bluuebunny/crossref_metadata_2025 huggingface dataset:
Sickness behavior in mice deficient in interleukin-6 during turpentine abscess and influenza pneumonitis
Authors: Kozak W. , Poli V. , Soszynski D. , Conn C. A. , Leon L. R. , Kluger M. J.
Published: December 2017

Interleukin-6 (IL-6), among other cytokines, is thought to be involved in the regulation of sickness behavior (e.g., anorexia, cachexia, fever, and lethargy) induced by infections bacterial and viral origin) and sterile tissue necrosis (burns and surgical traumas). Mice deficient in IL-6 (IL-6 KO) were generated by gene targeting. Homozygous IL-6 KO male and female mice and their appropriate controls were implanted with biotelemeters to monitor body temperature (Tb) and motor activity (Act). Normal circadian rhythms in Tb and Act as well as rates of food intake and weight gain did not differ significantly between sex-matched IL-6 KO and control groups at 30 degrees C in a 12:12-h light-dark cycle. Sterile tissue damage was induced in mice by subcutaneous injection of turpentine (0.1 ml, left hindlimb). Influenza pneumonitis was induced by intranasal inoculation of mouse-adapted influenza A virus (17.5 plaque-forming units). Lack of IL-6 completely prevented fever, anorexia, and cachexia because of turpentine abscess in both sexes. It did not prevent lethargy, although IL-6 KO mice recovered to normal Act significantly sooner than wild-type mice. Symptoms of sickness were only slightly modified during influenza virus infection in IL-6 KO mice. Attenuation of sickness behavior was more pronounced in IL-6 KO female than in male mice. We conclude that, although IL-6 is induced during both turpentine abscess and influenza infection, this cytokine appears to be more critical in induction of the symptoms of sickness behavior during sterile tissue abscess than during influenza infection.
Increased sympathetic activity in rat white adipose tissue during prolonged fasting
Authors: Migliorini R. H. , Garofalo M. A. , Kettelhut I. C.
Published: December 2017

The effect of prolonged fasting on sympathetic activity was examined in rat white adipose tissue (WAT) and, for comparison purposes, in interscapular brown adipose tissue (IBAT). Preliminary experiments showed that 6-hydroxydopamine or tyramine administration to fed animals produced similar reductions in norepinephrine (NE) content of WAT and IBAT. Fasting for 48 h did not affect tissue NE content significantly, but induced a threefold increase in [3H]NE uptake by retroperitoneal and epididymal adipose tissue, contrasting with a 50% reduction in IBAT. Measured with DL-alpha-methyl-p-tyrosine, NE fractional rates of turnover were faster and calculated turnover rates were three times higher in retroperitoneal and epididymal tissue from fasted rats than in tissues from fed controls. In experiments with [3H]NE, although fractional rates did not change significantly, calculated NE turnover also increased in retroperitoneal and epididymal tissue after food deprivation. In contrast, in IBAT, NE turnover either did not change (measured with DL-alpha-methyl-p-tyrosine) or, in the experiments with [3H]NE, decreased significantly after fasting. These and other data suggest that a centrally controlled selective activation of WAT sympathetic fibers contributes to fasting lipolysis.
Enhanced fluid intake by rats after capsaicin treatment
Authors: Curtis K. S. , Stricker E. M.
Published: December 2017

These studies examined stimulated fluid intake by rats in which vagally mediated signals of gastric distension were blunted by systemic treatment with the neurotoxin capsaicin, as verified by the loss of cholecystokinin-induced inhibition of feeding. After overnight food deprivation, intake of a 10% sucrose solution by capsaicin-treated rats was greater than that by control rats. Similarly, capsaicin-treated rats drank more water than did control rats when stimulated by plasma hyperosmolality after intraperitoneal administration of hypertonic NaCl or by isosmotic hypovolemia after subcutaneous administration of a hyperoncotic colloidal solution. Finally, during chronic administration of the mineralocorticoid deoxycorticosterone acetate, capsaicin-treated rats consumed more concentrated saline than did control rats. In all tests, intakes by capsaicin-treated rats were significantly greater than those by control rats within 5-15 min. These results suggest that early signals of gastric distension, such as those that occur during normal episodes of food, water, or NaCl intake, may modulate ongoing ingestion and that, with the attenuation of such general inhibitory signals, ingestion continues until gastric distension becomes larger and/or later postgastric signals are detected.
Schedule-induced psychological stress and molecular structures of cardiomyocytes
Authors: Rupp H. , Maisch B. , Brilla C. G.
Published: December 2017

To establish a psychological stress model, we characterized in rats the effects of chronic (5-6 wk) scheduled food pellet feeding (35 mg/80 s for 8 h/day). Because the scheduled intake of pellets required that rats have access to 80% of ad libitum intake, the effect of food restriction was also examined by withholding food intermittently for 24 or 48 h each, followed by 24 h free access to food. Cardiac norepinephrine concentration was significantly increased (1,076 +/- 169 vs. 693 +/- 107 ng/g, P < 0.05) in rats subjected to pellet feeding compared with pair-fed rats (same amount of pellets in one portion) or 24- or 48-h intermittently fasted rats; similarly, the epinephrine content of adrenal glands was increased (P < 0.05). Left ventricular rate of sarcoplasmic reticulum Ca2+ uptake was decreased (P < 0.05) compared with pair-fed rats, reaching values observed for 24-h fasted rats, whereas the proportion of alpha-myosin heavy chains was only slightly reduced. Thus the schedule-induced stress arising from pellet feeding exhibits features of stress models involving physical pain and appears to stimulate the adrenergic system with subsequent impairment of Ca2+ cycling that is typical of various heart diseases.
Na+-independent transport of bipolar and cationic amino acids across the luminal membrane of the small intestine
Authors: Munck B. G. , Munck L. K.
Published: December 2017

