bluuebunny/crossref_metadata_2025 huggingface dataset:
Central effects of endothelin-1 on vasopressin release, blood pressure, and renal solute excretion
Authors: Yamamoto T. , Kimura T. , Ota K. , Shoji M. , Inoue M. , Sato K. , Ohta M. , Yoshinaga K.
Published: December 2017

To assess central effects of endothelin-1 (ET-1) on plasma arginine vasopressin (AVP), plasma atrial natriuretic peptide (ANP), blood pressure, heart rate, and renal solute excretion, ET-1 dissolved in the artificial cerebrospinal fluid was infused intracerebroventricularly (icv) at a dose of either 0.35 ng.kg-1.min-1 (0.14 pmol; LET) or 3.5 ng.kg-1.min-1 (1.4 pmol; HET) for 45 min in conscious rats. In the control study, ET-1 was omitted from the vehicle. Moreover, [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),2-O-methyl-tyrosine]AVP (TMeAVP), a V1-blocker, and prazosin, an alpha 1-blocker, were peripherally administered. In the LET group, mean arterial blood pressure (MABP) increased without any changes in heart rate, plasma AVP and ANP, and renal solute excretion. In the HET group, MABP markedly increased with rises in plasma AVP and ANP, but urine flow, urinary osmolality, and urinary Na and K excretion decreased. TMeAVP attenuated the pressor response to ET-1, abolished rises in plasma ANP, and partially restored falls in urine flow. Prazosin after TMeAVP obviated the pressor response to ET-1. In the control, these parameters did not change, except for an increase in urinary solute excretion. These results showed that icv ET-1 stimulates the sympathetic nervous activity and plasma AVP, leading to increased blood pressure and renal vasoconstriction, with a reduction in renal water and electrolyte excretion.
Studies of adrenal steroidogenic enzymes in guinea pigs
Authors: Provencher P. H. , Tremblay Y. , Belanger B. , Belanger A.
Published: December 2017

In the present study we found that 3 beta-hydroxysteroid dehydrogenase 4-ene-5-ene-isomerase (3 beta-HSD), 17-hydroxylase and 17,20-lyase (P-450c17), and 21-hydroxylase (P-450c21) activities in a suspension of cells from guinea pig zona reticularis (RE) were 10- to 15-fold less than those measured in cells from zona fasciculata-glomerulosa (FG). Whereas the secretion of cortisol and C-19 steroids was remarkably increased during treatment of FG cells with adrenocorticotropic hormone (ACTH), no response could be detected when using cells from zona RE. By contrast, the measurement of a series of C-21 and C-19 steroids shows that the concentrations of several steroids were greater in the zona RE than in the zona FG. In addition, using Northern blot analysis, we have observed that the basal steady-state levels of mRNA for cholesterol side-chain cleavage (P-450scc), 3 beta-HSD, P-450c21, P-450c17, and P-450c11 were in the same range in the two zones and an administration of ACTH caused, in both zona FG and zona RE, a two- to threefold decrease in P-450c17 and P-450c21 steady-state mRNA levels, whereas P-450c11, 3 beta-HSD, and P-450scc steady-state mRNA levels remained unchanged. Our data suggest the presence of some factor(s) capable of rapidly deactivating the steroidogenic enzymes in the zona RE.
Physiological effects of 1,25-dihydroxyvitamin D3 in TM4 Sertoli cell line
Authors: Akerstrom V. L. , Walters M. R.
Published: December 2017

1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] receptors have been previously described in Sertoli cells. This study was performed to assess biological activity of the receptor in the mouse Sertoli cell line TM4. A 2-h preincubation with 0.01-25 nM 1,25(OH)2D3 resulted in a dose-dependent rapid uptake of 45Ca2+ within 5 min of addition of the isotope to the cells (27 +/- 8%, n = 4 experiments; P less than 0.05). This response was specific for 1,25(OH)2D3, in that it was not induced by 25-hydroxyvitamin D3, estradiol, cortisol, R 5020 (promegestone), or testosterone. However, a combination of testosterone and 1,25(OH)2D3 inhibited uptake by 23 +/- 8% (n = 3 experiments, P less than 0.01). That the mechanism responsible for 1,25(OH)2D3-stimulated uptake may involve 1,25(OH)2D3 receptor interaction is supported by the observation that cycloheximide inhibited the response. Conversely, there was no detectable change in uptake by 1,25(OH)2D3-treated cells after 24-h incubation with 0.1-5 nM 1,25(OH)2D3. Increased levels of DNA and protein content also resulted from a 2-h incubation with the steroid and were sustained up to 24 h without a concomitant increase in cell number or a detectable change in cell morphology. The presence of specific 1,25(OH)2D3 receptor-like binding sites was demonstrated by sucrose gradient analysis and hydroxylapatite assay. These data demonstrate that 1,25(OH)2D3 may play an important role in testicular function through regulation of receptor-mediated events.
Hepatic metabolism during fasting-refeeding transition in conscious pregnant rabbits
Authors: Pere M. C. , Baudelin A. , Briggs K. , Gilbert M.
Published: December 2017

