bluuebunny/crossref_metadata_2025 huggingface dataset:
Higher skeletal muscle protein synthesis and lower breakdown after chemotherapy in cachectic mice
Authors: Samuels S. E. , Knowles A. L. , Tilignac T. , Debiton E. , Madelmont J. C. , Attaix D.
Published: December 2017

The influence of cancer cachexia and chemotherapy and subsequent recovery of skeletal muscle protein mass and turnover was investigated in mice. Cancer cachexia was induced using colon 26 adenocarcinoma, which is characteristic of the human condition, and can be cured with 100% efficacy using an experimental nitrosourea, cystemustine (C6H12CIN3O4S). Reduced food intake was not a factor in these studies. Three days after cachexia began, healthy and tumor-bearing mice were given a single intraperitoneal injection of cystemustine (20 mg/kg). Skeletal muscle mass in tumor-bearing mice was 41% lower ( P < 0.05) than in healthy mice 2 wk after cachexia began. Skeletal muscle wasting was mediated initially by decreased protein synthesis (−38%; P < 0.05) and increased degradation (+131%; P < 0.05); later wasting resulted solely from decreased synthesis (∼−54 to −69%; P < 0.05). Acute cytotoxicity of chemotherapy did not appear to have an important effect on skeletal muscle protein metabolism in either healthy or tumor-bearing mice. Recovery began 2 days after treatment; skeletal muscle mass was only 11% lower than in healthy mice 11 days after chemotherapy. Recovery of skeletal muscle mass was affected initially by decreased protein degradation (−80%; P < 0.05) and later by increased protein synthesis (+46 to +73%; P < 0.05) in cured compared with healthy mice. This study showed that skeletal muscle wasted from cancer cachexia and after chemotherapeutic treatment is able to generate a strong anabolic response by making powerful changes to protein synthesis and degradation.
Reduced neuromuscular activity and force generation during prolonged cycling
Authors: St Clair Gibson A. , Schabort E. J. , Noakes T. D.
Published: December 2017

We examined neuromuscular activity during stochastic (variable intensity) 100-km cycling time trials (TT) and the effect of dietary carbohydrate manipulation. Seven endurance-trained cyclists performed two 100-km TT that included five 1-km and four 4-km high-intensity epochs (HIE) during which power output, electromyogram (EMG), and muscle glycogen data were analyzed. The mean power output of the 4-km HIE decreased significantly throughout the trial from 319 ± 48 W for the first 4-km HIE to 278 ± 39 W for the last 4-km HIE ( P < 0.01). The mean integrated EMG (IEMG) activity during the first 4-km HIE was 16.4 ± 9.8% of the value attained during the pretrial maximal voluntary contraction (MVC). IEMG decreased significantly throughout the trial, reaching 11.1 ± 5.6% during the last 4-km HIE ( P < 0.01). The study establishes that neuromuscular activity in peripheral skeletal muscle falls parallel with reduction in power output during bouts of high-intensity exercise. These changes occurred when <20% of available muscle was recruited and suggest the presence of a central neural governor that reduces the active muscle recruited during prolonged exercise.
Lactate-transport activity in RBCs of trained and untrained individuals from four racing species
Authors: Väihkönen Leena K. , Heinonen Olli J. , Hyyppä Seppo , Nieminen Mauri , Pösö A. Reeta
Published: December 2017

In red blood cells (RBC) of horses, both lactate-transport activity and lactate accumulation during races vary interindividually. To study whether similar variation in lactate transport is apparent also in RBCs of other racing species, blood samples were collected from 21 reindeer, 40 horses, 31 humans, and 38 dogs. Total lactate-transport activity was measured at 10 and 30 mM concentrations, and the roles of the monocarboxylate-transporter (MCT) and the inorganic anion-exchange transporter (band-3 protein) were studied with inhibitors. In the reindeer and in one-third of the horses, lactate transport was low and mediated mainly by band-3 protein and nonionic diffusion. In the humans, dogs, and the remaining two-thirds of the horses, lactate transport was high and MCT was the main transporter. No correlation existed between MCT activity and the athleticism of the species. In the horses and humans, training had no effect on lactate transport, but in the reindeer and sled dogs, training increased total lactate transport. These results show that among the racing species studied, only in horses was the distribution of lactate-transport activity bimodal, and the possible connection between RBC lactate and performance capacity, especially in this species, warrants further studies.
Phase-advance shifts of human circadian pacemaker are accelerated by daytime physical exercise
Authors: Miyazaki Toshihiko , Hashimoto Satoko , Masubuchi Satoru , Honma Sato , Honma Ken-Ichi
Published: December 2017

Effects of forced sleep-wake schedules with and without physical exercise were examined on the human circadian pacemaker under dim light conditions. Subjects spent 15 days in an isolation facility separately without knowing the time of day and followed a forced sleep-wake schedule of a 23 h 40-min period for 12 cycles, and physical exercise was imposed twice per waking period for 2 h each with bicycle- or rowing-type ergometers. As a result, plasma melatonin rhythm was significantly phase advanced with physical exercise, whereas it was not changed without exercise. The difference in phase was already significant 6 days after the start of exercise. The amplitude of melatonin rhythm was not affected. A single pulse of physical exercise in the afternoon or at midnight significantly phase delayed the melatonin rhythms when compared with the prepulse phase, but the amount of phase shift was not different from that observed in the sedentary controls. These findings indicate that physical exercise accelerates phase-advance shifts of the human circadian pacemaker associated with the forced sleep-wake schedule.
Fluid volume and osmoregulation in humans after a week of head-down bed rest
Authors: Bestle Morten Heiberg , Norsk Peter , Bie Peter
Published: December 2017

