bluuebunny/crossref_metadata_2025 huggingface dataset:
Blockade of AT1 receptors enhances baroreflex control of heart rate in conscious rabbits with heart failure
Authors: Murakami H. , Liu J. L. , Zucker I. H.
Published: December 2017

Because the renin-angiotensin system is activated in heart failure, we hypothesized that angiotensin II (ANG II) plays a role in altering baroreflex sensitivity in the setting of heart failure. Accordingly, we evaluated the baroreflex control of heart rate (HR) in conscious, chronically instrumented rabbits in the normal state and after the establishment of heart failure. Heart failure was induced by rapid ventricular pacing at a rate of 360-380 beats/min for an average of 14.5 +/- 1.4 days. The data were compared with normal rabbits instrumented in a similar fashion. Baroreflex curves were generated by inflation of implanted hydraulic occluders on the vena cava and aortic arch or by administration of phenylephrine and sodium nitroprusside. Experiments were carried out before and after intravenous administration of the AT1 antagonist L-158,809. Rabbits with heart failure exhibited significantly lower arterial pressure (81 +/- 3 vs. 69 +/- 4 mmHg, P < 0.05), elevated resting HR (230 +/- 5 vs. 260 +/- 10 beats/min, P < 0.05), and elevated left atrial pressure (3.6 +/- 0.7 vs. 13.1 +/- 0.7 mmHg, P < 0.05). ANG II blockade had little effect on resting or baroreflex parameters in normal rabbits. However, in rabbits with heart failure, L-158,809 enhanced baroreflex sensitivity (2.7 +/- 0.5 vs. 4.7 +/- 0.8 beats.min-1.mmHg-1; P < 0.05), primarily by increasing the minimum HR evoked during baroreceptor activation. beta 1-Blockade had no effect on any baroreflex parameter after L-158,809 in rabbits with heart failure. However, L-158,809 significantly reduced the minimum HR after pretreatment with atropine in rabbits with heart failure. These data suggest that ANG II plays a role in modulation of cardiac sympathetic tone in this model of heart failure and may be responsible for the depressed baroreflex sensitivity observed in heart failure.
Sodium appetite in the sham-drinking rat after chorda tympani nerve transection
Authors: Frankmann S. P. , Sollars S. I. , Bernstein I. L.
Published: December 2017

Sodium depletion in the neurologically intact rat (Intact) produces a prompt and robust intake of NaCl. After chorda tympani nerve transection (CTX), there is a longer latency and a reduced intake of NaCl. The CTX rat depends on remaining gustatory and postingestive information to direct NaCl intake. In the present study, the effect of the removal of the postingestive signals of ingested NaCl (by means of a chronic gastric fistula) on the NaCl intakes and licking patterns of Intact and CTX rats was studied. When the gastric fistula was open (Sham), ingested NaCl did not pass beyond the stomach, thus negative postingestive stimulation was absent. After overnight sodium depletion, when postingestive stimulation was present (i.e., gastric fistula closed; Real), the CTX group drank significantly less 0.3 M NaCl than the Intact group over the 2-h test [11.7 +/- 1.6 (CTX) vs. 15.3 +/- 2.8 (Intact) ml]. In contrast, when postingestive signals were absent (i.e., Sham) the Intact group ingested 52.5 +/- 4.4 ml, whereas the CTX group had ingested only 12.4 +/- 3.1 ml of 0.3 M NaCl. Lickometer data analysis revealed that even during the first minute of the test the CTX/Real group generated significantly fewer licks than any of the other groups. Thus, although the CTX group was sensitive to inhibitory postingestive signals in the early portion of the appetite test, the absence of these signals did not release the robust and sustained intake of NaCl characteristic of the Intact group. These results suggest that information provided by the chorda tympani nerve is critically important to the strong motivational properties of NaCl after sodium depletion.
Alkali therapy extends the period of survival during hypoxia: studies in rats
Authors: Halperin F. A. , Cheema-Dhadli S. , Chen C. B. , Halperin M. L.
Published: December 2017

The goal of this study was to evaluate whether sodium bicarbonate might be a useful form of therapy for hypoxic L-lactic acidosis; our aim was to determine if alkali could extend the time of survival in this setting. Hypoxia was induced in anesthetized, paralyzed, artificially ventilated rats by lowering inspired O2 to 5.5%, an amount sufficient to develop a severe degree of L-lactic acidosis. Measuring arterial blood gases frequently permitted maintenance of a near-constant arterial O2 content. Three groups of hypoxic rats were studied: first, no infusions (n = 10); second, sodium bicarbonate at a rate equal to H+ production in the no-infusion group (n = 12); and third, a control for the Na load in the second group as NaCl (n = 17). Survival was close to twofold longer in the sodium bicarbonate group. Part of this beneficial effect seemed to be increased anaerobic glycolysis, producing ATP along with L-lactic acid. In addition, there was a large decrease in the metabolic demand (consumption of O2) in the 7- to 15-min period in the sodium bicarbonate group. Rats exposed to hypoxia and infused with NaCl for 15 min or alkali for 15, 27, or 40 min were then returned to room air; all survived for the subsequent experimental period of 150 min. We found that there is both a rationale and experimental evidence for giving sodium bicarbonate to prolong survival during hypoxia.
Effect of electrical stimulation patterns on glucose transport in rat muscles
Authors: Johannsson E. , Jensen J. , Gundersen K. , Dahl H. A. , Bonen A.
Published: December 2017

