bluuebunny/crossref_metadata_2025 huggingface dataset:
Early captopril treatment prevents hypertrophy-dependent gene expression in hearts of SHR
Authors: Chen Songcang , Su Jinzi , Wu Kegui , Hu Wenyang , Gardner David G. , Chen Daguang
Published: December 2017

Treatment of spontaneously hypertensive rats (SHR) with captopril (100 mg ⋅ kg−1 ⋅ day−1) throughout development and during the first 16 wk of life leads to a reduction in blood pressure and left ventricular hypertrophy. Blood pressures and hypertrophy are reduced in these animals (vs. untreated SHR) for up to 24 wk after discontinuation of the drug. We used conventional blot hybridization and Western analysis to examine hypertrophy-dependent gene expression during this period. Ventricular expression of the atrial natriuretic peptide gene was reduced by >90% at 16 wk of age in the captopril-treated SHR. Expression increased in the 24 wk after discontinuation of treatment, but remained well below that of the untreated SHR. A similar reduction in ventricular c- myc gene expression was seen with captopril treatment. Neither renal expression of the atrial natriuretic peptide gene nor ventricular expression of the c- fos gene was affected by captopril. This study demonstrates that captopril treatment during a critical period of development in the SHR leads to a sustained reduction in hypertrophy-dependent myocardial gene expression, which does not revert to levels seen in the untreated SHR after discontinuation of the drug.
NO generation and action during changes in salt intake: roles of nNOS and macula densa
Authors: Wilcox Christopher S. , Deng Xiaolin , Welch William J.
Published: December 2017

Micropuncture studies of single nephrons have shown that macula densa solute reabsorption via a furosemide-sensitive pathway activates nitric oxide (NO) generation via neuronal NO synthase (nNOS). This pathway is enhanced during salt loading. We investigated the hypothesis that changes in NO generation via nNOS in the macula densa contribute to changes in whole kidney NO generation and action during alterations in salt intake. Groups of rats ( n = 6–10) were equilibrated to high-salt (HS) or low-salt (LS) diets and were administered a vehicle (Veh), 7-nitroindazole (7-NI; a relatively selective inhibitor of nNOS), or furosemide (F; an inhibitor of macula densa solute reabsorption) with volume replacement. Compared with LS, excretion of the NO metabolites, NO2plus NO3(NOX) was increased during HS (LS: 9.0 ± 0.5 vs. HS: 15.7 ± 0.8 μmol/24 h; P < 0.001), but this difference was prevented by 7-NI (LS: 7.4 ± 1.3 vs. HS: 9.4 ± 1.6 μmol/24 h; NS). During nonselective blockade of NOS with NG-nitro-l-arginine methyl ester (l-NAME), renal vascular resistance (RVR) increased more in HS than LS (HS: +160 ± 17 vs. LS: +83 ± 10%; P < 0.001). This difference in response to nonselective NOS inhibition was prevented by pretreatment with 7-NI (HS: +28 ± 6 vs. LS: +34 ± 8%; NS) or F with volume replacement (HS: +79 ± 11 vs. LS: +62 ± 4%; NS). In conclusion, compared with salt restriction, HS intake increases NO generation and renal action that depend on nNOS and macula densa solute reabsorption.
Complement reduction impairs the febrile response of guinea pigs to endotoxin
Authors: Sehic E. , Li S. , Ungar A. L. , Blatteis C. M.
Published: December 2017