Body fluid homeostasis was investigated during chronic bed rest (BR) and compared with that of acute supine conditions. The hypothesis was tested that 6° head-down BR leads to hypovolemia, which activates antinatriuretic mechanisms so that the renal responses to standardized saline loading are attenuated. Isotonic (20 ml/kg body wt) and hypertonic (2.5%, 7.2 ml/kg body wt) infusions were performed in eight subjects over 20 min following 7 and 10 days, respectively, of BR during constant sodium intake (200 meq/day). BR decreased body weight (83.0 ± 4.8 to 81.8 ± 4.4 kg) and increased plasma osmolality (285.9 ± 0.6 to 288.5 ± 0.9 mosmol/kgH2O, P < 0.05). Plasma ANG II doubled (4.2 ± 1.2 to 8.8 ± 1.8 pg/ml), whereas other endocrine variables decreased: plasma atrial natriuretic peptide (42 ± 3 to 24 ± 3 pg/ml), urinary urodilatin excretion rate (4.5 ± 0.3 to 3.2 ± 0.1 pg/min), and plasma vasopressin (1.7 ± 0.3 to 0.8 ± 0.2 pg/ml, P < 0.05). During BR, the natriuretic response to the isotonic saline infusion was augmented (39 ± 8 vs. 18 ± 6 meq sodium/350 min), whereas the response to hypertonic saline was unaltered (32 ± 8 vs. 29 ± 5 meq/350 min, P< 0.05). In conclusion, BR elicits antinatriuretic endocrine signals, but it does not attenuate the renal natriuretic response to saline stimuli in men; on the contrary, the response to isotonic saline is augmented.
Pulmonary surfactant in birds: coping with surface tension in a tubular lung
Authors: Bernhard Wolfgang , Gebert Andreas , Vieten Gertrud , Rau Gunnar A. , Hohlfeld Jens M. , Postle Anthony D. , Freihorst Joachim
Published: December 2017

As birds have tubular lungs that do not contain alveoli, avian surfactant predominantly functions to maintain airflow in tubes rather than to prevent alveolar collapse. Consequently, we have evaluated structural, biochemical, and functional parameters of avian surfactant as a model for airway surfactant in the mammalian lung. Surfactant was isolated from duck, chicken, and pig lung lavage fluid by differential centrifugation. Electron microscopy revealed a uniform surfactant layer within the air capillaries of the bird lungs, and there was no tubular myelin in purified avian surfactants. Phosphatidylcholine molecular species of the various surfactants were measured by HPLC. Compared with pig surfactant, both bird surfactants were enriched in dipalmitoylphosphatidylcholine, the principle surface tension-lowering agent in surfactant, and depleted in palmitoylmyristoylphosphatidylcholine, the other disaturated phosphatidylcholine of mammalian surfactant. Surfactant protein (SP)-A was determined by immunoblot analysis, and SP-B and SP-C were determined by gel-filtration HPLC. Neither SP-A nor SP-C was detectable in either bird surfactant, but both preparations of surfactant contained SP-B. Surface tension function was determined using both the pulsating bubble surfactometer (PBS) and capillary surfactometer (CS). Under dynamic cycling conditions, where pig surfactant readily reached minimal surface tension values below 5 mN/m, neither avian surfactant reached values below 15 mN/m within 10 pulsations. However, maximal surface tension of avian surfactant was lower than that of porcine surfactant, and all surfactants were equally efficient in the CS. We conclude that a surfactant composed primarily of dipalmitoylphosphatidylcholine and SP-B is adequate to maintain patency of the air capillaries of the bird lung.
Hypothalamic control of photoperiod-induced cycles in food intake, body weight, and metabolic hormones in rams
Authors: Lincoln Gerald A. , Rhind Stewart M. , Pompolo Sueli , Clarke Iain J.
Published: December 2017

This study used a hypothalamo-pituitary disconnected (HPD) sheep model to investigate the central regulation of long-term cycles in voluntary food intake (VFI) and body weight (BW). VFI, BW, and circulating concentrations of metabolic hormones [α-melanocyte-stimulating hormone (α-MSH), insulin-like growth factor-1 (IGF-1), insulin, and leptin] were measured in HPD and control Soay rams exposed to alternating 16 weekly periods of long and short days for 80 wk. In the controls, the physiology was cyclical with a 32-wk periodicity corresponding to the lighting regimen. VFI and BW increased under long days to a maximum early into short days, and there were associated increases in blood concentrations of α-MSH, insulin, and leptin. In the HPD rams, there were no significant photoperiod-induced changes in any of the parameters. VFI increased after surgery for 8 wk and then gradually declined, although BW increased progressively and the HPD rams became obese. Concentrations of α-MSH, insulin, and leptin in peripheral blood were permanently increased (>200%), and levels of IGF-1 decreased (<55%). The HPD lesion effectively destroyed the entire median eminence [no nerve terminals immunostained for tyrosine hydroxylase (TH) and gonadotropin-releasing hormone] and the adjacent arcuate nucleus (no perikarya immunostained for proopiomelanocortin or TH, and no cells expressed neuropeptide Y mRNA). The results support the conclusion that arcuate hypothalamic systems generate long-term rhythms in VFI, BW, and energy balance.
Central blockade of vasopressin V1receptors attenuates postexercise hypotension
Authors: Collins Heidi L. , Rodenbaugh David W. , DiCarlo Stephen E.
Published: December 2017