Transport of 2-[3H]deoxy-D-glucose (2-DG) was investigated during supramaximal stimulations of different muscles. In addition, we varied the net stimulation time (NST). In different treatments, NST occupied either 5, 7.5, 10, 15, 20, 30, or 50% of a 20-min stimulation period. After a bolus injection of 3H-labeled 2-DG, the greatest transport occurred in the extensor digitorum longus. In red gastrocnemius (RG; type IIa fibers) and white gastrocnemius (WG; type IIb fibers), the 2-DG transport rate was highest at 10% NST (8- to 12-fold increase) and decreased thereafter. In soleus (type I fibers), the 2-DG transport increased from 5 to 50% NST. Below 30% NST, 2-DG transport was greater in RG and WG muscles than in soleus (P < 0.05). GLUT-4 and 2-DG transport were not correlated during the contractions. Therefore, the percent NST affects 2-DG transport differentially in muscles of varying fiber types, and the transport rate is not related to the GLUT-4 content of the muscles.
Dynamics of the sleep EEG after an early evening nap: experimental data and simulations
Authors: Werth E. , Dijk D. J. , Achermann P. , Borbely A. A.
Published: December 2017

Increasing sleep pressure is associated with highly predictable changes in the dynamics of the sleep electroencephalogram (EEG). To investigate whether the effects of reduced sleep pressure also can be accounted for by homeostatic mechanisms, nighttime sleep following an evening nap was recorded in healthy young men. In comparison with the baseline night, sleep latency in the postnap night was prolonged, rapid eye movement sleep (REMS) latency was reduced, and EEG power density in non-REMS was decreased in the delta and theta band. The buildup of both EEG slow-wave activity (SWA; power density in the 0.75-to 4.5-Hz range) and spindle frequency activity (SFA; power density in the 12.25-to 15.0-Hz range) in non-REMS episodes was diminished (SWA: episodes 1-3; SFA: episode 1). The typical declining trend of SWA over consecutive non-REM sleep episodes was attenuated. The time course of SWA could be closely simulated with a homeostatic model of sleep regulation, although some discrepancies in level and buildup of SWA were apparent. We conclude that homeostatic mechanisms can largely account for the dynamics of the sleep EEG under conditions of reduced sleep pressure.
Circadian rhythm and response to light of extracellular glutamate and aspartate in rat suprachiasmatic nucleus
Authors: Honma S. , Katsuno Y. , Shinohara K. , Abe H. , Honma K.
Published: December 2017

Extracellular concentrations of glutamate and aspartate were measured in the vicinity of rat suprachiasmatic nucleus (SCN) by means of in vivo microdialysis. The concentrations of both excitatory amino acids (EAAs) were higher during the dark phase than during the light under the light-dark cycle, showing pulsatile fluctuations throughout the day. When rats were released into the complete darkness, the 24-h pattern in the aspartate continued for at least one cycle, whereas that in the glutamate disappeared. The nocturnal increases in the EAA levels were not due to the increase of locomotor activity during the nighttime, because the 24-h rhythms were also detected in animals under urethan anesthesia. The patterns of extracellular EAA levels were changed when rats were released into the continuous light. Circadian rhythm was not detected in the glutamate, whereas the 24-h pattern was maintained in the aspartate with the levels increased to various extents. A 30-min light pulse given either at zeitgber time (ZT) 1 or ZT 13 elevated the EAA levels during the latter half of the light pulse, except glutamate by a pulse at ZT 1. The extracellular EAA levels in the vicinity of the rat SCN showed the circadian rhythm with a nocturnal peak and increased in response to the continuous light and a brief light pulse. The aspartate level is considered to be regulated by the endogenous circadian rhythm, but the glutamate levels seems to be modified by the light-dark cycle.
Role of cardiac output in mediating arterial blood pressure oscillations
Authors: O'Leary D. S. , Woodbury D. J.
Published: December 2017

The objective of this study was to determine the role of cardiac output in mediating spontaneous fluctuations in mean arterial pressure (MAP) conscious dogs. Dogs were chronically instrumented to monitor MAP and cardiac output. Atrioventricular (AV) block was induced, and left ventricular and right atrial electrodes were implanted. After recovery, MAP was observed for 5 min under two conditions: 1) normal variation in heart rate and cardiac output via triggering the ventricular stimulator with each atrial depolarization (effectively reversing the AV block, AV-linked stimulation) and 2) computer control of ventricular rate to maintain cardiac output constant on a by-beat basis at the same level as observed during normal variations in heart rate and cardiac output. When cardiac output was held constant, large-amplitude, low-frequency oscillations in MAP were readily apparent. Spectral analysis by fast Fourier transform revealed that during constant cardiac output the power observed at low frequencies in the MAP spectrum represented 95.0 +/- 2.7% of the total power compared with 75.5 +/- 4.6% during normal variations in heart rate and cardiac output (P < 0.05). In addition, when cardiac output was held constant, the power observed at higher frequencies markedly decreased from 24.5 +/- 4.6% of total power during AV-linked stimulation to only 5.0 +/- 2.7% of total power during constant cardiac output (P < 0.05). We conclude that low-frequency oscillations in MAP are due to changes in peripheral resistance, whereas a significant amount of high-frequency changes in MAP stems from spontaneous changes in cardiac output.
In vivo increase of the human lens equatorial diameter during accommodation
Authors: Schachar R. A. , Tello C. , Cudmore D. P. , Liebmann J. M. , Black T. D. , Ritch R.
Published: December 2017