The role of sodium in transport of bipolar and cationic amino acids and their interactions were examined in vitro by measuring unidirectional influx across the brush-border membrane of intact rat jejunal and rabbit ileal epithelia. The chloride-dependent and beta-alanine inhibitable B(0,+) present in rabbit ileum was blocked by combining inhibition by beta-alanine with Na(+)- or Cl(-)-free conditions. Under these conditions, lysine influx across the brush-border membrane is Na+ independent. All Na+-independent influx of cationic and bipolar amino acids is by a system b(0,+) equivalent in the brush-border membrane of both species, where a system y+ is not present. System b(0,+) is shown to be a potent exchanger of intracellular leucine for extracellular lysine and of intracellular lysine for extracellular leucine. The model used to explain leucine stimulation of mucosa to serosa lysine transport can explain Na+ dependence of net lysine absorption. On the assumption that b(0,+) in situ, like the transporter induced by retroperitoneal brown adipose tissue in Xenopus laevi oocytes, acts as an obligatory exchanger, this model can also explain the effects of lysine on short-circuit current and net transport of sodium and the effect on transport capacity by preincubation at Na+-free conditions.
Leptin facilitates and inhibits sexual behavior in female hamsters
Authors: Wade G. N. , Lempicki R. L. , Panicker A. K. , Frisbee R. M. , Blaustein J. D.
Published: December 2017

Food deprivation decreases fertility in female mammals in part by inhibiting sexual behaviors. Genetically obese ob/ob mice, like food-deprived wild-type animals, are also infertile; treatment of ob/ob mice with leptin, the adipocyte-derived protein that they lack, corrects some of their reproductive deficiencies. We tested the hypothesis that leptin treatment would prevent the suppression of sexual receptivity that is caused by food deprivation in female Syrian hamsters. Instead, we found that treatment with murine leptin facilitated female sexual behavior in ad libitum-fed hamsters, but not in food-deprived animals. In food-deprived hamsters, leptin treatment actually intensified the inhibition of lordosis. Food deprivation decreased detectable estrogen receptor immunoreactivity (ERIR) in the ventromedial hypothalamus (VMH), but the leptin-induced changes in female sexual behavior were not accompanied by parallel changes in VMH ERIR. Thus leptin facilitates estrous behavior in hamsters, but it does not overcome the lordosis-inhibiting metabolic cues produced by acute food deprivation. Because circulating leptin levels are directly related to body fat content, an implication of these findings is that elevated levels of adipose tissue could have a positive influence on sexual responsiveness.
Dysregulation of arcuate nucleus preproneuropeptide Y mRNA in diet-induced obese rats
Authors: Levin B. E. , Dunn-Meynell A. A.
Published: December 2017

Neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC) produce metabolic and physiological effects that promote the development and maintenance of obesity. In turn, NPY metabolism in these neurons is inhibited by dopamine release. In this study, ARC prepro-NPY mRNA and ARC/median eminence (ME) dopamine turnover were assessed in chow-fed male Sprague-Dawley rats prone to develop diet-induced obesity (DIO) or to be diet resistant (DR) when fed a high-energy (HE) diet. By in situ hybridization, DIO-prone rats had 39% more ARC NPY mRNA expression than DR-prone rats under chow-fed conditions. DIO-prone rat ARC/ME dopamine levels were 14% higher, but dopamine half-life was 176% longer and turnover was 59% less than DR-prone rats. Neither a 48-h fast nor 50% energy intake restriction for 5 days affected the already increased ARC NPY mRNA levels in DIO-prone rats. Both manipulations increased NPY expression to the level of DIO-prone rats in DR-prone rats by 23 and 35%, respectively. Finally, when fed HE diet for 2 wk, neither DIO- nor DR-prone rats altered their ARC NPY expression despite the development of obesity and hyperinsulinemia in DIO rats. Thus DIO-prone rats overexpress and fail to regulate ARC NPY mRNA to energy restriction or hyperinsulinemia. This dysregulation is possibly secondary to reduced inhibition because of defective ARC/ME dopamine turnover. Both may be important predisposing factors in the development of DIO.
Effects of antisense oligodeoxynucleotides on peptide release from hypothalamoneurohypophysial explants
Authors: Ludwig M. , Morris M. , Sladek C. D.
Published: December 2017

Rapid effects of antisense oligodeoxynucleotides (AODNs) on the function of the neurohypophysial system have been reported previously. The present studies were designed to determine the effects of vasopressin (VP) and oxytocin (OT) AODNs on osmotically or potassium-stimulated VP and OT release from perifused hypothalamoneurohypophysial (HNS) explants. The AODNs were 18-mer phosphorothioate forms targeted toward the translation initiation sites of either VP or OT mRNA, or a mixed base sequence (4 microM). The explants were exposed to a ramp increase in NaCl (either 20 or 30 mosmol/6 h) or to 25 mM KCl. VP and OT release was measured by radioimmunoassay in sequential 20-min fractions of the perifusate. There was a peptide-specific inhibition by the AODNs of osmotically stimulated VP and OT release. VP AODN inhibited VP, but not OT release, and vice vorsa. However, the AODNs had no effect on potassium-stimulated peptide release, demonstrating that depolarization-secretion coupling was still intact. Furthermore, there were no significant differences in VP and OT mRNA and peptide content after antisense treatment. Thus these observations indicate that acute exposure to peptide AODNs interrupts osmotically stimulated VP and OT release in a peptide-specific manner.
Differential ventral septal vasopressin release is associated with sexual dimorphism in PGE2 fever
Authors: Chen X. , Landgraf R. , Pittman Q. J.
Published: December 2017

