bluuebunny/crossref_metadata_2025 huggingface dataset:
Prolonged NOS inhibition in the brain elevates blood pressure in normotensive rats
Authors: Sakima Atsushi , Teruya Hiroshi , Yamazato Masanobu , Matayoshi Rijiko , Muratani Hiromi , Fukiyama Koshiro
Published: December 2017

Systemic inhibition of nitric oxide synthase (NOS) evokes hypertension, which is enhanced by salt loading, partly via augmented sympathetic activity. We investigated whether inhibition of brain NOS elevates blood pressure (BP) in normotensive rats and, if so, whether the BP elevation is enhanced by salt loading. After a 2-wk low-salt (0.3%) diet, male Sprague-Dawley (SD) rats were divided into four groups. Groups 1 and 2 received a chronic intracerebroventricular infusion of 0.5 mg ⋅ kg−1 ⋅ day−1of N G-monomethyl-l-arginine (l-NMMA), and groups 3 and 4 were given artificial cerebrospinal fluid (aCSF). Groups 1 and 3 were placed on a high-salt (8%) diet, whereas groups 2 and 4 were on a low-salt diet. On day 9or 10, group 1 showed significantly higher mean arterial pressure (MAP) in a conscious unrestrained state (129 ± 3 mmHg vs. 114 ± 3, 113 ± 1, and 108 ± 3 mmHg in groups 2, 3, and 4, respectively, P < 0.05). On a high-salt diet, response of renal sympathetic nerve activity but not of BP to air-jet stress was significantly larger in rats givenl-NMMA than in rats given aCSF (29 ± 4% vs. 19 ± 3%, P < 0.05). When the intracerebroventricular infusions were continued for 3 wk, MAP was significantly higher in rats givenl-NMMA than in rats given aCSF irrespective of salt intake, although the difference was ∼7 mmHg. Thus chronic inhibition of NOS in the brain only slightly elevates BP in SD rats. Salt loading causes a more rapid rise in BP. The mechanisms of the BP elevation and its acceleration by salt loading remain to be elucidated.
Neural site of leptin influence on neuropeptide Y signaling pathways altering feeding and uncoupling protein
Authors: Kotz Catherine M. , Briggs Jacqueline E. , Pomonis James D. , Grace Martha K. , Levine Allen S. , Billington Charles J.
Published: December 2017

Inhibition of a signal that produces positive energy balance involving neuropeptide Y (NPY) projection from arcuate nucleus (Arc; site of NPY synthesis) to paraventricular nucleus (PVN; site of NPY release) is one potential mechanism of leptin action. NPY in the PVN increases feeding and decreases uncoupling protein (UCP) activity in brown fat, whereas leptin decreases NPY biosynthesis in the Arc, which presumably decreases PVN NPY. It is hypothesized that decreased NPY activity is necessary for the satiety and thermogenic effects of leptin. To test this, we first determined the effect of leptin on feeding in two paradigms: satiated rats and food-deprived rats. Leptin was effective in decreasing feeding in the satiated rats but ineffective in the food-deprived rats. Next, we determined that leptin decreases NPY and increases UCP gene expression. Finally, we injected leptin intracerebroventricularly before specific PVN NPY microinjection. We found that repletion of NPY in PVN by specific NPY microinjection reverses the feeding-inhibitory and thermogenic effects of centrally administered leptin, the first functional evidence indicating that leptin acts on the Arc-PVN feeding-regulatory pathway.
Evaluation of a nonhuman primate model to study circadian rhythms of calcium metabolism
Authors: Hotchkiss Charlotte E. , Jerome Christopher P.
Published: December 2017

We evaluated primate models for the study of circadian rhythms in calcium and bone metabolism. Blood and urine were collected from two cynomolgus macaques every 4 h for 24 h. Studies were initiated at three different clock times to separate the effects of repeated experimental sampling from circadian effects. Also, samples were collected from seven monkeys at times of expected maxima and minima. Some parameters exhibited the expected circadian rhythm with increases at night (serum total calcium) or in the early morning (urinary collagen cross-links). Others displayed the effects of the experimental procedure, either increasing (urinary creatinine and phosphorus) or decreasing (osteocalcin, urinary calcium) with repeated sampling. Serum phosphorus, cortisol, and type I procollagen were influenced by both clock time and experimental procedures. Alkaline phosphatase and parathyroid hormone did not show any differences with time or sampling. This data is consistent with findings in humans that bone resorption increases at night and that endogenous corticosteroids decrease bone formation. The usefulness of the monkey model is limited by the physiological stress of sample collection in these subjects.
TNF-α and myocardial depression in endotoxemic rats: temporal discordance of an obligatory relationship
Authors: Meng Xianzhong , Ao Lihua , Meldrum Daniel R. , Cain Brian S. , Shames Brian D. , Selzman Craig H. , Banerjee Anirban , Harken Alden H.
Published: December 2017

Exogenous tumor necrosis factor-α (TNF-α) induces delayed myocardial depression in vivo but promotes rapid myocardial depression in vitro. The temporal relationship between endogenous TNF-α and endotoxemic myocardial depression is unclear, and the role of TNF-α in this myocardial disorder remains controversial. Using a rat model of endotoxemia not complicated by shock, we sought to determine 1) the temporal relationship of changes in circulating and myocardial TNF-α with myocardial depression, 2) the influences of protein synthesis inhibition or immunosuppression on TNF-α production and myocardial depression, and 3) the influence of neutralization of TNF-α on myocardial depression. Rats were treated with lipopolysaccharide (LPS, 0.5 mg/kg ip). Circulating and myocardial TNF-α increased at 1 and 2 h, whereas myocardial contractility was depressed at 4 and 6 h. Pretreatment with cycloheximide or dexamethasone abolished the increase in circulating and myocardial TNF-α and preserved myocardial contractile function. Similarly, treatment with TNF binding protein immediately after LPS prevented myocardial depression. We conclude that endogenous TNF-α mediates delayed myocardial depression in endotoxemic rats and that inhibition of TNF-α production or neutralization of TNF-α preserves myocardial contractile function in endotoxemia.
Epidermal growth factor enhances spontaneous sleep in rabbits
Authors: Kushikata Tetsuya , Fang Jidong , Chen Zutang , Wang Ying , Krueger James M.
Published: December 2017

