bluuebunny/crossref_metadata_2025 huggingface dataset:
Blockade of type A, but not type B, CCK receptors postpones satiety in rhesus monkeys
Authors: Moran T. H. , Ameglio P. J. , Peyton H. J. , Schwartz G. J. , McHugh P. R.
Published: December 2017

The exogenous administration of the brain/gut peptide cholecystokinin (CCK) inhibits food intake in a variety of species, including subhuman primates and humans. To determine the role of endogenously released CCK in the control of food intake in rhesus monkeys, we examined the ability of the selective type A and type B CCK antagonists devazepide and L-365260 to affect total daily food intake and various meal patterns. Various doses of the antagonists were administered intragastrically 30 min before a daily 4-h feeding period. One-gram food pellets were delivered in response to lever pulls, and intake was computer monitored. Intragastric administration of the type A CCK receptor antagonist devazepide (10-320 micrograms/kg) significantly increased food intake in a dose-related fashion. The threshold for increasing intake was 32 micrograms/kg, and a maximal effect was obtained at a dose of 100 micrograms/kg that increased total 4-h food intake by 47%. The effect of devazepide on food intake was mediated by significant increases in the size and duration of the initial meal, lengthening of the subsequent intermeal interval, and a decrease in the satiety ratio (intermeal interval/1st meal size). In contrast, intragastric administration of the type B CCK receptor antagonist L-365260 (3.2-320 micrograms/kg) did not significantly affect total food intake or any of the meal parameters. These data demonstrate that endogenously released CCK acting through type A CCK receptors plays a role in regulating food intake in rhesus monkeys.
Involvement of central vs. peripheral mechanisms in mediating sympathoadrenal activation in endotoxic rats
Authors: Zhou Z. Z. , Jones S. B.
Published: December 2017

The contribution of central vs. peripheral mechanisms in mediating increases in plasma norepinephrine (NE) and epinephrine (Epi) during endotoxicosis were studied. Plasma catecholamine responses after endotoxin were assessed in conscious animals and in animals without central regulatory mechanisms (pithed rats). In conscious rats, endotoxin (1.5 mg/kg i.v.) induced a marked elevation in plasma NE after 90 min (3-fold), but elevations were not seen in pithed rats. Endotoxin also induced a profound increase (12- to 13-fold) in plasma Epi in conscious rats, but increases were less (2- to 3-fold) and delayed in pithed rats. These results suggest that central mechanisms are essential in plasma NE response to endotoxic challenge, whereas plasma Epi response involves both central and peripheral mechanisms, with the former being dominant. In conscious adrenal-denervated animals, plasma Epi was not elevated until 90 min postendotoxin. This delayed Epi elevation was approximately one-third of the maximal response observed in conscious adrenal-intact rats. In pithed adrenal-denervated rats, plasma Epi at 90 min postendotoxin was also increased to a level comparable to that in pithed adrenal-intact rats. These results imply that a significant fraction of peripheral release of Epi with endotoxicosis is nonneurogenic.
Modulation of systemic interleukin-6 induction by central interleukin-1
Authors: De Simoni M. G. , De Luigi A. , Gemma L. , Sironi M. , Manfridi A. , Ghezzi P.
Published: December 2017

Centrally administered interleukin (IL)-1 [both alpha and beta forms, 200 ng/rat intracerebroventricularly (icv)] results in a larger increase in serum IL-6 than after systemic injection, indicating the brain's role in the acute phase response. This action was prevented by the IL-1-receptor antagonist IL-1Ra (20 micrograms/rat icv). Neither antiserum against corticotropin-releasing factor (CRF) nor the alpha-helical-CRF antagonist (25 micrograms/rat icv) affected IL-6 induction by central IL-1 beta, which, however, was significantly prevented by the synthetic glucocorticoid dexamethasone [3 mg/kg intraperitoneally (ip)]. Naloxone, the opiate antagonist, but not naloxone methiodide, its quaternary salt that does not penetrate the blood-brain barrier (both administered at 10 mg/kg ip), antagonized this action of IL-1 beta. After intracerebroventricular IL-1 beta, IL-6 levels in brain areas (striatum, hippocampus, hypothalamus) were extremely low, suggesting that the brain does not significantly contribute to IL-6 synthesis in this condition. The results show that induction of high serum IL-6 levels by central IL-1 beta is mediated by brain IL-1 receptors and is sensitive to inhibition by corticosteroids. The inhibitory effect of naloxone suggests that central opiates are required for this action of IL-1 beta.
In vivo evidence for adrenal catecholamine release mediated by nonnicotinic mechanism: local medullary effect of VIP
Authors: Yamaguchi N.
Published: December 2017

The aim of the present study was 1) to develop a model in anesthetized dogs in which local infusion of a given substance could be made to the adrenal gland without any systemic effects and 2) to show in this model the potential existence of a nonnicotinic mechanism involved in adrenal catecholamine secretion. Plasma catecholamine concentrations were determined by an high-performance liquid chromatography method. The local infusion into the left adrenolumbar artery (0.5 ml/min for 1 min) of either dimethylphenylpiperazinium (0.3-3.0 micrograms/ml) or vasoactive intestinal peptide (0.1-10.0 micrograms/ml) resulted in dose-dependent increases in both epinephrine and norepinephrine secretions. Neither aortic pressure nor plasma catecholamine levels altered during the drug infusion. The net increases in adrenal catecholamine secretion obtained with dimethylphenylpiperazinium were abolished by the nicotinic blockade with pentolinium (2 mg/ml, 0.5 ml/min for 2 min). However, the net catecholamine responses to vasoactive intestinal peptide remained unaffected in the presence of the same dose of pentolinium. The results suggest that there exists a nonnicotinic mechanism that may be implicated in the local regulation of medullary catecholamine secretion in the dog adrenal gland. This model may be a useful tool for studying local physiological role(s) of various neurotransmitters and neuromodulators in the adrenal secretory function in vivo.
Circadian rhythms of thermoregulation in the squirrel monkey (Saimiri sciureus)
Authors: Robinson E. L. , Demaria-Pesce V. H. , Fuller C. A.
Published: December 2017