We tested the hypothesis that central arginine vasopressin (AVP) mediates postexercise reductions in arterial pressure (AP) and heart rate (HR). To test this hypothesis, nine spontaneously hypertensive rats (SHR) were instrumented with a 22-gauge stainless steel guide cannula in the right lateral cerebral ventricle and with a carotid arterial catheter. After the rats recovered, AP and HR were assessed before and after a single bout of dynamic exercise with the central administration of vehicle or the selective AVP V1-receptor antagonist d(CH3)5Tyr(Me)-AVP (AVP-X). AP and HR were significantly decreased below preexercise values with central administration of vehicle [ P < 0.05, change (Δ)−21 ± 4 mmHg and Δ−20 ± 6 beats/min, respectively]. In sharp contrast, after exercise with central administration of AVP-X, both AP (Δ+8 ± 5 mmHg) and HR (Δ+24 ± 9 beats/min) were not significantly different from preexercise values ( P > 0.05). Furthermore, AVP-X at rest did not significantly alter AP (181 ± 11 vs. 178 ± 11 mmHg, P > 0.05) or HR (328 ± 24 vs. 331 ± 22 beats/min, P > 0.05). Thus central blockade of AVP V1 receptors prevented postexercise reductions in AP and HR. These data suggest that AVP, acting within the central nervous system, mediates postexercise reductions in AP and HR in the SHR.
Neuroendocrine and renal effects of intravascular volume expansion in compensated heart failure
Authors: Gabrielsen Anders , Bie Peter , Holstein-Rathlou Niels Henrik , Christensen Niels Juel , Warberg Jørgen , Dige-Petersen Harriet , Frandsen Erik , Galatius Søren , Pump Bettina , Sørensen Vibeke B. , Kastrup Jens , Norsk Peter
Published: December 2017

To examine if the neuroendocrine link between volume sensing and renal function is preserved in compensated chronic heart failure [HF, ejection fraction 0.29 ± 0.03 (mean ± SE)] we tested the hypothesis that intravascular and central blood volume expansion by 3 h of water immersion (WI) elicits a natriuresis. In HF, WI suppressed ANG II and aldosterone (Aldo) concentrations, increased the release of atrial natriuretic peptide (ANP), and elicited a natriuresis ( P < 0.05 for all) compared with seated control. Compared with control subjects ( n = 9), ANG II, Aldo, and ANP concentrations were increased ( P < 0.05) in HF, whereas absolute and fractional sodium excretion rates were attenuated [47 ± 16 vs. 88 ± 15 μmol/min and 0.42 ± 0.18 vs. 0.68 ± 0.12% (mean ± SE), respectively, both P < 0.05]. When ANG II and Aldo concentrations were further suppressed ( P < 0.05) during WI in HF (by sustained angiotensin-converting enzyme inhibitor therapy, n = 9) absolute and fractional sodium excretion increased ( P < 0.05) to the level of control subjects (108 ± 34 μmol/min and 0.70 ± 0.23%, respectively). Renal free water clearance increased during WI in control subjects but not in HF, albeit plasma vasopressin concentrations were similar in the two groups. In conclusion, the neuroendocrine link between volume sensing and renal sodium excretion is preserved in compensated HF. The natriuresis of WI is, however, modulated by the prevailing ANG II and Aldo concentrations. In contrast, renal free water clearance is attenuated in response to volume expansion in compensated HF despite normalized plasma AVP concentrations.
Role of α-MSH in the regulation of consummatory behavior: immunohistochemical evidence
Authors: Olszewski Pawel K. , Wirth Michelle M. , Shaw Timothy J. , Grace Martha K. , Billington Charles J. , Giraudo Silvia Q. , Levine Allen S.
Published: December 2017

Central injection of α-melanocyte-stimulating hormone (α-MSH) decreases food intake, suggesting a role for this peptide in the mediation of satiety. Inasmuch as α-MSH also supports the development of taste aversions under certain conditions, the nature of its influence on ingestive behavior, i.e., whether it is related to satiety or aversion, remains unclear. In the present studies, we used immunostaining, including that for c-Fos as a marker of neuronal activation, to further substantiate the physiological role for α-MSH in the regulation of consummatory behavior. We found that an increase in activation of α-MSH neurons in the arcuate nucleus coincided with meal termination. Administration of powerful aversive agents, LiCl and CuSO4, did not stimulate α-MSH cells but did induce pronounced activation of oxytocin (OT) and vasopressin (VP) neurons, the final components of circuitry mediating aversion. We observed fewer Fos-positive OT/VP neurons after α-MSH injection into the lateral ventricle or into the hypothalamic paraventricular nucleus, treatments that cause mild or no aversion, respectively. The degree of activation of OT/VP neurons paralleled the magnitude of aversive response to a given treatment. Our data support the hypothesis that, in the arcuate nucleus, α-MSH acts as a satiety mediator independent from aversion-related mechanisms.
Interleukin-15 and interleukin-2 enhance non-REM sleep in rabbits
Authors: Kubota Takeshi , Brown Richard A. , Fang Jidong , Krueger James M.
Published: December 2017

Interleukin (IL)-15 and -2 share receptor- and signal-transduction pathway (Jak-STAT pathway) components. IL-2 is somnogenic in rats but has not been tested in other species. Furthermore, the effects of IL-15 on sleep have not heretofore been described. We investigated the somnogenic actions of IL-15 in rabbits and compared them with those of IL-2. Three doses of IL-15 or -2 (10, 100, and 500 ng) were injected intracerebroventriculary at the onset of the dark period. In addition, 500 ng of IL-15 and -2 were injected 3 h after the beginning of the light period. IL-15 dose dependently increased non-rapid eye movement sleep (NREMS) and induced fever. IL-15 inhibited rapid eye movement sleep (REMS) after its administration during the light period; however, all doses of IL-15 failed to affect REMS if given at dark onset. IL-2 also dose dependently increased NREMS and fever. IL-2 inhibited REMS, and this effect was observed only in the light period. IL-15 and -2 enhanced electroencephalographic (EEG) slow waves during the initial 9-h postinjection period, then, during hours 10–23postinjection, reduced EEG slow-wave activity. Current data support the notion that the brain cytokine network is involved in the regulation of sleep.
Estradiol treatment increases feeding-induced c-Fos expression in the brains of ovariectomized rats
Authors: Eckel Lisa A. , Geary Nori
Published: December 2017

