epinephrine (2.5 +/- 0.4 vs. 1.5 +/- 0.2 nM) and norepinephrine (1.5 +/- 0.2 vs. 1.1 +/- 0.1 nM) were significantly (P < 0.05) greater during high- compared with low-dose insulin infusions. Plasma glucagon was reduced during high compared with low infusions (104 +/- 9 vs. 150 +/- 19 ng/l, P < 0.05). Growth hormone, cortisol, and pancreatic polypeptide increased significantly but were not different during the two insulin infusions. Hepatic glucose production (HGP) was equal during the steady-state period (8.4 +/- 1.0 mumol.kg-1.min-1) of each infusion. Blood lactate levels (1,255 +/- 73 vs. 788 +/- 69 mumol/l, P < 0.02) were increased in high compared with low, but nonesterified fatty acid (205 +/- 43 vs. 579 +/- 65 mumol/l) and 3-hydroxybutyrate (40 +/- 36 vs. 159 +/- 51 mumol/l) were reduced (P < 0.002) during the high-compared with low-dose infusions.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of infused fructose on endogenous glucose production, gluconeogenesis, and glycogen metabolism
Authors: Tounian P. , Schneiter P. , Henry S. , Jequier E. , Tappy L.
Published: December 2017

To determine the mechanisms that prevent an increase in gluconeogenesis from increasing hepatic glucose output, six healthy women were infused with [1-13C]fructose (22 mumol.kg-1.min-1), somatostatin, insulin, and glucagon. In control experiment, non-13C-enriched fructose was infused at the same rate without somatostatin, and [U-13C]glucose was infused to measure specifically plasma glucose oxidation. Endogenous glucose production (EGP, [6,6-2H]glucose), net carbohydrate oxidation (CHOox, indirect calorimetry), and fructose oxidation (13CO2) were measured. EGP rate did not increase after fructose infusion with (13.1 +/- 1.2 vs. 12.9 +/- 0.3 mumol.kg-1.min-1) and without (10.3 +/- 0.5 vs. 9.7 +/- 0.5 mumol.kg-1.min-1) somatostatin, despite the fact that gluconeogenesis increased. Nonoxidative fructose disposal, corresponding mainly to glycogen synthesis, was threefold net glycogen deposition, the latter calculated as fructose infusion minus CHOox (14.8 +/- 1.1 and 4.3 +/- 2.0 mumol.kg-1.min-1). It is concluded that 1) the mechanism by which EGP remains constant when gluconeogenesis from fructose increases is independent of changes in insulin and 2) simultaneous breakdown and synthesis of glycogen occurred during fructose infusion.
Pancreatic endocrine responses to substance P and calcitonin gene-related peptide in conscious calves
Authors: Edwards A. V. , Bloom S. R.
Published: December 2017

Both substance P (SP) and calcitonin gene-related peptide (CGRP; 0.13 micrograms.min-1.kg-1 for 10 min) produced a significant rise in arterial plasma pancreatic polypeptide (PP) concentration, and additive responses were obtained when both peptides were infused simultaneously and/or with acetylcholine (0.7 micrograms.min-1.kg-1 ia). The PP response to SP was abolished by intravenous infusions of glucose, whereas those to CGRP and acetylcholine were not significantly affected. Neither SP nor CGRP had any effect on plasma insulin concentration, either in the presence or absence of exogenous glucose, whether infused singly or together, or in the presence of acetylcholine. SP, but not CGRP, produced a small but statistically significant rise in mean plasma glucagon concentration when infused together with acetylcholine. These results suggest that SP and CGRP may modulate the secretion of PP and glucagon in the normal conscious calf but not that of insulin. It is also possible that SP modulates secretion of pancreatic glucagon in these animals.
Central effects of mineralocorticoid antagonist RU-28318 on blood pressure of DOCA-salt hypertensive rats
Authors: Van den Berg D. T. , de Kloet E. R. , de Jong W.
Published: December 2017

