bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of amylin-related peptides on food intake, meal patterns, and gastric emptying in rats
Authors: Reidelberger Roger D. , Kelsey Linda , Heimann Dean
Published: March 2015

We previously demonstrated that amylin inhibits food intake and gastric emptying in rats with half-maximal effective doses (ED50s) of 8 and 3 pmol · kg−1 · min−1 and maximal inhibitions of 78 and 60%, respectively. In this study of identical design, rats received intravenous infusions of salmon calcitonin (sCT), rat calcitonin (rCT), rat calcitonin gene-related peptide (rCGRP), and rat adrenomedullin (rADM) for 3 h at dark onset, and food intake was measured for 17 h or for 15 min and gastric emptying of saline was measured during the final 5 min. sCT, rCGRP, and rADM inhibited food intake with estimated ED50s of 0.5, 26, and 35 pmol · kg−1 · min−1 and maximal inhibitions of 88, 90, and 49%, respectively. rCT was not effective at doses up to 100 pmol · kg−1 · min−1. sCT, rCGRP, rADM, and rCT inhibited gastric emptying with ED50s of 1, 130, 160, and 730 pmol · kg−1 · min−1 and maximal inhibitions of 60, 66, 60, and 33%, respectively. These results suggest that amylin and sCT may act by a common mechanism to decrease food intake, which includes inhibition of gastric emptying.
A new two-breath technique for extracting the cerebrovascular response to arterial carbon dioxide
Authors: Edwards Michael R. , Topor Zigniew L. , Hughson Richard L.
Published: March 2015

Cerebrovascular autoregulation is evaluated from spontaneous fluctuations in mean flow velocity (MFV) by transcranial Doppler ultrasound of the middle cerebral artery (MCA) with respect to changes in arterial blood pressure (BPMCA), but the effects of spontaneous fluctuations in arterial Pco 2 on MFV have been largely ignored. Autoregressive moving average analysis (ARMA), a closed-loop system identification technique, was applied to data from nine healthy subjects during spontaneous breathing, during inspiration of 10% CO2 for two breaths once per minute for 4 min, and during sustained breathing of 7% CO2. Cerebrovascular resistance index (CVRi) was calculated (CVRi = BPMCA/MFV). Reliable estimates of gain for BPMCA → MFV were obtained for spontaneous breathing and the two-breath method. In contrast, reliable gain estimates for Pco 2 → MFV or Pco 2 → CVRi were achieved only under the two-breath method. Pco 2 → MFV gain was smaller with the two-breath method than during sustained 7% CO2 ( P < 0.05). BPMCA was elevated by 7% CO2 but not by the two-breath method. The closed-loop model provides insight into interactions between BPMCA and Pco 2 on cerebrovascular control, but reliable solutions for Pco 2effects with ARMA analysis require perturbation by the two-breath method.
Adiposity signals and food reward: expanding the CNS roles of insulin and leptin
Authors: Figlewicz Dianne P.
Published: March 2015

The hormones insulin and leptin have been proposed to act in the central nervous system (CNS) as adiposity signals as part of a theoretical negative feedback loop that senses the caloric stores of an animal and orchestrates adjustments in energy balance and food intake. Much research has provided support for both the existence of such a feedback loop and the specific roles that insulin and leptin may play. Most studies have focused on hypothalamic sites, which historically are implicated in the regulation of energy balance, and on the brain stem, which is a target for neural and humoral signals relating to ingestive acts. More recent lines of research, including studies from our lab, suggest that in addition to these CNS sites, brain reward circuitry may be a target for insulin and leptin action. These studies are reviewed together here with the goals of providing a historical overview of the findings that have substantiated the originally hypothesized negative feedback model and of opening up new lines of investigation that will build on these findings and allow further refinement of the model of adiposity signal/CNS feedback loop. The understanding of how motivational circuitry and its endocrine or neuroendocrine modulation contributes to normal energy balance regulation should expand possibilities for future therapeutic approaches to obesity and may lead to important insights into mental illnesses such as substance abuse or eating disorders.
Expression and developmental regulation of the NMDA receptor subunits in the kidney and cardiovascular system
Authors: Leung Jocelyn C. , Travis Brett R. , Verlander Jill W. , Sandhu Satinder K. , Yang Song-Gui , Zea Arnold H. , Weiner I. David , Silverstein Douglas M.
Published: March 2015

Antagonists to the N-methyl-d-aspartate (NMDA) receptor bind to various extraneuronal tissues. We therefore assessed the expression of the main NMDA subunit, NR1, in various tissues. We demonstrate that NR1 appears to be most abundant in the rat kidney and heart. NR1 is present in total rat kidney, cortex, and medulla. Of the NR2 subunits, only the NR2C subunit protein is present in the kidney. The abundance of the NR1 subunit protein increases with kidney development. Both NR1 and NR2C are present in opossum kidney, Madin-Darby canine kidney, and LLC-PK1cells. Immunohistochemistry studies show that the NR1 subunit is present in the renal proximal tubule. NR1 is abundant in the atrium and ventricle but is also expressed in the aorta and pulmonary artery. The NR2 subunits are not expressed in the heart. NR1 subunit protein expression is constant throughout heart development. Finally, the NR1 subunit protein is expressed in heart cells (H9c2) grown in culture. These studies reveal the presence of the NMDA receptor in the kidney and the cardiovascular system.
In vivo downregulation of protein synthesis in the snailHelix apersaduring estivation
Authors: Pakay Julian L. , Withers Philip C. , Hobbs Andrew A. , Guppy Michael
Published: March 2015