The aim of the present study was to determine changes induced by pregnancy in the hepatic handling of nutrients during the fasting-refeeding transition. Net hepatic and gut substrate fluxes were determined by the Fick principle in conscious pregnant (day 30) and nonpregnant rabbits in the 2 h after consumption of a mixed meal. Hepatic glucose production was suppressed by approximately 50% in both groups from 15 to 90 min. Pregnant rabbits returned to control levels at 120 min. Pregnant females displayed a larger gut glucose output and a greater arterial hyperglycemia. The hepatic and gut balance of lactate as well as the arterial level was almost unchanged. In pregnant females the hepatic uptake and arterial concentration of free fatty acids (FFA) remained almost unchanged, whereas these measures decreased in nonpregnant females by approximately 55 and approximately 80%, respectively, at 120 min. The decline in hepatic output of beta-hydroxybutyrate was similar in both groups. In pregnant rabbits arterial levels of beta-hydroxybutyrate did not parallel changes in the hepatic release as in nonpregnant females. Pregnant females displayed a greater hyperinsulinemia both in the portal vein and the artery over the first hour. It is concluded that, in pregnant rabbits fed a mixed meal, the ability of the liver to handle glucose is impaired because of insulin resistance. The latter brings about a greater and prolonged arterial hyperglycemia, which is reinforced by peripheral insulin resistance. Furthermore, the higher level of FFA may also contribute to the hyperglycemia. As a result, a greater amount of glucose is diverted to other sites, presumably the uterus.
Control of fructose 2,6-diphosphate in muscle of exercising fasted rats
Authors: Winder W. W. , Duan C.
Published: December 2017

This study examined the role of epinephrine in controlling intramuscular signals that may accelerate lactate production in less active muscles during exercise. Sham-operated (sham) or adrenodemedullated (ADM) rats were fasted 24 h and then were killed at rest or after running for 15 or 30 min on a treadmill (21 m/min, 15% grade). One-half of the ADM rats were infused with epinephrine (6 micrograms/h) intravenously (jugular catheter) during exercise. ADM rats exhibited lower blood glucose, blood lactate, white quadriceps muscle content of lactate, glucose 6-phosphate, fructose 6-phosphate, and adenosine 3',5'-cyclic monophosphate (cAMP) during exercise than did sham rats or epinephrine-infused ADM rats. The white quadriceps muscle contents of fructose 2,6-diphosphate (F-2,6-P2) and glucose 1,6-diphosphate (G-1,6-P2) (allosteric activators of glycolysis) were at least two times as high in sham rats and in epinephrine-infused rats as in ADM rats during exercise. We conclude that the exercise-induced rise in epinephrine is responsible for the acceleration of glycolysis in less active muscle during exercise. This effect is likely mediated by epinephrine-induced increases in cAMP, F-2,6-P2, and G-1,6-P2.
NMR-invisible ATP in heart: fact or fiction?
Authors: Bak M. I. , Ingwall J. S.
Published: December 2017

31P-nuclear magnetic resonance (31P-NMR) spectroscopy is widely used to monitor sequential changes in the nucleoside triphosphate (NTP) pool in intact tissues. Recently, the validity of this technique to quantitate incremental changes in ATP in heart has been challenged. Accordingly, we compared NTP measured by 31P-NMR and by chemical techniques in isolated isovolumic rat hearts at 16 and 56 min of oxygenated perfusion and in hearts subjected to 28 min of hypoxia, with or without 28 min of reoxygenation, and 12 or 28 min of ischemia, with or without 28 min of reperfusion. NTP content was calculated from 31P-NMR spectra using an external standard. At the end of each protocol the heart was freeze-clamped, and NTP and ATP contents were determined by chemical assay. After 16 min of normoxic perfusion the values for NTP and ATP contents measured by both methods in the same hearts were indistinguishable. Results from all seven experimental conditions show no significant difference between methods (P = 0.262). Thus both methods detect the same incremental change in NTP and ATP.
Decreased T4-to-T3 conversion in brown adipose tissue of Zucker fa/fa pups before the onset of obesity
Authors: Marie V. , Dupuy F. , Bazin R.
Published: December 2017

To determine whether the capacity of thyroxine (T4)-to-3,5,3'-triiodothyronine (T3) conversion was altered in Zucker fa/fa pups, we measured thyroxine 5'-monodeiodinase (T(4)5'D) activity in brown adipose tissue (BAT) and liver of suckling and weaned fa/fa and Fa/fa littermates. In suckling fa/fa compared with Fa/fa rats, T(4)5'D was reduced by 30-55% in BAT and slightly increased in liver, while serum free T3 was significantly decreased (-30%). Altered T(4)5'D activity in BAT of fa/fa pups could be corrected by adrenergic stimulation. After weaning, in fa/fa rats, the capacity for T4-to-T3 conversion was totally restored in BAT while it was dramatically reduced in liver. The concentration of serum free T3 remained lower in fa/fa than in Fa/fa rats (-40%). These data confirm that BAT is a very early site of fa gene expression and are consistent with the hypothesis that a defect in the autonomic nervous system may be a primary cause of this genetic obesity. It is also suggested that, during suckling, BAT plays an important role in systemic production of T3.
Role of GH in regulating nocturnal rates of lipolysis and plasma mevalonate levels in normal and diabetic humans
Authors: Boyle P. J. , Avogaro A. , Smith L. , Bier D. M. , Pappu A. S. , Illingworth D. R. , Cryer P. E.
Published: December 2017

To define the role that nocturnal increments in growth hormone (GH) play in maintaining lipolysis, glycerol turnover was measured in six patients with GH deficiency and six normal subjects during sleep. Glycerol production initially decreased in both groups but then increased to 1.44 +/- 0.20 mumol.kg-1.min-1 by 0800 h in normal subjects, whereas GH deficiency was associated with a continuous fall to 0.77 +/- 0.10 mumol.kg-1.min-1, P less than 0.02. Nonesterified fatty acid levels paralleled these changes. Six GH-deficient patients received basal GH replacement including a pulse during sleep, which resulted in normal fasting fatty acid levels (P less than 0.05, replaced vs. chronic deficiency). To assess a possible link between the normal nocturnal increase in plasma mevalonate (the product of the rate-limiting step in cholesterol synthesis) and sleep-associated GH release, 11 GH-deficient patients and 11 normal subjects were studied. Peak nocturnal and fasting mevalonate concentrations were not correlated with GH level. We conclude that nocturnal growth hormone secretion is essential for maintaining lipolysis but that it is not related to normal increments in mevalonate and, by inference, to cholesterol synthesis during sleep
Plasma leucine kinetics and urinary nitrogen excretion in intensively treated diabetes mellitus
Authors: Lariviere F. , Kupranycz D. B. , Chiasson J. L. , Hoffer L. J.
Published: December 2017

