bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of circulating endotoxin and interleukin-6 in the ACTH and corticosterone response to intraperitoneal LPS
Authors: Lenczowski M. J. P. , Van Dam A.-M. , Poole S. , Larrick J. W. , Tilders F. J. H.
Published: December 2017

Peripheral administration of lipopolysaccharide (LPS) may activate the hypothalamus-pituitary-adrenal (HPA) axis by way of both neural and humoral mechanisms. We have investigated whether biologically active endotoxin appears in the general circulation after intraperitoneal administration of LPS (5 or 100 μg/kg) to rats and whether this is a prerequisite for activation of this HPA axis. Within 15 min, endotoxin appeared in the general circulation, whereas elevations of plasma adrenocorticotropic hormone (ACTH), corticosterone, and interleukin (IL)-6 concentrations were not detected until 90 min after LPS injection. At this time, a marked interindividual variation was observed in plasma concentrations of endotoxin, ACTH, corticosterone, and IL-6. Elevated levels of plasma endotoxin were associated with elevated levels of ACTH, corticosterone, and IL-6. Intravenous administration of the LPS antagonist cationic antimicrobial protein 18 (5 mg/kg), which did not affect cytokine production in the peritoneal cavity, markedly reduced plasma ACTH, corticosterone, and IL-6 levels after 5 μg/kg LPS. Our results suggest that circulating endotoxin is required for the activation of the HPA axis. They also favor a role for circulating IL-6 in this response.
Epinephrine inhibits endotoxin-induced IL-1β production: roles of tumor necrosis factor-α and IL-10
Authors: Van Der Poll Tom , Lowry Stephen F.
Published: December 2017

Epinephrine has been found to inhibit the production of the proinflammatory cytokine tumor necrosis factor (TNF)-α and to enhance the production of anti-inflammatory cytokine interleukin (IL)-10. To determine the effect of epinephrine on IL-1β production, the following experiments were performed: 1) blood obtained from subjects at 4–21 h after the start of a continuous infusion of epinephrine (30 ng ⋅ kg−1⋅ min−1) produced less IL-1β after ex vivo stimulation with lipopolysaccharide (LPS), compared with blood drawn from subjects infused with saline; 2) in whole blood in vitro, epinephrine caused a dose-dependent decrease in LPS-induced IL-1β production, which was likely mediated via adrenergic receptors; and 3) inhibition of TNF and enhancement of IL-10 both contributed to epinephrine-induced inhibition of IL-1β production. Epinephrine, either endogenously produced or administered as a component of sepsis treatment, may attenuate excessive activity of proinflammatory cytokines early in the course of systemic infection.
Estrogen protects transgenic hypertensive rats by shifting the vasoconstrictor-vasodilator balance of RAS
Authors: Brosnihan K. Bridget , Li Ping , Ganten Detlev , Ferrario Carlos M.
Published: December 2017

In pursuit of the hypothesis that estrogen shifts the vasoconstrictor-vasodilator balance of the renin-angiotensin system, we investigated the cardiovascular responses to administration of angiotensin-(1—7) [ANG-(1—7)] and angiotensin II (ANG II) in female transgenic (mRen2)27-positive [Tg(+)] and -negative [Tg(−)] rats in the presence and absence of 3 wk of estrogen replacement therapy. Fifty-three female Tg(−) and Tg(+) rats were oophorectomized and received either 17β-estradiol (1.5 mg/rat sc for 3 wk) or vehicle. At the end of 3 wk of estrogen treatment, mean blood pressure was lowered in freely moving chronically cannulated Tg(+) (159 ± 4 vs. 145 ± 5 mmHg, P < 0.05) and Tg(−) (119 ± 4 vs. 108 ± 2 mmHg, P < 0.05) rats. Moreover, the magnitude of the depressor component of the biphasic response to ANG-(1—7) was significantly enhanced in estrogen-treated Tg(+) rats, whereas the pressor component to ANG-(1—7) was attenuated in both Tg(+) and Tg(−) rats. Estrogen replacement significantly attenuated the pressor response to ANG II in both Tg(+) and Tg(−) rats. In addition, estrogen replacement therapy significantly reduced plasma ANG-converting enzyme activity in association with a reduction in circulating levels of ANG II. Tissue levels (kidney and aorta) of ANG-converting enzyme were also reduced with chronic estrogen replacement therapy. On the other hand, estrogen augmented the levels of plasma ANG-(1—7) in Tg(+) animals. Plasma renin activity was unchanged with estrogen treatment. These findings provide the first evidence demonstrating that estrogen is protective against hypertension, possibly by amplifying the vasodilator contributions of ANG-(1—7), while reducing the formation and vasoconstrictor actions of ANG II.
Role for epithelial Na+channels and putative Na+/H+exchangers in salt taste transduction in rats
Authors: Lundy Robert F. , Pittman David W. , Contreras Robert J.
Published: December 2017

The effects of the epithelial Na+channel antagonists amiloride and benzamil and the Na+/H+exchange antagonist 5-( N, N-dimethyl)-amiloride (DMA)-Cl on the integrated responses of the chorda tympani nerve to 30, 75, 150, 300, and 500 mM concentrations of NaCl, KCl, and NH4Cl were assessed in male Sprague-Dawley rats. Based on evidence from other systems, 1 and 25 μM amiloride and benzamil were chosen to selectively inhibit epithelial Na+channels and 1 μM DMA was chosen to selectively inhibit Na+/H+exchange. When added to stimulating salt solutions, amiloride, benzamil, and DMA were each effective in inhibiting responses to all three salts. The degree of inhibition varied with drug, salt, and salt concentration, but not drug dose. Amiloride suppressed NaCl responses to a greater degree than KCl and NH4Cl responses, whereas DMA suppressed NH4Cl responses to a greater degree than NaCl and KCl responses. In all but one case (25 μM amiloride added to KCl), drug suppression of taste nerve responses decreased with an increase in salt concentration. The present results suggest that 1) epithelial Na+channels in rat taste receptor cells may play a role in KCl and NH4Cl taste transduction; 2) a Na+/H+exchange protein may be present in taste receptor cells, representing a putative component, in addition to epithelial Na+channels, in salt taste transduction; and 3) salt taste detection and transduction may depend on the utilization of a combination of common and distinct transcellular pathways.
Lactate infusion to normal rats during hyperglycemia enhances in vivo muscle glycogen synthesis
Authors: Pagano Claudio , Granzotto Marnie , Giaccari Andrea , Fabris Roberto , Serra Roberto , Lombardi Anna Maria , Federspil Giovanni , Vettor Roberto
Published: December 2017