The vasopressinergic innervation of the ventral septal area (VSA) has been shown to be implicated in antipyresis. Because this system is less well developed in female rats, we hypothesized that female rats would display exaggerated febrile responses. We therefore examined the temperature responses of conscious and urethan-anesthetized rats of both sexes to centrally administered prostaglandin E2 (PGE2) and correlated these responses with the release and action of endogenous arginine vasopressin (AVP) in the VSA. Both conscious [25 ng/5 microliters PGE2 intracerebroventricularly (i.c.v.)] and anesthetized (VSA microdialyzed, 50 ng/5 microliters PGE2 i.c.v.) female rats had higher fevers than did males. Infusion of an AVP V1a receptor antagonist inverted question mark1 nmol [d(CH2)5Tyr(Me)]AVP inverted question mark plus PGE2 gave rise to higher fevers in males but not in females. Measurements of AVP in microdialysates of the VSA showed that the release of endogenous AVP was increased in response to PGE2 in males only. Baseline AVP release in both sexes was similar. The results suggest that there is a sex-related difference in PGE2 fever, which may be accounted for by the differential AVP release in the VSA.
Meal size and number: relationship to dopamine levels in the ventromedial hypothalamic nucleus
Authors: Meguid M. M. , Yang Z. J. , Laviano A.
Published: December 2017

Evidence shows a reciprocal relationship exists between the lateral hypothalamic area (LHA) and the ventromedial hypothalamic nucleus (VMN) in food intake regulation. Since a direct correlation between meal size and LHA-dopamine in Fischer rats was previously reported, we tested the hypothesis that an inverse association may exist between meal size and VMN-dopamine response. This was studied in awake 24-h food-deprived rats who were then allowed to eat freely for 20 min while the VMN-dopamine response was measured by microdialysis every 20 min for 2 h. In a second experiment, only one-half the amount freely eaten was provided during microdialysis. The following were observed. 1) Dopamine concentrations in VMN decreased during eating. 2) The degree and duration of decrease after the meal corresponded to the size of the meal. 3) When the decreased postmeal VMN-dopamine level had returned to baseline and food was available, rats ate once more. The findings show that, in normal rats, eating was associated with decreased dopamine levels in the VMN and was followed by a lag time during which no additional eating occurred. VMN dopamine levels thereby contribute to determining the duration of the intermeal interval and hence, by inference, the meal number.
LPS-induced anorexia in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice
Authors: Faggioni R. , Fuller J. , Moser A. , Feingold K. R. , Grunfeld C.
Published: December 2017

Administration of endotoxin (lipopolysaccharide, LPS) induces profound anorexia. Injection of leptin decreases food intake in mice. Recently, we reported that LPS and cytokines increase leptin levels in hamsters. To further investigate the role of leptin in the LPS-induced anorexia, we administered LPS to leptin receptor-deficient (db/db) and leptin-deficient (ob/ob) mice. We found that LPS caused anorexia in both db/db and ob/ob mice. As might be predicted if leptin had a role in anorexia, the db/db mice were somewhat resistant to LPS-induced anorexia. However the ob/ob mice were more sensitive to LPS-induced anorexia. No differences between db/db and ob/ob mice and their respective littermate were observed in circulating tumor necrosis factor levels after LPS. These data suggest that leptin per se is not essential for LPS-induced anorexia.
Glutathione systems and anoxia tolerance in turtles
Authors: Willmore W. G. , Storey K. B.
Published: December 2017

Effects of anoxic submergence (20 h at 5 degrees C) and subsequent 24 h aerobic recovery on glutathione levels and the activities of glutathione-related enzymes were examined in six tissues of Trachemys scripta elegans. Anoxia exposure resulted in tissue-specific changes in enzyme maximal activities, the most dramatic being suppression of gamma-glutamyl transpeptidase (gamma-GTPase) activity in anoxic kidney to only 2% of control. Anoxia exposure also caused significant decreases in activities of liver and heart glutathione-S-transferase (GST) (by 25 and 42%), heart glutathione reductase (GR) (by 67%), liver gamma-GTPase (by 71%), and red muscle glutaredoxin (GRN) (by 56%). By contrast, anoxia exposure increased the activities of GR in liver and red muscle (by 52 and 80%), glutathione synthetase (GS) in white muscle (by 300%), and GRN in white muscle (by 400%). During aerobic recovery after anoxia, GST activity decreased in red muscle, kidney, and brain (by 72, 56, and 39%); GR decreased in liver and red muscle (by 52 and 80%); and GRN fell in red muscle (by 56%). Other activities rose during recovery: GR in heart (by 64%), GS in heart and brain (by 200%), and gamma-GTPase in brain (by 63%). Tissue pools of total glutathione were high in comparison with other ectotherms. Levels decreased during anoxia in four organs to 49-67% of control values. During aerobic recovery the reduced glutathione-to-oxidized glutathione ratio (GSH/GSSG) increased in heart, kidney, and brain, indicating that oxidative stress did not occur in these organs. Rather than maintaining high levels of glutathione in tissues to prevent oxidative stress during aerobic recovery, turtles sustain high GSH/GSSG by regulating the activities of glutathione-using enzymes.
Intrinsic tone and passive mechanics of isolated renal arteries from virgin and late-pregnant rats
Authors: Gandley R. E. , Griggs K. C. , Conrad K. P. , McLaughlin M. K.
Published: December 2017