Several growth factors are implicated in sleep regulation. Epidermal growth factor (EGF) is found in the brain, and it influences the production of several sleep-promoting substances. We determined, therefore, whether administration of exogenous EGF affected spontaneous sleep in rabbits. Twenty-five rabbits were implanted with electroencephalographic electrodes, a brain thermistor, and an intracerebroventricular guide cannula. Three doses of EGF (0.5, 5, and 25 μg) were used. The animals were injected intracerebroventricularly with saline as control and one dose of EGF on 2 separate days. Five and twenty-five micrograms of EGF enhanced non-rapid eye movement sleep and increased brain temperature. The 25-μg dose of EGF also inhibited rapid eye movement sleep across the 23-h postinjection recording period. Results are consistent with the hypothesis that EGF, like other growth factors, could be involved in sleep regulation.
Regulation of muscle glycogenolytic flux during intense aerobic exercise after caffeine ingestion
Authors: Chesley Alan , Howlett Richard A. , Heigenhauser George J. F. , Hultman Eric , Spriet Lawrence L.
Published: December 2017

This study examined the effects of caffeine (Caf) ingestion on muscle glycogen use and the regulation of muscle glycogen phosphorylase (Phos) activity during intense aerobic exercise. In two separate trials, 12 untrained males ingested either placebo (Pl) or Caf (9 mg/kg body wt) 1 h before cycling at 80% maximum O2consumption (V˙o2 max) for 15 min. Muscle biopsies were obtained from the vastus lateralis at 0, 3, and 15 min of exercise. In this study, glycogen “sparing” was defined as a 10% or greater reduction in muscle glycogen use during exercise after Caf ingestion compared with Pl. Muscle glycogen use decreased by 28% (Pl 255 ± 38 vs. Caf 184 ± 24 mmol/kg dry muscle) after Caf in six subjects [glycogen sparers (Sp)] but was unaffected by Caf in six other subjects [nonsparers (NSp), Pl 210 ± 35 vs. Caf 214 ± 37 mmol/kg dry muscle]. In both groups, Caf significantly increased resting free fatty acid concentration, significantly increased epinephrine concentration by twofold during exercise, and increased the Phos a mole fraction at 3 min of exercise compared with Pl, although not significantly. Caf improved the energy status of the muscle during exercise in the Sp group: muscle phosphocreatine (PCr) degradation was significantly reduced (Pl 47.9 ± 3.6 vs. Caf 40.4 ± 6.7 mmol/kg dry muscle at 3 min) and the accumulations of free ADP and free AMP (Pl 6.8 ± 1.3 vs. Caf 3.1 ± 1.4 μmol/kg dry muscle at 3 min; Pl 8.7 ± 0.8 vs. Caf 4.7 ± 1.1 μmol/kg dry muscle at 15 min) were significantly reduced. Caf had no effect on these measurements in the NSp group. It is concluded that the Caf-induced decrease in flux through Phos (glycogen-sparing effect) is mediated via an improved energy status of the muscle in the early stages of intense aerobic exercise. This may be related to an increased availability of fat and/or ability of mitochondria to oxidize fat during exercise preceded by Caf ingestion. It is presently unknown why the glycogen-sparing effect of Caf does not occur in all untrained individuals during intense aerobic exercise.
Resistance of central nervous system interleukin-6 to glucocorticoid inhibition in monkeys
Authors: Reyes Teresa M. , Coe Christopher L.
Published: December 2017

The ability of both exogenous and endogenous glucocorticoids (GCs) to inhibit proinflammatory cytokine production was investigated in vivo. Specifically, we investigated the effects of elevated GC levels on interleukin (IL)-1-induced release of IL-6 into both blood and cerebrospinal fluid (CSF). Three experiments were conducted in rhesus macaques to elevate corticoid levels for at least 4 h before administration of IL-1β. The first study used dexamethasone pretreatment, the second utilized ACTH to stimulate endogenous cortisol release, while the third relied on a psychological challenge to stimulate the hypothalamic-pituitary-adrenal axis. Contrary to our a priori predictions, none of these treatments attenuated the IL-1-induced release of IL-6 into CSF. Additionally, the pattern in the blood response was similar, such that the IL-6 response was not blocked, although there was a trend toward a reduction of this response. These data indicated that the IL-1-induced IL-6 response is for the most part resistant to corticosteroid influence, such that even when a partial inhibition was sometimes evident in blood, cytokine release in the central nervous system was not affected.
Effects of conjugated linoleic acid on body fat and energy metabolism in the mouse
Authors: West David B. , Delany James P. , Camet Patricia M. , Blohm Fawn , Truett Alycia A. , Scimeca Joseph
Published: December 2017

Conjugated linoleic acid (CLA) is a naturally occurring group of dienoic derivatives of linoleic acid found in the fat of beef and other ruminants. CLA is reported to have effects on both tumor development and body fat in animal models. To further characterize the metabolic effects of CLA, male AKR/J mice were fed a high-fat (45 kcal%) or low-fat (15 kcal%) diet with or without CLA (2.46 mg/kcal; 1.2 and 1.0% by weight in high- and low-fat diets, respectively) for 6 wk. CLA significantly reduced energy intake, growth rate, adipose depot weight, and carcass lipid and protein content independent of diet composition. Overall, the reduction of adipose depot weight ranged from 43 to 88%, with the retroperitoneal depot most sensitive to CLA. CLA significantly increased metabolic rate and decreased the nighttime respiratory quotient. These findings demonstrate that CLA reduces body fat by several mechanisms, including a reduced energy intake, increased metabolic rate, and a shift in the nocturnal fuel mix.
AVP mediates the attenuated febrile response to administration of PGE1 in rats near term of pregnancy
Authors: Eliason Heather L. , Fewell James E.
Published: December 2017