Both hyperglycemia and hyperinsulinemia stimulate whole body and muscle glucose disposal. To define the impact of increased lactate concentration (4–5 mM) on muscle glucose disposal during hyperglycemia, we studied anesthetized normal rats infused with either sodium lactate or sodium bicarbonate as control. Animals were studied under hyperglycemic clamp (13 mM) using [3-3H]glucose ( study 1) and 2-deoxy-[1-3H]glucose ( study 2) to assess glucose rate of disappearance (Rd), glycolytic flux (GF), glycogen synthesis, and glucose utilization index by different tissues. Moreover, in study 3, the effect of lactate on the pattern of plasma insulin response to hyperglycemia was evaluated. In study 1, lactate infusion resulted in an increased Rd(38.7 ± 1.7 vs. 32.3 ± 1.3 mg ⋅ min−1⋅ kg−1; P < 0.01), which was explained by an enhanced rate of glycogen synthesis (23.0 ± 1.7 vs. 14.7 ± 1.2 mg ⋅ min−1⋅ kg−1; P < 0.001), whereas GF was unchanged. In study 2, lactate-infused animals showed an increased 2-deoxy-glucose disposal and a stimulated glycogen synthase activity as well as an increased glycogen accumulation at the end of the study in several skeletal muscles. In study 3, lactate did not induce any change in either early or late insulin response to hyperglycemia. In conclusion, our results show that muscle glycogen deposition may be enhanced by elevated lactate levels under hyperglycemic conditions and support a role for lactate in the regulation of glucose homeostasis.
Thermal relations of metabolic rate reduction in a hibernating marsupial
Authors: Song Xiaowei , Körtner Gerhard , Geiser Fritz
Published: December 2017

We tested whether the reduction of metabolic rate (MR) in hibernating Cercartetus nanus (Marsupialia, 36 g) is better explained by the reduction of body temperature (Tb), the differential (ΔT) between Tb and air temperature (Ta), or thermal conductance (C). Above the critical Ta during torpor (Ttc) of 4.8 ± 0.7°C, where the Tb was not regulated, the steady-state MR was an exponential function of Tb( r 2 = 0.92), and the overall Q10 was 3.3. However, larger Q10 values were observed at high Tb values during torpor, particularly within the thermoneutral zone (Q10 = 9.5), whereas low Q10 values were observed below Tb 20°C (Q10 = 1.9). The ΔT did not change over Ta 5–20°C, although MR fell, and therefore the two variables were not correlated. Below the Ttc, Tb was regulated at 6.1 ± 1.0°C and MR increased proportionally to ΔT. Our study suggests that MR in torpid C. nanus is largely determined by temperature effects and metabolic inhibition. In contrast, ΔT explains MR only below the Ttc and C appears to affect MR only indirectly via changes of Tb, suggesting that ΔT and C play only a secondary role in MR reduction during hibernation.
Heterogeneous actions of vasopressin on ANG II-sensitive neurons in the subfornical organ of rats
Authors: Anthes Norman , Schmid Herbert A. , Hashimoto Masaaki , Riediger Thomas , Simon Eckhart
Published: December 2017

The aim of this study was to investigate the effects of the antidiuretic hormone arginine vasopressin (AVP), which is released in vivo during dehydration and hypovolemia to prevent further water loss, on the activity of neurons in the subfornical organ (SFO). The SFO is a brain structure with an open blood-brain barrier and is critically involved in angiotensin II (ANG II)-dependent water intake. SFO neurons were recorded extracellularly in tissue slices of the rat brain and were tested for responsiveness to AVP and ANG II. About one-half of 159 neurons tested with an AVP concentration of 10−6 M in the superfusion medium were responsive, and approximately equal proportions were excited and inhibited. Neurons exhibiting the different response types did not differ from each other with respect to spontaneous discharge rate, latency, and duration of the response. Excitatory and inhibitory responses to AVP were dose dependent and reversible, and their threshold concentrations (10−8 to 10−9 M) were similar. Superfusion with a medium low in Ca2+ and high in Mg2+ showed that the excitatory effect is most likely direct, whereas the inhibitory effect largely depends on inhibitory synaptic interaction. About one-half of the SFO neurons excited by ANG II (10−7 M) were responsive to AVP (10−6 M), and equal proportions were inhibited and excited. Both excitatory and inhibitory AVP actions were blocked by the V1-receptor antagonist, Manning compound, and neurons responsive to AVP did not respond to the V2-receptor agonist [deamino-Cys1,d-Arg8]vasopressin. It is concluded that AVP, probably released from synaptic terminals, may increase or decrease the activity of neurons in the SFO, many of which are activated by ANG II. In contrast to previous experiments on ducks, in which the exclusively excitatory effect of the avian antidiuretic hormone arginine vasotocin on ANG II-sensitive SFO neurons correlates well with the dipsogenic effect of both peptides, a greater functional heterogeneity exists among AVP-responsive neurons in the rat SFO.
Physiological regulation of hypothalamic neuropeptide Y release in lean and obese rats
Authors: Stricker-Krongrad A. , Kozak R. , Burlet C. , Nicolas J. P. , Beck B.
Published: December 2017