It is well known that inadequate insulin therapy stimulates body protein loss in insulin-dependent diabetes mellitus (IDDM). It is less well known, however, that accelerated body protein loss (as indicated by increased leucine oxidation) occurs in IDDM even during conventional glycemic control. It is not known whether intensified insulin therapy fully normalizes protein oxidation or, more importantly, whether such therapy is sufficient to allow the adaptive decrease of protein oxidation that normally occurs when protein intake is restricted below the customary surfeit level. We used two measures of protein oxidation [daily urinary nitrogen (N) excretion over several days of intensive insulin therapy and plasma [1-13C]leucine oxidation during short-term strict euglycemia] to assess the response of 7 men with IDDM and 12 normal men after adaptation first to a control diet providing maintenance energy and conventional (surfeit) protein then to an isoenergetic protein-free diet. After adaptation to the protein-free diet and during short-term strict euglycemia achieved using intravenous insulin, leucine turnover and oxidation decreased equivalently in normal and diabetic subjects. However, daily urinary obligatory N excretion, which indicated the effect of the low-protein diet and intensive subcutaneous insulin therapy over several days, was increased by 18% in the diabetic group (P less than 0.05). Even mildly elevated average blood glucose values well within the guidelines for intensive therapy were strongly correlated with high rates of urinary N excretion (r = 0.97, P = 0.0002). Thus insulin therapy of IDDM that imposes strict euglycemia is compatible with a normal ability to diminish body protein oxidation in response to protein restriction.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of epinephrine on insulin-mediated glucose uptake in whole body and leg muscle in humans: role of blood flow
Authors: Laakso M. , Edelman S. V. , Brechtel G. , Baron A. D.
Published: December 2017

In vivo insulin-mediated glucose uptake (IMGU) occurs chiefly in skeletal muscle, where it is determined by the product of arteriovenous glucose difference (delta AVG) and blood flow (BF) rate into muscle. Epinephrine (Epi) reduces the rate of IMGU in whole body. To examine whether this is due to a reduction in delta AVG across or BF into skeletal muscle we constructed insulin dose-response curves for whole body IMGU and leg muscle IMGU- using euglycemic clamp ((+)[3-3H]glucose infusion) and leg balance techniques during insulin infusions ranging from 10 to 1,200 mU.m-2.min-1. We studied six subjects [wt 70 +/- 2 (SE) kg] during an Epi infusion at a single rate of 0.002 mg.kg-1.min-1 and six subjects (70 +/- 3 kg) during a saline infusion alone. Maximum whole body glucose uptake (WBGU) was similar during Epi and saline infusions [71.4 vs. 73.6 mmol.kg-1.min-1, P = not significant (NS)]. Compared with saline, maximum delta AVG was decreased during Epi infusion (1.04 vs. 1.31 mM, P less than 0.01). Compared with saline alone maximum leg BF was increased (5.3 vs. 4.3 dl/min, P less than 0.01) during Epi infusion. Thus maximum leg glucose uptake (LGU) was similar (696 vs. 821 pmol.leg-1.min-1, P = NS) during infusion of Epi and saline, respectively. Half-maximal effective dose for insulin's effect to stimulate WBGU, delta AVG, BF, and LGU was increased two- to threefold during Epi vs. saline infusions (P less than 0.01 for all values).(ABSTRACT TRUNCATED AT 250 WORDS)
Trophic action of local intraileal infusion of insulin-like growth factor I: polyamine dependence
Authors: Olanrewaju H. , Patel L. , Seidel E. R.
Published: December 2017

Experiments were performed to determine potential growth-promoting effects of human recombinant insulin-like growth factor I (hrIGF-I) in the gastrointestinal tract. IGF-I and IGF-II, but not insulin, were potent (half-maximal effective concentration 0.3 nM) and efficacious inducers of the growth-related enzyme ornithine decarboxylase (ODC) in the gut-derived cell line IEC-6. Maximal ODC induction was observed after treatment of cells with 10 nM IGF-I. In whole animal experiments, bolus intraileal injection of 10 nM hrIGF-I in anesthetized rats induced a 300% increase in ileal mucosal ODC activity, which was sensitive to inhibition with difluoromethylornithine (DFMO). Rats were implanted intraperitoneally with osmotic minipumps filled with 0.9% NaCl or 10 nM IGF-I that was delivered to the ileal lumen by a short Silastic catheter. Sixty-six hours of 1 microliter/h intraluminal IGF-I infusion produced an approximate doubling of mucosal wet weight (NaCl 50 mg vs. IGF-I 102 micrograms/2 cm mucosa) and total mucosal RNA, DNA, and protein content over that in rats that were infused with NaCl. Intraperitoneal treatment with 200 mg/kg DFMO three times per day had little effect on ileal mucosal mass, but completely inhibited the trophic response to IGF-I infusion. IGF-I infusion had no effect on body weight.
Is there a role for the adrenals in the development of hypercholesterolemia in Zucker fatty rats?
Authors: Alarrayed F. , Hartman A. D. , Porter J. R.
Published: December 2017