Rats have an attenuated febrile response to intracerebroventricular injection of PGE1 near the term of pregnancy, the mechanism of which is unknown. The present experiments were carried out to test the hypothesis that arginine vasopressin (AVP), functioning as an endogenous antipyretic substance in the central nervous system, mediates this attenuated febrile response. The febrile response to intracerebroventricular injection of 0.2 μg PGE1 was determined in pregnant and nonpregnant rats after an intracerebroventricular injection of either vehicle or a vasopressin V1-receptor antagonist. After intracerebroventricular administration of vehicle, intracerebroventricular administration of 0.2 μg PGE1 produced significant increases in core temperature in both nonpregnant and pregnant animals. The increase in core temperature, however, was attenuated both in magnitude and duration in pregnant compared with nonpregnant animals. After intracerebroventricular administration of a vasopressin V1-receptor antagonist, intracerebroventricular administration of 0.2 μg PGE1 produced significant increases in core temperature that were similar in nonpregnant and pregnant animals. Our data support the hypothesis that a pregnancy-related activation of AVP as an endogenous antipyretic substance in the central nervous system attenuates the febrile response to intracerebroventricular administration of PGE1 near term of pregnancy in rats.
Excretory transport of xenobiotics by dogfish shark rectal gland tubules
Authors: Miller David S. , Masereeuw Rosalinde , Henson John , Karnaky Karl J.
Published: December 2017

Marine elasmobranch rectal gland is a specialized, osmoregulatory organ composed of numerous blind-ended, branched tubules emptying into a central duct. To date, NaCl excretion has been its only described function. Here we use isolated rectal gland tubule fragments from dogfish shark ( Squalus acanthias), fluorescent xenobiotics, and confocal microscopy to describe a second function, xenobiotic excretion. Isolated rectal gland tubules rapidly transported the fluorescent organic anion sulforhodamine 101 from bath to lumen. Luminal accumulation was concentrative, saturable, and inhibited by cyclosporin A (CSA), chlorodinitrobenzene, leukotriene C4, and KCN. Inhibitors of renal organic anion transport (probenecid, p-aminohippurate), organic cation transport (tetraethylammonium and verapamil), and P-glycoprotein (verapamil) were without effect. Cellular accumulation of sulforhodamine 101 was not concentrative, saturable, or inhibitable. Rectal gland tubules did not secrete fluorescein, daunomycin, or a fluorescent CSA derivative. Finally, frozen rectal gland sections stained with an antibody to a hepatic canalicular multispecific organic anion transporter (cMOAT or MRP2) showed heavy and specific staining on the luminal membrane of the epithelial cells. We conclude that rectal gland is capable of active and specific excretion of xenobiotics and that such transport is mediated by a shark analog of MRP2, an ATP-driven xenobiotic transporter, but not by P-glycoprotein.
Osmotic and freezing tolerance in spermatozoa of freeze-tolerant and -intolerant frogs
Authors: Costanzo Jon P. , Mugnano John A. , Wehrheim Heidi M. , Lee Richard E.
Published: December 2017

The wood frog ( Rana sylvatica) is a freeze-tolerant species that encounters subzero temperatures during its winter breeding season, whereas the leopard frog ( R. pipiens) is freeze intolerant and breeds in spring. Osmotic and freezing tolerances of spermatozoa from these species were inferred from spermolysis rate, integrity of the plasma membrane as judged using vital dye assay, and motility rate. Sperm of R. sylvatica became motile in hypotonic media (≤220 mosmol/kg) and tolerated in vitro exposure to osmotic concentrations spanning nearly three orders of magnitude. Relative to sperm from R. sylvatica, which were unaffected by freezing at temperatures of −4°C or greater, R. pipiens sperm were more susceptible to osmotic damage and cryoinjury. These differences likely reflect cellular adaptations to somatic freezing in R. sylvatica. Unprotected sperm from both species were extensively damaged by freezing at −8°C, but the presence of glucose, the cryoprotectant used by R. sylvatica, or the permeant glycerol markedly diminished cryoinjury. These data suggest the feasibility of developing gamete cryopreservation protocols to aid efforts in conserving amphibian populations.
Effect of nitric oxide within the paraventricular nucleus on renal sympathetic nerve discharge: role of GABA
Authors: Zhang Kun , Patel Kaushik P.
Published: December 2017

Both nitric oxide (NO) and GABA are known to provide inhibitory inputs to the paraventricular nucleus (PVN) of the hypothalamus and are involved in the control of sympathetic outflow. The purpose of the present study was to examine the interaction of NO and GABA in the regulation of renal sympathetic nerve activity in rats. The responses of renal nerve activity, blood pressure, and heart rate to microinjection of sodium nitroprusside (SNP), an NO donor, into the PVN were measured in the presence and absence of blockade of the GABA system (bicuculline; 2 nmol). Microinjection of SNP (50, 100, and 200 nmol) into the PVN elicited significant decreases in renal nerve discharge, arterial blood pressure, and heart rate, reaching −36.4 ± 9.7%, −11 ± 5 mmHg, and −34 ± 14 beats/min, respectively, at the highest dose. These responses were eliminated by blockade of the GABA system. Conversely, microinjection of Nω-nitro-l-arginine methyl ester (l-NAME; 50, 100, and 200 nmol) elicited significant increases in the renal sympathetic nerve discharge, arterial blood pressure, and heart rate, reaching 88.9 ± 16.6%, 9 ± 1 mmHg, and 29 ± 9 beats/min, respectively, at the highest dose. These sympathoexcitatory responses were masked by prior blockade of the GABA system with bicuculline. The sympathoexcitatory effect of l-NAME was also eliminated by activation of the GABA system with muscimol. In conclusion, our data indicate that the inhibitory effect of endogenous NO within the PVN on the renal sympathetic nerve activity is mediated by GABA.
Endothelial dysfunction precedes hypertension in diet-induced insulin resistance
Authors: Katakam Prasad V. G. , Ujhelyi Michael R. , Hoenig Margarethe E. , Miller Allison Winecoff
Published: December 2017