The steroid hormone estradiol decreases meal size by increasing the potency of negative-feedback signals involved in meal termination. We used c-Fos immunohistochemistry, a marker of neuronal activation, to investigate the hypothesis that estradiol modulates the processing of feeding-induced negative-feedback signals within the nucleus of the solitary tract (NTS), the first central relay of the neuronal network controlling food intake, and within other brain regions related to the control of food intake. Chow-fed, ovariectomized rats were injected subcutaneously with 10 μg 17-β estradiol benzoate or sesame oil vehicle on 2 consecutive days. Forty-eight hours after the second injections, 0, 5, or 10 ml of a familiar sweet milk diet were presented for 20 min at dark onset. Rats were perfused 100 min later, and brain tissue was collected and processed for c-Fos-like immunoreactivity. Feeding increased the number of c-Fos-positive cells in the NTS, the paraventricular nucleus of the hypothalamus (PVN), and the central nucleus of the amygdala (CeA) in oil-treated rats. Estradiol treatment further increased this response in the caudal, subpostremal, and intermediate NTS, which process negative-feedback satiation signals, but not in the rostral NTS, which processes positive-feedback gustatory signals controlling meal size. Estradiol treatment also increased feeding-induced c-Fos in the PVN and CeA. These results indicate that modest amounts of food increase neuronal activity within brain regions implicated in the control of meal size in ovariectomized rats and that estradiol treatment selectively increases this activation. They also suggest that estradiol decreases meal size by increasing feeding-related neuronal activity in multiple regions of the distributed neural network controlling meal size.
Mineralocorticoids upregulate arterial contraction to epidermal growth factor
Authors: Florian Jennifer A. , Dorrance Anne , Webb R. Clinton , Watts Stephanie W.
Published: December 2017

The present studies test the hypothesis that contraction to EGF is dependent on mineralocorticoids and/or an elevation in systolic blood pressure (SBP). Endothelium-denuded thoracic aortas from sham normotensive, Nω-nitro-l-arginine (l-NNA) hypertensive, Wistar-Kyoto (WKY), and spontaneously hypertensive rats (SHR) were used in isolated tissue-bath experiments. Maximal contraction to epidermal growth factor [EGF; percentage of phenylephrine (PE; 10 umol/l)-induced contraction] was greater in strips from l-NNA (32 ± 5%) and SHR (53 ± 8%) rats compared with sham and WKY rats (17 ± 1 and 12 ± 4%, respectively). Wistar-Furth rats became only mildly hypertensive when given DOCA salt (134 ± 6 mmHg) compared with Wistar rats (176 ± 9 mmHg), but aortas from both strains had a similarly enhanced contraction to EGF (∼9 times the maximal contraction of sham aorta). Furthermore, in vitro incubation of aortas from Wistar and Wistar-Furth rats with aldosterone (10 nmol/l) increased EGF-receptor mRNA expression by >50%. These data indicate that arterial contraction to EGF may occur independent of hypertension and be stimulated by mineralocorticoids.
The α1- and α2-isoforms of Na-K-ATPase play different roles in skeletal muscle contractility
Authors: He Suiwen , Shelly Daniel A. , Moseley Amy E. , James Paul F. , James J. Howard , Paul Richard J. , Lingrel Jerry B.
Published: December 2017

The Na-K-ATPase, which maintains the Na+and K+gradients across the plasma membrane, can play a major role in modulation of skeletal muscle contractility. Although both α1- and α2-isoforms of the Na-K-ATPase are expressed in skeletal muscle, the physiological significance of these isoforms in contractility is not known. Evaluation of the contractile parameters of mouse extensor digitorum longus (EDL) was carried out using gene-targeted mice lacking one copy of either the α1- or α2-isoform gene of the Na-K-ATPase. The EDL muscles from heterozygous mice contain approximately one-half of the α1- or α2-isoform, respectively, which permits differentiation of the functional roles of these isoforms. EDL from the α1+/−mouse shows lower force compared with wild type, whereas that from the α2+/−mouse shows greater force. The different functional roles of these two isoforms are further demonstrated because inhibition of the α2-isoform with ouabain increases contractility of α1+/−EDL. These results demonstrate that the Na-K-ATPase α1- and α2-isoforms may play different roles in skeletal muscle contraction.
Spironolactone reduces cerebral infarct size and EGF-receptor mRNA in stroke-prone rats
Authors: Dorrance Anne M. , Osborn Heather L. , Grekin Roger , Webb R. Clinton
Published: December 2017

Remodeling of the cerebral vasculature contributes to the pathogenesis of cerebral ischemia. Remodeling is caused by increased smooth muscle proliferation and may be due to an increase in the responsiveness of vascular cells to epidermal growth factor (EGF). Aldosterone is a risk factor for stroke, and the literature suggests it may play a role in increasing the expression of the receptor for EGF (EGFR). We hypothesized that mRNA for the EGF-stimulated pathway would be elevated in the vasculature of stroke-prone spontaneously hypertensive rats (SHRSP) and that this and experimental ischemic cerebral infract size would be reduced by aldosterone inhibition with spironolactone. We found that spironolactone treatment reduced the size of cerebral infarcts after middle cerebral artery occlusion in SHRSP (51.69 ± 3.60 vs. 22.00 ± 6.69% of hemisphere-infarcted SHRSP vs. SHRSP + spironolactone P < 0.05). Expression of EGF and EGFR mRNA was higher in cerebral vessels and aorta from adult SHRSP compared with Wistar-Kyoto rats. Only the expression of EGFR mRNA was elevated in the young SHRSP. Spironolactone reduced the EGFR mRNA expression in the aorta (1.09 ± 0.25 vs. 0.56 ± 0.11 phosphorimage units SHRSP vs. SHRSP + spironolactone P < 0.05) but had no effect on EGF mRNA. In vitro incubation of aorta with aldosterone ± spironolactone produced similar results, suggesting a direct effect of aldosterone. Thus spironolactone may reduce the size of cerebral infarcts via a reduction in the expression of the EGFR mRNA, leading to reduced remodeling.
Programming effects in sheep of prenatal growth restriction and glucocorticoid exposure
Authors: Moss Timothy J. M. , Sloboda Deborah M. , Gurrin Lyle C. , Harding Richard , Challis John R. G. , Newnham John P.
Published: December 2017