The role of brain mineralocorticoid receptor (MR) sites in the pathogenesis of mineralocorticoid hypertension was studied after an intracerebroventricular injection of the MR antagonist RU-28318. Male Wistar rats received subcutaneously implanted deoxycorticosterone acetate (DOCA) pellets and were maintained on 0.9% saline as drinking solution. Under these conditions hypertension developed in approximately 5 wk as assessed in conscious rats by means of the tail-cuff technique. During the development of this hypertension (after 3 wk of DOCA-salt treatment) a single intracerebroventricular injection of the specific MR antagonist RU-28318 reduced systolic blood pressure (SBP) as measured with the tail-cuff method. A decrease in SBP was observed 2–24 h after this intracerebroventricular injection, with the lowest SBP values occurring at 8 h. In these animals (3 wk after DOCA implantation) continuous direct blood pressure recording via chronic cannulation revealed, on the day of the intracerebroventricular injection of RU-28318, a slight increase in arterial pressure during the light phase, followed by a decrease during the dark phase. In the established hypertensive rats (5 wk after DOCA RU-28318 on the arterial pressure or heart rate was detectable. It is concluded that central MR blockade during the development of the DOCA-salt hypertension reduces blood pressure within 24 h assessed with 1) the indirect method at certain time points after exposure to warming and stress and 2) the direct method during the dark phase of the diurnal cycle.
Measurement of secretogranin II release from individual adenohypophysial gonadotropes
Authors: Wei N. , Kakar S. S. , Neill J. D.
Published: December 2017

Secretogranin II (SG-II) is an acidic 86-kDa protein found in high abundance in the anterior pituitary gland. In the present studies, we investigated the secretion and the localization of SG-II using pituitary cells from female rats at all stages of the estrous cycle. Double immunofluorescence staining revealed that SG-II immunoreactivity was localized in low abundance in about half of all pituitary cells and in high abundance in all of the luteinizing hormone (LH)-immunoreactive cells (which represent approximately 5% of all pituitary cells). Using a reverse hemolytic plaque assay for measurement of SG-II release from individual pituitary cells in culture, we found that SG-II secretion was strongly stimulated by gonadotropin-releasing hormone in a dose-related fashion, and the amount of SG-II secretion was also related to the stage of the estrous cycle: it was highest at proestrus and lowest at estrus. SG-II plaque assay followed by LH immunofluorescence staining further revealed that all the SG-II-secreting cells contained LH immunoreactivity. At proestrus all the LH-immunoreactive cells secreted SG-II, whereas another days of the estrous cycle only a fraction of them did so. Thus our findings demonstrate a striking resemblance between SG-II and LH with regard to cell localization and secretory regulation.
Plasma arginine, citrulline, and ornithine kinetics in adults, with observations on nitric oxide synthesis
Authors: Castillo L. , Sanchez M. , Vogt J. , Chapman T. E. , DeRojas-Walker T. C. , Tannenbaum S. R. , Ajami A. M. , Young V. R.
Published: December 2017

The plasma fluxes of ornithine (Orn), arginine (Arg), and citrulline (Cit) and rate of conversion of labeled ornithine-to-citrulline (QOrn-->Cit) were estimated in six healthy adult men receiving an arginine-rich or arginine-free L-amino acid-based diet, each for 6 days. On day 7 an 8-h (3-h fast, 5-h fed) primed continuous intravenous infusion of L-[guanido-15N,15N] arginine, L-[ureido-13C]citrulline, L-[5,5,2H2]ornithine, and L-[5,5,5-2H3]leucine was conducted. Mean citrulline fluxes (mumol.kg-1.h-1) were 10.4-13.6 for the various conditions and/or diets and remained unchanged (P > 0.05). Arginine flux was lowered (P < 0.01) by 38% for fed state during arginine-free period. Ornithine fluxes for arginine-rich were (P < 0.01) reduced with the arginine-free diet. Rates of QOrn-->Cit declined by 30% (P < .05) during the fed arginine-free period. Short-term restriction in the dietary supply of arginine did not alter the rate of whole body nitric oxide synthesis. One subject showed a very high output of nitrate on arginine-free diet (6 times average for remaining subjects).
Cation channel mechanisms in ET-3-induced vasopressin secretion by rat hypothalamo-neurohypophysial explants
Authors: Rossi N. F.
Published: December 2017