The paraventricular nucleus (PVN) of the hypothalamus is an important site for the regulation of feeding behavior. Neuropeptide Y (NPY) injected into this nucleus strongly stimulates food intake. In the current study, we measured NPY release in the PVN of unrestrained rats through the push-pull technique. The rats were placed in their habitual environment and conditions of life. NPY release was augmented by >40% ( P < 0.01) in Long-Evans rats deprived of food for 12 h. It returned to the baseline as measured in ad libitum-fed rats 90 min after food access. Its stimulation by 55 mM KCl in refed animals indicated that the whole stock of NPY was not used during a short fast. During the light-dark transition, when feeding behavior is initiated, NPY release in lean Zucker rats showed a peak 20 min after lights off and then declined. It corresponded well with the first feeding episodes. In the obese Zucker rats, this peak was absent. NPY release was totally anarchic but at a high level. The feeding behavior of the obese rats was not as time delimited as in the lean rats. This study performed in very physiological conditions therefore indicates that NPY release could drive feeding behavior in the normal life. Its dysregulation in obese rats could participate in overeating and absence of feeding rhythm measured in these rats and speed up the development of their obesity.
Smokeless tobacco-exposed oral keratinocytes increase macromolecular efflux from the in situ oral mucosa
Authors: Rubinstein Israel , Gao Xiao-Pei , Pakhlevaniants Sergei , Oda Dolphine
Published: December 2017

The purpose of this study was to determine whether supernatants of cultured human oral keratinocytes (HOK) exposed to an aqueous extract of smokeless tobacco (STE) increase macromolecular efflux from the oral mucosa in vivo and, if so, whether bradykinin mediates in part this response. Subconfluent monolayers of HOK were incubated with STE or media, and supernatants were collected 24, 48, and 72 h thereafter. Using intravital microscopy, we found that suffusion of supernatants of STE- but not media-exposed HOK elicited significant concentration- and time-dependent increases in efflux of fluorescein isothiocyanate-labeled dextran (mol mass 70 kDa) from the in situ hamster cheek pouch ( P < 0.05). These effects were significantly attenuated by HOE-140 and NPC-17647 but not by des-Arg9,[Leu8]-bradykinin. Proteolytic activity was increased in supernatants of STE- but not media-exposed HOK. However, a mixture of leupeptin, Bestatin, anddl-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid had no significant effects on HOK supernatant-induced responses. Collectively, these data suggest that oral keratinocytes modulate smokeless tobacco-induced increase in macromolecular efflux from the in situ oral mucosa in part by elaborating proteases that may account for local bradykinin production.
Cellular proliferation and UCP content in brown adipose tissue of cold-exposed aging Fischer 344 rats
Authors: Florez-Duquet Maria , Horwitz Barbara A. , McDonald Roger B.
Published: December 2017

Previous investigations have demonstrated that older vs. younger rats respond to cold exposure with blunted cold-induced nonshivering thermogenesis of brown adipose tissue (BAT). This reduction in nonshivering thermogenesis is associated with reduced mass and blunted nonshivering thermogenic capacity of BAT. The purpose of this study was to test the hypothesis that brown fat in 26-mo-old Fischer 344 (F344) male rats has an impaired capacity to respond to the trophic stimulus of chronic cold exposure with increases in cell number, mass, and uncoupling protein (UCP) content. To test this hypothesis, the response of BAT to chronic cold exposure was evaluated in young and old rats. We exposed 6-, 12-, and 26-mo-old F344 male rats to 10°C for 5 days and measured interscapular BAT (IBAT) mass, cell size and proliferation, and mitochondrial UCP1content. Plasma concentrations of insulin-like growth factor I (IGF-I) and norepinephrine (NE) were also determined. The 26-mo-old rats did not increase IBAT mass, cell proliferation, or UCP1content in response to chronic cold, whereas the 6-mo-old rats had a nearly 2-fold cold-induced increase in IBAT mass, a 26-fold increase in cell proliferation, and a 4-fold increase in UCP1content. Cold exposure also produced an increase of 29, 19, and 20% in mature brown adipocyte cell size of the 6-, 12-, and 26-mo-old animals, respectively. Plasma levels of IGF-I were unaffected by cold at all ages, whereas NE levels were increased by the cold exposure and by increasing age. These data support the hypothesis that brown fat in old F344 rats does not respond to the trophic stimulus of chronic cold exposure to the same degree as younger animals. Moreover, these data indicate that the observed cold- or age-induced changes in levels of growth factors evaluated in this study were not associated with the lack of cold-induced preadipocyte proliferation or increased UCP1in brown fat of the 26-mo-old rats.
IL-1β mediates leptin induction during inflammation
Authors: Faggioni Raffaella , Fantuzzi Giamila , Fuller John , Dinarello Charles A. , Feingold Kenneth R. , Grunfeld Carl
Published: December 2017

Interleukins (IL) are key mediators of the host response to infection and inflammation. Leptin is secreted by adipose tissue and plays an important role in the control of food intake. Administration of lipopolysaccharide (LPS), tumor necrosis factor (TNF), or IL-1 acutely increases leptin mRNA and protein levels. To investigate the role of IL-1β and IL-6 in leptin expression during inflammation, we used IL-1β-deficient (−/−) and IL-6 −/− mice. Mice were injected intraperitoneally with LPS or subcutaneously with turpentine, as models of systemic or local inflammation, respectively. In IL-1β +/+ mice, both LPS and turpentine increased leptin mRNA and circulating leptin. In contrast, neither LPS nor turpentine increased leptin levels in IL-1β −/− mice. In IL-6 +/+ or IL-6 −/− mice, turpentine increased leptin protein to comparable levels. We conclude that IL-1β is essential for leptin induction by both LPS and turpentine in mice, but IL-6 is not.
Central infusion of melanocortin agonist MTII in rats: assessment of c-Fos expression and taste aversion
Authors: Thiele Todd E. , Van Dijk Gertjan , Yagaloff Keith A. , Fisher Stewart L. , Schwartz Michael , Burn Paul , Seeley Randy J.
Published: December 2017