The insulin-resistant (IR) syndrome may be an impetus for the development of hypertension (HTN). Unfortunately, the mechanism by which this could occur is unclear. Our laboratory and others have described impaired endothelium-mediated relaxation in IR, mildly hypertensive rats. The purpose of the current study is to determine if HTN is most likely a cause or result of impaired endothelial function. Sprague-Dawley rats were randomized to receive a fructose-rich diet for 3, 7, 10, 14, 18, or 28 days or were placed in a control group. The control group received rat chow. After diet treatment, animals were instrumented with arterial cannulas, and while awake and unrestrained, their blood pressure (BP) was measured. Subsequently, endothelium-mediated relaxation to acetylcholine was determined (in vitro) by measuring intraluminal diameter of phenylephrine-preconstricted mesenteric arteries (∼250 μM). Serum insulin levels were significantly elevated in all groups receiving fructose feeding compared with control, whereas there were no differences in serum glucose levels between groups. Impairment of endothelium-mediated relaxation starts by day 14 [mean percent maximal relaxation (Emax): 69 ± 10% of baseline] and becomes significant by day 18 (Emax: 52 ± 11% of baseline; P < 0.01). However, the mean BP (mmHg) does not become significantly elevated until day 28 [BP: 132 ± 1 ( day 28) vs. 116 ± 3 (control); P < 0.05]. These findings demonstrate that both IR and endothelial dysfunction occur before HTN in this model and suggest that endothelial dysfunction may be a mechanism linking insulin resistance and essential HTN.
No evidence for homeoviscous adaptation in a heterothermic tissue: tuna heat exchangers
Authors: Fudge Douglas S. , Stevens E. Don , Ballantyne James S.
Published: December 2017

Many poikilotherms are known to adjust the membrane composition of their cells in response to a temperature change so that membrane fluidity, and therefore function, is conserved. Such compensatory changes in membrane composition are considered “homeoviscous adaptations.” In this study, we examined a heterothermic tissue, the visceral rete mirabile of the bluefin tuna, for evidence of homeoviscous adaptation. We measured the proportions of phospholipid fatty acids and phospholipid head groups as a function of position along the rete thermal gradient, which has been estimated to be ∼10°C. We found no effect of position along the rete on the composition of either phospholipid fatty acids or head groups. Our results were unexpected in light of our previous demonstration of compensation of metabolic enzyme activity in the same tissue. The lack of evidence for a homeoviscous response may be due to the fluctuating nature of the thermal gradient along the visceral retia; i.e., membranes may be adapted to a eurythermal existence rather than being fine-tuned to a particular temperature.
Raised intracranial pressure increases CSF drainage through arachnoid villi and extracranial lymphatics
Authors: Boulton M. , Armstrong D. , Flessner M. , Hay J. , Szalai J. P. , Johnston M.
Published: December 2017

We demonstrated previously that about one-half of cerebrospinal fluid (CSF) removed from the cranial vault was cleared by extracranial lymphatic vessels. In this report we test the hypothesis that lymphatic drainage of CSF increases as intracranial pressure (ICP) is elevated in anesthetized sheep. Catheters were inserted into both lateral ventricles, cisterna magna, cervical lymphatics, and jugular vein. A ventriculocisternal perfusion system was employed to regulate CSF pressures and to deliver a protein tracer (125I-labeled human serum albumin) into the CSF compartment.131I-labeled human serum albumin was injected intravenously to permit calculation of plasma tracer loss and tracer recirculation into lymphatics. ICP was controlled by adjusting the height of the inflow reservoir and the cisterna magna outflow catheter appropriately. The experimental design consisted of a 3-h period of lower pressure followed by a 3-h period of higher pressure in the same animal (10–20 or 20–30 cmH2O). We determined that incremental changes in ICP were associated with higher CSF transport through lymphatic and arachnoid villi routes in all eight animals tested ( P = 0.004).
Role and mechanism of endothelin-B receptors in mediating ET-1-induced vasoconstriction in pig skin
Authors: Pang Cho Y. , Zhang Jianrong , Xu Huai , Lipa Joan E. , Forrest Christopher R. , Neligan Peter C.
Published: December 2017