The movement of the human lens equator during accommodation was examined in vivo. High-resolution ultrasound images of the lens equator were obtained from young human subjects whose amplitude of accommodation was controlled with 1% tropicamide and 2% pilocarpine. To avoid errors that otherwise arise from eye rotation or other movement, the cornea and sclera were used as positional references in comparative studies of the video images obtained from the unaccommodated and accommodated states. During accommodation, the movement at the lens equator involved small displacement; i.e., < 100 microns, and the equator did not move anteriorly or posteriorly but peripherally toward the sclera. These results indicate that the lens equator is under increased zonular tension during accommodation, in contradiction to Helmholtz's widely accepted theory of accommodation.
Adenosine A1 receptor and its gene expression in ventricles from spontaneously hypertensive rats
Authors: Kobayashi S. , Umemura S. , Toya Y. , Hirawa N. , Hayashi S. , Uchino K. , Ishii M.
Published: December 2017

We characterized the adenosine A1 receptor and the levels of its mRNA expression in the ventricles of 6- and 13-wk-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The binding of 2-chloro-[3H]cyclopentyladenosine ([3H]CCPA), an A1 agonist ligand, to ventricular membranes was saturable and reversible. The receptor density was significantly lower in SHR than in WKY at 13 wk. The dissociation constant values were not different among these groups. In Northern blot analysis using rat A1 receptor cDNA, levels of mRNA did not differ significantly in the two groups at 13 wk, but the level in SHR significantly exceeded that in WKY at 6 wk. Because plasma adenosine levels were reported to be increased at 13 wk in SHR and we found mRNA levels were similar at this age, the discrepancy between A1 receptor density and its mRNA levels might be related to the desensitization of A1 receptors. Although the implication of this decreased density of A1 receptors is not known, it may involve an increased susceptibility to ischemia.
Circadian rhythms in renal function in hypertensive TGR(mRen-2)27 rats and their normotensive controls
Authors: Pons M. , Schnecko A. , Witte K. , Lemmer B. , Waterhouse J. M. , Cambar J.
Published: December 2017

Patients with secondary hypertension frequently display abnormal circadian blood pressure profiles, characterized by a failure to decrease blood pressure at night. The transgenic TGR(mRen-2)27 rat strain, developing fulminant hypertension after the mouse salivary Ren-2 renin gene has been integrated into its genome, provides a fundamental model of genetic hypertension. Because of an inverse circadian blood pressure profile and an unchanged rhythmic pattern of heart rate compared with the normotensive Sprague-Dawley (SPR) strain, it was proposed to serve as an animal model of genetic hypertension. It was the aim of the present study to investigate the circadian rhythmicity in renal function of the transgenic rat to determine whether hypertension and disturbed circadian blood pressure profile would affect kidney function. Urinary water, electrolyte, and protein excretion, as well as glomerular filtration rate and renal plasma flow, were determined in unrestrained freely moving transgenic hypertensive (TGR) and SPR normotensive control rats by collecting urine and arterial blood every 4 h. Significant and similar circadian rhythms were found in renal excretion and hemodynamics in both normotensive and hypertensive strains. Peaks occurred in the active dark period, whereas troughs were found in daytime for all parameters. However, it has to be pointed out that, although the circadian profiles were not grossly perturbed in hypertensive animals, some small differences between SPR and TGR strains did exist in renal function. These discrepancies were precisely related to acrophase, showing a slight phase delay, and also to relative amplitude in TGR. This study demonstrates that the inverted circadian blood pressure profile affected only slightly the circadian rhythms in kidney function in TGR compared with SPR. These findings support the notion that time-dependent changes in systemic blood flow may be of greater importance for circadian regulation of kidney function than systemic blood pressure.
Development of heart rate power spectra reveals neonatal peculiarities of cardiorespiratory control
Authors: Patzak A. , Lipke K. , Orlow W. , Mrowka R. , Stauss H. , Windt E. , Persson P. B. , Schubert E.
Published: December 2017

Postnatal adaptation should be associated with changes in cardiac rhythmic behavior. To examine the development of heart rate variability, instantaneous heart rate (IHR) and the corresponding breathing signals of 16 healthy infants were analyzed. This was pursued by use of fast Fourier transformation beginning with the 1st day until the 6th mo of life. Power in the low-frequency range (LF, 0.02-0.2 Hz) and high-frequency range (HF, 0.2-1.5 Hz), total power (TP), the quotient LF/HF, and the frequency of the peak in LF and HF (LFF and HFF, respectively) were derived from the IHR spectrum. The peak frequency in HF (RF) was detected in the respiratory spectrum. Power and frequency of IHR rhythms undergo a marked development. TP, LF, and HF are lowest from the end of the 1st mo until the 2nd mo. LF predominates over HF, with LF/HF reaching its peak during 1- to 2-mo period. HF, recording respiratory related rhythms is negatively correlated with the breathing rate (BR). HFF and RF both show an increasing tendency during the 1st mo followed by a decrease down to the 6th mo. However, HFF is lower than RF if BR is high, mainly during the first 2 mo. The distinct changes in BR and its important influence on the IHR spectrum underscore the importance of monitoring respiration as a further measure in the diagnosis of infants. LFF is on average between 0.075 and 0.095 Hz, exhibiting an irregular course with minimum at the 10th, 21st-28th, and 90th day being apparent. The developmental pattern of LFF may by interpreted in terms of the maturation of the nervous system involved in the generation of circulatory rhythms.
Processing of vestibular and other inputs by the caudal ventrolateral medullary reticular formation
Authors: Steinbacher B. C. , Yates B. J.
Published: December 2017