Our aim was to determine the postnatal effects of single and repeated glucocorticoid injections during late gestation. Repeated (104, 111, 118, 125 days) or single (104 days) injections of betamethasone or saline were given to the ewe or by ultrasound guided injection to the fetus (term 150 days). Lambs were born spontaneously and studied at 3 and 6 mo and 1 yr of age. Arterial pressure was measured at each age, and we performed intravenous glucose tolerance tests at 6 mo and 1 yr. Repeated maternal, but not single maternal or fetal, betamethasone injections prolonged gestation, reduced weight at birth and 3 mo, and was associated with low arterial pressure at 3 mo but not at 6 mo and 1 yr. Glucose metabolism was altered in all betamethasone treatment groups, regardless of the number or route of injections. Our data demonstrate that glucocorticoid-induced fetal growth restriction is associated with a transient reduction in postnatal arterial pressure, but glucocorticoid exposure with or without growth restriction alters glucose metabolism.
Calcium deprivation alters gustatory-evoked activity in the rat nucleus of the solitary tract
Authors: McCaughey Stuart A. , Tordoff Michael G.
Published: December 2017

Calcium-deprived rats develop a compensatory appetite for substances that contain calcium. To investigate the role of gustatory factors in calcium appetite, we recorded the extracellular activity of single neurons in the nucleus of the solitary tract of calcium-deprived and replete rats. The activity evoked by a broad array of taste stimuli was examined in 51 neurons from replete rats and 47 neurons from calcium-deprived rats. There were no differences between the groups in the responses of all neurons combined. However, neurons with sugar-oriented response profiles gave significantly larger responses to 3, 10, and 100 mM CaCl2in the calcium-deprived group than did corresponding cells in the replete group. This difference in taste-evoked responding may underlie an increase in the palatability of CaCl2 and, in turn, contribute to the expression of calcium appetite.
α-2 And β-adrenergic receptors mediate NE's biphasic effects on rat thick ascending limb chloride flux
Authors: Plato Craig F.
Published: December 2017

The sympathetic neurotransmitter norepinephrine (NE) influences renal sodium excretion via activation of adrenergic receptors. The thick ascending limb (THAL) possesses both α-2 and β-adrenergic receptors. However, the role(s) different adrenergic receptors play in how isolated THALs respond to NE are unclear. We tested the hypothesis that both α-2 and β-adrenergic receptors are responsive to NE in the isolated THAL, with α-2 receptors inhibiting and β-receptors stimulating chloride flux ( JCl). THALs from male Sprague-Dawley rats were perfused in vitro, and the effects of 1) incremental NE, 2) the α-2 agonist clonidine, and 3) the β-agonist isoproterenol on JClwere measured. Low concentrations (0.1 nM) of NE decreased JClfrom a rate of 114.2 ± 8.1 to 93.5 ± 14.6 pmol · mm−1· min−1( P < 0.05), with the nadir occurring at 1 nM (67.7 ± 8.8 pmol · mm−1· min−1; P < 0.05). In contrast, greater concentrations of NE significantly increased JClfrom the nadir to a maximal rate of 131.0 ± 28.5 pmol · mm−1· min−1at 10 μM ( P < 0.05). To evaluate the adrenergic receptors mediating these responses, the THAL JClresponse to NE was measured in the presence of selective antagonists of β- and α-2 receptors. A concentration of NE (1 μM), which alone tended to increase JCl, decreased THAL JCl(from 148.9 ± 16.4 to 76.2 ± 13.6 pmol · mm−1· min−1; P < 0.01) in the presence of the β-antagonist propranolol. In contrast, a concentration of NE (0.1 μM), which alone tended to decrease JCl, increased THAL JCl(from 85.5 ± 20.1 to 111.8 ± 20.1 pmol · mm−1· min−1; P < 0.05) in the presence of the α-2 antagonist rauwolscine. To further clarify the role of different adrenergic receptors, selective adrenergic agonists were used. The α-2 agonist clonidine decreased JClfrom 102.4 ± 9.9 to 54.0 ± 15.7 pmol · mm−1· min−1, a reduction of 49.1 ± 11.0% ( P < 0.02). In contrast, the β-agonist isoproterenol stimulated JClfrom 95.3 ± 11.6 to 144.1 ± 15.0 pmol · mm−1· min−1, an increase of 56 ± 14% ( P < 0.01). We conclude that 1) the sympathetic neurotransmitter NE exerts concentration-dependent effects on JClin the isolated rat THAL, 2) selective α-2 receptor activation inhibits THAL JCl, and 3) selective β-receptor activation stimulates THAL JCl. These data indicate the response elicited by the isolated rat THAL to NE is dependent on the neurotransmitter concentration, such that application of NE in vitro biphasically modulates JClvia differential activation of α-2 and β-adrenergic receptors in a concentration-dependent manner.
Role of the renin-angiotensin system during alterations of sodium intake in conscious mice
Authors: Cholewa Brian C. , Mattson David L.
Published: December 2017