We investigated the functional importance and signal transduction pathways of endothelin (ET)-B receptors in mediating ET-1-induced vasoconstriction in pig skin. Skin vasoconstriction was studied by monitoring the perfusion pressure of isolated perfused pig skin flaps (6 × 16 cm) at a constant flow rate. Intra-arterial infusion of the ETA/Breceptor agonist ET-1, the ETBreceptor agonists sarafotoxin 6C (S6c) and BQ-3020, or the thromboxane A2mimetic U-46619 ( n = 4 or 5) caused a concentration-dependent skin vasoconstriction. The vasoconstrictor potency of ET-1 (EC503.1 × 10−9M) was lower ( P < 0.05) than that of S6c (EC501.8 × 10−9M) and similar to that of BQ-3020 (EC502.6 × 10−9M). The vasoconstrictor potency of ET-1, S6c, and BQ-3020 was at least 300-fold higher than that of U-46619 (EC500.9 × 10−6M). The skin vasoconstrictor effect of ET-1 (10−9–10−8M) was partially inhibited by 10−5M BQ-123, an ETAreceptor antagonist. Further inhibition was achieved with the combination of 10−5M BQ-123 and BQ-788 (an ETBreceptor antagonist) or with an ETA/Breceptor antagonist (10−5M bosentan or PD-145065) ( n = 5; P < 0.05). In addition, the skin vasoconstrictor effect of the ETBreceptor agonist BQ-3020 was completely blocked by 5 × 10−6M BQ-788 and partially inhibited by 5 × 10−6M of the phospholipase C (PLC) inhibitor 2-nitro-4-carboxyl- N, N-diphenylcarbamate (NCDC), an L-type Ca2+channel antagonist (nifedipine), a protein kinase C (PKC) inhibitor (chelerythrine), or removal of Ca2+from the perfusate ( n = 4 or 5; P < 0.05). The vasoconstrictor effect of S6c was also partially blocked by 5 × 10−6M of NCDC, nifedipine, or chelerythrine or by removal of Ca2+from the perfusate ( n = 4; P < 0.01). We conclude that ETBreceptors play a central role in mediating ET-1-induced vasoconstriction in pig skin, and the mechanism probably involves L-type Ca2+channels, PLC, and PKC.
Hemodynamic and hormonal responses to hemorrhage in conscious rabbits at mid- and late gestation
Authors: Brooks Virginia L. , Quesnell Rebecca R. , Kane Colleen M. , Keil Lanny C.
Published: December 2017

This study tests the hypothesis that conscious rabbits late in pregnancy (P), but not at midgestation (MP), are less able to maintain arterial pressure during hemorrhage. Blood volume (BV) was elevated ( P < 0.05) by an average of 13 ± 4 (MP) and 35 ± 3% (P). Rabbits were bled in both the nonpregnant (NP) and P state at 2% of the initial BV per minute. The hemorrhage was stopped after arterial pressure decreased. In NP rabbits, arterial pressure was well maintained near control pressures of 70 ± 2 mmHg until 38 ± 2% of the initial BV was removed and then rapidly fell to reach a nadir at 35 ± 2 mmHg. In contrast, in P rabbits, basal arterial pressure was lower (61 ± 2 mmHg; P < 0.05) and gradually decreased to below control after <25% of the initial BV was removed. Moreover, the rapid hypotensive phase was triggered with a lower percent BV removal (33 ± 2%; P < 0.05). Basal heart rate was higher during P (149 ± 5 vs. 189 ± 9 beats/min; P < 0.05), and reflex increases were delayed. The slope of the relationship between arterial pressure and vasopressin was not modified during P, although the line was shifted to a lower pressure ( P < 0.05). Larger increases in plasma renin activity and ANG II concentration were produced during hemorrhage in P rabbits. In contrast, no differences in the changes in arterial pressure, heart rate, and vasopressin were found between NP and MP rabbits during hemorrhage, although increases in renin and ANG II were greater at MP ( P < 0.05). In summary, although P conscious rabbits are less able to maintain blood pressure during hemorrhage, this change is not evident at MP. These data suggest that the factors that mediate the P-induced alterations in arterial pressure regulation are not operative until late in gestation.
Treatment of burned rats with insulin-like growth factor I inhibits the catabolic response in skeletal muscle
Authors: Fang Cheng-Hui , Li Bing-Guo , Wang Jing Jing , Fischer Josef E. , Hasselgren Per-Olof
Published: December 2017

Thermal injury is associated with a pronounced catabolic response in skeletal muscle, reflecting inhibited protein synthesis and increased protein breakdown, in particular myofibrillar protein breakdown. Administration of insulin-like growth factor I (IGF-I) has a nitrogen-sparing effect after burn injury, but the influence of this treatment on protein turnover rates in skeletal muscle is not known. In the present study, we examined the effect of IGF-I on muscle protein synthesis and breakdown rates following burn injury in rats. After a 30% total body surface area burn injury or sham procedure, rats were treated with a continuous infusion of IGF-I (3.5 or 7 mg ⋅ kg−1 ⋅ 24 h−1) for 24 h. Protein synthesis and breakdown rates were determined in incubated extensor digitorum longus muscles. Burn injury resulted in increased total and myofibrillar protein breakdown rates and reduced protein synthesis in muscle. The increase in protein breakdown rates was blocked by both doses of IGF-I and the burn-induced inhibition of muscle protein synthesis was partially reversed by the higher dose of the hormone. IGF-I did not influence muscle protein turnover rates in nonburned rats. The results suggest that the catabolic response to burn injury in skeletal muscle can be inhibited by IGF-I.
Ontogeny of hyperphagia in the Zucker (fa/fa) rat
Authors: Kowalski Timothy J. , Ster Andrea M. , Smith Gerard P.
Published: December 2017

The ontogeny of hyperphagic behavior in the Zucker fatty ( fa/ fa) rat was examined. Wild-type, +/ fa, and fa/ fapups aged postnatal day 5( P5), P9, P12, P15, and P18 were evaluated using a test that measured ingestive behavior independent of the dam. The independent ingestive test consisted of giving pups access to a test solution [half-and-half (cream and milk)] on a tissue on the floor of a test chamber for 20 min. The latency to ingest and the intake (weight gain and percent weight gain) were measured and normalized to +/ fa littermates. Pups were tested once to eliminate any effects of test experience. fa/ faPups ingested significantly more than lean pups (+/+ and +/ fa) on P12, P15, and P18, but not on P5 or P9. The latencies of fa/ fapups did not differ significantly from the latencies of +/+ pups except on P18, when the latencies of fa/ fapups were significantly shorter. The latencies of +/ fa pups were significantly longer than the latencies of fa/ faor +/+ pups on P5 and P12. These results demonstrate that hyperphagia in fa/ farats emerges between P9 and P12 under the test conditions used.
Slow restoration of LH pulsatility by refeeding in energetically disrupted women
Authors: Loucks Anne B. , Verdun Mark ,   (With the Technical Assistance of Rebecca Brown and Jean R. Thuma)
Published: December 2017