We tested the hypothesis that hypercorticosteronemia causes the hypercholesterolemia in young developing "fatty" rats. Obesity induced increases in corticosterone. Insulin, glucose, body weight, average daily food intake, plasma triglyceride, plasma phospholipids, liver weight, liver triglyceride, various adipose tissue parameters, and liver hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase activity were all ameliorated by adrenalectomy. Adrenalectomy exacerbated the hypercholesterolemia in obese animals and induced it in lean rats. Changes or lack of change in hepatic microsomal cholesterol, HMG-CoA reductase, and 7 alpha-hydroxylase, combined with the adrenalectomy-induced curtailment of tissue storage of cholesterol in adipose tissue, all contribute to the hypercholesterolemia caused by adrenalectomy. We suggest a mechanism whereby this may be related to elevated hepatic very low-density lipoprotein secretion rates. The elevated HMG-CoA reductase activity in obese rats results from the lower liver microsomal free cholesterol content. We conclude that the absence of glucocorticoids does not directly reduce plasma cholesterol in obese Zucker rats. The surprising elevation of cholesterol by adrenalectomy is due to other prevailing mechanisms in liver and adipose tissue, which curtail their capacity to store cholesterol.
Stimulation of angiotensinogen mRNA levels in rat pituitary by estradiol
Authors: Healy D. P. , Ye M. Q. , Yuan L. X. , Schachter B. S.
Published: December 2017

Angiotensin II (ANG II) is a putative paracrine hormone in the anterior pituitary. Angiotensinogen mRNA, however, is not detectable by Northern blot hybridization, suggesting that ANG II may not be synthesized within the pituitary. An alternative explanation may be that angiotensinogen gene activity is low under normal conditions, with angiotensinogen mRNA being below the level of detection. Utilizing a sensitive solution hybridization method, we sought to determine whether angiotensinogen mRNA could be detected in pituitaries from normal male rats or ovariectomized (OVX) rats treated with estradiol (E2) for 4 days. Very low levels of angiotensinogen mRNA were detected from male or OVX rat pituitaries, but E2 treatment resulted in a marked dose-dependent increase in pituitary angiotensinogen mRNA levels. Levels of angiotensinogen within the pituitary were not significantly different after the E2 treatment. Angiotensinogen mRNA levels in liver and brain were much higher than in the pituitary but were not altered significantly by the chronic E2 treatment. These results are consistent with the local synthesis of angiotensinogen in the pituitary and further suggest that pituitary angiotensinogen gene transcription is regulated by estrogen.
Apolipoprotein expression and cellular differentiation in Caco-2 intestinal cells
Authors: Wagner R. D. , Krul E. S. , Moberly J. B. , Alpers D. H. , Schonfeld G.
Published: December 2017

Caco-2 cells, cultured for 18 days on porous filter supports and conventional plastic culture dishes, were used to study the effects of cellular differentiation on the expression of apolipoprotein (apo) genes. Media of filter-grown cells accumulated more apo B as apo B-48 and contained three times the amount of edited apo B mRNA compared with plastic-grown cells. The accumulation of apo A-I by media of plastic-grown cells was higher than accumulation by filter-grown cells, despite similar concentrations of apo A-I mRNA. The apo A-IV was detectable in the culture media earlier with filter-grown cells compared with plastic-grown cells, despite similar apo A-IV mRNA concentrations. Plastic-grown cells contained more apo E mRNA, and their media accumulated more apo E than filter-grown cells. With the exception of apo A-I, apo gene expression changed with Caco-2 cell differentiation to resemble more closely the patterns seen in adult enterocytes. There were no effects or minimal effects of added retinoic acid, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], or thyroid hormone on apo accumulation in media of filter-grown cultures of Caco-2 cells. However, 1,25(OH)2D3 and thyroid hormone increased apo B, apo A-IV, and apo A-I mRNA concentrations, retinoic acid increased apo B mRNA concentrations alone, and all three reduced apo E mRNA concentrations. Ratios of edited to unedited apo B mRNA were unaffected. In conclusion, culture substratum importantly influences Caco-2 cell differentiation. Soluble factors that influence cellular differentiation may affect apo gene expression over and above effects mediated by the culture substratum.(ABSTRACT TRUNCATED AT 250 WORDS)
Endocrine effects of new bombesin/gastrin-releasing peptide antagonists in rats
Authors: Pinski J. , Yano T. , Groot K. , Cai R. Z. , Radulovic S. , Schally A. V.
Published: December 2017

Four new and specific pseudononapeptide bombesin/gastrin-releasing peptide (GRP) receptor antagonists, containing the D-forms of Trp or Trp analogue (Tpi) at position 6, were studied for their effects on the endocrine pancreas and GRP-(14-27)-induced gastrin release in pentobarbital-anesthetized rats. One of the analogues, D-Tpi6,Leu13-psi (CH2NH)Leu14-bombesin-(6-14) (RC-3095), was injected into the lateral brain ventricle just preceding intracerebroventricular administration of GRP-(14-27) to evaluate its antagonistic effect on GRP-induced serum growth hormone (GH) suppression. Analogues RC-3095, D-Trp6,Leu13-psi (CH2NH)Leu14-bombesin-(6-14) (RC-3125), and D-Trp6,Leu13-psi (CH2NH)Phe14-bombesin-(6-14) (RC-3420), but not D-Tpi6,Leu13-psi (CH2NH)Phe14-bombesin-(6-14) (RC-3105), significantly (P < 0.01) inhibited GRP-(14-27)-stimulated serum gastrin secretion. Analogues RC-3095, RC-3420, and RC-3105, but not RC-3125, demonstrated significant (P < 0.05) antagonistic activities on GRP-(14-27)-stimulated plasma glucagon secretion. Intracerebroventricular injection of RC-3095 (10 micrograms) immediately before GRP-(14-27) (1 microgram) completely prevented the GRP-(14-27)-induced serum GH suppression. These results indicate that 1) marked differences exist in the ability of these analogues to antagonize GRP-(14-27)-induced gastrin or glucagon release, suggesting the existence of different bombesin/GRP receptor subtypes, and 2) the central effect of bombesin/GRP on GH release from the pituitary is probably mediated through specific bombesin/GRP receptors.
Cyclooxygenase inhibitors blunt thromboxane action in human placental arteries by blocking thromboxane receptors
Authors: Wilkes B. M. , Hollander A. M. , Sung S. Y. , Mento P. F.
Published: December 2017