Protein synthesis is downregulated during metabolic depression in a number of systems where the metabolic depression is effected by obvious extrinsic cues. The metabolic depression of the estivating land snail Helix apersa occurs in the absence of any obvious physiological stress and has an intrinsic component independent of temperature, pH, O2status, or osmolality. We show that this metabolic depression is accompanied by a downregulation of protein synthesis in vivo. The rate of protein synthesis decreases in two major tissues during estivation: to 23% and 53% of the awake rate in hepatopancreas and foot muscle, respectively. We show from calculations of the theoretical contribution of protein synthesis to total O2consumption that the depression of protein synthesis must be a significant, obligate, in vivo component of metabolic depression in H. aspersa.
Increased H2O2counteracts the vasodilator and natriuretic effects of superoxide dismutation by tempol in renal medulla
Authors: Chen Ya-Fei , Cowley Allen W. , Zou Ai-Ping
Published: March 2015

A membrane-permeable SOD mimetic, 4-hydroxytetramethyl-piperidine-1-oxyl (tempol), has been used as an antioxidant to prevent hypertension. We recently found that this SOD mimetic could not prevent development of hypertension induced by inhibition of renal medullary SOD with diethyldithiocarbamic acid. The present study tested a hypothesis that increased H2O2counteracts the effects of tempol on renal medullary blood flow (MBF) and Na+excretion (UNaV), thereby restraining the antihypertensive effect of this SOD mimetic. By in vivo microdialysis and Amplex red H2O2microassay, it was found that interstitial H2O2levels in the renal cortex and medulla in anesthetized rats averaged 55.91 ± 3.66 and 102.18 ± 5.16 nM, respectively. Renal medullary interstitial infusion of tempol (30 μmol·min-1·kg-1) significantly increased medullary H2O2levels by 46%, and coinfusion of catalase (10 mg·min-1·kg-1) completely abolished this increase. Functionally, removal of H2O2by catalase enhanced the tempol-induced increase in MBF, urine flow, and UNaV by 28, 41, and 30%, respectively. Direct delivery of H2O2by renal medullary interstitial infusion (7.5-30 nmol·min-1· kg-1) significantly decreased renal MBF, urine flow, and UNaV, and catalase reversed the effects of H2O2. We conclude that tempol produces a renal medullary vasodilator effect and results in diuresis and natriuresis. However, this SOD mimetic increases the formation of H2O2, which constricts medullary vessels and, thereby, counteracts its vasodilator actions. This counteracting effect of H2O2may limit the use of tempol as an antihypertensive agent under exaggerated oxidative stress in the kidney.
Senescent terminal weight loss in the male F344 rat
Authors: Black Bill J. , McMahan C. Alex , Masoro Edward J. , Ikeno Yuji , Katz Michael S.
Published: March 2015

Loss of weight, often of unknown cause and culminating in death, commonly occurs in humans at advanced ages. Rats that live to old ages, such as the Fischer 344 (F344) strain, also exhibit a terminal loss in body weight. A presently held hypothesis is that the terminal weight loss in the F344 rat model is due to reduced food intake because of an alteration in hypothalamic function resulting in early satiation. We report findings on terminal weight loss and food intake in male F344 rats fed ad libitum (AL group) or a life-prolonging dietary regimen in which caloric intake was restricted (DR group). Rats in both dietary groups that did not exhibit a terminal weight loss died at younger ages than those exhibiting the loss. Terminal weight loss in the AL group was not associated with decreased food intake; indeed, half of the rats in this group had an increased food intake during the period of terminal weight loss. This finding is not in accord with the presently held hypothesis. In the DR group, terminal weight loss was associated with reduced food intake. Pathology (renal disease and neoplasms) did not explain the presence or absence of the association between reduced food intake and weight loss in either dietary group. The duration of the period of terminal weight loss was similar for the AL and DR groups. Apparently, restricting calories delays the occurrence but does not affect the duration of senescent terminal weight loss.
Contractile properties and myosin expression in rats born and reared in hypergravity
Authors: Picquet F. , Bouet V. , Canu M. H. , Stevens L. , Mounier Y. , Lacour M. , Falempin M.
Published: March 2015

The effects of hypergravity (HG) on soleus and plantaris muscles were studied in Long Evans rats aged 100 days, born and reared in 2- g conditions (HG group). The morphological and contractile properties and the myosin heavy chain (MHC) content were examined in whole muscles and compared with terrestrial control (Cont) age-paired rats. The growth of HG rats was slowed compared with Cont rats. A decrease in absolute muscle weight was observed. An increase in fiber cross-sectional area/muscle wet weight was demonstrated, associated with an increase in relative maximal tension. The soleus muscle changed into a slower type both in contractile parameters and in MHC content, since HG soleus contained only the MHC I isoform. The HG plantaris muscle presented a faster contractile behavior. Moreover, the diversity of hybrid fiber types expressing multiple MHC isoforms (including MHC IIB and MHC IIX isoforms) was increased in plantaris muscle after HG. Thus the HG environment appears as an important inductor of muscular plasticity both in slow and fast muscle types.
Insulin sensitivity and glucose effectiveness from three minimal models: effects of energy restriction and body fat in adult male rhesus monkeys
Authors: Gresl Theresa A. , Colman Ricki J. , Havighurst Thomas C. , Byerley Lauri O. , Allison David B. , Schoeller Dale A. , Kemnitz Joseph W.
Published: March 2015