Like leptin (OB protein), central infusion of the nonspecific melanocortin agonist MTII reduces food intake for relatively long periods of time (i.e., 12 h; W. Fan, B. A. Boston, R. A. Kesterson, V. J. Hruby, and R. D. Cone, Nature: 385: 165–168, 1997). To test the hypothesis that MTII may influence ingestive behavior via mechanisms similar to those that mediate the effects of leptin, we infused a single dose of MTII into the third ventricle (i3vt) of Long-Evans rats and examined three dependent measures that have been studied following i3vt infusion of leptin: 1) effects on long-term food intake and body weight (48 h), 2) patterns of c-Fos expression in the brain, and 3) conditioned taste aversion learning. Similar to leptin, MTII reduced 48-h food intake (1.0 nmol dose), reduced body weight at 24 and 48 h (0.1 and 1.0 nmol doses, respectively), and induced c-Fos expression in the paraventricular nucleus of the hypothalamus and the central nucleus of the amygdala. In contrast to leptin, MTII was found to produce conditioned taste aversions. These results are consistent with the hypothesis that MTII may influence regulatory behavior via mechanisms similar to those that mediate the effects of leptin.
CytochromeP-450-derived eicosanoids participate in the renal functional effects of ET-1 in the anesthetized rat
Authors: Oyekan A. O. , McGiff J. C.
Published: December 2017

We evaluated the contribution of cytochrome P-450 (CYP450)-dependent arachidonic acid (AA) metabolites and prostanoids to the renal hemodynamic and tubular effects of endothelin-1 (ET-1) in anesthetized rats. Either ET-1 (0.3, 1.0, and 3 pmol ⋅ kg−1⋅ min−1) or vehicle was infused intravenously during two to three 30-min clearance experimental periods. Only high-dose ET-1 increased mean arterial pressure: control, 75 ± 3 mmHg vs. experimental, 84 ± 4 mmHg. A dose-dependent diuretic-natriuretic response to ET-1 occurred despite progressive declines in glomerular filtration rate (GFR) and renal blood flow. In the face of a 36% reduction in GFR in response to the highest dose of ET-1, urinary sodium excretion (UNaV) increased threefold from 0.57 ± 0.11 to 1.6 ± 0.10 μmol ⋅ 100 g−1⋅ min−1. Indomethacin (5 mg/kg) decreased basal GFR from 1.2 ± 0.3 ml ⋅ 100 g−1⋅ min−1to 0.8 ± 0.1 ml ⋅ 100 g−1⋅ min−1and potentiated the GFR lowering action of ET-1 associated with reductions in UNaV and urine volume. Cobalt chloride (CoCl2) and dibromododec-11-enoic acid (DBDD), which diminish CYP450-dependent AA metabolism through different mechanisms, were used to identify CYP450 products mediating the renal functional actions of ET-1. DBDD (12.5 μg/min) reduced urinary excretion of 20-hydroxyeicosatetraenoic acid from 3.4 ± 0.9 (control) to 1.1 ± 0.6 ng/h and abolished the negative effects of ET-1 on GFR while decreasing the diuretic-natriuretic action of ET-1. Similar effects were produced by CoCl2. Clotrimazole, an inhibitor of epoxygenase activity, was without effect on ET-1-induced renal functional changes. Thus the capacity of ET-1 to enhance prostaglandin production was primarily expressed in terms of positive effects on renal hemodynamics. In contrast, CYP450 products promoted sodium excretion despite negative effects on renal hemodynamics.
Effect of a lysine-enriched diet onl-lysine transport by the brush-border membrane of the chicken jejunum
Authors: Torras-Llort M. , Soriano-García J. F. , Ferrer R. , Moretó M.
Published: December 2017

The influx ofl-lysine into apical vesicles from the chicken jejunum occurs through two systems, one with low Michaelis constant ( Km) and features of system b0,+and the other with relatively high Kmforl-lysine and with properties of system y+. In the present study the effect of a lysine-enriched diet (Lys, containing 68 g l-lysine/kg dietary protein, control animals 48 g/kg) onl-lysine uptake through both transport systems was investigated. Results show that 1) lysine enrichment had no effect on either body weight or the efficiency of food utilization. 2) In Lys-fed animals, the mediatedl-lysine influx was best fitted to the two-system model with y+and b0,+activity. 3) In the presence of an Na+gradient, totall-lysine uptake is significantly higher in Lys-fed animals than in control birds (about 40% increase). 4) Lys diet increases Kmb0,+6-fold (KSCN gradient) and 12-fold (NaSCN gradient) and maximum velocity ( Vmax) by 6- and 20-fold, respectively. The effects of Lys enrichment on the y+-like system are only observed on the Vmaxand in the presence of a Na+gradient (30% increase). 5) Na+is involved in the activation of the transport process in the Lys-fed chickens, but there is no correlation between external Na+concentration and l-lysine influx. In conclusion, both b0,+- and y+-like transport systems are upregulated by dietary lysine but with different kinetic profiles; the high-capacity y+-like carrier shows a Vmaxincrease without changes in Km, whereas the low-capacity b0,+-like system shows an increase in Vmaxas well as in the Km.
Determination of volumetric cerebrospinal fluid absorption into extracranial lymphatics in sheep
Authors: Boulton M. , Flessner M. , Armstrong D. , Hay J. , Johnston M.
Published: December 2017