The purpose of this study was to investigate whether there are alterations in the intrinsic properties of renal interlobar arteries during pregnancy. Renal interlobar arteries (internal diameter approximately 250 microns) from virgin and late-pregnant rats were mounted in a pressurized arteriograph system. Intrinsic tone was quantified as the percent difference in luminal diameter of each artery in the presence of physiological saline solution and while pharmacologically relaxed with papaverine. At pressures between 75 and 125 mmHg, tone was 35-50% less in arteries from pregnant rats (P < 0.05). Endothelial removal reduced tone in arteries from virgin rats but had no effect on arteries from pregnant rats. Analysis of stress-strain curves (rate constants: pregnant, 6.31 +/- 0.38; virgin, 7.81 +/- 0.78; P < 0.05) indicate that there is a decrease in arterial stiffness in gestation. Thus pregnancy is associated with a reduced intrinsic tone, possibly because of a reduction in an endothelial constrictor influence on the vascular smooth muscle in isolated rat renal interlobar arteries. This effect, coupled with the decreased arterial stiffness, demonstrates the significant arterial adaptation occurring during pregnancy.
Mechanisms of vasodilation elicited by VIP in sterically stabilized liposomes in vivo
Authors: Sejourne F. , Suzuki H. , Alkan-Onyuksel H. , Gao X. P. , Ikezaki H. , Rubinstein I.
Published: December 2017

The purpose of this study was to begin to determine the mechanisms underlying vasodilation elicited by vasoactive intestinal peptide (VIP) in sterically stabilized liposomes (SSL) in the in situ peripheral microcirculation. Using intravital microscopy, we found that suffusion of VIP in SSL (0.42 and 0.85 nmol) onto the hamster cheek pouch for 1 h elicited significant and prolonged concentration-dependent vasodilation (P < 0.05). Suffusion of VIP in SSL (0.1 nmol) for 7 min elicited a qualitatively similar response, although its magnitude was significantly smaller than that elicited by 1 h of suffusion of VIP in SSL (P < 0.05). The VIP-receptor antagonist VIP-(10-28), but not the amino-terminal fragment VIP-(1-12), significantly attenuated and delayed the onset of VIP in SSL-induced vasodilation (P < 0.05). The nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), but not NG-nitro-D-arginine methyl ester (D-NAME), abrogated VIP in SSL-induced responses. We conclude that VIP in SSL elicits significant and prolonged vasodilation in the in situ peripheral microcirculation, which is specific, partly receptor dependent, and partly transduced by the L-arginine/NO biosynthetic pathway.
Dopamine and diltiazem-induced natriuresis in the spontaneously hypertensive rat
Authors: Eisner G. M. , Asico L. D. , Albrecht F. E. , Jose P. A.
Published: December 2017

An attenuated natriuretic response to dopamine and D1 agonists in genetic hypertension has been attributed to an uncoupling of the renal D1 dopamine receptor from its G protein-effector protein complex. We have reported that in normotensive Wistar-Kyoto (WKY) rats the natriuresis induced by calcium channel blockers is caused in part by activation of renal D1 dopamine receptors. We tested the interaction between the renal D1 receptor and a calcium channel blocker, diltiazem, infused into a renal artery of anesthetized spontaneously hypertensive rats (SHR) acutely loaded with 5% saline. Diltiazem produced a 50% increase in renal blood flow and nearly tripled absolute and fractional sodium excretion; urine flow rate more than doubled, but glomerular filtration rate did not change. However, the D1 receptor antagonist SKF-83742, which had no effect by itself, did not diminish the response to diltiazem. In a separate group of concurrent experiments, we found that the diltiazem-induced natriuresis was associated with a decrease in Na(+)-K(+)-adenosinetriphosphatase activity in the renal medulla of SHR. In contrast, in WKY rats, no changes were noted in the renal medulla but a decrease in Na(+)-K(+)-adenosinetriphosphatase activity was noted in the renal cortex. Diltiazem had no effect on urinary dopamine excretion in either rat strain. We conclude that diltiazem induces natriuresis differently in SHR and WKY rats; it is independent of D1 receptors in SHR and is in great part mediated by renal hemodynamic, rather than by cortical tubular, effects. These studies support previous findings of a defective renal cortical tubular D1 mechanism in SHR.
Effect of aging on vasopressin and aquaporin responses to dehydration in Fischer 344-brown-Norway F1 rats
Authors: Swenson K. L. , Sands J. M. , Jacobs J. D. , Sladek C. D.
Published: December 2017

The plasma vasopressin (VP) response to 72 h of water deprivation is attenuated in 30-mo-old Fischer 344 (F344) rats relative to 4-mo-old rats. This appears to reflect an inability to increase VP synthesis. In contrast, elevated plasma VP has been reported in the Brown-Norway (BN) strain of rats secondary to reduced renal VP responsivity. The response to dehydration in the F1 cross of these strains (F344BNF1) was evaluated. Male rats, 4 and 30 mo old, were deprived of water for 72 h or allowed water ad libitum. In response to dehydration, plasma sodium and hematocrit were significantly increased in both young and aged rats (P < 0.05), but plasma VP, urine osmolality, and aquaporin 2 expression were only increased in the young rats (P < 0.05). Posterior pituitary content of immunoreactive VP was depleted in the young but not the old rats. Thus the aged F344BNF1 rats demonstrated a deficit in VP release in response to an apparently similar dehydration stimulus. This deficit was different from those previously reported for either the F344 or BN strains. Thus further studies are required to determine the abnormalities underlying this response.
Time course of milk accumulation-induced opening of mammary tight junctions, and blood clearance of milk components
Authors: Stelwagen K. , Farr V. C. , McFadden H. A. , Prosser C. G. , Davis S. R.
Published: December 2017