Endothelins modulate not only vasoregulation but also neurotransmission and hormone secretion, specifically vasopressin (AVP) secretion. The present studies were designed to ascertain the site of action and the participation of membrane cation channels mediating endothelin-3-induced AVP release. Experiments were performed using standard and compartmentalized hypothalamo-neurohypophysial explants. The stimulatory action of endothelin-3 on AVP release occurred at the neural lobe, consistent with the failure of sodium channel blockade to decrease AVP secretion. Calcium channel antagonism or chelation of extracellular calcium inhibited neurohormone release, but blockade of calcium mobilization from intracellular stores with 8-(diethyl-amino)octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8) did not. Inhibition of the calcium-activated potassium channel with charybdotoxin increased AVP levels dose dependently. Potassium ionophore abolished this response, as did TMB-8, but inhibition of calcium entry failed to do so. A subthreshold dose of charybdotoxin potentiated AVP secretion to submaximal stimulation with endothelin-3 that was prevented only by concomitant blockade of calcium influx and intracellular mobilization. The data support interaction between calcium and potassium channels at the secretory terminal. Collectively, these data are consistent with endothelin-3 receptor activation at the secretory terminal initiating calcium entry, thereby leading to depolarization independent of sodium conductances. This mechanism is opposed by hyperpolarizing forces linked to calcium accumulation, namely, the charybdotoxin-sensitive calcium-activate potassium channel. Interaction of the depolarizing and repolarizing systems enables grade AVP secretion from the neural lobe. These findings do not preclude the participation of other systems as well.
Direct cardiac effects of vasopressin: role of V1- and V2-vasopressinergic receptors
Authors: Walker B. R. , Childs M. E. , Adams E. M.
Published: December 2017

Experiments were performed to determine the possible direct effects of arginine vasopressin (AVP) on cardiac function in the nonworking Langendorff preparation. Hearts were isolated from male Wistar rats, and the coronary arteries were retrograde perfused at a constant rate through the aorta with a Krebs-Henseleit solution, which was continuously bubbled with 95% O2–5% CO2. The hearts were paced at 280 beats/min and measurements made of peak ventricular pressure (PVP), first derivative of left ventricular pressure (dP/dtmax), and coronary perfusion pressure (CPP). By maintaining constant coronary flow, the direct cardiac effects of AVP could be determined independent of changes in myocardial O2 delivery elicited by potential coronary vasoconstriction. Myocardial function was assessed at AVP concentrations of 0, 10, 25, 50, 100, 200, 400, and 500 pg/ml. Progressive coronary vasoconstriction was observed with increasing AVP concentration. In contrast, PVP and dP/dtmax increased at 50 and 100 pg/ml of AVP but fell at 400 and 500 pg/ml. The maximal PVP and dP/dtmax responses were at 50 pg/ml (+16 +/- 3 and +44 +/- 4%, respectively), whereas at 500 pg/ml both PVP and dP/dtmax were reduced below control (-30 +/- 4 and -34 +/- 5%, respectively). Pretreatment with the specific V1-vasopressinergic antagonist d(CH2)5Tyr(Me)AVP (40 ng/ml) totally blocked both the coronary vasoconstrictor and contractility responses to AVP. Furthermore, infusion of a specific V2-agonist was without effect even at high doses. These data suggest that although AVP causes dose-related coronary vasoconstriction over a wide range of AVP concentrations, the hormone may exert a positive inotropic effect at doses mimicking circulating levels encountered in a number of pathophysiological situations.(ABSTRACT TRUNCATED AT 250 WORDS)
Kinins induce abnormal vascular reactivity
Authors: Ellis E. F. , Holt S. A. , Wei E. P. , Kontos H. A.
Published: December 2017