We estimated the volumetric clearance of cerebrospinal fluid (CSF) through arachnoid villi and extracranial lymphatics in conscious sheep. Catheters were inserted into both lateral ventricles, the cisterna magna, multiple cervical lymphatics, thoracic duct, and jugular vein. Uncannulated cervical vessels were ligated.125I-labeled human serum albumin (HSA) was administered into both lateral ventricles.131I-HSA was injected intravenously to permit calculation of plasma tracer loss and tracer recirculation into lymphatics. From mass balance equations, total volumetric absorption of CSF averaged 3.37 ± 0.38 ml/h, with 2.03 ± 0.29 ml/h (∼60%) removed by arachnoid villi and 1.35 ± 0.46 ml/h (∼40%) cleared by lymphatics. With projected estimates for noncannulated ducts, total CSF absorption increased to 3.89 ± 0.33 ml/h, with 1.86 ± 0.49 ml/h (48%) absorbed by lymphatics. Additionally, we calculated total CSF drainage to be 3.48 ± 0.52 ml/h, with 54 and 46% removed by arachnoid villi and lymphatics, respectively, using previously published mass transport data from our group. We employed estimates of CSF tracer concentrations that were extrapolated from relationships observed in the study reported here. We conclude that 40–48% of the total volume of CSF absorbed from the cranial compartment is removed by extracranial lymphatic vessels.
Does the preoptic anterior hypothalamus receive thermoafferent information?
Authors: Berner Nancy J. , Heller H. Craig
Published: December 2017

The preoptic anterior hypothalamus (POAH) is considered the thermointegrative center of the mammalian brain. Studies on anesthetized and unanesthetized animals have demonstrated neurons in the POAH that respond to changes in both POAH temperature (TPOAH) and skin temperature (Ts). In these studies, however, electroencephalographic (EEG) activity was not monitored. Recent work has revealed the potential for arousal state selectivity of neurons combined with thermal influences on arousal state to create the appearance that cells are thermosensitive or thermoresponsive when in fact they may not be responding directly to temperature or to thermoafferent input. It is therefore necessary to reexamine the influence of central and peripheral temperature on POAH cells. In the present study, 66 POAH cells were recorded from urethan-anesthetized rats while EEG, TPOAH, and Ts were monitored. Seventy-five percent (41 of 55) of the cells were EEG state responsive; 22% (6 of 27) were TPOAH sensitive; and 33% (19 of 58) appeared to be Tsresponsive. However, when EEG state changes were taken into account, none of the cells that appeared to be Ts responsive were responding to Ts within any uniform EEG state. All changes in their firing rates were associated with EEG state changes. This study raises a question as to whether or not peripheral temperature information is integrated in the POAH. Consideration should be given to the possibility that Ts information is integrated lower in the neuroaxis. Monitoring EEG is essential in studies attempting to characterize the integrative properties of POAH neurons of anesthetized or unanesthetized animals. This caveat applies not just to thermoregulatory studies but to investigations of other integrative functions of the hypothalamus and many other brain regions as well.
Functional polarity of the tentacle of the sea anemoneAnemonia viridis: role in inorganic carbon acquisition
Authors: Furla Paola , Bénazet-Tambutté Sylvie , Jaubert Jean , Allemand Denis
Published: December 2017

The oral epithelial layers of anthozoans have a polarized morphology: photosynthetic endosymbionts live within endodermal cells facing the coelenteric cavity and are separated from the external seawater by the ectodermal layer and the mesoglea. To study if this morphology plays a role in the supply of inorganic carbon for symbiont photosynthesis, we measured the change in pH and the rate of OH−(H+) fluxes induced by each cell layer on a tentacle of the sea anemone Anemonia viridis. Light-induced pH increase of the medium bathing the endodermal layers led to the generation of a transepithelial pH gradient of ∼0.8 pH units across the tentacle, whereas darkness induced acidification of this medium. The light-induced pH change was associated with an increase of total alkalinity. Only the endodermal layer was able to induce a net OH−secretion (H+absorption). The light-induced OH−secretion by the endodermal cell layer was dependent on the presence of[Formula: see text] in the compartment facing the ectoderm and was sensitive to several inhibitors of ion transport. [14C][Formula: see text]incorporation into photosynthates confirmed the ectodermal supply, the extent of which varied from 25 to >90%, according to[Formula: see text] availability. Our results suggest that the light-induced OH−secretion by the endodermal cell layer followed the polarized transport of [Formula: see text] and its subsequent decarboxylation within the endodermal cell layer. This polarity may play a significant role both in inorganic carbon absorption and in the control of light-enhanced calcification in scleractinian corals.
Space-related bone mineral redistribution and lack of bone mass recovery after reambulation in young rats
Authors: Lafage-Proust Marie-Hélène , Collet Philippe , Dubost Jean Michel , Laroche Norbert , Alexandre Christian , Vico Laurence
Published: December 2017

This study reports the effects of a 14-day spaceflight followed by a 14-day reambulation period on bones of 56-day-old male rats compared with synchronous (S) and vivarium (V) control animals. Femur, tibia, and humerus bone mineral densities (BMD); bone calcium and phosphorus concentrations ([Ca2+] and [P]), measured by X-ray microanalysis (XRM), on tibia, vertebra, and calvaria; and histomorphometric data on proximal primary and secondary spongiosae (I and II SP, respectively) of the tibia and humerus were measured. After the flight in flown rats (compared with S), BMD was lower in the distal femur and remained similar to S in humerus and tibia, [Ca2+] and [P] were lower in tibia II SP and higher in calvaria, tibia I SP width and II SP bone volume were lower, resorption was markedly higher in tibia II SP, and no difference in formation parameters was observed. After reambulation, BMD was lower in long bones of both flight and S groups compared with V. Bone loss appeared in humeral II SP and worsened in tibial II SP in flown rats. Tibial formation parameters were higher in flown rats compared with V and S, indicating the onset of an active recovery. Tibial XRM [Ca2+] and [P] in flown rats remained below control levels.
Slow inactivation of cardiac L-type Ca2+channel induced by cold acclimation of guinea pig
Authors: Takagi Shuichi , Kihara Yasuki , Sasayama Shigetake , Mitsuiye Tamotsu
Published: December 2017