Eight cows in early lactation were used to study the effect of milk accumulation on the state of mammary tight junctions and to examine alpha-lactalbumin as an indicator of tight junction permeability in vivo. During three successive periods, the cows were milked twice (4 days), once (6 days), and twice daily (4 days). Plasma lactose, alpha-lactalbumin, and milk sodium concentrations were used as indicators of tight junction permeability. Furthermore, four cows were used to study the clearance of lactose and alpha-lactalbumin from the blood. Milk yield during once-daily milking decreased by 15.4% (P < 0.001). All indicators of mammary tight junction patency increased (P < 0.05) transiently during once-daily milking and indicated that tight junctions opened after approximately 18 h. Plasma alpha-lactalbumin and lactose were highly correlated (r = 0.82, P < 0.001), indicating the suitability of plasma alpha-lactalbumin as an indicator of tight junction status in vivo. Clearance of alpha-lactalbumin and lactose from the blood was best described by a biexponential model. Elimination half-lives for lactose and alpha-lactalbumin were 44 and 40 min, respectively. This study showed that milk stasis during early established lactation induces tight junctions to switch to a leaky state after approximately 18 h and to revert to the closed state shortly after milking.
Central injection of physostigmine attenuates exercise-induced pressor response in conscious cats
Authors: Ally A. , Hand G. A. , Mitchell J. H.
Published: December 2017

The effects of intracerebroventricular administration of physostigmine, a cholinesterase inhibitor, on the cardiovascular responses evoked by static voluntary exercise were investigated using conscious cats. Four cats were trained to press a bar (200-650 g) with one forelimb for at least 20 s. The changes in mean arterial pressure (MAP), heart rate (HR), and developed force during the first five trials in 30 min by each individual cat were averaged, and a mean of the four values was then calculated. After the cats exercised for 30 min, either artificial cerebrospinal fluid (CSF) or physostigmine (5 micrograms) was administered intracerebroventricularly. Before physostigmine, exercise trials by the cats increased MAP and HR by 17 +/- 3 mmHg and 42 +/- 4 beats/min, respectively. Administration of physostigmine did not alter the resting MAP and HR but attenuated the MAP and HR responses to exercise (5-30 min postphysostigmine: MAP = 8 +/- 3 mmHg, HR = 25 +/- 7 beats/min; 30-60 min postphysostigmine: MAP = 4 +/- 3 mmHg, HR = 19 +/- 8 beats/min). Intracerebroventricular administration of CSF had no effect on the cardiovascular responses to static exercise. Pretreatment with the muscarinic antagonist, atropine (25 micrograms icv), blocked the attenuating effects of subsequent intracerebroventricular administration of physostigmine. These results demonstrate that stimulation of central muscarinic receptors attenuates the cardiovascular responses to static exercise by conscious cats. In addition, the present study suggests that there is no tonic effect of central muscarinic receptors on the cardiovascular responses to voluntary exercise.
Physiological and cytokine responses in IL-1 beta-deficient mice after zymosan-induced inflammation
Authors: Fantuzzi G. , Sacco S. , Ghezzi P. , Dinarello C. A.
Published: December 2017

Interleukin (IL)-1 beta-deficient (IL-1 beta -/-) mice exhibited decreased zymosan-induced lethality and reduced production of IL-6 compared with wild-type controls (IL-1 beta +/+). In addition, IL-1 beta -/- mice had a diminished cellular infiltrate (33%) in the peritoneal cavity after zymosan. However, anorexia and hypoglycemia were not affected by the lack of IL-1 beta. The induction of corticosterone was only slightly reduced (14%) in IL-1 beta -/- mice. Peritoneal lavage fluid levels for IL-1 alpha, but not for tumor necrosis factor (TNF)-alpha, were also decreased. To evaluate the role of residual IL-1 alpha production in IL-1 beta -/- mice, we used IL-1-receptor antagonist (IL-1ra). In IL-1 beta +/+ mice, IL-1ra inhibited production of IL-6 after zymosan, without affecting TNF-alpha synthesis. There was no further inhibitory effect of IL-1ra on IL-6 production in IL-1 beta -/- mice, suggesting no role for IL-1 alpha in zymosan-induced IL-6. Our results demonstrate that IL-1 beta plays a significant, although not exclusive, role in the physiological and cytokine responses to zymosan-mediated inflammation.
Endothelin-1 limits increases in blood flow to native and collateral-dependent myocardium
Authors: Symons J. D. , Rendig S. V. , Fu L. W. , Longhurst J. C.
Published: December 2017

We hypothesized that blood flow to collateralized and noncollateralized myocardium is improved by antagonism of endothelin (ET) A receptors. Coronary collateral development was stimulated by placing an ameroid constrictor around the left circumflex coronary artery (LCx; collateralized region) in 11 swine. After 35 +/- 2 days, the left anterior descending coronary artery (LAD; noncollateralized region) was autoperfused at constant pressure using blood from a femoral artery. In group 1 (n = 6) transmural blood flow was measured using radioactive microspheres in the LAD, LCx, and border regions (i.e., area between LAD and LCx) during pacing stress while vehicle (phosphate-buffered saline) was infused into the LAD coronary artery (pace 1). Approximately 55 min later, a second period of pacing (pace 2) was performed in the presence of ETA receptor antagonism (BQ-123; 5 mg.ml-1.min-1 ic). In the time control group (group 2, n = 5) vehicle was infused during both pacing periods. Indexes of myocardial oxygen demand were similar between paces 1 and 2 in each group. Compared with the first pacing period, transmural blood flow (ml.100 g-1.min-1) was higher (P < 0.05) during ETA receptor antagonism (i.e., pace 2) in the LAD (105 +/- 8 vs. 139 +/- 9), border (51 +/- 5 vs. 83 +/- 7), and LCx regions (22 +/- 3 vs. 41 +/- 4, respectively) in group 1. In group 2, while perfusion in the border (98 +/- 17 vs. 103 +/- 16) and LCx regions (19 +/- 4 vs. 27 +/- 6) was similar in paces 1 and 2, LAD transmural flow was greater (134 +/- 9 vs. 160 +/- 13; P < 0.05) during the second pacing period. However, the percent increase in LAD flow comparing pace 1 with 2 was greater (P < 0.05) in group 1 (39 +/- 6%) compared with group 2 (20 +/- 7%). These data suggest that during the stress of pacing blood flow to collateralized and noncollateralized myocardium is improved in the presence of ETA receptor blockade.
Frequency-dependent modulation of renal blood flow by renal nerve activity in conscious rabbits
Authors: Janssen B. J. , Malpas S. C. , Burke S. L. , Head G. A.
Published: December 2017