Previous studies have shown that after experimental neural trauma or acute hypertension the brain produces superoxide anion radicals, and brain arterioles display endothelial lesions, dilation, and loss of normal reactivity in response to a decrease in CO2 tension. Because these abnormalities are prevented by pretreatment with free radical scavengers or inhibitors of the cyclooxygenase component of prostaglandin (PG) H synthase, arachidonic acid metabolism by PGH synthase with concomitant formation of tissue injuring oxygen radicals causes the vascular damage. The purpose of the present experiments was to determine whether kinins, which are known to stimulate arachidonate metabolism and to induce cerebral arteriolar dilation via production of superoxide anion, may be involved in initiating the cerebrovascular abnormalities produced by neural trauma in cats. The diameter and reactivity of untreated in vivo pial arterioles on one cerebral cortex was compared with the diameter and reactivity of pial arterioles on the contralateral cortex, which were pretreated topically with a competitive receptor antagonist, which is specific for kinins. Before fluid percussion neural trauma was induced, arterioles on both cerebral hemispheres constricted normally to a decrease in CO2 tension. After injury, the arterioles on the untreated cortex dilated and did not constrict in response to a decrease in arterial CO2 tension, whereas the arterioles pretreated with the kinin antagonist dilated less and displayed normal reactivity to CO2. These experiments demonstrate that a specific kinin receptor stimulates PGH synthase-dependent, free radical-mediated cerebrovascular injury. Given the ubiquitous distribution of the kallikrein-kinin system, we propose that kinins may be an important common mediator of systemic vascular injury and abnormal vascular reactivity.
Responses to coronary artery occlusion in conscious dogs with selective cardiac denervation
Authors: Shen Y. T. , Knight D. R. , Vatner S. F. , Randall W. C. , Thomas J. X.
Published: December 2017

The extent to which cardiac denervation alters responses to myocardial ischemia remains controversial. This study compared responses to 24-h coronary artery occlusion (CAO) on measurements of wall thickness (ultrasonic crystals), regional myocardial blood flow (microspheres), and infarct size (triphenyltetrazolium chloride technique) in three groups of conscious dogs with 1) selective posterior left ventricular (LV) wall denervation, 2) selective ventricular denervation, or in 3) intact dogs. After CAO, hemodynamic changes were not different among the three groups. Wall thickening in the ischemic zone became akinetic or paradoxical early after CAO and did not recover in any group over the 24-h monitoring period. Blood flow in the area at risk fell similarly in all groups. Infarct size, as a percentage of the area at risk, was 45 +/- 7% in intact, 48 +/- 6% in posterior LV wall-denervated, and 48 +/- 8% in ventricular-denervated group. There was, however, a lower (P less than 0.05) frequency of arrhythmic beats per minute after 3 h of CAO in the ventricular-denervated group (3.2 +/- 1.4) compared with the intact (11.3 +/- 4.1) or posterior wall-denervated (12.6 +/- 3.2) group. An additional group of ventricular-denervated dogs was studied to determine the effects of sequential, brief 2-min CAO at 2, 4, and 8 wk after denervation. Responses of regional wall thickening to CAO were not affected significantly even after 8 wk following ventricular denervation. Thus, in conscious dogs, neither selective ventricular denervation nor selective denervation of the posterior LV wall improved collateral blood flow, affected regional function favorably, or reduced infarct size after CAO.
Estimation of intramyocardial pressure and coronary blood flow distribution
Authors: Sun Y. , Gewirtz H.
Published: December 2017