Whole cell L-type Ca2+current was recorded in ventricular myocytes dissociated from guinea pigs that were bred at ambient temperatures ranging between daily averages of 4 and 29°C. The dynamic voltage range of inactivation, as measured using 400-ms conditioning pulses and a holding potential of −40 mV, extended from −50 to −20 mV in myocytes prepared in summer. In winter, the inactivation curve was shifted to more negative potentials than in summer. Double-pulse experiments revealed that the negative shift was due to slow-inactivation kinetics. The negative shift of inactivation could be induced in myocytes prepared from animals that had been kept at 5°C for >3 wk in the summer. The negative shift in Ca2+current inactivation could be abolished by adding guanosine 5′- O-(2-thiodiphosphate) (5 mM) to the pipette solution, but not by adding staurosporine (2 μM) or 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (100 μM) to the bath. The cold acclimation may introduce the slow inactivation of the cardiac L-type Ca2+channel through an unknown pertussis toxin-insensitive G protein.
Area postrema lesion attenuates the long-term hypotensive effects of losartan in salt-replete rats
Authors: Collister John P. , Osborn John W.
Published: December 2017

We reported that the AT1 receptor antagonist losartan decreases arterial pressure in sodium-replete rats and that this response is attenuated in area postrema-lesioned (APx) rats (J. P. Collister, B. J. Hornfeldt, and J. W. Osborn. Hypertension 27: 598–606, 1996). In that study, food intake for the 3-wk period after sham lesion was restricted to that observed in APx rats. Food-restricted sham rats had lower arterial pressures and attenuated responses to losartan compared with control rats fed ad libitum. The present study examined whether these differences persisted months, rather than weeks after APx or sham lesions. Losartan was administered for 10 days to APx and two groups of sham rats 3 mo after APx or sham surgery. The first sham group was food restricted (SFR) for 3 wk after surgery, whereas the second sham group was allowed ad libitum (SAL) access to food. By day 8of losartan administration, both sham groups demonstrated a marked hypotension (SFR: −38 ± 4; SAL: −33 ± 4 mmHg). This response was attenuated ( P < 0.05) on the same day in APx rats (−17 ± 3 mmHg). This trend continued throughout days 9 and 10. Because both sham groups responded similarly to losartan (yet significantly different from APx rats), these results demonstrate that transient decreases in food intake do not affect the response to losartan if rats are allowed an adequate recovery period. We conclude that the area postrema mediates part of the long-term hypotensive effects of AT1 receptor blockade in the conscious rat.
Differential orderliness of the GH release process in castrate male and female rats
Authors: Gevers Evelien , Pincus Steve M. , Robinson Iain C. A. F. , Veldhuis Johannes D.
Published: December 2017

Male- and female-specific modes of episodic growth hormone (GH) release are presumptively imposed by sex steroid hormones, and, although typically evident visually, are vividly distinguished quantitatively via a regularity statistic, approximate entropy (ApEn), in both the rat and human. GH secretory patterns may determine GH-stimulated growth and specific hepatic and muscle gene expression in the rat. Consequently, it is important to discern mechanisms that underlie their regulation. Here we have examined the impact of prepubertal gonadal suppression (at 4 wk of age) via surgical or pharmacological [gonadotropin-releasing hormone (GnRH) agonist] intervention on the regularity (ApEn) of GH release in male and female rats (at 10–11 wk of age) sampled at 10-min intervals for 10 h ( n = 60 points) during a lights-out (dark) period. We observed a graded hierarchy of mean disorderliness of GH release that was quantifiable by ApEn measures, with maximal to minimal disorderliness in the following rank order: intact female, GnRH agonist-treated female, ovariectomized female, orchidectomized male, GnRH agonist-treated male, and intact male. These observations suggest a continuum of sex steroid actions on the regularity of GH secretion and, by inference, on the interplay among GH-releasing hormone, somatostatin, and GH/insulin-like growth factor I negative feedback.
Effects of infusions of ACTH in the chronically catheterized pregnant ewe and her fetus
Authors: Lumbers Eugenie R. , Bernasconi C. , Burrell J. H.
Published: December 2017

To study the effects of elevated maternal levels of adrenocorticotropic hormone (ACTH) on the fetus, nine chronically catheterized pregnant ewes (132 ± 0.9 days of gestation) were infused intravenously for 3 days with Synacthen (5 μg ⋅ kg−1 ⋅ day−1). Four ewes were given 0.15 M saline intravenously over the same period. ACTH induced hypertension in the ewe. Mean arterial pressure (MAP) increased from 101 ± 4.4 to 114 ± 3.9 mmHg at 48 h ( P < 0.05); cardiac output increased from 8.6 ± 0.5 to 10.4 ± 1.0 l/min after 24 h ( P < 0.05). Within 2–4 h, maternal cortisol levels increased from 24.6 ± 6.3 to 287 ± 30 nM ( P < 0.05) and remained high. Fetal plasma cortisol levels increased from 20 ± 4.5 to 60 ± 4.5 nM ( P < 0.05) within 2–4 h and then increased further. Fetal MAP was increased at 24 h. There was no effect on fetal blood gases or pH. Ewes became hyperglycemic and lactacidemic by 24 h ( P < 0.05), and the fetuses were also hyperglycemic and lactacidemic ( P < 0.05) at this time. There were no changes in fetuses carried by saline-infused ewes. Both ewes and fetuses had raised plasma osmolalities and, since hematocrit fell, retained fluid. Ewes became hypokalemic; the fetuses did not, but there was an increase in fetal K excretion. Thus ACTH-induced hypertension in the ewe had minimal effects on fetal MAP, fetal blood gas status, and pH. The fetus, however, did show many of the other effects of maternal glucocorticoid and mineralocorticoid excess, partly because its cortisol levels were increased but also as a consequence of metabolic and endocrine changes in the ewe.
Hypoglycemic effects of a novel fatty acid oxidation inhibitor in rats and monkeys
Authors: Deems Rhonda O. , Anderson Robert C. , Foley James E.
Published: December 2017