The effects of cyclooxygenase inhibitors on thromboxane-mediated vasoconstriction in human placental arteries were studied in the isolated perfused fetoplacental cotyledon. The stable thromboxane agonist U-46619 caused a dose-related increase in perfusion pressure in the fetal side of the cotyledon. Meclofenamate (3.3 x 10(-5) M) significantly blunted the pressor response to U-46619, but not to angiotensin II, and inhibited thromboxane B2 formation in placental slices (IC50, 4.80 x 10(-8) M). The mechanism by which meclofenamate prevented thromboxane-induced vasoconstriction was studied using ligand-binding techniques in a membrane fraction prepared from placental cotyledons. Meclofenamate caused a dose-related inhibition of binding of the thromboxane receptor antagonist [3H]SQ 29548 with an IC50 of 2.61 x 10(-5) M. Scatchard analysis of equilibrium binding demonstrated that meclofenamate reduced the number of binding sites without altering the affinity of the receptor, suggesting a noncompetitive mechanism. Indomethacin also caused a dose-related inhibition of thromboxane binding (IC50, 3.27 x 10(-4) M). However, aspirin at a dose of 2.0 x 10(-3) M did not inhibit [3H]SQ 29548 binding. The data indicate that some cyclooxygenase inhibitors blunt thromboxane actions by interfering with binding at thromboxane receptor sites. These studies identify a new mechanism by which cyclooxygenase inhibition by some nonsteroidal anti-inflammatory drugs can prevent thromboxane action in fetoplacental blood vessels in vitro independent of reductions in thromboxane formation.
Effects of peptide YY on the human cardiovascular system: reversal of responses to vasoactive intestinal peptide
Authors: Playford R. J. , Benito-Orfila M. A. , Nihoyannopoulos P. , Nandha K. A. , Cockcroft J. , Todd S. , Ghatei M. A. , Domin J. , Bloom S. R. , Calam J.
Published: December 2017

Peptide YY (PYY) reverses the increased intestinal secretion stimulated by vasoactive intestinal peptide (VIP) in humans. VIP also dilates blood vessels, so we investigated the effect of PYY on the cardiovascular system. Six volunteers received PYY, 0.4 and 1.2 pmol.kg-1 x min-1 i.v. for 2 h, reproducing plasma levels seen postprandially and during a diarrheal illness, respectively. Cardiac function was assessed by echocardiography. PYY infused at 0.4 pmol.kg-1 x min-1 had no effect on cardiovascular parameters. PYY infused at 1.2 pmol.kg-1 x min-1 caused a fall in both stroke volume from 128 +/- 8 to 110 +/- 8 ml/beat (mean +/- 95 confidence interval, P < 0.01) and cardiac output from 7.2 +/- 0.4 to 6.1 +/- 0.4 l/min (P < 0.01). Effects of infusion of PYY into the brachial artery at doses of 0-16 pmol/min were assessed using venous occlusion plethysmography in six subjects. PYY infusion caused a dose-dependent fall in forearm blood flow. Six subjects received VIP, 5 pmol.kg-1 x min-1 i.v., causing a rise in heart rate from 55 +/- 3 to 70 +/- 3 beats/min and increased cardiac output from 7.3 +/- 1.1 to 13.1 +/- 1.1 l/min. The addition of PYY, 0.4 pmol.kg-1 x min-1 i.v., did not affect the heart rate significantly but decreased the cardiac output to 10.4 +/- 1.1 l/min (P < 0.01). Infusions of PYY into the brachial artery at 5 pmol/min decreased local vasodilation induced by VIP infused at 2 pmol/min at the same site by 40% (P < 0.01), even though this dose of PYY had no significant effect on local blood flow when given alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Single K+ channels in adrenal zona glomerulosa cells. II. Inhibition by angiotensin II
Authors: Kanazirska M. V. , Vassilev P. M. , Quinn S. J. , Tillotson D. L. , Williams G. H.
Published: December 2017

The effects of angiotensin II (ANG II) on single K+ channels were studied in rat and bovine adrenal zona glomerulosa (ZG) cells, using the patch-clamp technique. ANG II (0.1-10 nM) induced substantial inhibition of inward rectifier and delayed rectifier K+ channel activities in rat and bovine ZG cells. Analysis of single-channel activities showed that the ANG II-induced channel-blocking effect involved reductions in the probability of the open state (Po) and the mean open time. The changes in these channel parameters occurred at all test voltages, indicating that the effect of ANG II was voltage independent. ANG II could not interact directly with the extracellular sides of the membranes in these experiments using cell-attached patches. Therefore, the effect of ANG II on K+ channels must occur through an indirect cytosolic transduction pathway. The ANG II-induced block of K+ channels will result in membrane depolarization, which may activate voltage-dependent Ca2+ channels, thereby increasing cytosolic free Ca2+ and stimulating aldosterone secretion. These channel-modulating actions of ANG II may be an important step in the initial sequence of events underlying its transduction mechanism.
Effect of gender on insulin resistance associated with aging
Authors: Franssila-Kallunki A. , Schalin-Jantti C. , Groop L.
Published: December 2017

To examine whether age-related changes in energy metabolism are influenced by gender, 20 females and 20 males varying in age from 21 to 80 yr were studied with euglycemic insulin clamp in combination with indirect calorimetry and infusion of [3-3H]glucose. Lean body mass (LBM) was measured with the tritiated water technique. Fat percentage correlated with age in males (r = 0.60; P < 0.05) but not in females. Although the rates of insulin-stimulated total glucose disposal and nonoxidative glucose metabolism were similar in females and males, nonoxidative glucose metabolism expressed per kilogram body weight (r = -0.64; P < 0.01) or per kilogram LBM (r = -0.46; P < 0.05) was inversely correlated with age only in males. Basal metabolic rate expressed per kilogram body weight decreased with age in both sexes, but no correlation with age was observed when data were expressed per kilogram LBM. The data clearly demonstrate different effects of age on energy metabolism in males and females.
Fetal serine fluxes across fetal liver, hindlimb, and placenta in late gestation
Authors: Cetin I. , Fennessey P. V. , Sparks J. W. , Meschia G. , Battaglia F. C.
Published: December 2017