To characterize the intramyocardial pressure (IMP) and coronary blood flow distribution in a stenosed coronary circulation, we compared four analog circuits for modeling coronary impedance. The resistor (R)-diode (D) model simulates vascular collapse, and the capacitor (C) simulates compliance effect. Identification of the best model and magnitudes of the endocardial and epicardial IMPs (IMPendo and IMPepi) was done retrospectively using data from studies in 28 anesthetized swine. Performance evaluation was based on comparison of model predicted vs. observed coronary distal pressure (DP) waveforms and endocardial-to-epicardial (endo-epi) flow ratios as determined by radiolabeled microspheres. The R-D-C model gave the best performance at IMPendo = 1.1 times left ventricular pressure (LVP), and IMPepi = 0.1.LVP + 15 mmHg; with good fit to DP (r = 0.98, slope of regression line = 1.0) and estimates of endo-epi flow ratio (r = 0.78, slope = 1.01, P less than 0.02, SEE = 0.21, n = 139). The R-D model gave comparable results even though capacitance was omitted. Although R-C and R models predicted distal coronary pressure well, they failed to predict endo-epi flow ratios (r less than 0.50). The R-D-C and R-D models were applied in seven prospective studies. Both models generated reasonable estimates of endo-epi flow distribution (r = 0.78, n = 50). Thus the R-D-C or R-D models of the stenosed coronary circulation can be used to provide reliable estimates of transmural blood flow distribution.
Free radicals inhibit endothelium-dependent dilation in the coronary resistance bed
Authors: Stewart D. J. , Pohl U. , Bassenge E.
Published: December 2017

Oxygen free radicals contribute significantly to ischemia-reperfusion myocardial damage in vivo. We studied the effect of reactive products of O2 generated by electrolysis of the saline perfusate on coronary vasomotor tone and endothelium-mediated vasodilator responsiveness in 41 isolated rabbit hearts. Under constant flow conditions, electrolysis induced a progressive increase in perfusion pressure associated with a modest reduction in myocardial contractile function. The responses to the endothelium-independent vasodilators papaverine and adenosine tended to be increased by 1.5- to 2-fold, indicating that the increase in perfusion pressure was due, at least in part, to increased resistance vessel tone. However, resistance vessel dilations to the endothelium-dependent agents acetylcholine and serotonin were markedly reduced. Various degrees of protection against increases in perfusion pressure and inhibition of endothelium-dependent dilation during electrolysis were obtained with catalase, a scavenger of hydrogen peroxide; superoxide dismutase, a scavenger of superoxide; and desferrioxamine, which chelates iron and thereby inhibits hydroxyl radical production. Furthermore the action of nitroprusside, a direct-acting stimulator of soluble guanylate cyclase, was not diminished during the electrolytic treatment. We conclude that inhibition of endothelium-dependent dilation is a prominent action of reactive products of O2 in the coronary resistance bed. In combination with a free radical-induced increase in resistance vessel tone this might limit recovery of myocardial perfusion post ischemia.
Effects of 10- to 12-day treatment with L-thyroxine in rats with myocardial infarction
Authors: Gay R. G. , Graham S. , Aguirre M. , Goldman S. , Morkin E.
Published: December 2017

The effects of treatment with L-thyroxine (T4) for 10-12 days on left ventricular (LV) function and myosin isoenzyme content in rats with LV dysfunction after myocardial infarction were studied. Electrocardiogram (ECG) criteria were used to select animals with large myocardial infarctions. These animals were divided into six groups: control and five treatment groups that received daily subcutaneous injections of T4 (1.5, 3, 6, 10, or 15 micrograms/100 g body wt) for 10-12 days. Intravascular pressures were then measured with micromanometer-tipped catheters, and the hearts were analyzed for myosin isoenzyme distribution. The lowest dose of T4 (1.5 micrograms) produced no changes in heart rate, LV pressure or aortic pressure (AoP), myosin isoenzyme composition, or serum T4 levels. Larger doses of T4 (3, 6, 10, and 15 micrograms) produced increases in LV rate of pressure development (dP/dt), heart rate, and T4 levels but did not change LV pressure or AoP. Myosin isoenzyme composition in the control group showed increases in the proportion of the V3 form and decreases in the V1 form compared with the normal pattern. T4 administration produced dose-dependent increases in the V1 myosin isoform and corresponding decreases in the amount of the V2 and V3 forms. Heart rate increases observed with larger doses of T4 could be prevented by addition of propranolol (500 mg/l) to the drinking water. However, in rats treated with T4 and propranolol, LV pressure, AoP, LV dP/dt, and myosin isoenzyme composition were unchanged compared with T4-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)