Increased fatty acid oxidation contributes to hyperglycemia in patients with non-insulin-dependent diabetes mellitus. To improve glucose homeostasis in these patients, we have designed a novel, reversible inhibitor of carnitine palmitoyltransferase I (CPT I) that potently inhibits fatty acid oxidation. SDZ-CPI-975 significantly lowered glucose levels in normal 18-h-fasted nonhuman primates and rats. In rats, glucose lowering required fatty acid oxidation inhibition of ≥70%, as measured by β-hydroxybutyrate levels, the end product of β-oxidation. In cynomolgus monkeys, comparable glucose lowering was achieved with more modest lowering of β-hydroxybutyrate levels. SDZ-CPI-975 did not increase glucose utilization by heart muscle, suggesting that CPT I inhibition with SDZ-CPI-975 would not induce cardiac hypertrophy. This was in contrast to the irreversible CPT I inhibitor etomoxir. These results demonstrate that SDZ-CPI-975 effectively inhibited fatty acid oxidation and lowered blood glucose levels in two species. Thus reversible inhibitors of CPT I represent a class of novel hypoglycemic agents that inhibit fatty acid oxidation without inducing cardiac hypertrophy.
Lateral parabrachial nucleus serotonergic mechanisms and salt appetite induced by sodium depletion
Authors: Menani José Vanderlei , De Luca Laurival Antonio , Johnson Alan Kim
Published: December 2017

This study investigated the effects of bilateral injections of a serotonin (5-HT) receptor agonist into the lateral parabrachial nucleus (LPBN) on the intake of NaCl and water induced by 24-h water deprivation or by sodium depletion followed by 24 h of sodium deprivation (injection of the diuretic furosemide plus 24 h of sodium-deficient diet). Rats had stainless steel cannulas implanted bilaterally into the LPBN. Bilateral LPBN injections of the serotonergic 5-HT1/2 receptor antagonist methysergide (4 μg/200 nl at each site) increased hypertonic NaCl intake when tested 24 h after sodium depletion and after 24 h of water deprivation. Water intake also increased after bilateral injections of methysergide into the LPBN. In contrast, the intake of a palatable solution (0.06 M sucrose) under body fluid-replete conditions was not changed after bilateral LPBN methysergide injections. The results show that serotonergic mechanisms in the LPBN modulate water and sodium intake induced by volume depletion and sodium loss. The finding that sucrose intake was not affected by LPBN serotonergic blockade suggests that the effects of the methysergide treatment on the intakes of water and NaCl are not due to a mechanism producing a nonspecific enhancement of all ingestive behaviors.
Effect of sheep plasma and lymph on fibroblast proliferation
Authors: Drake R. E. , Teague R. A. , Gabel J. C.
Published: December 2017

Blood plasma contains many factors that influence cellular proliferation. However, cells within the tissue spaces of most organs are exposed to interstitial fluid, and the composition of interstitial fluid may be much different from plasma. Accordingly, the effect of interstitial fluid on cellular proliferation may be much different from the effect of plasma. The aim of this study was to test the effect of blood plasma and interstitial fluid (lymph) from the lung and intestine on the proliferation of fibroblasts. Plasma and lung and intestinal lymph were collected from anesthetized sheep and added to standard culture medium (final concentration = 10%). Cells (fibroblasts) were cultured from the lungs of the sheep and grown to confluence. Then the cells were subcultured at low density and incubated with the medium containing plasma or lymph. Control dishes contained only cells and medium. The cells were counted over a 6-day period. Cells incubated with medium alone grew very little over the 6-day period, but cells exposed to plasma increased ∼100-fold, and cells exposed to lymph increased ∼10-fold. We found no significant difference in cell growth for cells incubated with lung versus intestinal lymph. Our results show lung and intestinal lymph are less effective than plasma in stimulating cell growth.
Long-term measurement of arterial blood pressure in conscious mice
Authors: Mattson David L.
Published: December 2017

This study describes a technique for the direct daily measurement of arterial blood pressure, sampling of arterial blood, and continuous intravenous infusion in free-moving, conscious, Swiss-Webster mice. Catheters were chronically implanted in the femoral artery and vein, tunneled subcutaneously, exteriorized at the back of the neck in a lightweight tethering spring, and attached to a swivel device at the top of the cage. Time-control experiments ( n = 8) demonstrated stable values of mean arterial pressure (MAP, 116 ± 1 mmHg) and heart rate (HR, 627 ± 21 beats/min) for up to 35 days after catheter implantation. It was further observed that restraining mice ( n = 7) increased MAP by 10 ± 3 mmHg and HR by 78 ± 8 beats/min from the values observed under free-moving conditions. To demonstrate the chronic use of the venous catheter, intravenous infusion of N G-nitro-l-arginine methyl ester (l-NAME, 8.6 mg ⋅ kg−1 ⋅ day−1, n = 6) for 5 days significantly increased MAP from 117 ± 4 to 131 ± 4 mmHg without altering HR. In a final group of mice ( n = 5), orall-arginine (2% in drinking water) increased plasma arginine concentration from 90 ± 7 to 131 ± 17 μM and preventedl-NAME hypertension. These experiments illustrate the feasibility of long-term intravenous infusion, direct arterial blood pressure measurements, and arterial blood sampling in conscious mice.
Tumor necrosis factor in the heart
Authors: Meldrum Daniel R.
Published: December 2017