The present studies were performed to quantify circulating components of the renin-angiotensin-aldosterone axis and to determine the functional importance of this system during alterations in sodium intake in conscious mice. Increasing sodium intake from ∼200 to 1,000 μeq/day significantly decreased plasma renin concentration from 472 ± 96 to 304 ± 83 ng ANG I · ml−1· h−1( n = 5) but did not alter plasma renin activity from the low-sodium level of 7.7 ± 1.1 ng ANG I · ml−1· h−1. Despite the elevated plasma renin concentration, plasma ANG II in mice on low-sodium level averaged 14 ± 3 pg/ml and was significantly suppressed to 6 ± 1 pg/ml by high-sodium intake ( n = 7). Consistent with the modulation of ANG II, plasma aldosterone significantly decreased from 41 ± 8 to 8 ± 3 ng/dl when sodium intake was elevated ( n = 6). In a final set of experiments, the continuous infusion of ANG II (20 ng · kg−1· min−1) led to a mild salt-sensitive increase in mean arterial pressure from 108 ± 2 to 131 ± 2 mmHg as sodium intake was varied from low to high ( n = 7). In vehicle-infused mice, mean arterial pressure was unaltered from 109 ± 2 mmHg when sodium intake was increased ( n = 6). These studies indicate that the physiological suppression of circulating ANG II may be required to maintain a constancy of arterial pressure during alterations in sodium intake in normal mice.
Nitric oxide synthase and cGMP-mediated stimulation of renin secretion
Authors: Sayago Cecilia M. , Beierwaltes William H.
Published: December 2017

The interaction between nitric oxide (NO) and renin is controversial. cAMP is a stimulating messenger for renin, which is degraded by phosphodiesterase (PDE)-3. PDE-3 is inhibited by cGMP, whereas PDE-5 degrades cGMP. We hypothesized that if endogenous cGMP was increased by inhibiting PDE-5, it could inhibit PDE-3, increasing endogenous cAMP, and thereby stimulate renin. We used the selective PDE-5 inhibitor zaprinast at 20 mg/kg body wt ip, which we determined would not change blood pressure (BP) or renal blood flow (RBF). In thiobutabarbital (Inactin)-anesthetized rats, renin secretion rate (RSR) was determined before and 75 min after administration of zaprinast or vehicle. Zaprinast increased cGMP excretion from 12.75 ± 1.57 to 18.67 ± 1.87 pmol/min ( P < 0.003), whereas vehicle had no effect. Zaprinast increased RSR sixfold (from 2.95 ± 1.74 to 17.62 ± 5.46 ng ANG I · h−1 · min−1, P< 0.024), while vehicle had no effect (from 4.08 ± 2.02 to 3.87 ± 1.53 ng ANG I · h−1 · min−1). There were no changes in BP or RBF. We then tested whether the increase in cGMP could be partially due to the activity of the neuronal isoform of NO synthase (nNOS). Pretreatment with the nNOS inhibitor 7-nitroindazole (7-NI; 50 mg/kg body wt) did not change BP or RBF but attenuated the renin-stimulating effect of zaprinast by 40% compared with vehicle. In 7-NI-treated animals, zaprinast-stimulated cGMP excretion was attenuated by 48%, from 9.17 ± 1.85 to 13.60 ± 2.15 pmol/min, compared with an increase from 10.94 ± 1.90 to 26.38 ± 3.61 pmol/min with zaprinast without 7-NI ( P < 0.04). This suggests that changes in endogenous cGMP production at levels not associated with renal hemodynamic changes are involved in a renin-stimulatory pathway. One source of this cGMP may be nNOS generation of NO in the kidney.
Comparison of cerebrospinal fluid transport in fetal and adult sheep
Authors: Mollanji R. , Papaiconomou C. , Boulton M. , Midha R. , Johnston M.
Published: December 2017

We quantified cerebrospinal fluid (CSF) transport (conductance) and CSF outflow resistance in late-gestation fetal and adult sheep using two methods, a constant pressure infusion method and a bolus injection technique into the lateral ventricles. No significant differences in CSF conductance (fetus 0.013 ± 0.002, adult 0.014 ± 0.003 ml · min−1 · cmH2O−1) or CSF outflow resistance (fetus 83.7 ± 9.8, adult 84.7 ± 19.7 cmH2O · ml−1 · min) were observed. To confirm CSF transport to plasma in fetal animals,125I- or 131I-labeled human serum albumin (HSA) was injected into the lateral ventricles. The tracer entered fetal plasma with an average mass transport rate of 1.91 ± 0.47% injected/h ( n = 9). In two fetuses, we monitored the tracer appearance in plasma and cervical and thoracic duct lymph after injection of radioactive HSA into the ventricular CSF. As was the case in adult animals, fetal tracer concentrations increased in all three compartments over time, with the highest concentrations measured in lymph collected from the cervical lymphatics. These results 1) indicate that global CSF transport parameters in the late-gestation fetus and adult sheep are similar and 2) suggest an important role for extracranial lymphatic vessels in CSF transport before birth.
Endothelial function and myogenic reactivity in small mesenteric arteries of hyperlipidemic pregnant rats
Authors: Ramirez R. J. J. , Novak J. , Johnston T. P. , Gandley R. E. , McLaughlin M. K. , Hubel C. A.
Published: December 2017

Supraphysiological increases in serum triglycerides and cholesterol often occur during pregnancy, but their effects on vascular function are poorly understood. Intraperitoneal injection of the nontoxic surfactant poloxamer 407 (P-407) results in sustained elevation of triglycerides and cholesterol. We asked if P-407-induced hyperlipidemia during late pregnancy adversely affects mesenteric resistance artery vasodilator function. On days 13–15 of pregnancy, rats were given a single intraperitoneal injection of P-407, sterile water vehicle, or non-lipid-altering pluronic F-88 (P-88). Four days postinjection, serum triglycerides, cholesterol, free fatty acids, and the lipid peroxidation product malondialdehyde were significantly increased in P-407-treated rats. Mesenteric arteries from P-407-treated rats displayed significant increases in myogenic reactivity (constrictor responses to step increases in intraluminal pressure). The nitric oxide (NO) blocker Nα-methyl-l-arginine increased the myogenic response in control but not in P-407 arteries, normalizing group differences. Endothelial removal increased myogenic reactivity beyond that of prior NO synthase inhibition in controls and potentiated myogenic reactivity in P-407 arteries such that responses again converged. Relaxation responses to the endothelium-dependent vasodilator methacholine did not differ. We conclude that that P-407-induced hyperlipidemia during pregnancy increases myogenic reactivity due to selective attenuation of an NO-mediated vasodilator component of the myogenic response.
Abolished tubuloglomerular feedback and increased plasma renin in adenosine A1 receptor-deficient mice
Authors: Brown Russell , Ollerstam Anna , Johansson Björn , Skøtt Ole , Gebre-Medhin Samuel , Fredholm Bertil , Persson A. Erik G.
Published: December 2017