Although it is generally believed that circulating exogenous pyrogens [e.g., lipopolysaccharides (LPS)] induce fever via the mediation of endogenous pyrogens (EP) such as cytokines, the first of these, tumor necrosis factor-α, is usually not detectable in blood until at least 30 min after intravenous administration of LPS, whereas the febrile rise begins within 15 min after its administration. Moreover, although abundant evidence indicates that circulating LPS is cleared primarily by liver macrophages [Kupffer cells (KC)], these do not secrete EP in immediate response. This would imply that other factors, presumably evoked earlier than EP, may mediate the onset of the febrile response to intravenous LPS. It is well known that blood-borne LPS very rapidly activates the intravascular complement (C) system, some components of which in turn stimulate the quick release into blood of various substances that have roles in the acute inflammatory reaction. KC contain receptors for C components and are in close contact with afferent vagal terminals in the liver; the involvement of hepatic vagal afferents in LPS-induced fever has recently been shown. In this study, we tested the hypothesis that the initiation of fever by intravenous LPS involves, sequentially, the C system and KC. To test this postulated mechanism, we measured directly the levels of prostaglandin E2(PGE2) in the interstitial fluid of the preoptic anterior hypothalamus (POA), the presumptive site of the fever-producing controller, of conscious guinea pigs over their entire febrile course, before and after C depletion by cobra venom factor (CVF) and before and after elimination of KC by gadolinium chloride (GdCl3). CVF and GdCl3pretreatment each individually attenuated the first of the biphasic core temperature (Tc) rises after intravenous LPS, inverted the second into a Tcfall, and greatly reduced the usual fever-associated increase in POA PGE2. We conclude, therefore, that C activation may indeed be pivotal in the induction of fever by intravenous LPS and that substance(s) generated presumably by KC in almost immediate reaction to the presence of LPS and/or C may transmit pyrogenic signals via hepatic vagal afferents to the POA, where they rapidly induce the production of PGE2and, hence, fever.
Coronary vascular reactivity is improved by endothelin A receptor blockade in DOCA-salt hypertensive rats
Authors: Giulumian Ararat D. , Pollock David M. , Clarke Natalie , Fuchs Leslie C.
Published: December 2017

Endothelin-1 (ET-1) is thought to play an important role in the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Because hypertension is associated with an increased incidence of coronary artery disease, this study was designed to determine if coronary vascular contraction to ET-1 is altered in DOCA-salt hypertensive rats and to determine the effect of chronic treatment of DOCA-salt rats with the selective ETA receptor antagonist A-127722. Male Sprague-Dawley rats were divided into four groups: DOCA, Placebo, DOCA + A-127722, and Placebo + A-127722. A-127722 was administered in drinking water at a concentration of 8 mg/100 ml. After 3 wk, mean arterial pressure (MAP) was significantly enhanced in DOCA-salt compared with Placebo rats. A-127722 significantly inhibited the increase in MAP. Contraction to ET-1 (10−11 to 3 × 10−8 M) was measured in isolated coronary and mesenteric small arteries (200–300 μm, intraluminal diameter) maintained at a constant intraluminal pressure of 40 mmHg and was significantly impaired in vessels from DOCA-salt compared with Placebo rats. Dose-dependent contractions to KCl were also inhibited in coronary, but only minimally impaired in mesenteric, arteries of DOCA-salt rats. Inhibition of nitric oxide synthase activity did not restore contraction to ET-1 in coronary small arteries. However contractions to ET-1 were enhanced in mesenteric small arteries. Chronic treatment with A-127722 significantly restored contraction to ET-1 in coronary, but not in mesenteric, arteries of DOCA-salt rats. Because ETAreceptor blockade impairs the development of hypertension and improves coronary vascular reactivity, these data indicate that ET-1 plays an important role in coronary vascular dysfunction associated with DOCA-salt hypertension.
Mechanism of vasopressin natriuresis in the dog: role of vasopressin receptors and prostaglandins
Authors: Kompanowska-Jezierska Elzbieta , Emmeluth Claus , Grove Lisbeth , Christensen Poul , Sadowski Janusz , Bie Peter
Published: December 2017

Renal effects of physiological amounts of vasopressin were studied in conscious dogs during servocontrolled overhydration (2% body wt). During infusion of vasopressin (50 pg ⋅ min−1⋅ kg body wt−1), plasma vasopressin concentration increased to 2.30 ± 0.20 pg/ml compared with 0.12 ± 0.03 pg/ml during control (water diuresis). With vasopressin infusion, urine flow was significantly lower (0.30 ± 0.10 ml/min) and sodium excretion (UNaV) was significantly higher (58.0 ± 15.8 μmol/min) than without vasopressin (4.6 ± 0.4 ml/min and 14.4 ± 4.1 μmol/min, respectively). Deamino-[Cys1,d-Arg8]vasopressin, a V2receptor agonist (4 pg ⋅ min−1⋅ kg−1), mimicked the antidiuretic response (0.20 ± 0.03 ml/min) without changing UNaV (9.7 ± 4.4 μmol/min). Indomethacin given during arginine vasopressin (AVP) infusion suppressed prostaglandin E2excretion, intensified the antidiuresis (0.10 ± 0.02 ml/min), and abolished the natriuresis (13.4 ± 3.7 μmol/min). During AVP infusion, UNaV was highly correlated ( r = 0.85) with prostaglandin E2excretion. Blood pressure, glomerular filtration rate, plasma atrial natriuretic peptide concentration, and the rate of proximal tubule reabsorption (derived from lithium clearance) were similar in all series. The data indicate that, in the dog, physiological amounts of vasopressin can induce natriuresis, probably through activation of non-V2receptors and the intrarenal synthesis of prostaglandins.
Superoxide-dependent cerebrovascular effects of homocysteine
Authors: Zhang Fangyi , Slungaard Arne , Vercellotti Gregory M. , Iadecola Costantino
Published: December 2017