Lesions of the lateral medullary reticular formation caudal to the obex abolish vestibulosympathetic and somatosympathetic responses; this area also contains neurons that mediate baroreceptor reflexes. Recordings were made from neurons in the caudal medullary reticular formation of cats that were decerebrate or anesthetized using alpha-chloralose-urethan to determine whether common neurons responded to electrical stimulation of vestibular and hindlimb afferents and had cardiac-related (i.e., baroreceptor) inputs. Many neurons in the ventrolateral portion of the caudal reticular formation received labyrinthine inputs, and they were interspersed with neurons that received baroreceptor signals. However, virtually none of the units received convergent baroreceptor and vestibular inputs, suggesting that separate pathways from the caudal ventrolateral medulla mediate baroreceptor and vestibulosympathetic reflexes. Furthermore, the neurons that received labyrinthine signals could not be antidromically activated from electrodes inserted into the rostral ventrolateral medulla, which is known to mediate vestibulosympathetic responses; thus an indirect pathway must convey vestibular inputs from the caudal to rostral medullary reticular formation. Over 75% of both neurons with baroreceptor inputs and cells with vestibular signals responded to sciatic nerve stimulation, suggesting that more than one pathway from the caudal medulla may mediate somatosympathetic responses.
Transfer of Cl- across placenta of anesthetized rat
Authors: Stulc J. , Stulcova B. , Husain S. , Sibley C. P.
Published: December 2017

The mechanisms of Cl- transfer across the rat placenta have been investigated. Clearance across the intact placenta from mother to fetus (m-->f) of 51Cr-EDTA (paracellular diffusion marker) and 36Cl- (Kmf) was 1.9 +/- 0.1 and 37.3 +/- 4.1 microliters/min, respectively (mean +/- SE, n = 10), the large difference indicating that most m-->f transfer of Cl- is transcellular. The clearance of 36Cl- across the dually perfused placenta in m-->f and fetal-to-maternal directions was symmetrical and highly sensitive to the anion-exchange inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (0.1 mM). The Kmf of 36Cl- was not inhibited by anoxia and had a low temperature quotient (Q10 between 32 and 37 degrees C was 1.52). The m --> f transfer of Cl- seemed to be fully saturated at physiological concentrations of Cl-. 36Cl- could be displaced from the transporter on the maternal side by other anions with the following order of affinity: Cl- approximately NO3- > Br- > lactate- >> gluconate. It is concluded that most of the Cl- transfer across the rat placenta is effected by an anion exchanger.
Bispectral analysis of complex patterns of sympathetic nerve discharge
Authors: Gebber G. L. , Zhong S. , Paitel Y.
Published: December 2017

Bispectral analysis was used to demonstrate quadratic nonlinear coupling (i.e., phase locking) of different frequency components in inferior cardiac sympathetic nerve discharge (SND) of urethan-anesthetized rats. The complex patterns of SND analyzed included mixtures of 1) the cardiac-related and 10-Hz rhythms, 2) the 10-Hz rhythm and irregular 2-to 6-Hz oscillations, and 3) the 10-Hz rhythm and a lower frequency non-cardiac-related rhythm near 4 Hz. In some cases, the bicoherence function (normalized bispectrum) showed no phase locking of these frequency components. Cases of nil bicoherence are equated with linear superposition of frequency components, which implies the existence of multiple and noninteractive central circuits. Increased complexity of SND was observed in other cases, as evidenced by significant phase locking of different frequency components with or without frequency locking. Frequency locking (higher frequency rhythm is a multiple of lower) was confirmed by constructing Lissajous orbital plots showing covariation of voltages in selectively filtered bands of SND. We equate frequency locking with nonlinear coupling of the central generators of different sympathetic nerve rhythms and phase locking without frequency locking possibly with nonlinearities arising at levels below noncoupled central rhythm generators.
Role of CRH in the effects of 5-HT-receptor agonists on food intake and metabolic rate
Authors: Bovetto S. , Rouillard C. , Richard D.
Published: December 2017

Two series of experiments were conducted to investigate the role of corticotropin-releasing hormone (CRH) in the effects of 5-hydroxytryptamine (5-HT) on energy intake and energy expenditure. The first set of experiments was carried out to confirm the influence of 5-HT1A-, 5-HT1B-, 5-HT2A/2C-receptor agonists on the activation of the hypothalamic-pituitary-adrenal axis. Plasma corticosterone levels were measured, and a double-immunolabeling procedure was used to determine whether the neuronal activity marker, c-Fos protein (Fos), could be found within brain neurons containing CRH after treatments with 5-HT1A-, 5-HT1B-, 5-HT2A/2C-receptor agonists. The second series of experiments was conducted to assess the involvement of CRH in the effects of 5-HT on food intake and metabolic rate (VO2). The effects of the 5-HT1A-, 5-HT1B-, 5-HT2A/2C-receptor agonists on food intake and VO2 were measured in rats treated with the CRH antagonist, alpha-helical CRH-(9-41). In both experiments rats were intraperitoneally injected with either a vehicle (NaCl 0.9%), the 5-HT1A-receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT), the 5-HT1B-receptor agonist 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole succinate (RU-24969), or the 5-HT2A/2C-receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI). Fos immunoreactivity was detectable within the CRH-containing neurons of the paraventricular nucleus of the hypothalamus (PVH) after injection of each of the 5-HT-receptor agonists used. The CRH antagonist alpha-helical CRH-(9-41) attenuated the increases in metabolic rate induced by DOI and 8-OH-DPAT. alpha-Helical CRH did not, however, prevent the effects of RU-24969 and DOI on either nocturnal metabolic rate or food intake. The present results provide further evidence for a role of CRH in 5-HT-mediated thermogenic effect, which likely involves the 5-HT2A/2C receptor during the day and the 5-HT1A receptor during the night. Moreover, these results do not support a role for CRH in 5-HT anorectic effects, which likely involves 5-HT1B and 5-HT2A/2C receptors. Finally, the results of this study indicate that the stimulation of CRH-containing neurons located in the PVH does not necessarily predict changes in food intake and energy expenditure.
Modulation of procoagulant and fibrinolytic system components of mesothelial cells by inflammatory mediators
Authors: Sitter T. , Toet K. , Fricke H. , Schiffl H. , Held E. , Kooistra T.
Published: December 2017