In other energy-restricted mammals, a single large meal restores luteinizing hormone (LH) pulsatility within a few hours. To determine whether this is so in women, we measured LH pulsatility during the 5th day of low energy availability [dietary energy intake − exercise energy expenditure = 10 kcal ⋅ kg lean body mass (LBM)−1 ⋅ day−1] and during a 6th day of aggressive refeeding (90 kcal ⋅ kg LBM−1 ⋅ day−1) in 15 meals providing 4,100 kcal for an energy availability of 75 kcal ⋅ kg LBM−1 ⋅ day−1. Low energy availability raised β-hydroxybutyrate 1,000% ( P < 0.001) and reduced plasma glucose 15% ( P < 0.01), insulin 63% ( P < 0.001), and triiodothyronine 22% ( P < 0.005). In five of eight subjects, low energy availability also unambiguously suppressed LH pulse frequency 57% to 8.2 ± 1.5 pulses/24 h ( P < 10−4) and raised LH pulse amplitude 94% to 3.1 ± 0.3 IU/l ( P < 10−4), levels below the 5th and above the 95th percentile, respectively, in energy-balanced women. Aggressive refeeding restored β-hydroxybutyrate, glucose, and insulin, but not triiodothyronine. In the five women with unambiguously disrupted LH pulsatility, aggressive refeeding had no effect on LH pulse amplitude ( P > 0.9) and raised LH pulse frequency only slightly (2.4 ± 0.6 pulses/24 h, P = 0.04) and not above the fifth percentile. This striking contrast between women and other mammals may be another clue to the unidentified mechanism mediating the effect of energy availability on LH pulsatility.
NG-hydroxy-l-arginine and nitric oxide inhibit Caco-2 tumor cell proliferation by distinct mechanisms
Authors: Buga Georgette M. , Wei Liu Hua , Bauer Philip M. , Fukuto Jon M. , Ignarro Louis J.
Published: December 2017

The objective of this study was to elucidate the role and mechanism of nitric oxide (NO) synthase (NOS) in modulating the growth of the Caco-2 human colon carcinoma cell line. The two novel observations reported here are, first, that NG-hydroxy-l-arginine (NOHA) inhibits Caco-2 tumor cell proliferation, likely by inhibiting arginase activity, and, second, that NO causes cytostasis by mechanisms that might involve inhibition of ornithine decarboxylase (ODC) activity. Both arginase and ODC are enzymes involved in the conversion of arginine to polyamines required for cell proliferation. Cell growth was monitored by cell count, cell protein analysis, and DNA synthesis. NOHA (1–30 μM) and NO in the form of DETA/NO (1–30 μM) inhibited cell proliferation by 30–85%. The cytostatic effect of NOHA was prevented by addition of excess ornithine, putrescine, spermidine, or spermine to cell cultures, whereas the cytostatic effect of NO (DETA/NO) and α-difluoromethylornithine (ODC inhibitor) was unaffected by ornithine but was prevented by putrescine, spermidine, or spermine. The cytostatic effect of NOHA appeared to be independent of its conversion to NO, and the effect of NO appeared to be independent of cGMP. NOHA inhibited urea production by Caco-2 cells and inhibited arginase catalytic activity (85% at 3 μM), whereas NO (DEA/NO and SNAP) inhibited ODC activity (≥60% at 30 μM) without affecting arginase activity. Coculture of Caco-2 cells with lipopolysaccharide/cytokine-activated rat aortic endothelial cells markedly slowed Caco-2 cell proliferation, and this was blocked by NOS inhibitors. These observations that NOHA and NO may inhibit sequential steps in the arginine-polyamine pathway suggest a novel biological role for NOS in the inhibition of cell proliferation of certain tumor cells and possibly other cell types.
Chemical specificities and intestinal distributions of nutrient-driven satiety
Authors: Meyer J. H. , Hlinka M. , Tabrizi Y. , DiMaso N. , Raybould H. E.
Published: December 2017

We measured intakes of sham- and naturally feeding rats during gut perfusions of nutrients. Our objectives were to determine 1) which nutrient products in gut lumen suppressed intakes; 2) how suppression by various nutrients is distributed along gut; and 3) whether time courses of suppression were similar among different nutrients. We found that satiating nutrients consisted of fatty acids only longer than 10 carbons, of monomeric carbohydrates only with affinity for the glucose transporter, and, among several amino acids, of only phenylalanine and tryptophan. Dimeric maltose had about the same potency as an isocaloric mixture of longer glucose polymers; since responses to either were blocked by a glucosidase inhibitor, each probably acted after hydrolysis to free glucose. Effective nutrients suppressed intakes about equally on infusion into duodenum vs. midgut, and the same nutrients also suppressed intakes when infused into colon. Food intakes were suppressed only while maltose was infused, not after it was stopped, but suppression persisted for 2 h after stopping perfusions with fatty or amino acids.
Neuronal cell bodies in paraventricular nucleus affect renal hemodynamics and excretion via the renal nerves
Authors: Haselton James R. , Vari Richard C.
Published: December 2017