The minimal model of glucose disappearance (MINMOD version 3; MM3) and both the one-compartment (1CMM) and the two-compartment (2CMM) minimal models were used to analyze stable isotope-labeled intravenous glucose tolerance test (IVGTT) data from year 10 of a study of the effect of dietary restriction (DR) in male rhesus monkeys. Adult monkeys were energy restricted (R; n = 12) on a semipurified diet to ∼70% of control (C) intake (ad libitum-fed monkeys; n = 12). Under ketamine anesthesia, fasting insulin levels were greater among C monkeys. Insulin sensitivity estimates from all models were greater in R than C monkeys, whereas glucose effectiveness estimates were not consistently greater in R monkeys. Fasting plasma glucose as well as hepatic glucose production and clearance rates did not differ between groups. Body fat, in part, statistically mediated the effect of DR to enhance insulin sensitivity indexes. Precision of estimation and intermodel relationships among insulin sensitivity and glucose effectiveness estimates were in the ranges of those reported previously for humans and dogs, suggesting that the models may provide valid estimates for rhesus monkeys as well. The observed insulin sensitivity indexes from all models, elevated among R vs. C monkeys, may be explained, at least in part, by the difference in body fat content between these groups after chronic DR.
Role of 20-hydroxyeicosatetraenoic acid in the renal and vasoconstrictor actions of angiotensin II
Authors: Alonso-Galicia Magdalena , Maier Kristopher G. , Greene Andrew S. , Cowley Allen W. , Roman Richard J.
Published: March 2015

The present study examined the effects of ANG II on the renal synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) and its contribution to the renal vasoconstrictor and the acute and chronic pressor effects of ANG II in rats. ANG II (10−11to 10−7mol/l) reduced the diameter of renal interlobular arteries treated with inhibitors of nitric oxide synthase and cyclooxygenase, lipoxygenase, and epoxygenase by 81 ± 8%. Subsequent blockade of the synthesis of 20-HETE with 17-octadecynoic acid (1 μmol/l) increased the ED50for ANG II-induced constriction by a factor of 15 and diminished the maximal response by 61%. Graded intravenous infusion of ANG II (5–200 ng/min) dose dependently increased mean arterial pressure (MAP) in thiobutylbarbitol-anesthetized rats by 35 mmHg. Acute blockade of the formation of 20-HETE with dibromododecenyl methylsulfimide (DDMS; 10 mg/kg) attenuated the pressor response to ANG II by 40%. An intravenous infusion of ANG II (50 ng · kg−1· min−1) in rats for 5 days increased the formation of 20-HETE and epoxyeicosatrienoic acids (EETs) in renal cortical microsomes by 60 and 400%, respectively, and increased MAP by 78 mmHg. Chronic blockade of the synthesis of 20-HETE with intravenous infusion of DDMS (1 mg · kg−1· h−1) or EETs and 20-HETE with 1-aminobenzotriazole (ABT; 2.2 mg · kg−1· h−1) attenuated the ANG II-induced rise in MAP by 40%. Control urinary excretion of 20-HETE averaged 350 ± 23 ng/day and increased to 1,020 ± 105 ng/day in rats infused with ANG II (50 ng · kg−1· min−1) for 5 days. In contrast, urinary excretion of 20-HETE only rose to 400 ± 40 and 600 ± 25 ng/day in rats chronically treated with ANG II and ABT or DDMS respectively. These results suggest that acute and chronic elevations in circulating ANG II levels increase the formation of 20-HETE in the kidney and peripheral vasculature and that 20-HETE contributes to the acute and chronic pressor effects of ANG II.
Volume expansion during acute angiotensin II receptor (AT1) blockade and NOS inhibition in conscious dogs
Authors: Andersen Jens Lundbæk , Sandgaard Niels C. F. , Bie Peter
Published: March 2015

The responses to AT1-receptor blockade (candesartan 1 mg/kg) and to concomitant volume expansion (saline 35 ml/kg for 90 min) with and without nitric oxide synthase (NOS) inhibition ( NG-nitro-l-arginine methyl ester 30 μg · kg−1· min−1) were investigated in separate experiments in normal dogs.

AT1blockade decreased arterial pressure (106 ± 4 to 96 ± 5 mmHg) and increased glomerular filtration rate (GFR) by 17% and sodium excretion threefold. NOS inhibition increased arterial pressure (103 ± 3 to 116 ± 3 mmHg) and decreased GFR by 21% and reduced sodium excretion by some 80%. Volume expansion increased arterial pressure significantly in all series involving this procedure, most pronounced during combined AT1blockade and NOS inhibition (21 ± 4 mmHg). Volume expansion during AT1blockade elicited marked natriuresis (26 ± 11 to 274 ± 55 μmol/min) that was severely reduced by concomitant NOS inhibition (10 ± 3 to 45 ± 11 μmol/min), but still much larger than that seen with volume expansion during NOS inhibition alone (2 ± 1 to 23 ± 7 μmol/min). Volume expansion during AT1blockade increased GFR (+30%), less so during combined AT1blockade and NOS inhibition (+13%), but it did not increase GFR significantly ( P = 0.07) during NOS inhibition alone. Plasma ANG II increased greater than sevenfold with AT1blockade and doubled with NOS inhibition (paired t-test, P < 0.05), whereas it decreased by 50–80% during volume expansion irrespective of pretreatment, i.e., during NOS inhibition, volume expansion did not generate subnormal plasma ANG II concentrations.