To examine the influence of the various frequency components of renal sympathetic nerve activity (RSNA) on renal blood flow (RBF) dynamics, a Doppler flow probe and renal nerve electrode were implanted on the left renal artery of 10 rabbits. Experiments were performed 4-9 days after surgery. Physiological changes in RSNA were induced by subjecting the rabbits to periods of breathing hypoxic gas mixtures. Signals were sampled at 1 kHz and analyzed by spectral analysis. During moderate hypoxia (arterial PO2 = 44 +/- 1 mmHg), arterial pressure and heart rate did not change, averaged RSNA increased by 90 +/- 7%, and RBF fell by 18 +/- 3%. In a separate group of renal-denervated rabbits (n = 6), no changes in RBF occurred during hypoxia. In intact rabbits, 53 +/- 4% of spectral density power of RSNA was found at the cardiac frequency and the remainder was predominantly coupled to respiration (approximately 0.9 Hz). During moderate hypoxia the amplitude of the RSNA oscillations increased 17 +/- 6 times at the cardiac frequency and 10 +/- 3 times at the respiration-related frequency. Modulation of RBF variability by the fluctuations of RSNA at the cardiac- and respiration-related frequency was, however, small. The normalized transfer gain between RSNA and RBF was approximately 0.1 at > 0.5 Hz. This means that, at > 0.5 Hz, maximally 10% of the amplitude of the RSNA oscillations is transmitted to corresponding RBF fluctuations. These transfer properties did not change during hypoxia. At < 0.5 Hz the transfer gain between RSNA and RBF increased. During moderate hypoxia, 0.3-Hz coherent oscillations of RSNA and RBF were found. In renal-denervated rabbits, 0.3-Hz oscillations in RBF were absent. Thus the renal vasculature was able to follow relatively low-frequency (< 0.5-Hz) fluctuations of RSNA and responded with corresponding oscillations in RBF. In contrast, the renal vasculature responded with increased constriction at the high-frequency (> 0.5-Hz) fluctuations of RSNA. These findings suggest that, in conscious rabbits, high-frequency oscillations of RSNA contribute to the vasoconstrictor tone, whereas the lower frequencies of RSNA contribute to the variability of RBF.
Central noradrenergic system modulates plasma interleukin-6 production by peripheral interleukin-1
Authors: Huang Q. H. , Takaki A. , Arimura A.
Published: December 2017

The role of the central noradrenergic system in systemic interleukin-6 (IL-6) production induced by intravenously administered recombinant human interleukin-1 beta (IL-1 beta) was examined in rats. Pretreatment of rats intracerebroventricularly with 6-hydroxydopamine (6-OHDA, 100 or 200 micrograms/rat) significantly attenuated the increase in plasma IL-6 levels caused by IL-1 beta (2 micrograms/kg i.v.). A modest inhibition of the IL-1 beta-induced plasma IL-6 production was observed following pretreatment with prazosin (20 micrograms/rat i.c.v.) but not after administration of idazoxan or propranolol. There were no significant increases in the IL-6 content in the hypothalamus, medulla oblongata, and cortex of the brain after intravenous IL-1 beta. Adrenalectomy produced an augmented plasma IL-6 response to intravenous IL-1 beta, whereas chemical sympathectomy with intraperitoneal injection of 6-OHDA (50 or 100 mg/kg) decreased the IL-1 beta-induced plasma IL-6 levels. Nor-epinephrine (NE), in the dose range 10(-6)-10(-4) M, significantly increased the IL-6 levels in the rat spleen lymphocyte culture media. At doses of 10(-9)-10(-7) M, NE enhanced the effect of IL-1 beta on the IL-6 release by spleen lymphocytes in a dose-dependent manner. These findings suggest that the plasma IL-6 response to intravenous IL-1 beta is partially mediated through the activation of the central noradrenergic system and a consequent increase in the sympathetic outflow to the peripheral tissues and that the NE released from the sympathetic terminals may function as a mediator and/or modulator to facilitate the synthesis/release of IL-6 in the sympathetic nerve-innervated organs.
Neuropeptide stimulation of the nitric oxide signaling pathway in Drosophila melanogaster Malpighian tubules
Authors: Davies S. A. , Stewart E. J. , Huesmann G. R. , Skaer N. J. , Maddrell S. H. , Tublitz N. J. , Dow J. A.
Published: December 2017