Human peritoneal mesothelial cells (HMC) play a critical role in maintaining the intraperitoneal balance between fibrinolysis and coagulation by expressing the fibrinolytic enzyme tissue-type plasminogen activator (t-PA) as well as a specific plasminogen activator inhibitor, PAI-1, and the procoagulant protein tissue factor (TF). Of three compounds known to stimulate t-PA synthesis in cultured human endothelial cells, i.e., retinoic acid, the protein kinase C activator 4 beta-phorbol 12-myristate 13-acetate (PMA), and sodium butyrate, only butyrate (1 mM) caused about a threefold increase in t-PA synthesis and mRNA expression in HMC after 24 h of incubation, without markedly affecting PAI-1 synthesis. PMA (10 nM) induced a threefold increase in urokinase-type plasminogen activator (u-PA) mRNA, but u-PA antigen levels in the HMC conditioned media remained below the detection level (0.5 ng/ml), possibly as a result of rapid uptake and degradation by the u-PA receptor. The u-PA receptor mRNA levels were about fivefold enhanced above control levels after PMA treatment of the cells. An increase in intracellular adenosine 3',5'-cyclic monophosphate levels by forskolin (10 microM) diminished t-PA and PAI-1 levels 43 and 17%, respectively. Among the inflammatory mediators tested [tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha, and bacterial lipopolysaccharide], TNF-alpha (10-1,000 U/ml) showed the strongest procoagulant effects. We found that the isoflavone compound genistein (25 micrograms/ml) prevented the TNF-alpha-induced expression of PAI-1 and TF while also slightly counteracting the decrease in t-PA synthesis. The protein kinase C inhibitor R0-318220 (3 microM) only moderately opposed the TNF-alpha-induced changes in t-PA and PAI-1 synthesis but completely prevented the induction of TF mRNA. In summary, our results demonstrate that t-PA synthesis in HMC is relatively insensitive to pharmacological stimulation. To restore the balance between fibrinolysis and coagulation under inflammatory conditions, attempts to interfere with the TNF-alpha-signaling pathway were more successful.
Brief hypoxic stress downregulates E. coli-induced IL-1 alpha and IL-1 beta gene expression in perfused liver
Authors: Matuschak G. M. , Johanns C. A. , Chen Z. , Gaynor J. , Lechner A. J.
Published: December 2017

Hepatic cytokine gene expression is independently stimulated by circulating microbial products and reductions in the cellular O2 supply. Although these stimuli occur sequentially after gram-negative bacteremia, it is unknown whether their interplay augments production of interleukin (IL)-1 by the liver. We studied the effects of intraportal Escherichia coli (EC) bacteremia and secondary constant-flow hypoxia (Po2, approximately 46 Torr for 30 min) on IL-1 alpha and IL-1 beta gene expression in ex situ buffer-perfused rat livers over 180 min (n = 67). At t = 0, normoxic EC and normal saline (NS) controls received 10(9) live EC serotype 055:B5 and 0.9% NaCl, respectively; in livers subjected to EC+hypoxia-reoxygenation (H/R) and NS+H/R, hypoxia began 0.5 h after EC or NS and was followed by 120 min of reoxygenation. Portal and hepatic venous perfusates were serially analyzed for bacterial colony-forming units, O2 uptake, and aspartate aminotransferase. At 60 min (peak hypoxia) and 180 min, cDNAs for IL-1 alpha and IL-1 beta were hybridized to whole liver RNA, and IL-1 beta protein levels in venous perfusates were assessed. Intrahepatic levels of reduced glutathione (GSH) were measured as an index of oxidative stress. Compared with normoxic EC, IL-1 alpha transcripts decreased at 180 min in EC+H/R livers (P < 0.0001) as did IL-1 beta mRNA (P < 0.05), despite similar EC clearance, GSH levels, posthypoxic O2 uptake, and aspartate aminotransferase release. Hepatic secretion of IL-1 beta likewise fell in EC+H/R vs. EC controls (P < 0.005). Prostaglandin H synthase-2 (COX-2) message accumulation was not enhanced by H/R, and indomethacin did not reverse H/R-mediated suppression of IL-1 production. In contrast, H/R-related falls in EC-induced IL-1S expression were reversed by allopurinol or catalase. Thus brief hypoxic stress of the liver causing neither GSH depletion nor functional impairment downregulates postbacteremic IL-1 expression by a mechanism involving O2 radicals but not cyclooxygenase metabolites.
Changes in insulin action, triglycerides, and lipid composition during sucrose feeding in rats
Authors: Pagliassotti M. J. , Prach P. A. , Koppenhafer T. A. , Pan D. A.
Published: December 2017