Recent evidence indicates that elevated plasma levels of homocysteine are a risk factor for ischemic cerebrovascular diseases. However, little is known about cerebrovascular effects of homocysteine. Homocysteine could impair cerebrovascular function by metal-catalyzed production of activated oxygen species. We studied whether homocysteine, in the presence of Cu2+, alters reactivity of cerebral circulation and, if so, whether this effect depends on[Formula: see text] generation. In halothane-anesthetized rats the parietal cortex was exposed and superfused with Ringer solution. Cerebrocortical blood flow (CBF) was monitored by a laser-Doppler probe. With Ringer solution superfusion, CBF increased with hypercapnia (+134 ± 7%;[Formula: see text] = 50–60 mmHg) and topical application of 10 μM ACh (+35 ± 3%), the NO donor S-nitroso- N-acetylpenicillamine (SNAP, 500 μM; +66 ± 6%), or 1 mM papaverine (+100 ± 6%; n = 5). Superfusion with 40 μM Cu2+alone did not perturb resting CBF or responses to hypercapnia, ACh, SNAP, or papaverine ( P > 0.05, n = 5). However, superfusion of homocysteine-Cu2+reduced resting CBF (−28 ± 4%) and attenuated ( P < 0.05) responses to hypercapnia (−31 ± 9%), ACh (−73 ± 6%), or SNAP (−48 ± 4%), but not papaverine. The effect was observed only at 1 mM homocysteine. Cerebrovascular effects of homocysteine-Cu2+were prevented by coadministration of superoxide dismutase (SOD; 1,000 U/ml; n = 5). SOD alone did not affect resting CBF or CBF reactivity ( n = 5). The observation that homocysteine-Cu2+attenuates the response to hypercapnia, ACh, and SNAP, but not the NO-independent vasodilator papaverine, suggests that homocysteine-Cu2+selectively impairs NO-related cerebrovascular responses. The fact that SOD prevents such impairment indicates that the effect of homocysteine is[Formula: see text] dependent. The data support the conclusion that [Formula: see text], generated by the reaction of homocysteine with Cu2+, inhibits NO-related cerebrovascular responses by scavenging NO, perhaps through peroxynitrite formation. [Formula: see text]-mediated scavenging of NO might be one of the mechanisms by which hyperhomocysteinemia predisposes to cerebrovascular diseases.
Urinary acidification and net acid excretion in adult rats treated neonatally with enalapril
Authors: Guron Gregor , Marcussen Niels , Friberg Peter
Published: December 2017

Neonatal blockade of the renin-angiotensin system in rats induces irreversible renal histological abnormalities, including papillary atrophy and an impaired urinary concentrating ability. The aim was to investigate urinary acidification and net acid excretion in adult Wistar rats treated neonatally with enalapril (10 mg ⋅ kg−1⋅ day−1) or vehicle from 5 to 24 days of age. Analyses were performed in both metabolic balance studies and renal clearance experiments performed under pentobarbital sodium anesthesia. There were no differences between groups in urine pH or urinary excretion rates of bicarbonate, titratable acid, or ammonium, neither during control conditions nor after chronic NH4Cl loading (assessed before and after Na2SO4infusion). Glomerular filtration rate, maximal tubular bicarbonate reabsorption, and the urine-to-blood[Formula: see text] gradient in alkaline urine during NaHCO3infusion did not differ between groups. Neonatally enalapril-treated rats showed a urine concentration defect and papillary damage. In conclusion, neonatal enalapril treatment produces a differentiated abnormality in tubular function in which urine concentration is impaired but urinary acidification and net acid excretion are intact.
Cafeteria feeding induces interleukin-1β mRNA expression in rat liver and brain
Authors: Hansen Michael K. , Taishi Ping , Chen Zutang , Krueger James M.
Published: December 2017