Activation of the nitric oxide (NO) and guanosine 3', 5'-cyclic monophosphate (cGMP) signaling pathway stimulates fluid secretion by the Drosophila melanogaster Malpighian tubule. The neuropeptide cardioacceleratory peptide 2b (CAP2b) has been previously shown to stimulate fluid secretion in this epithelium by elevating intracellular cGMP levels. Therefore, it was of interest to investigate if CAP2b acts through NO in isolated tubules and thus presumably through stimulation of a tubule NO synthase (NOS). We show here by reverse-transcription polymerase chain reaction that Drosophila NOS (dNOS) is expressed in Malpighian tubules. Biochemical assays of NOS activity in whole tubules show that CAP2b significantly stimulates NOS activity. Additionally, fluid secretion and cyclic nucleotide assays show that CAP2b-induced elevation of intracellular cGMP levels and fluid secretion rates are dependent on the activation of a soluble guanylate cyclase. Treatment of tubules with a specific NOS inhibitor abolishes the CAP2b-induced rise in intracellular cGMP levels. These data indicate that CAP2b stimulates NOS and therefore, endogenous NO production, which, in turn, stimulates a soluble guanylate cyclase. This is the first demonstration of stimulation of an endogenous NOS by a defined peptide in Drosophila.
Developmental increases in glucose transporter concentration in the sheep placenta
Authors: Ehrhardt R. A. , Bell A. W.
Published: December 2017

To explore the molecular basis for the gestational increase in glucose transport capacity of the sheep placenta in vivo, placentas from twin-pregnant ewes at days 75, 110, and 140 postcoitus (n = 6/group) were analyzed for glucose transporter (GT) concentration. Concentration (pmol/mg protein) of D-glucose-inhibitable binding sites, measured by [3H]cytochalasin B binding analysis, increased 3.4 times from mid- to late pregnancy. Concurrently, abundance of GLUT-1 and GLUT-3 protein, measured by immunoblotting with specific polyclonal antibodies, increased 2.3 and 2.9 times, respectively, while abundance of GLUT-1 and GLUT-3 mRNA, measured by Northern blotting, increased 1.8 and 3.9 times, respectively. GLUT-4 protein was undetectable at all stages of pregnancy. Quantitative immunoblotting indicated that GLUT-1 accounted for 86.8 +/- 1.6% at day 75 and 56.1 +/- 4.1% at day 140 of total cytochalasin B binding sites. Thus increases in GT concentration explain much of the gestational increase in glucose transfer capacity observed in vivo. The gestational decline in relative contribution of GLUT-1 to cytochalasin binding, together with the greater developmental increases in GLUT-3 mRNA and protein, further suggests that the relative importance of GLUT-3 increases with gestational age.
Multifiber renal SNA recordings predict mean arterial blood pressure in unanesthetized rat
Authors: Burgess D. E. , Hundley J. C. , Li S. G. , Randall D. C. , Brown D. R.
Published: December 2017

The goal of this analysis was to quantify the relationship between renal sympathetic nerve activity (SNA) and mean arterial blood pressure (MAP). We previously recorded renal SNA and MAP in conscious rats during a stressful behavioral stimulus and during a nonstressful stimulus. We then formulated a set of two linear, first-order differential equations that uses our SNA recordings after a time delay (the input) to predict fluctuations in MAP (the output). Our model has four parameters: 1) the cardiovascular time constant T that characterizes the frequency response function between the effector elements controlled by the sympathetic nerves and the cardiovascular system (1-5 s); 2) the effector time constant Te determined by the coupling between the sympathetic nervous system and the effectors (0.0-0.6 s); 3) the efferent time delay tau e between a change in SNA and a change in MAP (0.4-0.6 s); and 4) a proportionality constant C between fluctuations in SNA and fluctuations in MAP (0.3-3.4 mmHg/nV). The parameters of the model were determined that minimize the residual error between the simulated time series and the actual data time series for a stressful stimulus. Then we tested the ability of the transfer function to predict the MAP response to a nonstressful stimulus. In five of seven rats tested, the model's predictions were good, with mean cross-correlation coefficients for the predicted trials between 0.62 and 0.83. We show that multifiber renal SNA recordings can reliably predict changes in MAP in the unanesthetized rat. Thus the overall sympathetic drive to the cardiovascular system is indexed by renal SNA, although the vasomotor effectors driven by renal SNA control only approximately 20% of the blood cow.
Effect of restraint stress on food intake and body weight is determined by time of day
Authors: Rybkin Igor I. , Zhou You , Volaufova Julia , Smagin Gennady N. , Ryan Donna H. , Harris Ruth B. S.
Published: December 2017

Three experiments were conducted to investigate the effect of restraint stress applied at different times of the light-dark cycle on feeding behavior and body weight of rats. Sprague-Dawley rats were restrained for 3 h in restraining tubes either at the start or the end of the light cycle. There was a significant reduction in food intake on the day of restraint and no change in food intake during a 10-day recovery period in either experiment. Reductions of food intake on the day of restraint were about the same for both restrained groups compared with their controls. When stress was applied in the evening, eating was inhibited during the first 2 h after restraint, whereas in rats restrained in the morning, feeding was suppressed twice: during the 4 h after restraint and during the first 2 h of the dark cycle. Restraint induced a significant weight loss that was greater in the rats stressed in the morning. Neuropeptide Y (NPY) levels determined at the time of food suppression for both experiments (beginning of the dark cycle) revealed an elevation of NPY in the paraventricular nucleus of rats stressed in the morning compared with other groups, but no difference in hypothalamic NPY mRNA expression. Expression of uncoupling protein mRNA in brown adipose tissue and leptin mRNA in epididymal fat, measured at the start of the dark period, was not altered by stress. There was an elevation of dopamine turnover in the hypothalami of rats restrained at the end of light cycle, but not those restrained in the morning. These results show that restraint stress has a greater effect on metabolism and energy balance when it is applied in the morning. Additional studies are needed to elucidate mechanisms involved in the suppression of food intake 9 h after restraint.
Neural regulation of kidney function by the somatosensory system in normotensive and hypertensive rats
Authors: Zhang Tao , Huang Chunlong , Johns Edward J.
Published: December 2017