In the present study, the time course of change in sucrose-induced insulin resistance, triglyceride (TG) concentration, and liver fatty acid composition was examined. Male rats (n = 8-10/group per time point) was fed a high-starch (ST) diet for 2 wk and were then equicalorically fed ST or a high-sucrose (SU) diet for 1, 2, 5, or 8 wk. Body weight and percent body fat were similar between ST and SU diets at all time points. Glucose infusion rate (GIR) was significantly (P < 0.05) lower in the SU diet (9.2 +/- 0.9, 7.4 +/- 0.5, 6.2 +/- 1.0, and 6.0 +/- 0.9 mg.kg-1.min-1) vs. the ST diet (15.1 +/- 1.7, 15.7 +/- 0.7, 14.7 +/- 1.9, and 14.2 +/- 0.9 mg.kg-1.min-1) at 1, 2, 5, and 8 wk, respectively. Reduced suppression of glucose appearance accounted for 85, 50, 45, and 40% of the reduction in GIR at these same time points. Muscle glycogen synthesis was reduced (P < 0.05 vs. ST diet) in the SU diet at 2, 5, and 8 wk. Fasting plasma TG concentration was inversely related (r = -0.79, P < 0.001) to muscle glycogen synthesis, and liver TG concentration was positively related (r = 0.59, P < 0.01) to glucose appearance. Liver fatty acid composition was similar between diet groups. In summary, the SU diet produced insulin resistance in liver before muscle. TG concentration appears to be related to sucrose-induced insulin resistance in liver and muscle.
Effect of extended sleep deprivation on tumor growth in rats
Authors: Bergmann B. M. , Rechtschaffen A. , Gilliland M. A. , Quintans J.
Published: December 2017

To assess the effect of chronic sleep deprivation on host defense, we observed growth and regression of a subdermal allogenic carcinoma (Walker 256 rat tumor) in rats undergoing 10 days of total sleep deprivation (TSD rats), yoked stimulus control (TSC) rats that were partially sleep deprived, and home cage control (HCC) rats. Tumor size was measured daily. Integrated tumor size was smaller in TSD rats than in both TSC (P = 0.04) and HCC rats (P = 0.0003). Thus host defense against these tumors (as defined by reduction in tumor size) was improved by sleep deprivation. This improvement could be a nonspecific effect, e.g., tumor growth can be inhibited by a catabolic state (dietary restriction). TSD and TSC rats lost body weight, indicating a catabolic state. However, tumor size was not predicted by body weight change, but was predicted by change in sleep time (P = 0.02). Host defense enhancement could alternatively result from enhanced immune response. Early tumor size (5 days) was similar in the three groups, but peaked sooner in TSD rats than in both TSC (P = 0.05) and HCC rats (P = 0.01), leading to large differences in size later. Immune-suppressed rats also showed little difference from HCC rats in early growth but large differences later. Thus host defense in an in vivo model that manifests a systemic immune response can be enhanced by sleep deprivation with timing, which is consistent with an enhancement of the immune response.
Subthreshold stimulation of a serotonin 5-HT3 reflex attenuates cardiovascular reflexes
Authors: Veelken R. , Hilgers K. F. , Ditting T. , Fierlbeck W. , Geiger H. , Schmieder R. E.
Published: December 2017

Volume-sensitive and chemosensitive cardiopulmonary reflexes modulate volume homeostasis via renal sympathetic nerve activity (RSNA). Blunting of volume-sensitive cardiopulmonary reflexes is associated with volume retention, e.g., in hypertension, whereas the role of chemosensitive cardiopulmonary reflexes is largely unknown. To elucidate the possible role of chemosensitive cardiopulmonary reflexes in control of volume homeostasis, we investigated whether subthreshold stimulation of 5-HT3 receptors modulates the control of RSNA by volume-sensitive cardiopulmonary reflexes or the arterial baroreceptor reflex in rats. Phenyl biguanide (PBG) was infused intravenously to stimulate 5-HT3 receptors. Higher doses of PBG lowered RSNA, but a dose of 6 micrograms/min, given as a background infusion throughout the experiment, did not change arterial pressure, heart rate (HR), or RSNA. Ten minutes after beginning the 6 micrograms/min PBG infusion, a 15-min volume expansion (0.9% saline, 5 or 10% body weight) was started to stimulate volume-sensitive cardiopulmonary reflexes. In separate experiments, 5-min ramp infusions of methoxamine and nitroglycerin to stimulate the arterial baroreceptor reflex (evaluated by a 4-parameter logistic regression) were performed 15 min after beginning the PBG background infusion (6 micrograms/min). During PBG infusion, the RSNA responses to volume expansions were significantly impaired (5% body weight: PBG -6 +/- 6%, n = 7 vs. control -39 +/- 9%, n = 6, P < 0.001; 10% body weight: PBG -33 +/- 6%, n = 8 vs. control -52 +/- 5%, n = 7, P < 0.05). The 5-HT3 receptor antagonist odansetron (GR-38032F) abolished these effects of PBG. The maximum HR gain of the arterial baroreceptor reflex was impaired but the arterial baroreceptor control of RSNA was unaffected by PBG background infusion. We conclude that 5-HT3-serotonergic cardiopulmonary chemoreceptors blunt the RSNA decrease to volume loading. This mechanism may facilitate volume retention when cardiac serotonin is increased.
Ventricular remodeling during development and recovery from modified tachycardia-induced cardiomyopathy model
Authors: Yamamoto K. , Burnett J. C. , Meyer L. M. , Sinclair L. , Stevens T. L. , Redfield M. M.
Published: December 2017