Several lines of evidence support the existence of an oligosynaptic projection from the paraventricular nucleus of the hypothalamus (PVN) to the kidney in the rat. We sought to provide evidence that this neural pathway is capable of influencing renal function in rats. Bilateral microinjections of bicuculline (Bic; 1 nmol) into the PVN decreased glomerular filtration rate (59%), effective renal plasma flow (71%), urine flow (UV; 57%), and urinary sodium excretion (UNaV; 54%), accompanied by increased mean arterial pressure (17%) and heart rate (17%). These results were not obtained when Bic was injected outside the PVN or when vehicle (0.9% saline) was injected into the PVN. Bilateral renal denervation (5–7 days before the experiments) significantly reduced the renal vasoconstriction, attenuated the antidiuresis, and abolished the antinatriuresis evoked by PVN stimulation. On the other hand, both the antidiuresis and antinatriuresis evoked by PVN stimulation were undiminished after treatment with either of two vasopressin receptor antagonists ([β-mercapto-β,β-cyclopentamethylenepropionyl1, O-Et-Tyr2,Val4,Arg8]vasopressin, a vasopressin V1 receptor antagonist, or [adamantaneacetyl1, O-Et-d-Tyr2,Val4,aminobutyryl6,Arg8,9]-vasopressin, a V2 receptor antagonist). In renal-denervated rats treated with the same V2 receptor antagonist, PVN stimulation produced highly variable increases in both UV and UNaV, which overall were not statistically different than zero. We conclude that the activation of neurons in PVN evokes 1) renal vasoconstriction accompanied by antinatriuresis, both of which are attributable to the renal nerves, and 2) decreased water excretion, which is mediated by the renal nerves and vasopressin V2 receptors.
Evidence for increased cardiac compliance during exposure to simulated microgravity
Authors: Koenig Steven C. , Convertino Victor A. , Fanton John W. , Reister Craig A. , Gaffney F. Andrew , Ludwig David A. , Krotov Vladimir P. , Trambovetsky Eugene V. , Latham Rickey D.
Published: December 2017

We measured hemodynamic responses during 4 days of head-down tilt (HDT) and during graded lower body negative pressure (LBNP) in invasively instrumented rhesus monkeys to test the hypotheses that exposure to simulated microgravity increases cardiac compliance and that decreased stroke volume, cardiac output, and orthostatic tolerance are associated with reduced left ventricular peak dP/d t. Six monkeys underwent two 4-day (96 h) experimental conditions separated by 9 days of ambulatory activities in a crossover counterbalance design: 1) continuous exposure to 10° HDT and 2) ∼12–14 h per day of 80° head-up tilt and 10–12 h supine (control condition). Each animal underwent measurements of central venous pressure (CVP), left ventricular and aortic pressures, stroke volume, esophageal pressure (EsP), plasma volume, α1- and β1-adrenergic responsiveness, and tolerance to LBNP. HDT induced a hypovolemic and hypoadrenergic state with reduced LBNP tolerance compared with the control condition. Decreased LBNP tolerance with HDT was associated with reduced stroke volume, cardiac output, and peak dP/d t. Compared with the control condition, a 34% reduction in CVP ( P= 0.010) and no change in left ventricular end-diastolic area during HDT was associated with increased ventricular compliance ( P = 0.0053). Increased cardiac compliance could not be explained by reduced intrathoracic pressure since EsP was unaltered by HDT. Our data provide the first direct evidence that increased cardiac compliance was associated with headward fluid shifts similar to those induced by exposure to spaceflight and that reduced orthostatic tolerance was associated with lower cardiac contractility.
Pregnancy-induced changes in rabbit medial collateral ligament vasoregulation
Authors: McDougall Jason J. , Giles Ryan W. , Bray Robert C. , Hart David A.
Published: December 2017

The ligaments of weight-bearing joints are known to become mechanically inferior during pregnancy, and it has been postulated that this may be due to changes in tissue perfusion. Calcitonin gene-related peptide (CGRP) and epinephrine exert a tonic influence on the vasculature of the medial collateral ligament (MCL), and the present study examined whether these vasoactive influences were altered by pregnancy. Ligament perfusion experiments were performed on primigravid New Zealand White rabbits with the use of laser Doppler perfusion imaging. In pregnant animals ( day 29), MCL basal perfusion fell significantly compared with control; however, values returned to normal 5 days postpartum. In normal joints, topical application of CGRP resulted in a dose-dependent increase in MCL perfusion, whereas epinephrine administration caused a dose-dependent fall in blood flow. During pregnancy, the vasodilator effect of CGRP was completely abolished, whereas adrenergic vasoconstriction was greater than normal. Both responses returned postpartum. Pregnancy in the rabbit produces hypoemia in the MCL, and this phenomenon may be effected by a tempering of CGRP dilator responses and an augmentation of α-adrenoceptor-mediated vasoconstriction.
Stability of circadian timing with age in Syrian hamsters
Authors: Davis Fred C. , Viswanathan N.
Published: December 2017

The causes of age-related disruptions in the timing of human sleep and wakefulness are not known but may include changes in both the homeostatic and circadian regulation of sleep. In Syrian hamsters the free running period of the circadian activity/rest rhythm has been reported to shorten with age. Although this has been observed under a variety of experimental conditions, the changes have been small and their consistency uncertain. In the present study, the wheel running activity/rest rhythm was continuously measured in male Syrian hamsters ( Mesocricetus auratus) in dim constant light (<1 lx) from 8 wk of age until death. Fifteen hamsters survived to at least 90 wk (28%). The average free running period of these hamsters did not change with age. In 18 hamsters that died between 50 and 88 wk, free running period also did not change before death. In contrast to free running period, other measures related to activity level changed significantly with age and before death. Despite changes in the expression of the activity/rest rhythm, the free running period of the hamster circadian pacemaker remained remarkably stable with age.
Leptin does not fully account for the satiety activity of adipose tissue-conditioned medium
Authors: Weigle David S. , Hutson Amy M. , Kramer Janet M. , Fallon Margaret G. M. , Lehner Joyce M. , Lok Si , Kuijper Joseph L.
Published: December 2017