In conclusion, 1) acute AT1blockade leads to hyperfiltration, natriuresis, and hyperresponsiveness to volume expansion, 2) these responses are >85% inhibitable by unspecific NOS inhibition, and 3) NOS inhibition alone is followed by increases in plasma ANG II, hypofiltration, and severe antinatriuresis that may be counterbalanced but not overwhelmed by volume expansion. Thus NOS inhibition virtually abolishes the volume expansion natriuresis, at least in part, due to the lack of appropriate inhibition of the renin-angiotensin-aldosterone system.
Temperature dependency of force loss and Ca2+homeostasis in mouse EDL muscle after eccentric contractions
Authors: Warren Gordon L. , Ingalls Christopher P. , Armstrong R. B.
Published: March 2015

The goals of this study were first to determine the effect of temperature on the force loss that results from eccentric contractions in mouse extensor digitorum longus (EDL) muscles and then to evaluate a potential role for altered Ca2+homeostasis explaining the greater isometric force loss observed at the higher temperatures. Isolated muscles performed five eccentric or five isometric contractions at either 15, 20, 25, 30, 33.5, or 37°C. Isometric force loss, caffeine-induced force, lactate dehydrogenase (LDH) release, muscle accumulation of45Ca2+from the bathing medium, sarcoplasmic reticulum (SR) Ca2+uptake, and resting muscle fiber free cytosolic Ca2+concentration ([Ca2+]i) were measured. The isometric force loss after eccentric contractions increased progressively as temperature rose; at 15°C, there was no significant loss of force, but at 37°C, there was a 30–39% loss of force. After eccentric contractions, caffeine-induced force was not affected by temperature nor was it different from that of control muscles at any temperature. Loss of cell membrane integrity and subsequent influx of extracellular Ca2+as indicated by LDH release and muscle45Ca2+accumulation, respectively, were minimal over the 15–25°C range, but both increased as an exponential function of temperature between 30 and 37°C. SR Ca2+uptake showed no impairment as temperature increased, and the eccentric contraction-induced rise in resting fiber [Ca2+]iwas unaffected by temperature over the 15–25°C range. In conclusion, the isometric force loss after eccentric contractions is temperature dependent, but the temperature dependency does not appear to be readily explainable by alterations in Ca2+homeostasis.
Increased lipogenesis in isolated hepatocytes from cold-acclimated ducklings
Authors: Bedu E. , Chainier F. , Sibille B. , Meister R. , Dallevet G. , Garin D. , Duchamp C.
Published: March 2015

Thermogenic endurance and development of metabolic cold adaptation in birds may critically depend on their ability to synthesize and use fatty acids (FA) as fuel substrates. Hepatic lipogenesis and the capacity to oxidize FA in thermogenic tissues were measured in cold-acclimated (CA) ducklings ( Cairina moschata) showing original mechanisms of metabolic cold adaptation in the absence of brown adipose tissue, the specialized thermogenic tissue of rodents. The rate of FA synthesis from [U-14C]glucose and from [1-14C]acetate, measured in incubated hepatocytes isolated from 5-wk-old thermoneutral (TN; 25°C) or CA (4°C) fed ducklings, was higher than in other species. Hepatic de novo lipogenesis was further increased by cold acclimation with both glucose (+194%) and acetate (+111%) as precursor. Insulin slightly increased (+11–14%) hepatic lipogenesis from both precursors in CA ducklings, whereas glucagon was clearly inhibitory (−29 to −51%). Enhanced de novo lipogenesis was associated with higher (+171%) hepatocyte activity of glucose oxidation and larger capacity (+50 to +100%) of key lipogenic enzymes. The potential for FA oxidation was higher in liver (+61%) and skeletal muscle (+29 to +81%) homogenates from CA than from TN ducklings, suggesting that the higher hepatic lipogenesis may fuel oxidation in thermogenic tissues. Present data underline the high capacity to synthesize lipids from glucose in species like muscovy ducks susceptible to hepatic steatosis. Lipogenic capacity can be further increased in the cold and may represent an important step in the metabolic adaptation to cold of growing ducklings.
Sympathetic nerve regulation to heating is altered in senescent rats
Authors: Kenney Michael J. , Fels Richard J.
Published: March 2015

Renal and splanchnic sympathetic nerve discharge (SND) responses to increased (38–41°C) internal temperature were determined in anesthetized young (3–6 mo old), mature (12 mo old), and senescent (24 mo old) Fischer 344 (F344) rats. We hypothesized that SND responses would be altered in senescent and mature rats as demonstrated by attenuated sympathoexcitatory responses to heating and by the absence of hyperthermia-induced SND pattern changes. The following observations were made. 1) Renal and splanchnic SND responses were significantly increased during heating in young and mature but not in senescent rats. 2) At 41°C, renal and splanchnic SND responses were higher in young compared with senescent rats, and renal SND was higher in mature than in senescent rats. 3) Heating changed the SND bursting pattern in young, but not in mature or senescent, rats. 4) SND responses to heating did not differ between baroreceptor-innervated (BRI) and sinoaortic-denervated (SAD) senescent rats but were higher in SAD compared with BRI young rats. These results demonstrate an attenuated responsiveness of sympathetic neural circuits to heating in senescent F344 rats.
Comparative trends in shortening velocity and force production in skeletal muscles
Authors: Medler Scott
Published: March 2015

Skeletal muscles are diverse in their properties, with specific contractile characteristics being matched to particular functions. In this study, published values of contractile properties for >130 diverse skeletal muscles were analyzed to detect common elements that account for variability in shortening velocity and force production. Body mass was found to be a significant predictor of shortening velocity in terrestrial and flying animals, with smaller animals possessing faster muscles. Although previous studies of terrestrial mammals revealed similar trends, the current study indicates that this pattern is more universal than previously appreciated. In contrast, shortening velocity in muscles used for swimming and nonlocomotory functions is not significantly affected by body size. Although force production is more uniform than shortening velocity, a significant correlation with shortening velocity was detected in muscles used for locomotion, with faster muscles tending to produce more force. Overall, the contractile properties of skeletal muscles are conserved among phylogenic groups, but have been significantly influenced by other factors such as body size and mode of locomotion.
Blocking cerebrospinal fluid absorption through the cribriform plate increases resting intracranial pressure
Authors: Mollanji R. , Bozanovic-Sosic R. , Zakharov A. , Makarian L. , Johnston M. G.
Published: March 2015