The hypothesis that adenosine acting on adenosine A1 receptors (A1R) regulates several renal functions and mediates tubuloglomerular feedback (TGF) was examined using A1R knockout mice. We anesthetized knockout, wild-type, and heterozygous mice and measured glomerular filtration rate, TGF response using the stop-flow pressure (Psf) technique, and plasma renin concentration. The A1R knockout mice had an increased blood pressure compared with wild-type and heterozygote mice. Glomerular filtration rate was similar in all genotypes. Proximal tubular Psf was decreased from 36.7 ± 1.2 to 25.3 ± 1.6 mmHg in the A1R+/+ mice and from 38.1 ± 1.0 to 27.4 ± 1.1 mmHg in A1R+/− mice in response to an increase in tubular flow rate from 0 to 35 nl/min. This response was abolished in the homozygous A1R−/− mice (from 39.1 ± 4.1 to 39.2 ± 4.5 mmHg). Plasma renin activity was significantly greater in the A1R knockout mice [74.2 ± 14.3 milli-Goldblatt units (mGU)/ml] mice compared with the wild-type and A1R+/− mice (36.3 ± 8.5 and 34.1 ± 9.6 mGU/ml), respectively. The results demonstrate that adenosine acting on A1R is required for TGF and modulates renin release.
Role of GABA within the nucleus tractus solitarii in the hypoxic ventilatory decline of awake rats
Authors: Tabata Masao , Kurosawa Hajime , Kikuchi Yoshihiro , Hida Wataru , Ogawa Hiromasa , Okabe Shinichi , Tun Ye , Hattori Toshio , Shirato Kunio
Published: December 2017

The purpose of this study was to examine our hypothesis that γ-aminobutyric acid (GABA) in the nucleus tractus solitarii (NTS) may be related to the hypoxic ventilatory decline (HVD) and that chemoreceptor stimulation was essential to activate this mechanism. We used unanesthetized, freely moving rats in this study. An in vivo microdialysis technique was used to measure the extracellular GABA concentration ([GABA]o), and an in vivo microinjection technique was used to examine the effects of the GABA agonists and antagonists on the ventilation during hypoxia. The GABA agonists injected into the NTS attenuated the ventilation during hypoxia. By hypoxic exposure, [GABA]o was increased during the HVD. However, by carotid body denervation (CBD), this GABA increase was abolished. Although GABA antagonists microinjected into the NTS during the HVD phase significantly increased the depressed ventilation, this effect on the ventilation was abolished by CBD. These results suggest that the GABA in the NTS has a pivotal role in the HVD and that this mechanism is not activated without chemoreceptor stimulation.
Fatty acid kinetics and carbohydrate metabolism during electrical exercise in spinal cord-injured humans
Authors: Kjær Michael , Dela Flemming , Sørensen Fin Biering , Secher Niels H. , Bangsbo Jens , Mohr Thomas , Galbo Henrik
Published: December 2017

Motor center activity and reflexes from contracting muscle have been shown to be important for mobilization of free fatty acids (FFA) during exercise. We studied FFA metabolism in the absence of these mechanisms: during involuntary, electrically induced leg cycling in individuals with complete spinal cord injury (SCI). Healthy subjects performing voluntary cycling served as controls (C). Ten SCI (level of injury: C5-T7) and six C exercised for 30 min at comparable oxygen uptake rates (∼1 l/min), and [1-14C]palmitate was infused continuously to estimate FFA turnover. From femoral arteriovenous differences, blood flow, muscle biopsies, and indirect calorimetry, leg substrate balances as well as concentrations of intramuscular substrates were determined. Leg oxygen uptake was similar in the two groups during exercise. In SCI, but not in C, plasma FFA and FFA appearance rate fell during exercise, and plasma glycerol increased less than in C ( P < 0.05). Fractional uptake of FFA across the working legs decreased from rest to exercise in all individuals ( P < 0.05) but was always lower in SCI than in C ( P < 0.05). From rest to exercise, leg FFA uptake increased less in SCI than in C subjects (14 ± 3 to 57 ± 20 vs. 41 ± 13 to 170 ± 57 μmol · min−1 · leg−1; P < 0.05). Muscle glycogen breakdown, leg glucose uptake, carbohydrate oxidation, and lactate release were higher ( P < 0.05) in SCI than in C during exercise. Counterregulatory hormonal changes were more pronounced in SCI vs. C, whereas insulin decreased only in C. In conclusion, FFA mobilization, delivery, and fractional uptake are lower and muscle glycogen breakdown and glucose uptake are higher in SCI patients during electrically induced leg exercise compared with healthy subjects performing voluntary exercise. Apparently, blood-borne mechanisms are not sufficient to elicit a normal increase in fatty acid mobilization during exercise. Furthermore, in exercising muscle, FFA delivery enhances FFA uptake and inhibits carbohydrate metabolism, while carbohydrate metabolism inhibits FFA uptake.
Role of endogenous PACAP in catecholamine secretion from the rat adrenal gland
Authors: Fukushima Yasuo , Hikichi Hirohiko , Mizukami Kazuhiko , Nagayama Takahiro , Yoshida Makoto , Suzuki-Kusaba Mizue , Hisa Hiroaki , Kimura Tomohiko , Satoh Susumu
Published: December 2017