The heart is a tumor necrosis factor (TNF)-producing organ. Both myocardial macrophages and cardiac myocytes themselves synthesize TNF. Accumulating evidence indicates that myocardial TNF is an autocrine contributor to myocardial dysfunction and cardiomyocyte death in ischemia-reperfusion injury, sepsis, chronic heart failure, viral myocarditis, and cardiac allograft rejection. Indeed, locally (vs. systemically) produced TNF contributes to postischemic myocardial dysfunction via direct depression of contractility and induction of myocyte apoptosis. Lipopolysaccharide or ischemia-reperfusion activates myocardial P38 mitogen-activated protein (MAP) kinase and nuclear factor kappa B, which lead to TNF production. TNF depresses myocardial function by nitric oxide (NO)-dependent and NO-independent (sphingosine dependent) mechanisms. TNF activation of TNF receptor 1 or Fas may induce cardiac myocyte apoptosis. MAP kinases and TNF transcription factors are feasible targets for anti-TNF (i.e., cardioprotective) strategies. Endogenous anti-inflammatory ligands, which trigger the gp130 signaling cascade, heat shock proteins, and TNF-binding proteins, also control TNF production and activity. Thus modulation of TNF in cardiovascular disease represents a realistic goal for clinical medicine.
Disordered food intake and obesity in rats lacking cholecystokinin A receptors
Authors: Moran Timothy H. , Katz Laura F. , Plata-Salaman Carlos R. , Schwartz Gary J.
Published: December 2017

Otsuka Long-Evans Tokushima Fatty (OLETF) rats develop obesity, hyperglycemia, and non-insulin-dependent diabetes mellitus and do not express cholecystokinin A (CCK-A) receptors, the receptor subtype mediating the satiety actions of CCK. In short-term feeding tests, male OLETF rats were completely resistant to exogenous CCK, and their response to bombesin was attenuated. Comparisons of liquid meal consumption in OLETF and control Long-Evans Tokushima (LETO) rats demonstrated that 1) OLETF rats had greater intakes during 30-min scheduled daytime meals and significantly larger and fewer spontaneous nighttime meals and 2) although the initial rates of licking were the same, OLETF rats maintained the initial rate longer and the rate at which their licking declined was slower. In 24-h solid food access tests, OLETF rats consumed significantly more pellets than LETO controls, and this increase was attributable to significant increases in meal size. Together, these data are consistent with the interpretation that the lack of CCK-A receptors in OLETF rats results in a satiety deficit leading to increases in meal size, overall hyperphagia, and obesity.
Determinants of cardiac tyrosine hydroxylase activity during exercise-induced sympathetic activation in humans
Authors: Eisenhofer Graeme , Rundqvist Bengt , Friberg Peter
Published: December 2017

This study assessed whether the mechanisms regulating cardiac norepinephrine (NE) synthesis with changes in NE release are influenced by functions of sympathetic nerves affecting transmitter turnover independently of transmitter release. Differences in arterial and coronary venous plasma concentrations of NE and its metabolites and of dihydroxyphenylalanine (DOPA), the immediate product of tyrosine hydroxylase (TH), were examined before and during cycling exercise. Relative increases during exercise in cardiac tyrosine hydroxylation (as reflected by the %increase in cardiac DOPA spillover) matched closely corresponding increases in NE turnover, but were much lower than increases in NE release. The much larger relative increases in release than turnover of NE were largely attributable to the extensive contribution to transmitter turnover from intraneuronal metabolism of NE leaking from storage vesicles. This contribution remains unchanged during sympathetic activation so that the relative increase in NE turnover is much smaller than that in exocytotic release of NE. To replenish the NE lost from stores during sympathetic activation, TH activity need increase only in proportion to the smaller increase in turnover rather than the larger relative increase in release. The ability to “gear down” increases in tyrosine hydroxylation relative to increases in NE release provides sympathetic nerves the capacity for a more extended range of sustainable release rates than otherwise possible.
Carbon dioxide transport in alligator blood and its erythrocyte permeability to anions and water
Authors: Jensen Frank B. , Wang Tobias , Jones David R. , Brahm Jesper
Published: December 2017

Deoxygenation of alligator red blood cells (RBCs) caused binding of two [Formula: see text] equivalents per hemoglobin (Hb) tetramer at physiological pH. At lowered pH, some[Formula: see text] binding also occurred to oxygenated Hb. The erythrocytic total CO2content was large, and Hb-bound [Formula: see text], free[Formula: see text], and carbamate contributed about equally in deoxygenated cells. The nonbicarbonate buffer values of RBCs and Hb were high, and the Hb showed a significant fixed acid Haldane effect. Binding of [Formula: see text] on deoxygenation occurred without a change in RBC intracellular pH, revealing equivalence between oxylabile[Formula: see text] and H+binding. Erythrocyte volume, plasma pH, and plasma [Formula: see text]concentration also varied little with the degree of oxygenation. Diffusional water permeability was higher in oxygenated than deoxygenated RBCs. The RBCs have rapid band 3-mediated Cl−and[Formula: see text] transport, which was not affected by degree of oxygenation, but net fluxes of Cl−and[Formula: see text] via the anion exchanger are small during blood circulation at rest. Most of the CO2taken up into the blood as it flows through tissue capillaries is carried within the erythrocytes as Hb-bound [Formula: see text] until CO2is excreted when blood flows through pulmonary capillaries.