his study was designed to characterize left ventricular (LV) function and mass in a modified cardiomyopathy model in the dog in which right ventricular pacing rates are gradually increased throughout 38 days. On the last day of the pacing protocol, ejection fraction was reduced (25 +/- 3 vs. 60 +/- 1%) and LV end-diastolic diameter index (a ratio of LV end-diastolic diameter to body weight, 2.09 +/- 0.02 vs. 1.79 +/- 0.08 mm/kg) and LV mass index (a ratio of LV mass to body weight, 5.2 +/- 0.3 vs. 4.3 +/- 0.2 g/kg) were greater than in the normal dogs (P < 0.05, respectively). Cardiac filling pressures increased, and LV diastolic function and coronary blood flow were impaired. After 4 wk of recovery from the progressive pacing protocol, LV end-diastolic diameter index (2.12 +/- 0.06 mm/kg) and LV mass index (5.6 +/- 0.2 g/kg) remained increased. Ejection fraction was improved (38 +/- 4%) but still depressed. LV diastolic function, coronary blood flow, and cardiac filling pressures returned to levels seen in the normal dogs. This modified cardiomyopathy model associated with LV hypertrophy complements the conventional tachycardia-induced cardiomyopathy model without LV hypertrophy.
Allometry of mitochondrial proton leak: influence of membrane surface area and fatty acid composition
Authors: Porter R. K. , Hulbert A. J. , Brand M. D.
Published: December 2017

We investigated why liver mitochondria from small mammals are leakier to protons than those from larger mammals. Sixty-nine percent (+/-23%) of the proton leak differences appeared to relate to membrane area (less inner membrane surface area in larger animals); any residual differences must reflect differences in membrane properties. There were differences in phospholipid fatty acid composition; unsaturation index, monounsaturates, palmitate (16:0), stearate (18:0), docosahexaenoate [22:6(n-3)], and the 22:6(n-3)/22:5(n-3) ratio all correlated with body mass. Proton flux per square centimeter did not correlate significantly with body mass or, in general, with phospholipid fatty acid composition, suggesting little role for fatty acid composition in determining proton leak in mammals of different body mass. However, unsaturation index and n-3 polyunsaturated fatty acid content correlated significantly with proton leak per milligram phospholipid when literature data from reptiles and rats in different thyroid states were included, giving some support to suggestions of a general role for phospholipid fatty acid composition in determining mitochondrial proton leak.
Na(+)-D-glucose cotransport by intestinal BBMVs of the Antarctic fish Trematomus bernacchii
Authors: Maffia M. , Acierno R. , Cillo E. , Storelli C.
Published: December 2017

Intestinal nutrient absorption in fish adapted to low temperature was investigated by isolating, with a Mg(2+)-precipitation procedure, brush-border membrane vesicles (BBMVs) from intestines of the Antarctic teleost Trematomus bernacchii. In particular, D-glucose transport was analyzed by measuring both 1) fluorescence changes of the electrical potential-sensitive dye 3,3'-diethylthiadicarbocyanine iodide [DiS-C2(5)] and 2) intravesicular uptake of D-[14C]glucose. Results demonstrated that transport of D-glucose across intestinal BBMs of the Antarctic fish is stimulated by the presence of a transmembrane Na+ gradient (out > in) and was specifically inhibited by phloridzin. Furthermore, Na(+)-dependent D-glucose uptake was strongly enhanced by the presence of an electrical potential (inside-negative) across the membrane. There was a marked difference in temperature dependence of Na(+)-sugar cotransport between the Antarctic fish and a temperate fish, such as the European yellow eel., Na(+)-dependent D-glucose uptake in T. bernacchii intestinal BBMV reached its maximal rate at -2-0 degree C (close to fish living temperature) and was exponentially inactivated by incubation at higher temperatures. Kinetic analysis of D-glucose influx indicated the presence of a single Na(+)-dependent carrier process (apparent maximal carrier-mediated influx = 0.233 +/- 0.009 nmol.mg protein-1.min-1; apparent half-saturation constant for carrier-mediated influx = 0.157 +/- 0.026 mmol/l) and a nonsaturable transfer component (apparent diffusional permeability of membrane to the sugar = 0.233 +/- 0.016 microliter.mg protein-1.min-1). The Na(+)-dependent carrier-mediated mechanism was specific for sugars, since it was partially inhibited by the presence in the extravesicular medium of other monosaccharides, but not by ascorbic acid or amino acids of different types. These data suggest that in the intestine of Antarctic fish luminal D-glucose transport takes place by a specific Na(+)-dependent electrogenic secondary active transport working well at subzero temperatures.
Impairment of vascular function is associated with an age-related increase of lipid peroxidation in rats
Authors: Davidge S. T. , Hubel C. A. , McLaughlin M. K.
Published: December 2017

We tested the hypothesis that an increase in endogenous lipid peroxidation over time is associated with an impairment of endothelium-dependent vascular function in resistance-sized mesenteric arteries that is due in part to alterations of arachidonate metabolism. Susceptibility to red blood cell hemolysis and sera levels of malondialdehyde were increased (P < 0.05) from 20 wk (n = 12) to 40 wk (n = 12) in female Sprague-Dawley rats. Arteries were studied in a myograph by examining the endothelial modification of phenylephrine vasoconstriction and the relaxation responses of the mesenteric arteries to methacholine. We observed the following. 1) An increase in sensitivity to alpha 1-adrenergic stimulation occurred between 20 and 40 wk of age. Cyclooxygenase inhibition decreased the sensitivity to phenylephrine only in the arteries from the 40-wk-old rats, indicating that a cyclooxygenase-dependent vasoconstrictor was modifying the phenylephrine response. 2) Nitric oxide synthase inhibition caused a greater increase in phenylephrine sensitivity in the arteries from the 20-wk-old rats than those from the 40-wk-old rats, indicating that nitric oxide modification of phenylephrine sensitivity decreased with age. 3) Endothelium-independent relaxations were not affected between 20 and 40 wk of age. 4) At 40 wk, the sensitivity to the methacholine-mediated relaxation response decreased without impairing the maximal relaxation response. This reduced sensitivity was removed with cyclooxygenase inhibition or thromboxane A2/prostaglandin H2 (PGH2) receptor blockade. 5) Aortas from the 40-wk-old rats had an increased expression of PGH synthase. Collectively, these observations indicate that, in the female rat, an increase in lipid peroxidation over time is associated with changes in endothelium-dependent vascular function that were due in part to a cyclooxygenase-dependent vasoconstrictor.
IL-1 type I receptor mediates acute phase response to turpentine, but not lipopolysaccharide, in mice
Authors: Leon L. R. , Conn C. A. , Glaccum M. , Kluger M. J.
Published: December 2017