Phase or amplitude differences between rhythms in heat production (HP) and heat loss (HL) have been suggested to account for the circadian rhythm in body temperature (Tb). To describe the relationships among these rhythms in a primate, five unrestrained squirrel monkeys (1.0-1.3 kg) were studied using combined direct and indirect calorimetry, with telemetry of Tb and activity, in a 24-h light-dark cycle (LD 12:12) at 25 +/- 0.5 degrees C. Dry (D; sensible) HL, evaporative (E) HL, HP (oxygen consumption and CO2 production), Tb, and activity were measured at 10-min intervals for a week. Tb, activity, HP, and HL displayed daily rhythms, peaking during the light period. Although the timing of peaks was not significantly different, the diurnal increase in Tb was seen to result from a delayed increase in DHL, and possibly, EHL, relative to increased HP. The nocturnal decrease in Tb was due to different time courses of decrease in HP and HL, with no clear lag in HL. The rhythm in Tb therefore resulted from both phase and time course differences in HP and HL rhythms.
Steady-state osmotic modulation of cationic conductance in neurons of rat supraoptic nucleus
Authors: Oliet S. H. , Bourque C. W.
Published: December 2017

Whole cell patch-clamp recordings were obtained from isolated rat supraoptic nucleus magnocellular neurosecretory cells (MNCs). Under current clamping, hyperosmolality produced by the addition of 10-30 mM mannitol depolarized each of 25 cells tested. In contrast, reducing fluid osmolality from 295 to 265 mosmol/kgH2O had the reverse effect, hyperpolarizing 18 of 21 MNCs. Voltage-clamp recordings in 43 cells revealed that the effects of hypo- and hyperosmolality, respectively, were caused by decreases and increases in a nonselective cation conductance reversing near -41 mV. Current-voltage analysis in Na(+)-free solution revealed that the reversal potentials of currents elicited by increases and decreases in osmolality both shifted to a value near -90 mV, suggesting that a single ionic conductance is modulated by these stimuli. The relation between cationic conductance and osmolality was specific, sensitive (+2.14%.mosmol-1.kgH2O-1), and well-fit by linear regression (r = 0.96; n = 22 cells) between 275 and 325 mosmol/kgH2O. These results indicate that MNCs express a depolarizing current that is active under steady-state conditions and that the up- or downregulation of this current contributes to the excitation or inhibition of these cells upon acute exposure to hypo- or hyperosmolar conditions.
c-fos antisense in rostral ventral medulla reduces arterial blood pressure
Authors: Suzuki S. , Pilowsky P. , Minson J. , Arnolda L. , Llewellyn-Smith I. J. , Chalmers J.
Published: December 2017

The effect of blocking the expression of c-fos in the rostral ventral medulla (RVM) on the control of arterial blood pressure was determined. In six male Wistar-Kyoto rats (WKY), unilateral injection of an antisense oligonucleotide to c-fos mRNA suppressed the expression of Fos-like immunoreactivity in neurons in the RVM in response to inhibition of depressor neurons in the caudal ventrolateral medulla (CVLM). Under pentobarbital anesthesia the mean arterial pressure of rats injected with antisense oligonucleotide (n = 10) bilaterally into RVM was significantly reduced after 6 h compared with sense-treated controls (n = 9) (76.5 +/- 3.7 vs. 92.4 +/- 3.5 mmHg; P < 0.05). Furthermore, the pressor response to bilateral injection of muscimol into CVLM was significantly smaller in rats injected with antisense oligonucleotide 6 h earlier (n = 6) compared with sense-treated controls (n = 6) (changes in mean arterial pressure, +40.3 +/- 3.6 vs. +68.7 +/- 4.8 mmHg, P < 0.005). These studies demonstrate that expression of c-fos in the RVM can be blocked in vivo by treatment with an antisense oligonucleotide, and that basal and stimulated expression of the c-fos gene is important in the central control of arterial blood pressure.
Sympathetic activity and blood pressure are tightly coupled at 0.4 Hz in conscious rats
Authors: Brown D. R. , Brown L. V. , Patwardhan A. , Randall D. C.
Published: December 2017

Interactions of sympathetic nerve activity (SNA) with blood pressure (BP) and heart rate (HR) were assessed in conscious rats while they rested quietly in a cloth sock (n = 7), roamed freely in their home cage (n = 6), and then after anesthesia with pentobarbital (30 mg/kg; n = 7). The power and coherence spectra below 3 Hz were calculated from data collected for 9.56 min. In the conscious rat, SNA spectral power peaked at 0.4 Hz, whereas the majority of spectral power for both BP and HR occurred at frequencies lower than 0.4 Hz. However, there was an inconspicuous peak in the BP power spectra at 0.4 Hz that was not seen in the HR spectra. Coherence between SNA and BP peaked at a frequency of approximately 0.4 Hz, the same frequency at which the SNA spectral peaks occurred. In contrast, at frequencies below 0.4 Hz where maximum BP power occurred, the coherence was considerably lower. Anesthesia with pentobarbital lowered spectral power for BP, SNA, and HR but essentially did not change the coherence between SNA and BP. Interactions between respiration and each of the other variables were weak in the conscious rat. However, prominent respiratory interactions at approximately 1.2 Hz were evident after anesthesia. These data indicate a close coupling between SNA and BP at 0.4 Hz, raising the possibility that the BP spectral power at 0.4 Hz reliably reflects sympathetic activity.
The nocturnal increase in human cerebrospinal fluid production is inhibited by a beta 1-receptor antagonist
Authors: Nilsson C. , Stahlberg F. , Gideon P. , Thomsen C. , Henriksen O.
Published: December 2017