Cerebrospinal fluid (CSF) drains through the cribriform plate (CP) in association with the olfactory nerves. From this location, CSF is absorbed into nasal mucosal lymphatics. Recent data suggest that this pathway plays an important role in global CSF transport in sheep. In this report, we tested the hypothesis that blocking CSF transport through this pathway would elevate resting intracranial pressure (ICP). ICP was measured continuously from the cisterna magna of sheep before and after CP obstruction in the same animal. To block CSF transport through the CP, an external ethmoidectomy was performed. The olfactory and adjacent mucosa were removed, and the bone surface was sealed with tissue glue. To restrict our analysis to the cranial CSF system, CSF transport into the spinal subarachnoid compartment was prevented with a ligature tightened around the thecal sac between C1 and C2. Sham surgical procedures had no significant effects, but in the experimental group CP obstruction elevated ICP significantly. Mean postobstruction steady-state pressures (18.0 ± 3.8 cmH2O) were approximately double the preobstruction values (9.2 ± 0.9 cmH2O). These data support the concept that the olfactory pathway represents a major site for CSF drainage.
PGE2 increases release of substance P from renal sensory nerves by activating the cAMP-PKA transduction cascade
Authors: Kopp Ulla C. , Cicha Michael Z. , Smith Lori A.
Published: March 2015

Increasing renal pelvic pressure increases afferent renal nerve activity (ARNA) by a PGE2-mediated release of substance P (SP) from renal pelvic nerves. The role of cAMP activation in the PGE2-mediated release of SP was studied by examining the effects of the adenylyl cyclase (AC) activator forskolin and AC inhibitor dideoxyadenosine (DDA). Forskolin enhanced the bradykinin-mediated release of SP from an isolated rat renal pelvic wall preparation, from 7.3 ± 1.3 to 15.6 ± 3.0 pg/min. PGE2 at a subthreshold concentration for SP release mimicked the effects of forskolin. The EP2 receptor agonist butaprost, 15 μM, and PGE2, 0.14 μM, produced similar increases in SP release, from 5.8 ± 0.8 to 17.0 ± 2.3 pg/min and from 8.0 ± 1.3 to 21.6 ± 2.7 pg/min. DDA blocked the SP release produced by butaprost and PGE2. The PGE2-induced release of SP was also blocked by the PKA inhibitors PKI14–22 and H-89. Studies in anesthetized rats showed that renal pelvic administration of butaprost, 10 μM, and PGE2, 0.14 μM, resulted in similar ARNA responses, 1,520 ± 390 and 1,170 ± 270% · s (area under the curve of ARNA vs. time) that were blocked by DDA. Likewise, the ARNA response to increased renal pelvic pressure, 7,180 ± 710% · s, was blocked by DDA. In conclusion, PGE2activates the cAMP-PKA pathway leading to a release of SP and activation of renal pelvic mechanosensory nerve fibers.
Role of renal NO production in the regulation of medullary blood flow
Authors: Cowley Allen W. , Mori Takefumi , Mattson David , Zou Ai-Ping
Published: March 2015

The unique role of nitric oxide (NO) in the regulation of renal medullary function is supported by the evidence summarized in this review. The impact of reduced production of NO within the renal medulla on the delivery of blood to the medulla and on the long-term regulation of sodium excretion and blood pressure is described. It is evident that medullary NO production serves as an important counterregulatory factor to buffer vasoconstrictor hormone-induced reduction of medullary blood flow and tissue oxygen levels. When NO synthase (NOS) activity is reduced within the renal medulla, either pharmacologically or genetically [Dahl salt-sensitive (S) rats], a super sensitivity to vasoconstrictors develops with ensuing hypertension. Reduced NO production may also result from reduced cellular uptake of l-arginine in the medullary tissue, resulting in hypertension. It is concluded that NO production in the renal medulla plays a very important role in sodium and water homeostasis and the long-term control of arterial pressure.
TNF-α enhances contraction and inhibits endothelial NO-cGMP relaxation in systemic vessels of pregnant rats
Authors: Giardina Jena B. , Green Gachavis M. , Cockrell Kathy L. , Granger Joey P. , Khalil Raouf A.
Published: March 2015

Tumor necrosis factor-α (TNF-α) is elevated in the plasma of preeclamptic women and may have a role in pregnancy-induced hypertension. However, whether the hemodynamic effects of TNF-α reflect the direct effects on vascular reactivity is unclear. We tested the hypothesis that TNF-α impairs endothelium-dependent relaxation and enhances vascular contraction in systemic vessels of pregnant rats. We measured isometric contraction in aortic strips isolated from virgin and pregnant Sprague-Dawley rats (nontreated vs. treated for 2 h with 10–1,000 pg/ml TNF-α). In endothelium-intact vascular strips, TNF-α caused greater enhancement of phenylephrine (Phe) contraction in pregnant than virgin rats. TNF-α caused significant inhibition of ACh- and bradykinin-induced vascular relaxation and nitrite/nitrate production that were more prominent in pregnant than virgin rats. N G-nitro-l-arginine methyl ester [l-NAME, 100 μM, an inhibitor of nitric oxide (NO) synthase] or 1H-[1,2,4]oxadiazolo[4,3]-quinoxalin-1-one (ODQ, 1 μM, an inhibitor of cGMP production in smooth muscle) inhibited ACh relaxation and enhanced Phe contraction in nontreated but to a lesser extent in TNF-α-treated vessels, particularly those of pregnant rats. Endothelium removal enhanced Phe contraction in nontreated but not TNF-α-treated vessels, especially those of pregnant rats. Relaxation of Phe contraction with the NO donor sodium nitroprusside was not different between nontreated and TNF-α-treated vessels. Thus TNF-α enhances vascular contraction and inhibits endothelium-dependent NO-cGMP-mediated vascular relaxation in systemic vessels, particularly those of pregnant rats. The results support a direct role for TNF-α as a possible mediator of increased vascular resistance associated with pregnancy-induced hypertension.
Restricted feeding with scheduled sucrose access results in an upregulation of the rat dopamine transporter
Authors: Bello Nicholas T. , Sweigart Kristi L. , Lakoski Joan M. , Norgren Ralph , Hajnal Andras
Published: March 2015