This investigation examined the renal sympathetic nerve and renal excretory responses to somatosensory stimulation in normotensive and stroke-prone spontaneously hypertensive rats (SHRSP). Somatosensory activation was achieved by either subcutaneous capsaicin administration or exposure of the airways tract to irritant fumes from acetic acid in chloralose-urethan-anesthetized animals. In Wistar rats, blood pressure increased between 10 and 20% ( P < 0.001–0.01), renal perfusion pressure was maintained unchanged, renal hemodynamics were unaltered, and urine flow and sodium excretion were decreased by 25 to 50% ( P < 0.001–0.05). In the SHRSP, the somatosensory-induced increases in blood pressure were slightly larger (∼15–20% P < 0.05) than those of the Wistar rats, whereas the excretory responses were one-half those of the normotensive animals ( P < 0.05). The somatosensory challenges reflexly increased integrated renal sympathetic nerve activity in both normotensive and hypertensive rats. The power spectral analysis demonstrated that the increases in percentage power at heart rate frequency and total power were two to three times more ( P < 0.05) in the Wistar rats compared with the SHRSP. The reduced ability of the SHRSP to modulate the energy in the renal sympathetic nerve signal at heart rate frequency might explain in part the attenuated functional responses to the somatosensory challenges.
Pivotal role of the renin-angiotensin system in Lyon hypertensive rats
Authors: Lantelme Pierre , Lo Ming , Luttenauer Laurent , Sassard Jean
Published: December 2017

We assessed the role of the renin-angiotensin system (RAS) in Lyon genetically hypertensive (LH) and normotensive (LN) rats by measuring 1) kidney renin and prorenin contents; 2) effects of early, prolonged angiotensin-converting enzyme (ACE) inhibition on blood pressure (BP) and regional hemodynamics; and 3) acute and chronic responses to angiotensin II (ANG II) and norepinephrine (NE). At the adult age, LH rats differed from LN rats by elevated BP, left ventricle weight, and vascular resistances, especially in the kidneys, associated with lower kidney renin and prorenin contents. ACE inhibition (perindopril, 3 mg ⋅ kg−1 ⋅ 24 h−1 orally from 3 to 15 wk of age) suppressed the development of hypertension, cardiac hypertrophy, and the increase in renal vascular resistances. No specific hypersensitivity to ANG II could be disclosed in acute conditions. In perindopril-treated LH rats, a 4-wk infusion of ANG II (200 ng ⋅ kg−1 ⋅ min−1) but not of NE (1,000 ng ⋅ kg−1 ⋅ min−1) restored hypertension, mimicked the hemodynamic alterations seen in untreated LH rats, and produced a brief sodium retention. It is concluded that in LH rats, despite a low basal renin secretion, hypertension and hemodynamic abnormalities 1) are fully dependent on an active RAS and 2) may involve an enhanced sensitivity to the chronic effects of ANG II.
Influence of anesthesia on bladder hyperactivity induced by middle cerebral artery occlusion in the rat
Authors: Yokoyama Osamu , Yoshiyama Mitsuharu , Namiki Mikio , De Groat William C.
Published: December 2017

The effect of anesthesia or an N-methyl-d-aspartate (NMDA) glutamatergic antagonist (MK-801) on bladder hyperactivity induced by unilateral middle cerebral artery (MCA) occlusion was examined in female rats. Before infarction, control bladder contractions were monitored in two groups of rats: 1) awake and 2) urethan anesthetized. The awake rats were then anesthetized with halothane, and MCA occlusion was performed in both groups. After recovery from halothane, bladder capacity in awake rats was significantly reduced (60.8 ± 1.3%) 0.5–4.5 h after MCA occlusion but not changed in urethan-anesthetized rats. MK-801 (0.1 mg/kg iv) administered before MCA occlusion blocked the reduction in bladder capacity in awake rats 1.5–4.5 h after MCA occlusion. Bladder capacity was not changed by sham operation in either the awake or urethan-anesthetized rats. Urethan administered after recovery from halothane anesthesia increased bladder capacity in MCA-occluded awake rats but not in sham-operated awake rats. Infarct areas in halothane, urethan-anesthetized, or MK-801-treated rats were not significantly different. These results indicate that cerebral infarction induces bladder hyperactivity in awake rats and that urethan or MK-801 inhibits the development of this hyperactivity, most likely by blocking glutamatergic transmission in the brain.
Nonlinear dynamics of the frequency locking of baroreceptor and sympathetic rhythms
Authors: Gebber Gerard L. , Zhong Sheng , Zhou Shi-Yi , Barman Susan M.
Published: December 2017

We used phase plane analysis to identify modes of frequency locking of the 10-Hz rhythm in sympathetic nerve discharge (SND) to the cardiac cycle in urethan-anesthetized, baroreceptor-innervated cats. Frequency locking occurred in rational ratios predicted by a generic mathematical construct called the Farey tree. Both simple harmonic ratios (e.g., 1:3) and complex ratios (e.g., 2:5) comprised of relatively prime integers (no common divisor) were identified under natural conditions. Frequency locking in such ratios is attributed to forcing of the 10-Hz oscillator by pulse-synchronous baroreceptor afferent nerve activity (BNA). Ventricular pacing changed the frequency of the 10-Hz rhythm as well as heart rate so as to maintain or change the ratio of frequency locking in a predictable way. Intriguingly, frequency locking of the 10-Hz rhythm to medullary raphe sympathoinhibitory stimuli in simple harmonic ratios was accompanied by increased power in the 10-Hz band of SND, whereas locking in complex ratios led to decreased 10-Hz power. These findings raise the possibility that pulse-synchronous BNA also exerts divergent actions on the 10-Hz rhythm depending on the ratio of frequency locking. Augmented 10-Hz power can be attributed to the resonant properties of oscillators that are periodically forced at the same phase in their cycle.