Eleven studies of fetal serine fluxes were performed in chronically catheterized fetal lambs by continuous infusion of [1-13C]- and [U-14C]serine into a fetal brachial vein. At tracer serine steady state, samples were collected from the fetal abdominal aorta, umbilical vein, fetal hepatic vein, and fetal femoral vein and from the maternal femoral artery and uterine vein. Analyses were performed for plasma serine and glycine concentration, for serine and glycine 13C mole percent enrichment, and for whole blood 14CO2 and O2 concentrations. Uterine and umbilical blood flows were also measured. The placenta had a significant net uptake of fetal serine (2.1 +/- 0.5 mumol.min-1.kg-1, P < 0.01). Fetal plasma serine disposal rate (DR) was 42.5 +/- 3.9 mumol.min-1.kg-1.CO2 production from decarboxylation of fetal plasma serine represented 7.9 +/- 0.5% of DR, or 10.1 +/- 1.2 mumol CO2.min-1.kg-1. Fetal plasma glycine enrichment was 59.7 +/- 4.9% of fetal plasma serine enrichment. There was a significant loss of tracer serine from the fetal circulation into the placenta accounting for approximately 45% of infused tracer. Fifteen percent of this was converted to glycine and released into the umbilical circulation. There was a significant uptake of tracer serine by both fetal liver and fetal hindlimb with a significant CO2 production by both sites with serine oxidation predominantly in the carcass. These results indicate a high fetal serine disposal rate in the lamb, with rapid fetoplacental serine exchange, resulting in a net uptake of fetal serine by the placenta.(ABSTRACT TRUNCATED AT 250 WORDS)
Meal stimulation of albumin synthesis: a significant contributor to whole body protein synthesis in humans
Authors: De Feo P. , Horber F. F. , Haymond M. W.
Published: December 2017

The present studies were performed to test the hypothesis that the liver, by increasing the synthesis of specific plasma proteins during the absorption of an amino acid meal, may play an important role in the temporary "storage" of ingested essential amino acids and to explore the effects of glucocorticosteroids and recombinant human growth hormone (rhGH) on these processes. The fractional synthetic rates of albumin and fibrinogen were determined using simultaneous infusions of intravenous [1-14C]leucine and intraduodenal [4,5-3H]leucine after 22 h fasting and during absorption of glucose and amino acids in four groups of normal subjects treated for 1 wk with placebo, prednisone (0.8 mg.kg-1.day-1), rhGH (0.1 mg.kg-1.day-1), or combined treatment. When compared with the fasted state and independent of the route of tracer delivery and hormonal treatment, albumin, but not fibrinogen, synthesis increased (P < 0.0001) during absorption of a mixed glucose amino acid meal in all groups. This increase in albumin synthesis accounted for 28% of the increase in whole body protein synthesis associated with feeding and for 24, 22, and 14% in the prednisone, rhGH, and combined treatment groups, respectively. These data suggest that the stimulation of albumin synthesis observed during feeding prevents irreversible oxidative losses of a significant fraction of ingested essential amino acids and may serve as a vehicle to capture excess dietary amino acids and transport them to peripheral tissues to sustain local protein synthesis.
Inhibition of hepatic ketogenesis by tumor necrosis factor-alpha in rats
Authors: Beylot M. , Vidal H. , Mithieux G. , Odeon M. , Martin C.
Published: December 2017

Tumor necrosis factor-alpha (TNF-alpha) stimulates hepatic lipogenesis. Therefore, it could play a role in the control of ketogenesis. To test this hypothesis, we measured simultaneously free fatty acids (FFA; [1–13C]palmitate) and ketone body (KB; [3,4–13C2]acetoacetate) kinetics, before and after intraperitoneal injection of saline or TNF-alpha, in postabsorptive rats or rats starved for 24 h. In both groups of rats, TNF-alpha injection did not modify insulinemia and induced a moderate increase of FFA concentrations and appearance rates (P < 0.05). Despite increased FFA availability, ketogenesis was impaired after TNF-alpha injection, as shown by lower KB concentrations and appearance rates; this effect was more important in postabsorptive than in starved rats. The percentage of FFA flux used for ketogenesis was decreased by TNF-alpha in the postabsorptive group (P < 0.05) and starved (P < 0.05) rats. In both groups, maximal liver acetyl-coenzyme A carboxylase activity and estimated phosphorylation state were not modified by TNF-alpha injection, but hepatic concentrations of citrate were increased (P < 0.05). This increased citrate level could be related to a mobilization of glucose stored as glycogen since liver glycogen was decreased by TNF-alpha injection (P < 0.05). In conclusion, TNF-alpha injection in rats decreased hepatic ketogenesis. This action could be related to an increased mobilization and utilization of carbohydrate stores.
Local cerebral glucose utilization in brains of lean and genetically obese (fa/fa) rats
Authors: Doyle P. , Rohner-Jeanrenaud F. , Jeanrenaud B.
Published: December 2017