Recent studies suggest that the mesoaccumbens dopamine system undergoes neurochemical alterations as a result of restricted feeding conditions with access to sugars. This effect appears to be similar to the neuroadaptation resulting from drugs of abuse and may underlay some pathological feeding behaviors. To further investigate the cellular mechanisms of these alterations, the present study used quantitative autoradiography and in situ hybridization to assess dopamine membrane transporter (DAT) protein density and mRNA expression in restricted-fed and free-fed adult male rats. The restricted feeding regimen consisted of daily limited access to either a normally preferred sucrose solution (0.3 M) or a less preferred chow in a scheduled (i.e., contingent) fashion for 7 days. Restricted-fed rats with the contingent sucrose access lost less body weight, ate more total food, and drank more fluid than free-fed, contingent food, or noncontingent controls. In addition, these animals had selectively higher DAT binding in the nucleus accumbens and ventral tegmental area. This increase in protein binding also was accompanied by an increase in DAT mRNA levels in the ventral tegmental area. In contrast to the restricted-fed groups, no differential effect in DAT regulation was observed across free-fed groups. The observed alteration in behavior and DAT regulation suggest that neuroadaptation in the mesoaccumbens dopamine system develops in response to repeated feeding on palatable foods under dietary constraints. This supports the notion that similar cellular changes may be involved in restrictive eating disorders and bingeing.
Interruption of the rat circadian clock by short light-dark cycles
Authors: Usui Setsuo , Okazaki Terue , Honda Yoshiko
Published: March 2015

Ninety male Sprague-Dawley rats were exposed to 1:1-h light-dark (LD1:1) cycles for 50–90 days, and then they were released into constant darkness (DD). During LD1:1 cycles, behavioral rhythms were gradually disintegrated, and circadian rhythms of locomotor activity, drinking, and urine 6-sulfatoxymelatonin excretion were eventually abolished. After release into DD, 44 (49%) rats showed arrhythmic behavior for >10 days. Seven (8%) animals that remained arrhythmic for >50 days in DD were exposed to brief light pulses or 12:12-h light-dark cycles, and then they restored their circadian rhythms. These results indicate that the circadian clock was stopped, at least functionally, by LD1:1 cycles and was restarted by subsequent light stimulation.
Natriuresis induced by mild hypernatremia in humans
Authors: Andersen Lars Juel , Andersen Jens Lundbæk , Pump Bettina , Bie Peter
Published: March 2015

The hypothesis that increases in plasma sodium induce natriuresis independently of changes in body fluid volume was tested in six slightly dehydrated seated subjects on controlled sodium intake (150 mmol/day). NaCl (3.85 mmol/kg) was infused intravenously over 90 min as isotonic (Iso) or as hypertonic saline (Hyper, 855 mmol/l). After Hyper, plasma sodium increased by 3% (142.0 ± 0.6 to 146.2 ± 0.5 mmol/l). During Iso a small decrease occurred (142.3 ± 0.6 to 140.3 ± 0.7 mmol/l). Iso increased estimates of plasma volume significantly more than Hyper. However, renal sodium excretion increased significantly more with Hyper (291 ± 25 vs. 199 ± 24 μmol/min). This excess was not mediated by arterial pressure, which actually decreased slightly. Creatinine clearance did not change measurably. Plasma renin activity, ANG II, and aldosterone decreased very similarly in Iso and Hyper. Plasma atrial natriuretic peptide remained unchanged, whereas plasma vasopressin increased with Hyper (1.4 ± 0.4 to 3.1 ± 0.5 pg/ml) and decreased (1.3 ± 0.4 to 0.6 ± 0.1 pg/ml) after Iso. In conclusion, the natriuretic response to Hyper was 50% larger than to Iso, indicating that renal sodium excretion may be determined partly by plasma sodium concentration. The mechanism is uncertain but appears independent of changes in blood pressure, glomerular filtration rate, the renin system, and atrial natriuretic peptide.
Acute food deprivation and chronic food restriction differentially affect hypothalamic NPY mRNA expression
Authors: Bi Sheng , Robinson Benjamin M. , Moran Timothy H.
Published: March 2015

Although acute food deprivation and chronic food restriction both result in body weight loss, they produce different metabolic states. To evaluate how these two treatments affect hypothalamic peptide systems involved in energy homeostasis, we compared patterns of hypothalamic neuropeptide Y (NPY), agouti-related protein (AgRP), proopiomelanocotin (POMC), and leptin receptor gene expression in acutely food-deprived and chronically food-restricted rats. Both acute food deprivation and chronic food restriction reduced body weight and circulating leptin levels and resulted in increased arcuate NPY and decreased arcuate POMC gene expression. Arcuate AgRP mRNA levels were only elevated in acutely deprived rats. NPY gene expression was increased in the compact subregion of the dorsomedial hypothalamus (DMH) in response to chronic food restriction, but not in response to acute food deprivation. Leptin receptor expression was not affected by either treatment. Double in situ hybridization histochemistry revealed that, in contrast to the situation in the arcuate nucleus, NPY and leptin receptor mRNA-expressing neurons were not colocalized in the DMH. Together, these data suggest that arcuate and DMH NPY gene expression are differentially regulated. DMH NPY-expressing neurons do not appear to be under the direct control of leptin signaling.
Periconceptional nutrition programs development of the cardiovascular system in the fetal sheep
Authors: Edwards L. J. , McMillen I. C.
Published: March 2015