To determine whether leptin alone accounts for the satiety activity secreted by native adipose tissue, we prepared culture media conditioned by microdissected adipose tissue from overfed Long-Evans rats, fa/ farats, or db/ dbmice ( media A, B, and C, respectively). Medium A significantly suppressed food intake following intracerebroventricular delivery to Long-Evans rats (2-h chow intake = 68 ± 5% of baseline, P< 0.001). Media B and C significantly suppressed food intake following intraperitoneal delivery to ob/ obmice (24-h chow intake = 56 ± 7% of baseline for medium B, P= 0.001; 4-day chow intake = 78 ± 3% of baseline for medium C, P= 0.004). Using a leptin receptor-based bioassay, we determined that the leptin concentration of medium C was 392 ± 18 ng/ml. This concentration was 20-fold lower than the concentration of recombinant murine leptin required to produce a similar degree of feeding suppression following 5 days of administration to ob/ obmice. Neither medium conditioned by adipose tissue from ob/ obmice nor medium conditioned by adipose tissue from fa/ farats and subsequently immunodepleted of leptin had significant satiety activity. We conclude that leptin is necessary but not sufficient to account for the satiety activity of native adipose tissue, perhaps due to the production by adipocytes of a cofactor that augments the ability of leptin to suppress feeding.
Innervation of mammalian white adipose tissue: implications for the regulation of total body fat
Authors: Bartness Timothy J. , Bamshad Maryam
Published: December 2017

We review the extensive physiological and neuroanatomical evidence for the innervation of white adipose tissue (WAT) by the sympathetic nervous system (SNS) as well as what is known about the sensory innervation of this tissue. The SNS innervation of WAT appears to be a part of the general SNS outflow from the central nervous system, consisting of structures and connections throughout the neural axis. The innervation of WAT by the SNS could play a role in the regulation of total body fat in general, most likely plays an important role in regional differences in lipid mobilization specifically, and may have a trophic affect on WAT. The exact nature of the SNS innervation of WAT is not known but it may involve contact with adipocytes and/or their associated vasculature. We hypothesize that the SNS innervation of WAT is an important contributor to the apparent “regulation” of total body fat.
White adipose tissue sympathetic nervous system denervation increases fat pad mass and fat cell number
Authors: Youngstrom Timothy G. , Bartness Timothy J.
Published: December 2017

The sympathetic nervous system (SNS) drive on white adipose tissue (WAT) was varied to test its effects on fat cell number (FCN) under conditions in which lipolysis would be minimized and therefore partially separable from SNS trophic effects. The inguinal subcutaneous WAT (IWAT) pad of Siberian hamsters was chosen because 1) it is innervated by the SNS, 2) short day (SD) exposure increases its SNS drive (∼250%) without proportionately increasing lipolysis, and 3) surgical denervation eliminates its SNS innervation. IWAT was either unilaterally surgically or sham denervated, while the contralateral pad was left intact. In long day- or SD-exposed hamsters (11 wk), IWAT denervation decreased norepinephrine content (∼80%) and increased fat pad mass (∼200%) and FCN (∼250 and ∼180%, respectively) compared with the contralateral intact pads, but did not affect fat cell size (FCS). The denervation-induced increased FCN in SDs occurred despite naturally occurring decreased food intake. SDs decreased IWAT FCS regardless of the surgical treatment. These results support an important role of WAT SNS innervation in the control of FCN in vivo.
Sufficiency of postprandial plasma levels of islet amyloid polypeptide for suppression of feeding in rats
Authors: Arnelo Urban , Reidelberger Roger , Adrian Thomas E. , Larsson Jörgen , Permert Johan
Published: December 2017

Our objective was to study whether islet amyloid polypeptide (IAPP) produces satiety by an endocrine mechanism. We used a rat model to determine whether postprandial plasma levels of IAPP are comparable to those required to inhibit feeding when IAPP is administered by continuous intravenous infusion. Food intake in rats with aortic catheters increased plasma IAPP levels from a fasting level of 10.8 ± 0.5 pM to a peak level of 19.0 ± 1.0 pM at 2.2 ± 0.5 h. In rats with jugular vein and aortic catheters, the threshold intravenous dose for IAPP suppression of feeding was between 1 and 3 pmol ⋅ kg−1 ⋅ min−1. The 3 pmol ⋅ kg−1 ⋅ min−1dose decreased 4-h intake by ∼25% by decreasing meal frequency rather than meal size. This dose increased plasma IAPP by ∼24 pM. These results suggest that postprandial plasma levels of IAPP are not quite sufficient to independently produce satiety.
Gender difference in age-related changes in muscle sympathetic nerve activity in healthy subjects
Authors: Matsukawa Toshiyoshi , Sugiyama Yoshiki , Watanabe Takemasa , Kobayashi Fumio , Mano Tadaaki
Published: December 2017

Muscle sympathetic nerve activity (MSNA) was measured directly along with blood pressure at rest in 69 healthy women (20–79 yr old) and 76 age-matched healthy men (16–80 yr old). All were nonobese and normotensive. In the women and men the MSNA was positively correlated with age (women: y = 0.788 x − 5.418, r = 0.846, P < 0.0001; men: y = 0.452 x + 12.565, r = 0.751, P < 0.0001). The regression intercept of y was significantly lower ( P < 0.0001) in the women than in the men, and the regression slope was significantly steeper ( P < 0.0001) in the women. The MSNA was lower in women than in men among those <30 ( P = 0.0012), 30–39 ( P = 0.0126), and 40–49 yr old ( P = 0.0462) but was similar in women and men among those 50–59 ( P = 0.1911, NS) and ≥60 yr old ( P = 0.1739, NS). The results suggest that MSNA increases with age in women and men and that the activity is markedly lower in young women than in men but is markedly accelerated with age.