This study examined the role of the interleukin-1 (IL-1) type I receptor (IL-1RtI) in the acute phase response (APR) to inflammation in mice. Turpentine (100 microliters/mouse) injected subcutaneously induced fever, lethargy, body weight loss, and anorexia in IL-1RtI wild-type mice. Knockout mice lacking the IL-1RtI were resistant to these effects of turpentine, supporting a role for this receptor in the APR to local inflammation. The intraperitoneal injection of a low (50 micrograms/kg) or high (2.5 mg/kg) dose of lipopolysaccharide (LPS) induced similar APRs in IL-1RtI wild-type and knockout mice. IL-1RtI knockout mice were resistant to the APR induced by peripherally injected murine IL-1 beta, suggesting that it is not the interaction of endogenous IL-1 beta with IL-1RtII that induces an APR to LPS in these mice. We speculate that the absence of IL-1RtI in these knockout mice results in the sensitization of other cytokine pathways to mediate the APR to LPS.
Effect of hypoxemia on tissue glycogen content and glycolytic enzyme activities in fetal sheep
Authors: Stratford L. L. , Hooper S. B.
Published: December 2017

We have tested the hypothesis that prolonged fetal hypoxemia causes a reduction in glycogenolytic enzyme activities and/or a depletion of fetal glycogen stores. We compared the effects of short (4 h) and prolonged (24 h) periods of reduced maternal uterine blood flow (RUBF) on glycogen content and on the activities of glucose-6-phosphatase (G-6-Pase), glycogen phosphorylase (GPase), and glycogen synthase (GSase) in selected fetal tissues. RUBF was reduced in 10 pregnant sheep at 135 days of gestation (term approximately 146 days) for either 4 h (n = 5) or 24 h (n = 5); 5 other fetuses were used as controls. During RUBF, fetal SaC2 was decreased from 61.6 +/- 3.9 to 22.0 +/- 1.4% at 4 h and to 26.7 +/- 1.2% at 24 h. Hepatic glycogen content was significantly reduced at 4 h of RUBF, but was not reduced further at 24 h. Fetal liver GPase (active and total enzyme activity) and G-6-Pase activities were reduced at 4 h of RUBF but tended to return toward control values at 24 h. Similarly, hepatic GSase activity tended to decrease at 4 h of RUBF, although the reduction was not quite significant (P = 0.08). We conclude that RUBF causes a reduction of fetal glycogen stores and a reduction in G-6-Pase and GPase activity at 4 h. Fetal tissue glycogen contents were not reduced further at 24 h, compared with 4 h of RUBF, which indicates that fetal glycogenolysis is reduced during this time, probably because of the inhibition of GPase and G-6-Pase. It is not known why the activities of these enzymes are reduced during prolonged RUBF, when circulating epinephrine and norepinephrine concentrations are high.
Role of extra- and intracellular Ca2+ in the lymphatic myogenic response
Authors: Atchison D. J. , Johnston M. G.
Published: December 2017

We used an actively contracting in vitro preparation of bovine mesenteric lymph vessels to study the effect of selected calcium channel modulators on the ability of these vessels to propel fluid. We found that blocking the dihydropyridine receptor with nifedipine and diltiazem inhibited pumping at concentrations within the range used clinically (10(-7) and 10(-6) M, respectively). Intracellular calcium modulation using ryanodine (10(-6) M) also inhibited pumping. Furthermore, we studied the effect of these agents on the relationship between lymph flow and transmural pressure, a relationship normally described by a bell-shaped curve. Diltiazem, 10(-6) M, attenuated pumping over the range of pressures studied. On the other hand, ryanodine at 10(-7) M, a concentration capable of inhibiting pumping at a constant transmural pressure, had no effect on the pressure-flow relationship when transmural pressure was manipulated. Thus we have determined that calcium movement via the L-type channel contributes significantly to the regulation of lymph pump activity and that intracellular calcium flux plays a less significant role that may be modified by transmural pressure.
Neurophysiological modeling of voiding in rats: bladder pressure and postganglionic bladder nerve activity
Authors: Le Feber J. , Van Asselt E. , Van Mastrigt R.
Published: December 2017

A model was developed that describes the relations between bladder pressure and both efferent and afferent nerve activity in postganglionic bladder nerves in urethan-anesthetized rats. Nerve activity was calculated as the 100-ms time integral of the rectified nerve signal. Afferent and efferent nerve signals were measured separately by crushing the nerve proximally or distally. A linear relation was found between bladder pressure and afferent nerve activity (fit error < 7%), and the relation between bladder pressure and efferent nerve activity was described by a low-pass filter (fit error < 90%). In most experiments, combined (efferent and afferent) nerve activity was measured. Absence of efferent nerve activity was assumed during the pressure decrease immediately after voiding. From this episode, the afferent nerve activity was estimated for the entire measurement. Efferent nerve activity was then estimated assuming linear addition in the bidirectionally conducting nerves. The model described the measured data very well (fit error < 7%), and the model parameters showed a good reproducibility in each rat (SD was approximately 30% of the mean).