It has been proposed that fetal adaptations to intrauterine nutrient deprivation permanently reprogram the cardiovascular system. We investigated the impact of restricted periconceptional nutrition and/or restricted gestational nutrition on fetal arterial blood pressure (BP), heart rate, rate pressure product, and the fetal BP responses to ANG II and the angiotensin-converting enzyme inhibitor captopril during late gestation. Restricted periconceptional nutrition resulted in an increase in fetal mean arterial BP between 115 and 125 days gestation (restricted 41.5 ± 2.8 mmHg, n = 12; control 38.5 ± 1.5 mmHg, n = 13) and between 135 and 147 days gestation (restricted 50.5 ± 2.2 mmHg, n = 8; control 42.5 ± 1.9 mmHg, n = 10) as well as an increase in the rate pressure product in twin, but not singleton, fetuses between 115 and 147 days gestation. Mean BP and fetal plasma ACTH were also positively correlated in twin, but not singleton, fetuses. This is the first demonstration that maternal undernutrition during the periconceptional period results in an increase in fetal arterial BP. This increase occurs concomitantly with an increase in fetal ACTH but is not dependent on activation of the fetal renin-angiotensin system.
Somatostatin alters intake of amino acid-imbalanced diets and taste buds of tongue in rats
Authors: Scalera Giuseppe
Published: March 2015

The present studies were designed to evaluate a potential dose-dependent effect of somatostatin (SRIF) administered peripherally on intake of either a low-protein basal diet or threonine-imbalanced diet (THR-IMB), on body weight gain (ΔBW), gut motility, and on the histology of taste buds in rats. SRIF administration had a dual effect related to its concentration, increasing the intake of THR-IMB diet at low concentration and decreasing THR-IMB diet at high concentration. During the light phase, SRIF treatment increased the intake of THR-IMB diet, suggesting that the usual anorectic effect induced by intake of THR-IMB diet was attenuated. High-dosage SRIF decreases gastrointestinal motility, which, in turn, can decrease food intake and ΔBW. The combination of THR-IMB diet regimen and SRIF treatment also induced significant modifications on the taste buds of the tongue. The feeding response to an amino acid-imbalanced diet includes a learned aversion to the diet, and animals may use taste in establishing that aversion. Modifications of taste buds of SRIF-treated rats eating THR-IMB diet might explain the increase of imbalanced diet intake if treated rats perceive this food as less aversive.
Interleukin-10 and nerve growth factor have reciprocal upregulatory effects on intestinal epithelial cells
Authors: Ma Donglai , Wolvers Danielle , Stanisz Andrzej M. , Bienenstock John
Published: March 2015

The intestinal mucosa is in a constant state of controlled inflammation, but the processes whereby this occurs are poorly understood. The aims of this study were to look at the role of IL-10 and nerve growth factor (NGF) in intestinal epithelial cell regulation. The human colon epithelial cell lines T84, HT-29, and CACO-2 were used. RT-PCR, flow cytometry analysis, and immunohistochemistry were applied to measure the cytokine changes in epithelial cells induced by recombinant cholera toxin and its B subunit, IL-10, and NGF. Cholera toxin B subunit caused selective dose-dependent increased mRNA for IL-10 in T84 cells and the protein in T84, HT-29, and CACO-2 cells. IL-10 dose dependently selectively increased NGF mRNA in T84 cells and intracellular protein synthesis in all three epithelial cell lines. The effect of NGF was reciprocal, selective, and dose dependent because it increased mRNA for IL-10 and IL-10 synthesis. Our results suggest that the epithelium may actively participate in downregulation through innate mechanisms involving IL-10 and NGF. The reciprocal interaction suggests for the first time that NGF may be involved in local downregulation by mucosal epithelium and thus may play a potent protective role in response to injury, by prevention of undue inflammation.
Lactoferrin enhances opioid-mediated analgesia via nitric oxide in the rat spinal cord
Authors: Hayashida Ken-ichiro , Takeuchi Takashi , Shimizu Hirohiko , Ando Kunio , Harada Etsumori
Published: March 2015

Lactoferrin (LF) is a multifunctional protein that is found in milk, neutrophils, and other biological fluids, and its receptors have also been identified in the central nervous system. Recently, we found that bovine milk-derived LF (BLF) produced analgesia via a μ-opioid receptor-mediated response in the spinal cord. However, the precise mechanism of this analgesic effect remains unclear. In this study, spinally applied BLF produced analgesia that was reversed by coadministration with a nitric oxide (NO) synthase inhibitor, NG-nitro-l-arginine methyl ester, during phases 1 and 2 in the formalin test. Spinal coadministration of a μ-opioid receptor agonist, morphine, with a subeffective dose of BLF produced a much more highly potentiated analgesia than that produced by morphine alone during phases 1 and 2 in the formalin test. This potentiated analgesia by morphine with BLF was reversed by a μ-opioid receptor antagonist, d-Phe-Cys-Tyr-d-Trp-Orn-Thr-NH2, or by NG-nitro-l-arginine methyl ester. In the tail-flick test, continuous spinal infusion of morphine via an osmotic minipump over 6 days resulted in development of tolerance by day 4, but no tolerance of BLF was observed throughout the experiment. These results suggest that BLF acts as an enhancer of the spinal opioidergic system via an NO-mediated mechanism.
Circadian phase-shifting effects of nocturnal exercise in older compared with young adults
Authors: Baehr Erin K. , Eastman Charmane I. , Revelle William , Olson Susan H. Losee , Wolfe Lisa F. , Zee Phyllis C.
Published: March 2015