The local cerebral glucose utilization (LCGU) of brains from Wistar, lean Zucker (FA/FA), and obese Zucker (fa/fa) rats was investigated using the method of Sokoloff et al. (L. Sokoloff, M. Reiwich, C. Kennedy, M.H. Des Rosiers, C.S. Patlak, K.D. Pettigrew, O. Sakurada, and M. Shinohara. J. Neurochem. 28: 897–916, 1977.). The LCGU of obese Zucker (fa/fa) rats was decreased in comparison to the relatively high values obtained for the lean Zucker (FA/FA) rats in all gray matter areas studied, on average to the extent of 50%. When compared with Wistar rats, several brain areas of lean Zucker (FA/FA) animals had a normal glucose uptake. When these normal areas were assessed for common efferent and afferent pathways, it was found that many of these common connections had normal glucose utilizations. In direct comparison to the obese fa/fa rat, the LCGU rates of these areas were decreased, hinting that this would also be the case for their functional activity. Because these areas (limbic, thalamic, hypothalamic, autonomic) have been reported to be potentially relevant for bringing about the behavioral and neuroendocrine alterations known to occur in obese fa/fa rats, it is proposed that they represent dysfunctions that are partly responsible for the obesity syndrome of the fa/fa strain.
Growth hormone response to GRF and insulin-induced hypoglycemia in Yorkshire and Meishan pigs
Authors: Bonneau M.
Published: December 2017

Plasma glucose and porcine growth hormone (GH) responses to insulin and/or growth hormone-releasing factor (GRF) challenges were determined in Yorkshire (Y) and Meishan (MS) castrated male pigs at 140 days of age. The decline in glucose levels observed during the first 30 min after insulin injection was similar between the two breeds. In Y pigs, GH concentrations increased sharply after insulin injection. The GH response to insulin was much smaller in MS than in Y pigs (101 +/- 82 vs. 1,077 +/- 124 ng.min.ml-1, P < 0.001 after 0.30 U/kg insulin). The GH response to GRF (10 micrograms/kg) did not differ significantly between the two breeds. The GH response was larger after combined insulin (0.20 U/kg) plus GRF than after GRF alone in Y pigs (1,512 +/- 229 vs. 463 +/- 401 ng.min.ml-1, P < 0.05), whereas it did not differ in MS pigs (714 +/- 164 vs. 507 +/- 127 ng.min.ml-1, P < 0.10). The present data demonstrate that the GH response to insulin is dramatically altered in MS pigs. A possible explanation to this result is that somatostatin tone would not be depressed by insulin-induced hypoglycemia in MS pigs.
Age-related impairment of K(+)- and ACTH-stimulated aldosterone secretion by rat adrenal capsules
Authors: Radke K. J.
Published: December 2017

It has been suggested that the decrease in plasma aldosterone concentration with advancing age is due to a direct effect of aging on adrenal cortical function. In this study, aldosterone secretion by adrenal capsules from male Fischer 344 rats that were 3–5, 11–13, and 19–21 mo of age was evaluated. Adrenal capsules, comprising the capsule, zona glomerulosa, and small portions of the zona fasciculata-reticularis, were perifused in vitro. Basal aldosterone secretion progressively decreased with aging. In response to concentrations of KCl that ranged from 5.0 to 9.0 mM and to adrenocorticotropic hormone (ACTH) that ranged from 10(-11) to 10(-8) M, threshold sensitivity of adrenal capsules to these secretagogues decreased with aging. Moreover, the magnitude of change in K(+)- and ACTH-stimulated aldosterone secretion and maximal aldosterone response of the adrenal capsules to KCl decreased with aging. Thus it is concluded that aging directly affects basal aldosterone secretion by rat adrenal capsules and that there is an age-related impairment of threshold sensitivity and responsiveness of adrenal capsules to the secretagogues, KCl and ACTH.
Endothelium-dependent vasorelaxation evoked by desmopressin and involvement of nitric oxide in rat aorta
Authors: Yamada K. , Nakayama M. , Nakano H. , Mimura N. , Yoshida S.
Published: December 2017

It is known that in vivo administration of desmopressin (DDAVP; a selective V2-vasopressin receptor agonist) results in prostacyclin-independent vasodilation. The in vitro effects of DDAVP and its mechanisms were examined using rat aortic strips. DDAVP from a concentration of 1 x 10(-9) M caused a concentration-dependent relaxation of the aorta precontracted with norepinephrine (10(-7) M) with intact endothelium. However, no relaxation was induced in aorta with the endothelium removed. The DDAVP-induced relaxation was not influenced by the presence of indomethacin but was inhibited by L-NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of nitric oxide (NO) synthesis. The inhibition by L-NMMA was reversed by the addition of L-arginine but not D-arginine. Further, the endothelium-dependent relaxation due to DDAVP was potentiated by superoxide dismutase, a scavenger of superoxide anions, and was inhibited by hemoglobin. DDAVP induced an increase in guanosine 3',5'-cyclic monophosphate levels in the aorta with endothelium but not in aorta without endothelium, and this was suppressed by L-NMMA and hemoglobin. The suppression by L-NMMA was also partially reversed by L-arginine but not by D-arginine. Two selective V2-receptor antagonists had no effect on the DDAVP-induced vasorelaxation. Selective V1-receptor antagonists (a peptidic and a nonpeptidic) caused a concentration-dependent but nonparallel shift to the right of the concentration-response curves to DDAVP. However, DDAVP did not affect the tension of the strip with or without endothelium in nonprecontracted aorta.(ABSTRACT TRUNCATED AT 250 WORDS)
Exogenous substrate uptake by fetal lambs during reduced glucose delivery
Authors: Milley J. R.
Published: December 2017

Normally, metabolism of exogenous glucose accounts for one-half of the normal fetal metabolic rate. When fetal glucose delivery is restricted for 2 wk, endogenous production increases to maintain glucose use. Such increased glucose production must originate either from increased uptake of other exogenous substrates (lactate or amino acids) or from use of endogenous substrates (via glycogenolysis or gluconeogenesis). Our purpose was to find if exogenous fetal substrate uptake increased during decreased fetal glucose delivery. Catheters were placed in eight lamb fetuses under general maternal anesthesia, and the animals were allowed 6 days to recover. Umbilical venoarterial blood concentration differences of antipyrine (during fetal antipyrine infusion), glucose, lactate, amino nitrogen-containing substances, and oxygen were measured before and after fetal glucose delivery was diminished by 3 h of maternal insulin infusion (5-10 mU.kg-1.m-1). Fetal substrate uptakes and substrate/oxygen quotients (i.e., the proportion of oxidative metabolism supported by complete oxidation of each exogenous substrate) were calculated. No increase occurred in the uptake of other exogenous substrates during deficient glucose delivery. Because even complete oxidation of all exogenous substrates did not meet fetal oxidative requirements, the fetus must oxidize endogenous substrates. If such a pattern of substrate use were to continue, fetal growth retardation would result.
Aminoacylation of initiator methionyl-tRNA(i) under conditions inhibitory to initiation of protein synthesis
Authors: Ojamaa K. M. , Kimball S. R. , Jefferson L. S.
Published: December 2017