A circadian variation in human cerebrospinal fluid (CSF) production has recently been demonstrated using magnetic resonance phase imaging. A nightly peak in CSF production was found at approximately 0200, when production is approximately twice the daytime values. In the present study, we have investigated the effect of a beta 1-receptor antagonist, atenolol, on the production of CSF, specifically the nocturnal production peak. CSF production was measured in fourteen healthy volunteers of both sexes in the time interval 1500-1800, with or without drug administration (100 mg orally) at 1800, and a second measurement was made in the time interval 2300-0200. In the absence of drug administration, all nine volunteers showed a significant increase in CSF production at night, from 0.34 +/- 0.06 ml/min in the time interval 1500-1800 to 0.61 +/- 0.05 (SE) ml/min (P < 0.005), confirming the presence of a circadian variation in these individuals. One week later, the experiment was repeated in five of these volunteers, plus an additional five volunteers, but with the administration of 100 mg atenolol orally immediately after the first measurement (at 1800). In five of the volunteers a decrease in CSF production was seen at midnight compared with daytime production values; in two volunteers CSF production remained unchanged, while three volunteers showed increased production. The average CSF production was 32% lower at night (0.27 +/- 0.10 ml/min) compared with the afternoon (0.40 +/- 0.07 ml/min), after administration of atenolol (P = 0.37).(ABSTRACT TRUNCATED AT 250 WORDS)
Stimulation of oxytocin release within the supraoptic nucleus and into blood by CCK-8
Authors: Neumann I. , Landgraf R. , Takahashi Y. , Pittman Q. J. , Russell J. A.
Published: December 2017

Simultaneous microdialysis in brain and blood was used to monitor the effects of systemic and central cholecystokinin octapeptide (CCK-8) on the release of oxytocin and vasopressin within the hypothalamic supraoptic nucleus (SON) as well as into blood of urethan-anesthetized female rats. Administration of CCK-8 (20 micrograms/kg iv) increased oxytocin contents in 30-min microdialysates sampled simultaneously within the SON (1.8-fold) and blood (2.4-fold, both P < 0.05) compared with prestimulation levels. In another experiment, after bilateral administration of CCK-8 directly into the SON (10 ng/0.5 microliter) via a microdialysis/infusion probe, oxytocin contents in dialysates sampled from the left and right SON were increased 2.3- and 1.7-fold (P < 0.05), respectively. In simultaneously sampled dialysates from the jugular vein, oxytocin content increased 2.3-fold (P < 0.05). In contrast, oxytocin in dialysates sampled outside the hypothalamic nuclei was not altered by systemic or central CCK-8. The direct infusion of CCK-8 into both SON increased the release of vasopressin within the SON 1.7-fold (P < 0.05) but failed to significantly change vasopressin release into blood. The present findings show a coordinated regulation of intranuclear and systemic release of oxytocin in response to systemic and central CCK-8 and provide further evidence for a possible involvement of endogenous oxytocin in the complex regulation of ingestive and reproductive behaviors induced by CCK-8 at the brain level.
Catecholaminergic innervation of white adipose tissue in Siberian hamsters
Authors: Youngstrom T. G. , Bartness T. J.
Published: December 2017

When Siberian hamsters are transferred from long summerlike days (LDs) to short winterlike days (SDs) they decrease their body weight, primarily as body fat. These SD-induced decreases in lipid stores are not uniform. Internally located white adipose tissue (WAT) pads are depleted preferentially of lipid, whereas the more externally located subcutaneous WAT pads are relatively spared. These data suggest a possible differential sympathetic neural control over catecholamine-induced lipolysis and that lipolytic rates are greater for internal vs. external WAT pads. Moreover, if these differential rates of lipolysis are due to differential sympathetic nervous system (SNS) drives on the pads, then fat pad-specific catecholaminergic innervation may exist. Therefore, we tested whether inguinal WAT (IWAT; an external pad) and epididymal WAT (EWAT; an internal pad) were innervated differentially. In addition, we tested whether norepinephrine (NE) turnover (TO) reflected the presumed greater SNS drive on EWAT vs. IWAT after SD exposure. Injections of fluorescent tract tracers [Fluoro-Gold or indocarbocyanine perchlorate (DiI)] demonstrated projections from the SNS ganglia T13-L3 to both fat pads. Retrograde labeling revealed a relatively separate pattern of distribution of labeled neurons in the ganglia projecting to each pad. In vivo anterograde transport of DiI resulted in labeling in both IWAT and EWAT that included staining around individual adipocytes and occasionally retrogradely labeled cells. The proportionately greater decrease in EWAT compared with IWAT mass after 5 wk of SD exposure was reflected in greater EWAT NE TO than found in their LD counterparts for this pad.(ABSTRACT TRUNCATED AT 250 WORDS)
Fallacy of indexing renal and systemic hemodynamic measurements for body surface area
Authors: Turner S. T. , Reilly S. L.
Published: December 2017

Renal plasma flow, glomerular filtration rate, and cardiac output are traditionally indexed for body surface area by expressing these traits as per-surface-area ratios. Indexing is intended to remove interindividual variation attributable to differences in body size. Regression is an alternative method commonly used to adjust other biological traits for the effects of a covariate, such as body surface area. The purpose of this study was to compare the indexing and regression methods of adjusting renal plasma flow, glomerular filtration rate, and cardiac output for interindividual differences in body surface area. We estimated renal plasma flow by the clearance of p-aminohippurate, glomerular filtration rate by clearance of inulin, and cardiac output by thoracic electrical impedance in a sample of 78 unrelated females and 78 unrelated males (ages 20-49.9 yr) from the general population of Rochester, MN. The indexing method created negative dependencies of renal plasma flow and cardiac output on body surface area and failed to eliminate the positive dependency of glomerular filtration rate on body surface area. Moreover, indexing obscured differences in mean renal plasma flow between females and males and created differences in mean cardiac output between the genders. In contrast, the regression method consistently eliminated dependencies of each trait on body surface area and did not lead to inappropriate inferences about mean differences in these traits between females and males. We conclude that the indexing method of adjusting renal plasma flow, glomerular filtration rate, and cardiac output for interindividual differences in body surface area should be abandoned and replaced by use of the regression method.
Descending pathways necessary for vestibular influences on sympathetic and inspiratory outflow
Authors: Yates B. J. , Siniaia M. S. , Miller A. D.
Published: December 2017

The objective of this study was to determine which brain stem regions that have projections to sympathetic preganglionic neurons or phrenic motoneurons ae necessary for vestibulosympathetic or vestibulorespiratory responses in decerebrate cats. Bilateral kainic acid injections into the rostral ventrolateral medulla abolished splanchnic nerve responses to electrical stimulation of the vestibular nerve, suggesting that this region is critical for the production of vestibulosympathetic responses. In contrast, injections into the caudal medullary raphe nuclei had no apparent effect on the responses. Neither the dorsal nor the ventral respiratory group appears to be necessary for mediating vestibular influences on the phrenic nerve, suggesting that nonrespiratory neurons (such as vestibulospinal neurons) may be important for producing vestibulorespiratory responses.
Choroid plexus electrolytes and ultrastructure following transient forebrain ischemia
Authors: Palm D. , Knuckey N. , Guglielmo M. , Watson P. , Primiano M. , Johanson C.
Published: December 2017

A temporal profile of lateral and fourth ventricle rat choroid plexus (LVCP and 4VCP, respectively) tissue injury and recovery was determined using alterations in K, Na, and H2O content and ultrastructure after 10 min of transient forebrain ischemia (TFI). At 0.5 h postischemia the LVCP displayed a maximum reduction in K content by 32% and a significant increase in Na content by 85% and H2O content by 22%. LVCP tissue K, Na, and H2O content returned to sham values by 24 h postischemia. Ultrastructural changes appeared more severe between 0.5 and 12 h postischemia, whereas by 24 h, normal ultrastructure was restored. Elevations in 4VCP tissue Na (P < 0.05) and H2O content, which were less than those in LVCP, gradually reached a maximum by 24 h compared with sham. No change in 4VCP tissue ultrastructure was observed. These results indicate that the LVCP tissue is more vulnerable than 4VCP in the bilateral carotid artery occlusion model but that it recovers in a timely manner after TFI. Furthermore, the ability of the LVCP tissue to rapidly recover suggests its functional importance in helping to restore brain homeostasis.
Sepsis-induced attenuation of glucagon and 8-BrcAMP modulation of the phosphoenolpyruvate carboxykinase gene
Authors: Deutschman C. S. , De Maio A. , Clemens M. G.
Published: December 2017

Sepsis is associated with alterations in hepatic gluconeogenesis. We have previously demonstrated that this change is associated with reduced expression of the phosphoenolpyruvate carboxykinase (PEPCK) gene, despite an endogenous hormonal milieu that should favor increased expression of the gene. To further elucidate the mechanisms involved, we induced sepsis in fasted Sprague-Dawley rats via cecal ligation and single puncture, with sham-operated animals serving as controls, and we performed two sets of experiments. First, liver tissue was obtained from septic and sham-operated animals at 2, 6, 16, and 24 h after the induction of sepsis. Northern blot hybridization analysis revealed a progressive, sepsis-induced decrease in expression of PEPCK and an increase in the expression of beta-fibrinogen, an acute-phase reactant. In the second set of experiments, we tested whether this reduced expression resulted from an attenuated response to 1) glucagon and 2) 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP). Twenty-four hours after the induction of sepsis, the liver was isolated and perfused with either Krebs buffer with substrate only (unstimulated controls), Krebs buffer + substrate + 10(-8) M glucagon, or Krebs buffer + substrate + 10(-5) M 8-BrcAMP. In sham-operated animals, perfusion with glucagon increased PEPCK mRNA levels and activity, whereas perfusion with buffer alone did not change mRNA levels and decreased activity. Glucagon perfusion of septic livers did not change either PEPCK mRNA levels or activity. Perfusion of sham-operated animals with 8-BrcAMP increased PEPCK mRNA levels and activity, whereas perfusion with buffer alone resulted in a decrease in mRNA levels and activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Activation of sympathetic outflow by recombinant human interleukin-1 beta in conscious rats
Authors: Kannan H. , Tanaka Y. , Kunitake T. , Ueta Y. , Hayashida Y. , Yamashita H.
Published: December 2017

The present study was undertaken to determine the effects of interleukin-1 beta (IL-1 beta) on renal sympathetic nerve activity (RSNA), arterial blood pressure (AP), heart rate (HR), and body temperature in conscious rats. Either intravenous or intracerebroventricular administration of IL-1 beta elicited increases in AP, HR, and RSNA accompanied by a rise in body temperature. The maximum changes in AP, HR, and RSNA occurred 10-15 min after intravenous injection of IL-1 beta (100 ng) and 20-25 min after intracerebroventricular injection (5 ng). The responses induced by the intravenous and intracerebroventricular injections lasted for approximately 15-30 min and did not appear when the animals were pretreated with the cyclooxygenase inhibitor indomethacin (10 mg/kg iv). Moreover, intracerebroventricular injection of prostaglandin E2 (1 microgram) produced responses similar to those induced by IL-1 but with shorter latency. Plasma norepinephrine and adrenocorticotropic hormone concentrations were increased after IL-1 beta injection. The results suggested that IL-1 beta augments cardiovascular and sympathetic outflow through the central action of prostaglandin E2 in conscious rats.
Endothelin-mediated effect of erythropoietin on blood pressure and renal hemodynamics in hypertensive rats
Authors: Tojo A. , Doumoto M. , Oka K. , Numabe A. , Kimura K. , Yagi S.
Published: December 2017

Erythropoietin (EPO) has been reported to induce hypertension in hemodialysis patients with family history of hypertension. In this study, to reveal the mechanism of EPO-induced hypertension, we examined the acute effect of EPO on blood pressure (BP) and renal hemodynamics in genetically hypertensive rats, and we also tested the effect of BQ-123, an endothelin ETA-receptor blocker, on EPO-induced changes in hemodynamics. Male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY), aged 9-12 wk, were anesthetized, and BP was monitored through the carotid artery. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured before and after an intravenous injection of EPO (1,000 U/kg body wt). In another group of SHR, BQ-123 was continuously infused (1.2 mg.kg body wt-1.h-1) during the experiments. The acute injections of EPO increased BP significantly in SHR in a dose-dependent manner, whereas WKY did not show a significant increase in BP after EPO injections. The effect of EPO on BP in SHR was blocked by BQ-123. In SHR, an acute injection of EPO decreased RPF significantly (from 1.78 +/- 0.16 to 1.49 +/- 0.18 ml.min-1.100 g body wt-1, P < 0.05) without a change in GFR, whereas WKY did not show significant changes in either RPF or GFR. The effect of EPO on RPF in SHR was completely blocked by BQ-123 (from 1.92 +/- 0.26 to 1.88 +/- 0.28 ml.min-1.100 g wt-1, NS). EPO caused a significant increase in plasma endothelin ET-1 in SHR (from 2.3 +/- 0.6 to 6.3 +/- 1.6 pg/ml, P < 0.05), but not in WKY. In conclusion, acute administration of EPO raised blood pressure and reduced RPF in SHR, and these vasoconstrictive effects of EPO are mediated via ETA receptors by an enhanced ET-1 release.
7-Nitroindazole attenuates vasodilation from cerebellar parallel fiber stimulation but not acetylcholine
Authors: Iadecola C. , Yang G. , Xu S.
Published: December 2017

We used the relatively selective inhibitor of neuronal nitric oxide synthase 7-nitroindazole (7-NI) to test the hypothesis that the increases in local cerebellar blood flow (BFcrb) elicited by activation of the cerebellar parallel fibers (PF) are mediated by neuronal production of nitric oxide. In halothane-anesthetized rats, the cerebellar cortex was exposed and superfused with Ringer solution (37 degrees C; pH 7.3-7.4). The PF were stimulated electrically (100 microA, 30 Hz, 40 s), while BFcrb was monitored at the site of stimulation by a laser-Doppler flow probe. In vehicle-treated rats (n = 5), PF stimulation increased BFcrb by 61 +/- 5% (P < 0.05; analysis of variance and Tukey's test). 7-NI attenuated the increase in BFcrb dose dependently (10-100 mg/kg i.p.; n = 5 animals/dose) and by 55 +/- 7% at 100 mg/kg (P < 0.05). The attenuation of the response to PF stimulation was correlated with the degree of inhibition of calcium-dependent brain nitric oxide synthase activity, measured ex vivo by the citrulline assay (n = 21). 7-NI also attenuated the cerebrovasodilation elicited by hypercapnia (PCO2 = 50-60 mmHg) but did not affect the vasodilation evoked by acetylcholine (10 microM; n = 4; P > 0.05; t-test), a response mediated by endothelial nitric oxide synthase. 7-NI did not attenuate the BFcrb increase evoked by the nitric oxide donor S-nitroso-N-acetylpenicillamine (1 mM; n = 5; P > 0.05; t-test). Similarly, 7-NI did not affect resting systemic arterial pressure. These observations suggest that selective inhibition of neuronal nitric oxide synthase by 7-NI attenuates the increases in BFcrb evoked by PF stimulation. The findings provide additional support to the hypothesis that the increase in BFcrb evoked by PF stimulation is mediated, in part, by glutamate-induced activation of neuronal nitric oxide synthase.
Gonadal and photoperiodic influences on body mass regulation in adult male and female prairie voles
Authors: Kriegsfeld L. J. , Nelson R. J.
Published: December 2017

Nontropical animals commonly use the annual change in photoperiod to phase seasonal adjustments that promote survival and reproduction. To cope with the energetic requirements of winter, many rodents alter body mass in anticipation of winter. Photoperiodic adjustments are often mediated by the pineal hormone melatonin; melatonin can exert a primary effect on body mass or secondarily affect body mass by changing blood gonadal steroid levels. The present study sought to determine if prairie voles (Microtus ochrogaster) alter body mass in response to short photoperiods. The role of the gonads in body mass regulation was also assessed. In experiment 1, males housed in short days increased body mass at a greater rate than long-day animals. Gonadectomy enhanced the body mass gain in short-day voles. These data suggest that the gonads contribute to short photoperiod-induced changes in body mass in male voles. In experiment 2, females housed in short days increased body mass at a greater rate than long-day animals, regardless of whether the animals were ovariectomized. Ovariectomy did not affect body mass in either long- or short-day animals, suggesting that the ovaries do not contribute to photoperiod-mediated changes in body mass in female prairie voles. Taken together, these studies suggest that male and female prairie voles use photoperiodic information to time seasonal changes in body mass.
Cardiac output and renal function during insulin hypertension in Sprague-Dawley rats
Authors: Brands M. W. , Lee W. F. , Keen H. L. , Alonso-Galicia M. , Zappe D. H. , Hall J. E.
Published: December 2017

Hyperinsulinemia has been reported to cause hypertension in rats; however, the renal and hemodynamic mechanisms are not known. In this study, changes in renal function, cardiac output (CO), and total peripheral resistance (TPR) were measured during chronic insulin infusion in eight rats (approximately 350 g). After a 4-day control period, a 7-day insulin infusion was begun (1.5 mU.kg-1.min-1 iv), together with glucose (22 mg.kg-1.min-1 iv) to prevent hypoglycemia. Mean arterial pressure (MAP), CO, TPR, and heart rate were measured 24 h/day. MAP increased from 92 +/- 1 to 100 +/- 2 mmHg on day 1 and was 108 +/- 4 mmHg by day 7 of insulin. CO tended to decrease during insulin infusion, although not significantly, averaging 94 +/- 4% of the control value of 121 +/- 7 ml/min. Heart rate did not change significantly from the control value of 384 +/- 8 beats/min. TPR increased significantly to 122 +/- 11% of control by day 7. In five rats, glomerular filtration rate and effective renal plasma flow decreased to 73 +/- 4 and 66 +/- 5% of control, respectively, during insulin. Urinary sodium excretion averaged 2.6 +/- 0.1 and 2.7 +/- 0.1 meq/day during the control and insulin-infusion periods, respectively. These results indicate that insulin hypertension in rats is initiated by an increase in TPR rather than by increased CO. Also, the fact that sodium balance was maintained at elevated arterial pressure suggests that the ability of the kidneys to excrete sodium was impaired chronically during insulin infusion.
Differentiated sympathetic neural control of the kidney
Authors: DiBona G. F. , Sawin L. L. , Jones S. Y.
Published: December 2017

Anatomic and neurophysiological methods were used to identify functionally specific subgroups of renal sympathetic nerve fibers. The distribution of diameters of the predominating unmyelinated fibers showed a major mode at 1.1 microns and a minor mode at 1.6 microns. The conduction velocity was 2.10 +/- 0.10 m/s, consistent with unmyelinated C fibers. Analysis of strength-duration relationships during renal nerve stimulation showed that both rheobase and chronaxie values for renal blood flow were greater than those for urinary flow rate and were independent of stimulation frequency. This difference suggests a higher stimulation threshold (smaller diameter) for those renal nerve fibers involved in the renal blood flow response (renal vasoconstriction) compared with those for the urinary flow rate response (antidiuresis) to renal nerve stimulation. Single renal units that responded to preganglionic splanchnic nerve stimulation were studied. Those with spontaneous activity (88%) responded to stimulation of arterial baroreceptors, arterial and central chemoreceptors, and peripheral thermoreceptors, whereas those that lacked spontaneous activity (12%) responded only to stimulation of peripheral thermoreceptors (known to produce renal vasoconstriction). A minority population of single renal units has been identified that, although renal vasoconstrictor, does not exhibit other characteristic features of vasoconstrictor neurons (i.e., responsiveness to stimulation of arterial baroreceptors and arterial and central chemoreceptors). These findings suggest the existence of functionally specific subgroups of renal nerve fibers.
Inhibition of nitric oxide synthase produces hypothermia and depresses lipopolysaccharide fever
Authors: Scammell T. E. , Elmquist J. K. , Saper C. B.
Published: December 2017

The labile gas nitric oxide (NO) mediates a wide variety of thermoregulatory processes including vasomotor control, brown fat thermogenesis, and neuroendocrine regulation. Additionally, during endotoxemia, NO modulates the release of cytokines and hypothalamic peptides. To determine the role of NO in thermoregulation and fever, we intravenously injected the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and measured its effects on body temperature during normal thermoregulation and endotoxemia in awake, unrestrained rats. L-NAME produced a stereoselective, dose-dependent hypothermia that lasted up to 4 h after bolus intravenous injection. Intravenous lipopolysaccharide (LPS) produced fever in a dose-dependent manner, which was preceded by hypothermia at higher doses alpha-LPS. NOS inhibition reduced the febrile response to LPS and produced marked hypothermia with a low dose of LPS. These findings indicate that NO may play an important role in thermoregulation and suggest that NO is required for the production of fever.
Muscle-specific and inducible expression of 293-base pair beta-myosin heavy chain promoter in transgenic mice
Authors: Wiedenman J. L. , Tsika G. L. , Gao L. , McCarthy J. J. , Rivera-Rivera I. D. , Vyas D. , Sheriff-Carter K. , Tsika R. W.
Published: December 2017

The DNA regulatory element(s) involved in beta-myosin heavy chain (beta-MHC) induction by the physiological stimulus of mechanical overload have not been identified as yet. To delineate regulatory sequences that are required for mechanical overload induction of the beta-MHC gene, transgenic mouse lines were generated that harbor transgenes containing serial deletions of the human beta-MHC promoter to nucleotides -293 (beta 293), -201 (beta 201), and -141 (beta 141) from the transcription start site (+1). Mechanically overloaded adult plantaris and soleus muscles contained 11- and 1.9-fold increases, respectively, in endogenous beta-MHC-specific mRNA transcripts (Northern blot) compared with sham-operated controls. Expression assays (chloramphenicol acetyltransferase specific activity) revealed that only transgene beta 293 expression was muscle specific in both fetal and adult mice and was induced in the plantaris (10- to 27-fold) and soleus (2- to 2.5-fold) muscles by mechanical overload. Histochemical staining for myosin adenosinetriphosphatase activity revealed a fiber-type transition of type II to type I in the overloaded plantaris and soleus muscles. These transgenic data suggest that sequences located between nucleotides -293 and +120 may be sufficient to regulate the endogenous beta-MHC gene in response to developmental signals and to the physiological signals generated by mechanical overload in fast- and slow-twitch muscles.
Central insulin and macronutrient intake in the rat
Authors: Chavez M. , Riedy C. A. , Van Dijk G. , Woods S. C.
Published: December 2017

When rats are maintained on a standard laboratory diet, the infusion of low doses of insulin into the cerebroventricular system causes a reduction of food intake and body weight. It was recently reported that, if rats are maintained on a high-fat diet (56% calories as fat), they are insensitive to this action of insulin. To investigate further the effect of dietary composition on responsiveness to central insulin, we carried out two experiments. In experiment 1, rats were maintained on one of four equicaloric diets (providing 7, 22, 39, or 54% of calories as fat) before and during a 6-day third-ventricular infusion (i3vt) of insulin (10 mU/day) or saline. Rats consuming 7 or 22% of calories as fat had a significant reduction of both food intake (-17.2 +/- 2.9 and -14.6 +/- 3.3 g, respectively) and body weight (-50 +/- 5 and -41 +/- 5 g, respectively) from baseline over the insulin-infusion infusion period. Rats consuming 39 or 54% calories as fat did not reliably alter food intake (-4.0 +/- 3.9 and -1.9 +/- 3.7 g, respectively) or body weight (-10 +/- 6 and -6 +/- 4 g, respectively) in response to i3vt of insulin. In experiment 2, rats were offered a choice of three macronutrients (carbohydrates, fats, and proteins) in separate jars in their home cages. After they had adapted to the diets, they were infused i3vt with insulin or saline. Insulin caused a significant reduction of body weight relative to saline-infused controls (body wt: -23.1 +/- 4 g) and a reduction in food intake that was selective for dietary fat. These data suggest that the effects of central insulin administration are highly dependent on the macronutrient content of the diet as well as the ability of rats to select their own diets.
Cardiac sympathetic afferent reflex in dogs with congestive heart failure
Authors: Wang W. , Zucker I. H.
Published: December 2017

It is well accepted that sympathetic tone is elevated in chronic heart failure (HF) and that the cardiac sympathetic afferent reflex is a sympathoexcitatory reflex. There have been no studies designed to examine the role of this reflex in control of sympathetic outflow in the HF state. In this study we tested the hypothesis that cardiac sympathetic afferent reflexes are enhanced in HF and are, therefore, capable of contributing to the increase in sympathetic outflow in this disease state. Ventricular pacing was carried out in 14 dogs until signs of HF were evident. Fourteen sham dogs served as controls. At the time of the acute experiment the dogs were anesthetized with alpha-chloralose. The hemodynamic [arterial pressure and heart rate (HR)] and renal sympathetic nerve activity (RSNA) responses to left ventricular epicardial application of two doses of bradykinin (BK) and capsaicin (Cap) were determined in the sinoaortic-denervated and vagotomized state. The MAP, RSNA, and HR responses to BK were greater in the HF group compared with the sham group. The RSNA response to BK (50 micrograms) in the HF group was significantly increased (34.0 +/- 5.9 vs. 11.5 +/- 4.2%, P < 0.05). The MAP, RSNA, and HR responses to Cap in the HF group were similar to the responses to BK. The RSNA response to Cap in the HF group was significantly increased (29.8 +/- 11.3 vs. 13.8 +/- 2.3% for 10 micrograms, P < 0.05 and 46.5 +/- 10.7 vs. 18.7 +/- 3.1% for 100 micrograms, P < 0.05). The cyclooxygenase blocker indomethacin (5 mg/kg i.v.) attenuated the reflex responses to BK in the HF group. These data suggest that the enhanced cardiac sympathetic afferent reflex to epicardial BK in HF appears to be mediated by altered levels of prostaglandin synthesis. Blockade of cardiac sympathetic afferents with topical lidocaine reduced baseline of RSNA significantly more in the HF state than in the normal state (-24.2 +/- 3.6 vs. -4.3 +/- 4.5%, P < 0.05). We conclude from these data that the cardiac sympathetic afferent reflex is sensitized in the HF state and speculate that this enhanced cardiac sympathetic afferent reflex may contribute to the sustained higher sympathetic tone in chronic HF.
Cutaneous microvascular flow in the foot during simulated variable gravities
Authors: Chang D. S. , Breit G. A. , Styf J. R. , Hargens A. R.
Published: December 2017

Our objective was to understand how weight bearing with varying gravitational fields affects blood perfusion in the sole of the foot. Human subjects underwent whole body tilting at four angles: upright [1 gravitational vector from head to foot (Gz)], 22 degrees (0.38 Gz), 10 degrees (0.17 Gz), and supine (0 Gz), simulating the gravitational fields of Earth, Mars, Moon, and microgravity, respectively. Cutaneous capillary blood flow was monitored on the plantar surface of the heel by laser Doppler flowmetry while weight-bearing load was measured. At each tilt angle, subjects increased weight bearing on one foot in graded load increments of 1 kg beginning with zero. The weight bearing at which null flow first occurred was determined as the closing load. Subsequently, the weight bearing was reduced in reverse steps until blood flow returned (opening load). Mean closing loads for simulated Earth gravity, Mars gravity, Moon gravity, and microgravity were 9.1, 4.6, 4.4, and 3.6 kg, respectively. Mean opening loads were 7.9, 4.1, 3.5, and 3.1 kg, respectively. Mean arterial pressures in the foot (MAP(foot)) calculated for each simulated gravitational field were 192, 127, 106, and 87 mmHg, respectively. Closing load and opening load were significantly correlated with MAP(foot) (r =0.70, 0.72, respectively) and were significantly different (P < 0.001) from each other. The data suggest that decreased local arterial pressure in the foot lowers tolerance to external compression. Consequently, the human foot sole may be more prone to cutaneous ischemia during load bearing in microgravity than on Earth.
Regulation of microvascular filtration in the myocardium by interstitial fluid pressure
Authors: Stewart R. H. , Rohn D. A. , Mehlhorn U. , Davis K. L. , Allen S. J. , Laine G. A.
Published: December 2017

We hypothesized that myocardial microvascular filtration rate (Jv) could be manipulated by varying end-diastolic myocardial interstitial hydrostatic (P(int)) pressure. Dogs under general anesthesia were instrumented with intramyocardial capsules to measure P(int) and with prenodal myocardial lymphatic trunk cannulas and superior vena caval balloon-tipped catheters to manipulate myocardial lymph flow. Because, for a given surface area, the lymph-to-plasma protein concentration ration (CL/CP) varies inversely with JV, CL/CP was utilized as an index of changes in JV. When lymphatic outflow pressure (P0) was elevated to abolish lymph flow and force myocardial interstitial fluid volume to expand, P(int) rose significantly from 15.0 +/- 0.8 to 27.6 +/- 1.0 mmHg and CL/CP increased significantly from 0.75 +/- 0.04 to 0.85 +/- 0.04, indicating a decrease in JV. When P0 was lowered and lymph flow resumed, P(int) and CL/CP decreased significantly to 15.3 +/- 0.9 mmHg and 0.75 +/- 0.04, respectively, indicating an increase in JV. We conclude that myocardial microvascular filtration rate may be modulated by changes in P(int) resulting from alterations in myocardial interstitial fluid volume secondary to variations in lymph flow from the heart.
Body temperature and sleep in intact and ovariectomized female rats
Authors: Li H. , Satinoff E.
Published: December 2017

The present study examined intact and ovariectomized adult rats to assess the effects of removal of sex hormones on body temperature (Tb) and sleep. Subjects were 12 female rats, aged 5-8 mo, half of which were bilaterally ovariectomized (OVX). Sleep or waking and Tb were recorded under a 12:12-h light-dark cycle. There was a strong coupling between level of Tb and the three conditions of waking, slow-wave sleep (SWS), and rapid eye movement sleep (REMS): Tb was significantly positively correlated with waking and significantly negatively correlated with SWS and REMS. These correlations were even higher in OVX rats. In the light, OVX rats had more SWS and stayed awake less than did the intact rats. OVX rats had more REMS than did intact rats in both light and dark. Mean Tb and daily Tb amplitude were the same in both groups. These results suggest that ovariectomy increases and, by extension, gonadal steroids decrease, the coupling between Tb and sleep.
Cutaneous vasoconstriction in conscious rabbits during alerting responses detected by hippocampal theta-rhythm
Authors: Yu Y. H. , Blessing W. W.
Published: December 2017

We determined whether alerting stimuli cause cutaneous vasoconstriction in conscious rabbits. We compared ear blood flow with renal, mesenteric, and femoral flows at rest and in response to nonnoxious alerting stimuli, which induced theta-rhythm (4-9 Hz) in the simultaneously recorded hippocampal electroencephalogram (EEG). theta-Inducing stimuli (e.g., whistles and fur touches) reduced ear flow by 95 +/- 6%, commencing 1-2 s after the EEG change and lasting 45 s. Renal flow did not significantly change with alerting stimuli, mesenteric and femoral flows slightly decreased, arterial pressure transiently rose (+10 +/- 3 mmHg), and heart rate fell (+43 +/- 9 beats/min). At rest, the coefficient of variation for ear flow (62 +/- 6%) was greater than for other flows (P < 0.01). Phentolamine (1 mg/kg iv) reduced this coefficient to 29 +/- 4% (P < 0.01). Our study demonstrates that alerting responses in conscious rabbits are associated with selective cutaneous vasoconstriction, without increase in flow to skeletal muscle.
Bicarbonate and CO2 transport across the skin of the leopard frog, Rana pipiens: effect of PGF2alpha
Authors: Candia O. A. , Yorio T.
Published: December 2017

The amphibian skin represents an important organ for osmoregulation and, like the mammalian kidney, maintains acid-base balance by secreting protons or base. However, the lack of a reliable and accurate method to measure the contribution of unidirectional fluxes of HCO3- ions to this mechanism has been an obstacle for the determination of the role of bicarbonate in epithelial acid-base homeostasis. Recently, one of us developed a method that allows for the reliable determination of transepithelial fluxes of bicarbonate, and this method was applied to determine unidirectional fluxes of (14)CO2 and H(14)CO3 under a variety of conditions. We report that the combined CO2 and HCO3- mucosal-to-serosal flux under 5% CO2 was 40% larger than the opposing flux, giving a net flux in the mucosal-to-serosal direction. This net flux was inhibited by acetazolamide. In CO2-free conditions, there was no detectable net flux; however, acetazolamide and PGF(2alpha) attenuated the mucosal-to-serosal flux and established an apparent secretion of HCO3-. A model is presented that depicts twelve vectors or components to the CO2 plus HCO3- fluxes in the frog skin. This model can accurately reproduce the experimental values measured from unidirectional fluxes of CO2 and HCO3- under a variety of conditions and can explain the effects of PGF(2alpha) on unidirectional 14C-labeled fluxes as a consequence of inhibition of H+ secretion to the apical bath, similar to what was previously suggested by our laboratory using a different methodological approach. The present method, utilizing radiolabeled HCO3-, may be useful as a means to evaluate the mechanism of action of hormones and drugs that may regulate acid-base homeostasis by altering proton and bicarbonate transport processes.