Exercise can phase shift the circadian rhythms of young adults if performed at the right time of day. Similar research has not been done in older adults. This study examined the circadian phase-delaying effects of a single 3-h bout of low-intensity nocturnal exercise in older ( n = 8; 55–73 yr old) vs. young ( n = 8; 20–32 yr old) adults. The exercise occurred at the beginning of each subject's habitual sleep time, and subjects sat in a chair in dim light during the corresponding time in the control condition. The dim-light melatonin onset (DLMO) was used as the circadian phase marker. The DLMO phase delayed more after the exercise than after the control condition. On average, the difference in phase shift between the exercise and control conditions was similar for older and young subjects, demonstrating that the phase-shifting effects of exercise on the circadian system are preserved in older adults. Therefore, exercise may potentially be a useful treatment to help adjust circadian rhythms in older and young adults.
Analysis of afferent, central, and efferent components of the baroreceptor reflex in mice
Authors: Ma Xiuying , Abboud Francois M. , Chapleau Mark W.
Published: March 2015

Studies of genetically modified mice provide a powerful approach to investigate consequences of altered gene expression in physiological and pathological states. The goal of the present study was to characterize afferent, central, and efferent components of the baroreceptor reflex in anesthetized Webster 4 mice. Baroreflex and baroreceptor afferent functions were characterized by measuring changes in renal sympathetic nerve activity (RSNA) and aortic depressor nerve activity (ADNA) in response to nitroprusside- and phenylephrine-induced changes in arterial pressure. The data were fit to a sigmoidal logistic function curve. Baroreflex diastolic pressure threshold (Pth), the pressure at 50% inhibition of RSNA (Pmid), and baroreflex gain (maximum slope) averaged 74 ± 5 mmHg, 101 ± 3 mmHg, and 2.30 ± 0.54%/mmHg, respectively ( n = 6). The Pth, Pmid, and gain for the diastolic pressure-ADNA relation (baroreceptor afferents) were similar to that observed for the overall reflex averaging 79 ± 9 mmHg, 101 ± 4 mmHg, and 2.92 ± 0.53%/mmHg, respectively ( n = 5). The central nervous system mediation of the baroreflex and the chronotropic responsiveness of the heart to vagal efferent activity were independently assessed by recording responses to electrical stimulation of the left ADN and the peripheral end of the right vagus nerve, respectively. Both ADN and vagal efferent stimulation induced frequency-dependent decreases in heart rate and arterial pressure. The heart rate response to ADN stimulation was nearly abolished in mice anesthetized with pentobarbital sodium ( n = 4) compared with mice anesthetized with ketamine-acepromazine ( n = 4), whereas the response to vagal efferent stimulation was equivalent under both types of anesthesia. Application of these techniques to studies of genetically manipulated mice can be used to identify molecular mechanisms of baroreflex function and to localize altered function to afferent, central, or efferent sites.
Comparative analysis of expression and secretion of placental leptin in mammals
Authors: Zhao Jing , Kunz Thomas H. , Tumba Nancy , Clamon Schulz Laura , Li Chris , Reeves Monica , Widmaier Eric P.
Published: March 2015

Increased plasma level of leptin appears to be a ubiquitous feature of pregnant mammals. The mechanisms by which leptin levels are increased may be species specific, however, with some species upregulating adipose leptin production and others expressing leptin in the placenta. Placental leptin expression was examined in representative species of the two most abundant mammalian orders, Rodentia and Chiroptera, and in cultured human choriocarcinoma (BeWo) cells. Leptin mRNA was expressed in BeWo cells and in placentas of Myotis lucifugus (little brown bat), Eptesicus fuscus (big brown bat), and Rattus norvegicus (laboratory rat), but not the common laboratory mouse Mus musculus. cAMP stimulated secretion of leptin from BeWo cells and also stimulated leptin mRNA expression in the cells. In addition to adipose and placental tissue, leptin transcript in M. lucifugus was detectable in heart, spleen, and liver, but not in lung, brain, and kidney. Hepatic expression was also observed in E. fuscus, but not in mice or rats, and did not appear to result from hepatic fat deposition. Leptin cDNA was cloned and sequenced from M. lucifugus placenta and shared up to 95% homology with other mammalian leptin cDNAs. It is concluded that 1) placental leptin expression and secretion are species-specific traits, 2) placental leptin production represents one of three major mechanisms for achieving high circulating maternal leptin levels during pregnancy, the others being upregulation of adipose leptin production and production of circulating leptin-binding proteins, and 3) hepatic leptin expression in pregnant insectivorous bats may be an adaptation resulting from the presence of extremely low amounts of subcutaneous fat during pregnancy and lactation in these species.
High-resolution magnetic resonance imaging tracks changes in organ and tissue mass in obese and aging rats
Authors: Tang Haiying , Vasselli Joseph R. , Wu Ed X. , Boozer Carol N. , Gallagher Dympna
Published: March 2015

Magnetic resonance imaging (MRI) has the ability to discriminate between various soft tissues in vivo. Whole body, specific organ, total adipose tissue (TAT), intra-abdominal adipose tissue (IAAT), and skeletal muscle (SM) weights determined by MRI were compared with weights determined by dissection and chemical analysis in two studies with male Sprague-Dawley rats. A 4.2-T MRI machine acquired high-resolution, in vivo, longitudinal whole body images of rats as they developed obesity or aged. Weights of the whole body and specific tissues were determined using computer image analysis software, including semiautomatic segmentation algorithms for volume calculations. High correlations were found for body weight ( r = 0.98), TAT ( r = 0.99), and IAAT ( r = 0.98) between MRI and dissection and chemical analyses. MRI estimated the weight of the brain, kidneys, and spleen with high accuracy ( r > 0.9), but overestimated IAAT, SM, and liver volumes. No differences were detected in organ weights using MRI and dissection measurements. Longitudinal MRI measurements made during the development of obesity and aging accurately represented changes in organ and tissue mass.