We elucidated the contribution of endogenous pituitary adenylate cyclase-activating polypeptide (PACAP) to neurally evoked catecholamine secretion from the isolated perfused rat adrenal gland. Infusion of PACAP (100 nM) increased adrenal epinephrine and norepinephrine output. The PACAP-induced catecholamine output responses were inhibited by the PACAP type I receptor antagonist PACAP- (6-38) (30–3,000 nM) but were resistant to the PACAP type II receptor antagonist [Lys1,Pro2,5,Ara3,4,Tyr6]-vasoactive intestinal peptide (LPAT-VIP; 30–3,000 nM). Transmural electrical stimulation (ES; 1–10 Hz) or infusion of ACh (6–200 nM) increased adrenal epinephrine and norepinephrine output. PACAP-(6–38) (3,000 nM), but not LPAT-VIP, also inhibited the ES-induced catecholamine output responses. However, PACAP-(6–38) did not affect the ACh-induced catecholamine output responses. PACAP at low concentrations (0.3–3 nM), which had no influence on catecholamine output, enhanced the ACh-induced catecholamine output responses, but not the ES-induced catecholamine output responses. These results suggest that PACAP is released from the nerve endings to facilitate the neurally evoked catecholamine secretion through PACAP type I receptors in the rat adrenal gland.
Eel urea transporter is localized to chloride cells and is salinity dependent
Authors: Mistry Abinash Chandra , Honda Shinji , Hirata Taku , Kato Akira , Hirose Shigehisa
Published: December 2017

Urea transporters (UTs) in the ureotelic vertebrates have been well-characterized, but little is known about those of the ammonotelic teleost fishes. To clarify the physiological roles of UTs in the ammonotelic teleosts, we determined the structure, tissue and cellular localizations, and regulation of expression of eel UT (eUT) by cDNA cloning, Northern analysis, and immunohistochemistry. A full-length cDNA (∼1.9 kb) coding for a UT of 486 amino acid residues was isolated from a seawater eel gill cDNA library. Sequence comparison with those of other species indicated that the eUT is a short isoform with 10 transmembrane spans and has longer NH2- and COOH-terminal cytoplasmic tails compared with the mammalian counterparts. Northern blot analysis demonstrated high expression of eUT mRNA confined in the gill and a substantial increase of its levels when eels were transferred from freshwater to seawater. Immunohistochemistry showed that eUT is localized on the basolateral membranes of the chloride cells, establishing, at the cellular level, the site of urea excretion in the eel, an ammonotelic teleost.
Does nitric oxide contribute to the basal vasodilation of pregnancy in conscious rabbits?
Authors: Brooks Virginia L. , Clow Kathy A. , Welch Lisa S. , Giraud George D.
Published: December 2017

Pregnancy produces marked systemic vasodilation, but the mechanism is unknown. Experiments were performed in conscious rabbits to test the hypotheses that increased nitric oxide (NO) production contributes to the increased vascular conductance, but that the contribution varies among vascular beds. Rabbits were instrumented with aortic and vena caval catheters and ultrasonic flow probes implanted around the ascending aorta, superior mesenteric artery, terminal aorta, and/or a femoral artery. Hemodynamic responses to intravenous injection of N ω-nitro-l-arginine (l-NA; 20 mg/kg or increasing doses of 2, 5, 10, 15, and 20 mg/kg) were determined in rabbits first before pregnancy (NP) and then at the end of gestation (P). l-NA produced similar increases in arterial pressure between groups, but the following responses were larger ( P < 0.05) when the rabbits were pregnant: 1) decreases in total peripheral conductance [−3.7 ± 0.3 (NP), −5.0 ± 0.5 (P) ml · min−1 · mmHg−1], 2) decreases in mesenteric conductance [−0.47 ± 0.05 (NP), −0.63 ± 0.07 (P) ml · min−1 · mmHg−1], 3) decreases in terminal aortic conductance [−0.43 ± 0.05 (NP), −0.95 ± 0.19 ml · min−1 · mmHg−1 (P)], and 4) decreases in heart rate [−41 ± 4 (NP), −62 ± 5 beats/min (P)]. Nevertheless, total peripheral and terminal aortic conductances remained elevated in the pregnant rabbits ( P < 0.05) after l-NA. Furthermore, decreases in cardiac output and femoral conductance were not different between the reproductive states. We conclude that the contribution of NO to vascular tone increases during pregnancy, but only in some vascular beds. Moreover, the data support a role for NO in the pregnancy-induced increase in basal heart rate. Finally, unknown factors in addition to NO must also underlie the basal vasodilation observed during pregnancy.
Sleep, performance, circadian rhythms, and light-dark cycles during two space shuttle flights
Authors: Dijk Derk-Jan , Neri David F. , Wyatt James K. , Ronda Joseph M. , Riel Eymard , Ritz-De Cecco Angela , Hughes Rod J. , Elliott Ann R. , Prisk G. Kim , West John B. , Czeisler Charles A.
Published: December 2017

Sleep, circadian rhythm, and neurobehavioral performance measures were obtained in five astronauts before, during, and after 16-day or 10-day space missions. In space, scheduled rest-activity cycles were 20–35 min shorter than 24 h. Light-dark cycles were highly variable on the flight deck, and daytime illuminances in other compartments of the spacecraft were very low (5.0–79.4 lx). In space, the amplitude of the body temperature rhythm was reduced and the circadian rhythm of urinary cortisol appeared misaligned relative to the imposed non-24-h sleep-wake schedule. Neurobehavioral performance decrements were observed. Sleep duration, assessed by questionnaires and actigraphy, was only ∼6.5 h/day. Subjective sleep quality diminished. Polysomnography revealed more wakefulness and less slow-wave sleep during the final third of sleep episodes. Administration of melatonin (0.3 mg) on alternate nights did not improve sleep. After return to earth, rapid eye movement (REM) sleep was markedly increased. Crewmembers on these flights experienced circadian rhythm disturbances, sleep loss, decrements in neurobehavioral performance, and postflight changes in REM sleep.