Inhibition of protein synthesis in perfused rat liver deprived of either methionine or tryptophan results from a defect in peptide-chain initiation. Similarly, the decreased rate of protein synthesis in liver from rats deprived of food for 24 h and in skeletal muscle after 2 days of diabetes results from a defect in initiation. In the present study, the tissue content of tRNA(iMet) and its level of aminoacylation were measured in these conditions to determine whether methionyl-tRNA(iMet) formation is a mechanism involved in the regulation of initiation. The extent of aminoacylation of tRNA(iMet) in livers perfused with supplemented medium or medium deficient in either methionine or tryptophan was 64 +/- 2, 61 +/- 3, and 66 +/- 2% of the total accepting activity, respectively. The total tissue content of tRNA(iMet), expressed as a percentage of total RNA, was 1.7 +/- 0.1, 1.6 +/- 0.1, and 1.6 +/- 0.1 for the three conditions, respectively. In livers from starved rats, the extent of aminoacylation of tRNA(iMet) was 80 +/- 7% and the total tissue content of tRNA(iMet) was 1.9 +/- 0.1% compared with control values of 82 +/- 6 and 2.0 +/- 0.1%, respectively. In skeletal muscle from diabetic rats, the extent of aminoacylation of tRNA(iMet) was 79 +/- 4% and the total tissue content of tRNA(iMet) was 2.0 +/- 0.3% compared with values of 79 +/- 5 and 2.0 +/- 0.2% for control animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Metabolic and hemodynamic effects of insulin on human hearts
Authors: Ferrannini E. , Santoro D. , Bonadonna R. , Natali A. , Parodi O. , Camici P. G.
Published: December 2017

Myocardial muscle is considered to be a target tissue for insulin action, but direct measurements of insulin's effects on cardiac hemodynamics and intermediary metabolism in humans are scarce. We combined great cardiac vein (GCV)/arterial catheterization with the euglycemic insulin clamp technique and thermodilution in six healthy middle-aged (53 +/- 2 yr) volunteers. In the fasting state, the myocardium extracted free fatty acid (FFA), lactate, pyruvate, glycerol, and beta-hydroxybutyrate (6.4 +/- 0.8, 6.2 +/- 1.0, 0.58 +/- 0.12, 0.44 +/- 0.15, and 11 +/- 2 mumol/min, respectively) and consumed 0.26 +/- 0.02 mmol/min oxygen. As fasting plasma insulin (73 +/- 6 pmol/l) was raised and clamped at 503 +/- 16 pmol/l for 100 min while maintaining euglycemia (approximately 5 mmol/l), arterial levels of lactate and pyruvate rose (by 121 and 159%, respectively), whereas FFA, glycerol, and beta-hydroxybutyrate fell (by 69, 48, and 85%, respectively, all P < 0.001). Correspondingly, net myocardial uptake of glucose, lactate, and pyruvate increased to 18.9 +/- 3.5, 32.0 +/- 2.3, and 2.7 +/- 0.5 mumol/min, respectively, whereas net extraction of circulating FFA, glycerol, and beta-hydroxybutyrate was abolished (all P < 0.001). The stimulation of lactate and pyruvate uptake was the result of both increased arterial supply and enhanced myocardial extraction ratio (from 19 +/- 3 to 51 +/- 6% for lactate, from 26 +/- 5 to 44 +/- 5% for pyruvate, P < 0.001 for both). This shift from fat to carbohydrate fuel usage occurred in the absence of changes in oxygen consumption, heart rate, GCV blood flow, aortic pressures, coronary vascular resistance, and left ventricular end-diastolic pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Glucose transporters and glucose transport in skeletal muscles of 1- to 25-mo-old rats
Authors: Gulve E. A. , Henriksen E. J. , Rodnick K. J. , Youn J. H. , Holloszy J. O.
Published: December 2017

It is widely thought that aging results in development of insulin resistance in skeletal muscle. In this study, we examined the effects of growth and aging on the concentration of the GLUT-4 glucose transporter and on glucose transport activity in skeletal muscles of female Long-Evans rats. Relative amounts of immunoreactive GLUT-4 protein were measured in muscle homogenates of 1-, 10-, and 25-mo-old rats by immunoblotting with a polyclonal antibody directed against GLUT-4. In the epitrochlearis, plantaris, and the red and white regions of the quadriceps muscles, GLUT-4 immunoreactivity decreased by 14-33% between 1 and 10 mo of age and thereafter remained constant. In flexor digitorum brevis (FDB) and soleus muscles, GLUT-4 concentration was similar at all three ages studied. Glucose transport activity was assessed in epitrochlearis and FDB muscles by incubation with 2-deoxyglucose under the following conditions: basal, submaximal insulin, and either maximal insulin or maximal insulin combined with contractile activity. Glucose transport in the epitrochlearis muscle decreased by approximately 60% between 1 and 4 mo of age and then did not decline further between 4 and 25 mo of age. Transport activity in the FDB assessed with a maximally effective insulin concentration decreased only slightly (< 20%) between 1 and 7 mo of age. Aging, i.e., the transition from young adulthood to old age, was not associated with a decrease in glucose transport activity in either the epitrochlearis or the FDB.(ABSTRACT TRUNCATED AT 250 WORDS)