Food intake affects gut-immune function and can provide a strong intestinal antigen challenge resulting in activation of host defense mechanisms in the digestive system. Previously, we showed that feeding rats a cafeteria diet increases non-rapid eye movement sleep by a subdiaphragmatic mechanism. Food intake and sleep regulation and the immune system share the regulatory molecule interleukin-1β (IL-1β). Thus this study examined the effects of a cafeteria diet on IL-1β mRNA and IL-1 receptor accessory protein (IL-1RAP) mRNA expression in rat liver and brain. Rats were fed normal rat chow or a palatable diet consisting of bread, chocolate, and shortbread cookies (cafeteria diet). After 3 days, midway between the light period of the light-dark cycle, rats were killed by decapitation. Feeding rats a cafeteria diet resulted in increased IL-1β mRNA expression in the liver and hypothalamus compared with rats fed only the normal rat chow. In addition, cafeteria feeding decreased IL-1RAP mRNA levels in the liver and brain stem. These results indicate that feeding has direct effects on cytokine production and together with other data suggest that the increased sleep that accompanies increased feeding may be the result of increased brain IL-1β. These results further suggest that cytokine-to-brain communication may be important in normal physiological conditions, such as feeding, as well as being important during inflammatory responses.
Fos expression in rat brain during depletion-induced thirst and salt appetite
Authors: Thunhorst R. L. , Xu Z. , Cicha M. Z. , Zardetto-Smith A. M. , Johnson A. K.
Published: December 2017

The expression of Fos protein (Fos immunoreactivity, Fos-ir) was mapped in the brain of rats subjected to an angiotensin-dependent model of thirst and salt appetite. The physiological state associated with water and sodium ingestion was produced by the concurrent subcutaneous administration of the diuretic furosemide (10 mg/kg) and a low dose of the angiotensin-converting enzyme (ACE) inhibitor captopril (5 mg/kg; Furo/Cap treatment). The animals were killed 2 h posttreatment, and the brains were processed for Fos-ir to assess neural activation. Furo/Cap treatment significantly increased Fos-ir density above baseline levels both in structures of the lamina terminalis and hypothalamus known to mediate the actions of ANG II and in hindbrain regions associated with blood volume and pressure regulation. Furo/Cap treatment also typically increased Fos-ir density in these structures above levels observed after administration of furosemide or captopril separately. Fos-ir was reduced to a greater extent in forebrain than in hindbrain areas by a dose of captopril (100 mg/kg sc) known to block the actions of ACE in the brain. The present work provides further evidence that areas of lamina terminalis subserve angiotensin-dependent thirst and salt appetite.
Interleukin-1β-converting enzyme-deficient mice resist central but not systemic endotoxin-induced anorexia
Authors: Burgess William , Gheusi Gilles , Yao Jianhua , Johnson Rodney W. , Dantzer Robert , Kelley Keith W.
Published: December 2017

Interleukin-1β (IL-1β) mediates many of the behavioral responses to infection and inflammation, and IL-1β-converting enzyme (ICE) processes intracellular IL-1β, leading to its maturation and secretion. Here we demonstrate that intracerebroventricular injections of lipopolysaccharide (LPS) produced a greater reduction in both food intake and food-motivated behavior in wild-type compared with ICE-deficient (ICE −/−) mice. This defect occurred although ICE −/− mice were able to fully respond to intracerebroventricular injections of IL-1β. In contrast, ICE −/− mice remained fully responsive to intraperitoneal injections of LPS. These results indicate that brain, but not peripheral, IL-1β plays a critical role in the depression in food intake that occurs during inflammation.
Activation of angiotensinogen gene in cardiac myocytes by angiotensin II and mechanical stretch
Authors: Tamura Kouichi , Umemura Satoshi , Nyui Nobuo , Hibi Kiyoshi , Ishigami Tomoaki , Kihara Minoru , Toya Yoshiyuki , Ishii Masao
Published: December 2017

Circulating and cardiac renin-angiotensin systems (RAS) play important roles in the development of cardiac hypertrophy. Mechanical stretch of cardiac myocytes induces secretion of ANG II and evokes hypertrophic responses. