bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms of pHi recovery from NH4Cl-induced acidosis in anoxic isolated turtle heart: a 31P-NMR study
Authors: Shi H. , Hamm P. H. , Meyers R. S. , Lawler R. G. , Jackson D. C.
Published: December 2017

Mechanisms of intracellular pH (pHi) recovery from NH4Cl-induced acidosis were investigated on isolated perfused hearts of the turtle, Chrysemys picta bellii, using 31P nuclear magnetic resonance (NMR) spectroscopy at 20 degrees C. A major goal was to assess the activity of these mechanisms under anoxic conditions. Based on calculated buffer capacity and a pHi recovery range at 20 degrees C of 6.75-6.95 (normal pHi 7.2-7.4), mean H' efflux rate during perfusion with CO2-free N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES)-buffered Ringer was only 15% (normoxia) and 25% (anoxia) of that with HCO3-buffered Ringer. With HCO3 solution, anoxic H1 efflux rate was approximately 50% of normoxia (0.333 vs. 0.645 mmol.l-1.min-1), but in TES solution, H1 efflux rate was unaffected by anoxia. To further characterize the transporters, we used blockers [the Na(+)-H+ antiport inhibitor 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) and the anion exchanger inhibitor 4,4'diisothiocyanostilbene-2, 2'-disulfonic acid (DIDS)], ion substitution, and temperature change. EIPA (10 microM) inhibited H+ efflux rate by 40% in anoxic TES solution; DIDS (0.5 mM) blocked H+ efflux rate by 85% in anoxic HCO3 solution. No pHi recovery was observed in either normoxic or anoxic Na(+)-free solutions, but normal recovery was observed in the absence of extracellular Cl-. Recovery of pHi occurred 2-3 times faster at 30 degrees C than at 20 degrees C. ATP was unaffected by any manipulation in this study, whereas creatine phosphate (CP) fell during anoxia, and both CP and mechanical performance changed in parallel to pHi. We conclude that pHi regulation functions during anoxia, although at a reduced rate, and that recovery from acidosis is dominated, during both normoxia and anoxia, by a DIDS-sensitive Na+ and HCO3(-)-dependent mechanism, whereas EIPA-sensitive Na(+)-H+ antiport plays a less important role.
Neuroendocrine mechanisms by which selective Leydig cell castration unleashes increased pulsatile LH release
Authors: Veldhuis J. D. , Zwart A. D. , Iranmanesh A.
Published: December 2017

A novel pharmacological model of acute reversible Leydig cell "castration" induced by a steroidogenic enzyme inhibitor, ketoconazole, achieves marked hypoandrogenemia in healthy men with an attendant 2.5-fold increase in 24-h mean serum luteinizing hormone (LH) concentrations. Mechanistically, the unleashing of amplified pulsatile LH release can be accounted for by any of three distinct models of deconvolution-estimated gonadotropin secretion, all of which are marked by a nearly twofold acceleration in LH secretory burst frequency. In addition, the models variously also predict concomitant prolongation of the endogenous LH half-life, an augmented LH secretory burst mass and duration, and/or the emergence of significant basal LH secretion. The nyctohemeral (cosinor analysis) rhythmicity of serum LH concentrations is not disturbed when androgenic negative-feedback signaling is withdrawn abruptly, but the apparent process randomness of LH release increases, as quantified by higher approximate entropy values. Thus we conclude that an intact (closed loop) androgen-mediated negative-feedback network in the adult human male is required to sustain low-frequency pulsatile LH release in a quantifiably orderly manner.
Neurochemical mechanisms behind gill microcirculatory responses to hypoxia in trout: in vivo microscopy study
Authors: Sundin L. , Nilsson G. E.
Published: December 2017

In vivo microscopy combined with systemic blood flow and pressure measurements were used to examine the hemodynamic and microcirculatory responses to hypoxia in gills of rainbow trout and to clarify if the underlying mechanisms are adrenergic, cholinergic, serotonergic, or adenosinergic. Hypoxia (P(O2) 1.07-1.33 kPa) reduced, halted, or reversed the blood flow in the distal portion of the efferent filamental artery (EFA). Simultaneously, a large overflow to the central venous system appeared, allowing a continuous flow through many of the secondary lamellae. No vasoconstriction could be observed in this portion of the filament, showing that a vasoconstriction occurred elsewhere, possibly at the EFA sphincter, because the gill resistance (R(G)) increased. These effects were mimicked by prebranchial injection of acetylcholine, a treatment that also strongly constricted the distal efferent filamental vasculature. Atropine blocked most of the hypoxia-induced hemodynamic changes, although a minor increase in R(G) remained. The latter appeared to be of a nonadrenergic noncholinergic origin, being unaffected by additional treatment with an alpha-adrenoreceptor antagonist. It was also unaffected by blockers of serotonin and adenosine-A1 receptors. Other responses seen included a cholinergic maintenance of the systemic resistance during hypoxia and an alpha-adrenoceptor-mediated posthypoxic hypertension. This study demonstrates that hypoxia evoked a cholinergic reflex vasoconstriction located at proximal parts of the efferent filamental vasculature.
Central infusion of GLP-1, but not leptin, produces conditioned taste aversions in rats
Authors: Thiele T. E. , Van Dijk G. , Campfield L. A. , Smith F. J. , Burn P. , Woods S. C. , Bernstein I. L. , Seeley R. J.
Published: December 2017

Leptin (ob protein) and glucagon-like peptide-1-(7-36) amide (GLP-1) are peptides recently proposed to be involved in the regulation of food intake. Although the ability of exogenous leptin and GLP-1 to modulate consummatory behavior is consistent with the suggestion that these peptides are endogenous regulatory agents, central administration of these peptides may have aversive side effects, which could explain the anorexia. In the present experiment, exposure to a saccharine taste was immediately followed by central administration of leptin or GLP-1 to determine if these drugs could produce a conditioned taste aversion (CTA) in rats. At doses equated for producing comparable reductions in short-term food intake, GLP-1, but not leptin, generated a robust CTA. Although leptin caused no aversion, this peptide was the only drug to cause relatively long-term reductions in food consumption (16 h) and body weight (24 h). Hence, the results indicate that central GLP-1 produces aversive side effects, and it is argued that these nonspecific effects may explain the anorectic actions of GLP-1.
Chronic stress induces sensitization in sympathoadrenal responses to stress in borderline hypertensive rats
Authors: Mansi J. A. , Drolet G.
Published: December 2017

The effects of acute foot shock on cardiovascular and sympathoadrenal responses were investigated in chronically stressed borderline hypertensive rats (BHR) and Wistar-Kyoto (WKY) rats. Male BHRs were divided into two groups; the maturation group (Mat) was not stressed, whereas the chronic stress group (AJS) received 8 wk (5 days/wk, 30 min/day) of air-jet stress coupled with immobilization. After chronic stress, the rats were cannulated in the femoral artery and jugular vein. Resting mean arterial pressure (MAP), heart rate (HR), and plasma norepinephrine (NE) levels were higher in the AJS group. In contrast, chronic stress failed to increase basal arterial pressure or HR in WKY rats. In response to acute foot shock, the Mat group had higher MAP increases, at which they plateaued, whereas the AJS rats displayed a progressive decline in MAP. This was associated with higher plasma NE and epinephrine levels but a smaller increase in adrenocorticotropic hormone in AJS versus Mat rats. This hyperactivity in the sympathoadrenal system of chronically stressed BHRs may, in part, account for their mild hypertension.
Influence of forced respiration on nonlinear dynamics in heart rate variability
Authors: Kanters J. K. , Hojgaard M. V. , Agner E. , Holstein-Rathlou N. H.
Published: December 2017

Although it is doubtful whether the normal sinus rhythm can be described as low-dimensional chaos, there is evidence for inherent nonlinear dynamics and determinism in time series of consecutive R-R intervals. However, the physiological origin for these nonlinearities is unknown. The aim of this study was to test whether the known nonlinear input from spontaneous respiration is a source for the nonlinearities in heart rate variability. Twelve healthy subjects were examined in supine position with 3-h electrocardiogram recordings during both spontaneous and forced respiration in accordance with a metronome set to 12 min(-1). Nonlinear dynamics were measured as the correlation dimension and the nonlinear prediction error. Complexity expressed as correlation dimension was unchanged from normal respiration, 9.1 +/- 0.5, compared with forced respiration, 9.3 +/- 0.6. Also, nonlinear determinism expressed as the nonlinear prediction error did not differ between spontaneous respiration, 32.3 +/- 3.4 ms, and forced respiration, 31.9 +/- 5.7. It is concluded that the origin of the nonlinear dynamics in heart rate variability is not a nonlinear input from the respiration into the cardiovascular oscillator. Additional studies are needed to elucidate the mechanisms behind the nonlinear dynamics in heart rate variability.
Obligatory role of NO in glutamate-dependent hyperemia evoked from cerebellar parallel fibers
Authors: Yang G. , Iadecola C.
Published: December 2017

Electrical stimulation of cerebellar parallel fibers (PF) increases cerebellar blood flow (BFcrb), a response that is attenuated by glutamate receptor antagonists and NO synthase (NOS) inhibitors. We investigated whether administration of NO donors could counteract attenuation by NOS inhibitors of vasodilation produced by PF stimulation. In halothane-anesthetized rats the cerebellar cortex was exposed and superfused with Ringer solution. PF were stimulated with microelectrodes (100 microA, 30 Hz), and BFcrb was recorded by a laser-Doppler probe. During Ringer superfusion, PF stimulation increased BFcrb by 56 +/- 7% and hypercapnia by 72 +/- 5% (n = 5). Superfusion with the nonselective NOS inhibitor N-nitro-L-arginine (L-NNA, 1 mM) reduced resting BFcrb and attenuated the response to PF stimulation (-47 +/- 5%) and hypercapnia (-46 +/- 7%; PCO2 = 50-60 mmHg). After L-NNA, superfusion with the NO donors 3-morpholinosydnonimine (100 microM, n = 5) or S-nitroso-N-acetyl-penicillamine (5 microM, n = 5) reestablished resting BFcrb (P > 0.05 vs. before L-NNA) and reversed L-NNA-induced attenuation of the response to hypercapnia (P > 0.05 vs. before L-NNA) but not PF stimulation (P > 0.05 vs. after L-NNA). Similar results were obtained when NOS activity was inhibited with the inhibitor of neuronal NOS 7-nitroindazole (50 mg/kg i.p.). Like NO donors, the guanosine 3',5'-cyclic monophosphate analog 8-bromoguanosine 3',5'-cyclic monophosphate (n = 5), administered after L-NNA, restored resting BFcrb and counteracted inhibition of the response to hypercapnia but not PF stimulation. In contrast to NO donors and 8-bromoguanosine 3',5'-cyclic monophosphate, the NO-independent vasodilator papaverine (100 microM, n = 5) had no effect on attenuation of responses to PF stimulation or hypercapnia. Thus NO donors are unable to reverse the effect of NOS inhibition on vasodilation produced by PF stimulation. The data support the hypothesis that the vascular response to PF stimulation, at variance with hypercapnia, requires NOS activation and NO production. Thus NO plays an obligatory role in vasodilation produced by increased functional activity in cerebellar cortex.
Basal and stimulated nitric oxide in control of kidney function in the aging rat
Authors: Hill C. , Lateef A. M. , Engels K. , Samsell L. , Baylis C.
Published: December 2017

To investigate the activity of nitric oxide (NO) in control of renal hemodynamics during aging, studies were conducted on conscious Sprague-Dawley rats aged 3-5 mo (young, Y) and 18-22 mo (old, O). Blood pressure (BP) and renal vascular resistance (RVR) were higher in O vs. Y in control, and acute systemic NO synthesis inhibition (NOSI) increased BP and RVR, with an enhanced renal vasoconstrictor response in O. Infusion of the NO substrate L-arginine produced similar, selective renal vasodilation in both groups. The endothelium-dependent vasodilator acetylcholine caused similar falls in BP and RVR, whereas sodium nitroprusside produced an exaggerated depressor response in O vs. Y without falls in RVR in either age group. Urinary excretion of the stable NO oxidation products (NOx) decreased with age, suggesting a decline in the overall somatic NO production. In conclusion, basal tonically produced NO has a more pronounced role in maintenance of renal perfusion in aging, whereas L-arginine- and agonist-stimulated renal vasodilation is not impaired with age. NO production from some source may be reduced with aging, as indicated by falls in 24-h NOX excretion, although the similarity in pressor response and enhanced renal vasoconstrictor response to NOSI suggests that the role of NO in control of total peripheral and renal vascular resistance is maintained.
Intracellular acidification inhibits opposum kidney cell phosphate uptake
Authors: Yanagawa N. , Jo O. D.
Published: December 2017

The aim of our study is to examine the effect of intracellular pH (pHi) on inorganic phosphate (Pi) uptake by a proximal tubular cell line, the opposum kidney (OK) cells. The OK cell pHi (7.48 +/- 0.02; n = 12) was altered to levels between 6.5 and 8.5 by the high-K+ nigericin method, and cell uptakes were measured at 7.5 extracellular pH. It was found that pHi acidification suppressed Pi uptake with a decrease in maximal reaction rate, whereas alkalinization had no significant effect. Other Na(+)-dependent transport systems for glucose and amino acid were not affected by these pHi changes. The inhibition of cell Pi uptake by pHi acidification was not prevented by protein synthesis inhibitors (actinomycin D or cycloheximide) or by Na+/H+ exchange inhibitor [5-(N-ethyl-N-isopropyl)-amiloride]. pHi acidification caused a significant decrease in cellular adenosine 3',5'-cyclic monophosphate (cAMP) content, and cAMP-dependent protein kinase inhibitor (H-89) also did not prevent inhibition of cell Pi uptake by pHi acidification. However, pHi acidification stimulated protein kinase C (PKC) activity and inhibition of PKC by PKC inhibitors (bisindolylmaleimide, calphostin C, or staurosporine) or prolonged exposure to phorbol ester abrogated the inhibitory effect of pHi acidification on cell Pi uptake. In summary, these studies showed that pHi acidification inhibits Pi uptake in OK cells, probably through PKC activation. These effects of pHi acidification may thus contribute to increase acid excretion in systemic acidosis.
Central infusion of the AT1 receptor antagonist losartan inhibits thirst but not sodium appetite in cattle
Authors: Blair-West J. R. , Denton D. A. , McKinley M. J. , Weisinger R. S.
Published: December 2017

Experiments in cattle compared the effects of intracerebroventricular (i.c.v.) infusions of losartan and PD-123319 on water intake caused by water restriction, i.c.v. infusion of hypertonic NaCl, or i.c.v. infusion of angiotensin II (ANG II). The effects of these receptor antagonists on sodium intake caused by sodium depletion were also examined. Losartan infusion caused dose-dependent inhibition of the high water intake caused by the physiological stimulus of water restriction or by ANG II infusion but did not affect salt appetite. PD-123319 infused at equimolar or greater (in ANG II experiments) doses did not affect water intake or salt intake due to sodium depletion. The results of these i.c.v. infusion experiments confirm our earlier proposal that the physiological regulation of water intake in cattle may be mediated by ANG II acting centrally via AT1 receptors. The dose of losartan that inhibited thirst in cattle did not inhibit sodium appetite, nor did an equimolar dose of PD-123319.
Discrete thalamic lesions attenuate winter adaptations and increase body weight
Authors: Purvis C. C. , Duncan M. J.
Published: December 2017

The midline thalamus (e.g., the paraventricular thalamic nuclei and the reuniens nucleus) of Siberian hamsters and other mammals has been reported to contain specific binding sites for melatonin, a hormone that is essential for photoperiodically induced winter adaptations such as reproductive quiescence, loss of body weight, daily torpor, and the winter molt. The first experiment investigated whether the midline thalamus is necessary for these winter adaptations. Adult Siberian hamsters received discrete neurotoxic lesions of the paraventricular thalamic nuclei or the reuniens nucleus while under pentobarbital sodium-induced anesthesia. After recovery, the hamsters were monitored for winter adaptations while they were exposed to short photoperiods (10 h light/day) for 12 wk at 22 degrees C then for 60 days at 7 degrees C. Lesions of the reuniens nucleus, but not of the paraventricular thalamic nuclei, significantly inhibited short photoperiod-induced loss of body weight and tended to increase food consumption and decrease daily torpor. The second experiment showed that lesions of the reuniens nucleus increased body weight gain compared with that in controls during exposure to long photoperiods at 22 degrees C for 16 wk. In summary, these findings show that the reuniens nucleus is an important site for regulation of body weight and suggest that lesions of the reuniens nucleus may attenuate winter metabolic adaptations by causing an increase in body weight.
Localization of the vasopressin V1a and V2 receptors within the renal cortical and medullary circulation
Authors: Park F. , Mattson D. L. , Skelton M. M. , Cowley A. W.
Published: December 2017

Arginine vasopressin (AVP) is a potent vasoconstrictor that preferentially reduces renal medullary blood flow through the stimulation of the vasopressin V1a receptor (V1aR). Studies have also shown that the vasopressin V2 receptor (V2R) may modulate AVP-mediated vasoconstriction. At present, the distribution of the V1aR and V2R within the renal cortical and medullary microcirculation has not been determined. This study was designed to localize the transcriptional and translational sites of the V1aR and V2R in microdissected intrarenal vascular segments from both the cortex and medulla, specifically the interlobar, arcuate, and interlobular arteries; afferent and efferent arterioles; glomeruli; and single outer medullary vasa recta capillaries using reverse transcription-polymerase chain reaction and Western blot analyses. The results indicated that V1aR mRNA and proteins were present in the isolated cortical or medullary vasculature, but the V2R mRNA and proteins were not found. This study suggests that the vasoconstrictor action of AVP within the renal medulla is mediated through the V1aR and that the modulatory V2R-mediated vasodilation is probably through the release of paracrine hormones found within the renal interstitial or tubular cells.
Serotonergic afferents mediate activity-dependent entrainment of the mouse circadian clock
Authors: Edgar D. M. , Reid M. S. , Dement W. C.
Published: December 2017

The circadian pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus receives serotonergic afferents from the midbrain raphe nuclei, but the functional role of this projection is unclear. In rodents, locomotor activity increases serotonin content in the SCN, and serotonergic agonists phase shift the circadian clock in a manner closely similar to voluntary bouts of vigorous exercise, suggesting that serotonergic afferents could be part of the activity-dependent entrainment mechanism. We investigated this possibility by selectively lesioning serotonin terminals within and adjacent to the SCN by local microinjection of 5,7-dihydroxytryptamine in mice pretreated with desipramine. This treatment decreased serotonin content 96 +/- 1% and 5-hydroxyindole-3-acetic acid content below levels of detection (nearly 100%) but did not decrease norepinephrine content or neuropeptide Y immunoreactivity in the SCN. These lesions did not alter subsequent running activity levels, yet rendered mice unable to synchronize to a regularly scheduled 2-h wheel running paradigm that entrained sham-lesioned controls. Serotonin afferents are thus necessary for activity-dependent entrainment in the mouse.
Effects of energy limitation on Ca2+ and K+ homeostasis in anoxia-tolerant and anoxia-intolerant hepatocytes
Authors: Krumschnabel G. , Schwarzbaum P. J. , Biasi C. , Dorigatti M. , Wieser W.
Published: December 2017

To gain more insight into the mechanistic basis of anoxia tolerance and intolerance, a comparative study was conducted on calcium homeostasis in goldfish and trout hepatocytes subjected to different forms of energy limitation. Using the fluorescent Ca2+ indicator fura 2, we observed that both chemical anoxia and true anoxia led to an increase of the concentration of cytosolic free calcium (Ca2+i) in the anoxia-sensitive hepatocytes of rainbow trout, whereas Ca2+i was maintained at control levels in the anoxia-tolerant hepatocytes of goldfish. Various lines of evidence suggest an intracellular origin of the Ca2+ increase observed in trout cells. Cyclosporin A, a specific inhibitor of the mitochondrial permeability transition pore in mammalian cells, was ineffective in preventing the Ca2+ increase, whereas a high dose of fructose depressed the Ca2+ surge by approximately 50%. The latter effect was not accompanied by improvement of the energetic state of the cells. A comparison of chemical anoxia with true (physiological) anoxia revealed that both treatments affected energy metabolism to a similar degree in trout hepatocytes, whereas the decrease of ATP seen in goldfish hepatocytes during chemical anoxia was absent during true anoxia. Elevation of Ca2+i with the calcium ionophore A-23187 led to a decoupling of unidirectional K+ fluxes in both normoxic and anoxic trout cells, whereas in goldfish hepatocytes the coupling of K+ fluxes was not affected by the rise of Ca2+i.
Mechanisms in the pressor effects of hepatic portal venous fatty acid infusion
Authors: Grekin R. J. , Dumont C. J. , Vollmer A. P. , Watts S. W. , Webb R. C.
Published: December 2017

Portal venous infusion of oleate solution has pressor effects. We have examined efferent mechanisms, measured the response to sustained infusion, and determined the effect of linoleate. Eight conscious animals received concurrent infusions of prazosin or vehicle with portal venous infusion of oleate. Oleate alone increased mean arterial pressure from 109.0 +/- 4.1 to 123.0 +/- 5.8 mmHg (P = 0.02), whereas no increase in blood pressure occurred when oleate was infused with prazosin. In 10 rats, concurrent infusion of losartan had no effect on the pressor activity of portal oleate infusion. Twenty-two animals received portal oleate or vehicle as a continuous infusion for 7 days. Mean arterial pressure (126.1 +/- 2.0 vs. 107.8 +/- 2.6 mmHg, P < 0.001) and heart rate (383 +/- 5 vs. 366 +/- 5, P = 0.0257) were increased in oleate-infused animals. No differences in plasma fatty acids, glucose, insulin, pressor hormones, liver enzymes, or in vitro arterial pressor responsiveness were observed. Portal venous infusion of linoleate increased arterial pressure by 12.2 +/- 3.2 mmHg (P = 0.033). These results indicate that alpha-adrenergic activity is necessary for the acute pressor effects of portal oleate, that sustained portal oleate infusion results in persistent blood pressure elevation, and that other long-chain fatty acids besides oleate have pressor effects.
Vitamin B12 enhances GABA content but reduces glutamate content in the rat suprachiasmatic nucleus
Authors: Ikeda M. , Azuma S. , Inoue S.
Published: December 2017

The present study attempted to elucidate effects of vitamin B12 (VB12) on the rat suprachiasmatic nucleus (SCN), which is the locus of the circadian clock in mammals, by evaluating the contents of its major neurotransmitters, gamma-aminobutyric acid (GABA) and glutamate (Glu). First, contents of these amino acids were analyzed from tissue samples prepared at three different circadian times (CTs) in free-running rats under constant dim illumination. The content of GABA was highest in the middle of the resting phase (CT 6), intermediate early in the active phase (CT 14), and lowest late in the active phase (CT 20), whereas Glu content indicated inverse circadian variations. Subsequently, effects of intracerebroventricularly infused VB12 were assayed at CT 20. Compared with the saline-infused control, the infusion of VB12 (30 nmol/30 microliters) at CT 12-15 significantly increased GABA content but decreased Glu content. The quantitative balance of these amino acids after VB12 infusion was similar to that at CT 6 in noninfused rats. These results suggest that infusion of VB12 to active rats shifts the ratio of SCN neurotransmitters toward that observed in resting rats.
NaCl ingestion ameliorates plasma indexes of calcium deficiency
Authors: Tordoff M. G.
Published: December 2017

Rats deprived of dietary calcium ingest large volumes of concentrated NaCl solutions. To examine why, some physiological consequences of ingesting NaCl solution were measured. Male Sprague-Dawley rats fed diet containing 150 or 25 mmol Ca2+/kg were killed at 20, 40, 80, or 160 min after they started to drink solutions of 0.125% saccharin+3% glucose (S+G), 50 mM CaCl2, or 300 mM NaCl. Relative to rats fed the 25 mmol Ca2+/kg diet given nothing to drink, those fed the same diet that drank NaCl or CaCl2 but not S+G had elevated plasma ionized calcium concentrations and reduced plasma parathyroid hormone (PTH) concentrations. Rats fed the 150 mmol Ca2+/kg diet did not show these changes. In a follow-up experiment, rats fed the 25 mmol Ca2+/kg diet that drank NaCl had elevated plasma ionized calcium and reduced PTH and 1,25-dihydroxyvitamin D concentrations over the following 4-6 h. An in vitro study found that plasma ionized calcium concentrations were modulated by NaCl concentration directly. These findings indicate that NaCl ingestion can temporarily enhance the calcium status of calcium-deprived rats.
Postnatal development of the ob gene system: elevated leptin levels in suckling fa/fa rats
Authors: Rayner D. V. , Dalgliesh G. D. , Duncan J. S. , Hardie L. J. , Hoggard N. , Trayhurn P.
Published: December 2017

The postnatal development of the ob gene system has been examined in Zucker fa/fa and +/fa plus +/+ (referred to as +/?) rats. White adipose tissue was taken from animals aged 1 to 28 days. Before weaning, white fat was predominantly subcutaneous, the amount increasing rapidly after birth. ob mRNA was detected by Northern blotting in samples of inguinal fat at 1 day of age and thereafter. Circulating leptin, measured by enzyme-linked immunosorbent assay, was also detectable from 1 day of age, the level rising to a peak by 10 days of age and then declining. The fa/fa genotype was determined from the size of the product after Msp I digestion of the Ob-receptor gene obtained by polymerase chain reaction amplification of genomic DNA. No statistically significant difference in ob mRNA level between fa/fa and +/? animals was obtained before 25 days of age. However, leptin levels were significantly higher in the fa/fa mutant by 10 days of age, despite the absence of any significant elevation in the weight of the major fat depots or in ob mRNA level. It is concluded that the ob gene is expressed and leptin produced early in postnatal life in rats; the elevation of circulating leptin in suckling fa/fa animals indicates that dysregulation of the leptin system occurs before the overt development of the obese phenotype.
GABA release in the dorsal raphe nucleus: role in the control of REM sleep
Authors: Nitz D. , Siegel J.
Published: December 2017

The cessation of firing of serotonergic dorsal raphe neurons is a key controlling event of rapid eye movement (REM) sleep. We tested the hypothesis that this cessation of activity is due to gamma-aminobutyric acid (GABA) release using the in vivo microdialysis technique. We found that REM sleep is accompanied by a selective increase in GABA release, but not by a change in glutamate or glycine release in the dorsal raphe nucleus. Microinjection of the GABA agonist muscimol into the dorsal raphe increased REM sleep, although microperfusion of the GABA antagonist picrotoxin blocked REM sleep. These results implicate GABA release as a critical element in the production of the REM sleep state and in the control of discharge in serotonergic neurons across the sleep/wake cycle.
Long-term captopril treatment restores natriuresis after carotid baroreceptor activation in the SHR
Authors: Valentin J. P. , Mazbar S. A. , Humphreys M. H.
Published: December 2017

In anesthetized Sprague-Dawley rats, intermittent bilateral carotid artery traction (BilCAT) caused a transient decrease in mean arterial pressure (MAP) of 28 +/- 3 mmHg and led to a progressive increase in sodium excretion (UNaV) that nearly doubled 45-90 min after initiation of the repetitive application of BilCAT (P < 0.001). This natriuresis was accompanied by an increase in glomerular filtration rate (GFR) from 2.70 +/- 0.3 to 3.2 +/- 0.3 ml/min (P < 0.001), no change in renal plasma flow [clearance of p-aminohippurate (PAH)], and an increase in the fractional excretion of lithium. Rats with bilateral renal denervation exhibited neither natriuresis nor an increase in GFR in response to BilCAT despite similar vasodepression caused by the maneuver. Normotensive Wistar-Kyoto (WKY) rats responded to BilCAT like Sprague-Dawley rats, whereas spontaneously hypertensive rats (SHR) exhibited an exaggerated vasodepressor response to BilCAT (-51 +/- 3 mmHg) without increasing either UNaV or GFR. Separate groups of WKY and SHR were treated from 4 wk of age with captopril added to the drinking water at a concentration of 1 g/l. At 12-14 wk, both groups had lower MAP compared with untreated animals. Captopril treatment did not alter either the natriuretic response or the increase in GFR seen in untreated WKY after BilCAT, and the maneuver produced equivalent degrees of vasodepression as in controls. However, treated SHR now responded to BilCAT with increases in both UNaV and GFR that closely resembled the responses seen in Sprague-Dawley and WKY rats. These results suggest that BilCAT produces natriuresis through a pathway dependent on the renal nerves. This pathway does not function in untreated SHR despite similar vasodepression. Long-term treatment with captopril restores this reflex pathway in SHR, lending support to the concept that angiotensin II is critically linked to heightened sympathetic nerve activity and abnormal sodium metabolism in this strain.
Effects of an eight-day space flight on microvibration and physiological tremor
Authors: Gallasch E. , Moser M. , Kozlovskaya I. B. , Kenner T. , Noordergraaf A.
Published: December 2017

Microgravity was used to study accelerometrically recorded microvibration (MV) and postural tremor (PT) at reduced muscle tone on one cosmonaut before, during, and after an 8-day space flight on the Russian Mir station. MV of the relaxed forearm in the 1 g environment showed the typical 7- to 13-Hz resonance oscillations triggered by the heart beat. In 0 g, these pulsations shifted to below 5 Hz and the waveform became similar to an ultralow frequency acceleration ballistocardiogram. PT of the arm stretched forward showed an irregular waveform in 1 g. In 0 g, the higher-frequency components were reduced and again an ultralow frequency ballistocardiogram emerged. As a control, hand force tremor was recorded as well; it was not affected by the gravity condition. A second-order analog with muscle stiffness (C) as parameter was used to evaluate the measurements. For MV it could be shown that cardiac impacts produce damped resonance oscillations when C is high enough (1 g). At low C (0 g), this resonance phenomenon is essentially filtered out. For PT both neuromuscular and cardiovascular forces produce an irregular output; when C is lowered (0 g) the higher-frequency content is strongly reduced. It is concluded that both MV and PT waveforms are sensitive to musculoskeletal stiffness, such that at the lowest stiffness achieved the cardiac impact dominates. In 1 g, the cosmonaut's data were not significantly different from the results in a control group (n = 6).
Development of diurnal organization of EEG slow-wave activity and slow-wave sleep in the rat
Authors: Frank M. G. , Heller H. C.
Published: December 2017

This study characterizes the development of diurnal patterns of slow-wave sleep (SWS) distribution and SWS electroencephalographic (EEG) delta-power (DP) density in 12- to 24-day-old rats (P12-P24). Diurnal organization in sleep-wake distribution was established by P20. A decline in SWS DP across the light phase did not appear until P24. Before P20, SWS DP increased across the light phase in a pattern inverse to that typically seen in adult rats. At P20, SWS DP was evenly distributed across the light phase, and at P24, SWS DP declined across the light phase. The transient dissociation between diurnal organization in sleep-wake cycles and SWS DP suggests that circadian and homeostatic sleep regulatory mechanisms develop at different rates in the postnatal period.
Effects of natriuretic peptides and nitroprusside on venous function in trout
Authors: Olson K. R. , Conklin D. J. , Farrell A. P. , Keen J. E. , Takei Y. , Weaver L. , Smith M. P. , Zhang Y.
Published: December 2017

Active venous regulation of cardiovascular function is well known in mammals but has not been demonstrated in fish. In the present studies, the natriuretic peptides (NP) rat atrial natriuretic peptide (ANP) and trout ventricular natriuretic peptide (VNP), clearance receptor inhibitor SC-46542, and sodium nitroprusside (SNP) were infused into unanesthetized trout fitted with pressure cannulas in the ventral aorta, dorsal aorta, and ductus Cuvier, and a ventral aorta (VA) flow probe was used to measure cardiac output (CO). In another group, in vivo vascular (venous) capacitance curves were obtained during ANP or SNP infusion. The in vitro effects of NP on vessels and the heart were also examined. ANP, VNP, and SC-46542 decreased central venous pressure (PVen), CO, stroke volume (SV), and gill resistance (RG), whereas systemic resistance (RS) and heart rate (HR) increased. Dorsal aortic pressure (PDA) transiently increased and then fell even though RS remained elevated. ANP decreased mean circulatory filling pressure (MCFP), increased vascular compliance at all blood volumes, and increased unstressed volume in hypovolemic fish. ANP had no direct effect on the heart. ANP responses in vivo were not altered in trout made hypotensive by prior treatment with the angiotensin-converting enzyme inhibitor lisinopril. SNP reduced ventral aortic pressure (PVA), PDA, and RS, increased CO and HR, but did not affect PVen, SV, or RG. SNP slightly decreased MCFP but did not affect compliance or unstressed volume. In vitro, large systemic arteries were more responsive than veins to NP, whereas SNP relaxed both. These results show that, in vivo, NP decrease venous compliance, thereby decreasing venous return, CO, and arterial pressure. Conversely, SNP hypotension is due to decreased RS. This is the first evidence for active regulation of venous capacitance in fish, which probably occurs in small veins or venules. The presence of venous baroreceptors is also suggested.
Systemic immune changes following meal intake in humans
Authors: Hansen K. , Sickelmann F. , Pietrowsky R. , Fehm H. L. , Born J.
Published: December 2017

Food intake represents a high intestinal antigen exposition requiring host defense. Besides local immune activation, this defense includes a coordinate systemic immune response, which may serve to support local immunity. This study examined influences of a standardized high-protein meal on peripheral blood mononuclear cell counts; on the in vitro mitogen-stimulated production of tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, and interferon-gamma; on the in vivo plasma levels of tumor necrosis factor-alpha and interleukin-6; and on plasma concentrations of cortisol and growth hormone. Ten healthy men (18-35 yr) participated in two experimental sessions in a balanced order. On one occasion, subjects fasted; on the other, they received a high-protein meal at 1230. Blood was sampled every 15 min. Whereas the numbers of neutrophils and platelets were increased for more than 2.5 h after meal intake (P < 0.01) lymphocyte counts decreased (P < 0.01). Meal intake also decreased the production of interferon-gamma but did not affect the production and plasma levels of the other cytokines. Changes in immune cell distribution and function were accompanied by a strong postprandial rise in plasma cortisol concentrations. Some of the systemic immune changes, like the emigration of lymphocytes, probably into extravascular abdominal tissues, may serve to support local immune defense.
L-threonine injection into PPC modifies food intake, lateral hypothalamic activity, and sympathetic discharge
Authors: Monda M. , Sullo A. , De Luca V. , Pellicano M. P. , Viggiano A.
Published: December 2017

Food intake and the firing rate of lateral hypothalamic neurons and nerves innervating interscapular brown adipose tissue (IBAT), along with IBAT and colonic temperatures, were monitored in male Sprague-Dawley rats fed a threonine-free diet. These variables were measured before and after a bilateral injection of L-threonine (2 nmol into each side) into the prepiriform cortex (PPC). The same variables were also monitored in 1) rats fed a threonine-free diet and injected with saline, 2) animals fed a standard diet and injected with L-threonine, and 3) rats fed a standard diet and injected with saline. The results showed that injection of L-threonine into PPC increases food intake and firing rate of lateral hypothalamic neurons, whereas it decreases the sympathetic discharge and body temperature in animals fed a threonine-free diet. No changes were found in the animals fed a standard diet. These findings suggest a correlation between 1) threonine level in the PPC and 2) lateral hypothalamic activity and sympathetic discharge to IBAT.
Influence of age on the sympathetic neural adjustments to alterations in systemic oxygen levels in humans
Authors: Davy K. P. , Jones P. P. , Seals D. R.
Published: December 2017

We tested the hypothesis that aging influences the regulation of sympathetic nervous system activity (SNA) and arterial blood pressure during alterations in systemic O2 levels in humans. To accomplish this, we performed direct (intraneural) measurements of SNA to skeletal muscle (MSNA) in 10 young and 7 older healthy normotensive men during room air breathing (normoxic-control), moderate isocapnic hypoxemia [15 min of 10% fractional inspired O2 (FIO2)], and hyperoxemia (10 min of 50% FIO2). After hypoxemia, arterial O2 saturation (SaO2) declined similarly in the young and older men. MSNA (burst frequency and total minute activity) increased significantly (P < 0.05) in both groups. The magnitudes of the absolute increases in MSNA and the delta MSNA/delta SaO2 were not significantly different in the young and older men; however, because of higher normoxic baseline levels, the percentage increases in burst frequency were smaller (P = 0.02) and those for total minute activity tended to be smaller (P = 0.11) in the older men. Arterial blood pressure increased modestly (P < 0.05) and similarly in both groups, although the older men demonstrated a smaller increase in heart rate. After hyperoxemia [corrected], SaO2 increased and MSNA decreased (both P < 0.05) similarly in the young and older men. Arterial blood pressure did not change significantly from normoxic control levels in either group; however, a small (P < 0.05) reduction in heart rate was observed in both groups. In conclusion, aging does not obviously influence the regulation of absolute levels of MSNA or arterial blood pressure during alterations in systemic O2 levels in healthy men, although older men demonstrate a smaller percentage increase in MSNA from their elevated baseline levels, as well as an attenuated tachycardia in response to acute hypoxemia. As such, the present results are consistent with our previous findings on aging and sympathocirculatory control during other types of acute stress in humans.
Effect of carbon dioxide on autonomic cardiovascular responses to systemic hypoxia in conscious rats
Authors: Hirakawa H. , Nakamura T. , Hayashida Y.
Published: December 2017

The contribution of the autonomic nervous system to the cardiovascular response to hypoxia with different levels of CO2 was investigated in conscious rats. Wistar rats were chronically instrumented for measurement of arterial blood pressure (ABP), electrocardiogram, and renal sympathetic nerve activity (RSNA). They were exposed to 1) hypocapnic hypoxia (Hypo), 2) isocapnic hypoxia (Iso), and 3) hypercapnic hypoxia (Hyper). Hypo caused a decrease in ABP, an increase in heart rate (HR) and RSNA, and a slight increase in plasma norepinephrine (NE). Iso caused no significant change in ABP or HR but did cause an increase in RSNA and plasma NE. Hyper caused an increase in ABP, a decrease in HR, and an increase in RSNA and plasma NE. In sinoaortic-denervated (SAD) rats, ABP and RSNA decreased and HR tended to decrease during Iso. SAD abolished the bradycardic response during Hyper. Atropine abolished the bradycardic response during Hyper, and HR tended to increase during all three kinds of hypoxia. In all three kinds of hypoxia, ABP and renal sympathetic nervous responses in atropine-treated rats were not significantly different from those in intact rats. These results indicate that Hypo causes sympathetic activation and parasympathetic inhibition while Iso and Hyper cause sympathetic and parasympathetic activation via peripheral chemoreceptors. The MABP-RSNA curve tended to shift to the left and the maximum gain of the baroreflex response tended to decrease during Hypo. In contrast, this curve shifted to the right and the maximum gain of the baroreflex response increased during Iso and Hyper, suggesting that baroreflex function is affected by arterial CO2 levels. We concluded that cardiovascular responses during hypoxia are modified by arterial Pco2 levels and mediated by the autonomic nervous system.
Social cues modulate free-running circadian activity rhythms in the diurnal rodent, Octodon degus
Authors: Goel N. , Lee T. M.
Published: December 2017

Two experiments assessed the effects of social cues and daily disturbance on the circadian locomotor activity rhythms of Octodon degus housed in constant darkness. In experiment 1, females in free-running conditions were housed alone or with entrained female partners ("donors") in cages on either side of a mesh barrier. Donors were removed daily and entrained to 1 h of light, and as a control, the cages of singly housed animals were rustled daily coincident with donor removal and replacement. None of the animals housed alone entrained to daily disturbances presented during the active phase, and seven of eight degus failed to show changes in the circadian period (tau) or phase of their rhythms. In contrast, although the presence of entrained donors did not elicit full entrainment of free-running rhythms, five of six animals demonstrated partial entrainment for 5-12 days (of 30 days), four of six altered phase of activity onset, and six of six lengthened tau of circadian rhythms. In experiment 2, females whose free-running circadian activity rhythms were at least 10 h out of phase were housed together in pairs. None of the pairs demonstrated mutual synchronization of their activity rhythms, although 8 of 12 degus modified phase of activity onset and 9 of 12 animals altered tau. We conclude social information in the absence of light, is sufficient for partial entrainment and for changes in tau and phase of free-running rhythms in this diurnal rodent.
Effect of substance P on C1 and other bulbospinal cells of the RVLM in neonatal rats
Authors: Li Y. W. , Guyenet P. G.
Published: December 2017

Sixty-two bulbospinal neurons were recorded in the rostral ventrolateral medulla (RVLM) of neonatal rats using patch electrodes. Sixty-one percent of the recorded neurons identified by histology contained tyrosine-hydroxylase (C1 cells). Substance P increased the spontaneous firing rate of all recorded cells but had no effect on spike configuration. The peptide depolarized neurons that were silenced by injection of hyperpolarizing current and increased their input resistance. All cells (n = 12) were activated by a neurokinin (NK)1 receptor agonist but most were unaffected by an NK2- or an NK2-selective compound. In voltage clamp, substance P produced a current that was linearly related to the membrane voltage. This current reversed polarity close to the potassium equilibrium potential in 11 of 23 cells. It reversed at more hyperpolarized potentials or not at all in the rest of the cells. In conclusion, substance P upregulates the intrinsic discharge rate of C1 and other putative sympathoexcitatory cells in neonatal rats. This effect is mediated via NK1 receptors. The depolarization is mediated by a reduction in resting potassium conductance and possibly by an additional cationic conductance. These results support the possibility that substance P could play a role "in vivo" in setting the basal level of discharge of the vasomotor cells of RVLM and therefore in regulating sympathetic vasomotor tone.
NE inhibits cerebrovascular mast cell exocytosis induced by cholinergic and peptidergic agonists
Authors: Reynier-Rebuffel A. M. , Callebert J. , Launay J. M. , Seylaz J. , Aubineau P.
Published: December 2017

Autonomic and sensory nerves frequently contact mast cells contained in rabbit leptomeningeal arteries. We have previously shown that parasympathetic and peptidergic neurotransmitters can stimulate mast cell granule exocytosis and serotonin (5-HT) release. In the present study, we examined ex vivo the possible action of the main sympathetic neurotransmitter, norepinephrine (NE), on this exocytotic process. NE, which had no effect on mast cell 5-HT content per se, totally inhibited carbachol-induced 5-HT release and partially reduced neuropeptide-induced 5-HT release. Pretreatment with the alpha 1-adrenergic blocker did not affect the inhibitory effect of NE. Pretreatment with specific beta 1- or beta 2-adrenergic blockers antagonized this action, but the beta 2-blocker exerts a more specific dose-dependent antagonism. Together with our previous data, these results indicate that the equilibrium between autonomic and sensory nerves may determine the release of 5-HT from mast cells (parasympathetic and sensory nerves can trigger exocytosis while the sympathetics can inhibit it). Such a mechanism could be implicated in pathophysiological events in which autonomic dysfunction is likely to be involved, such as vascular headache or other phenomena involving inflammation.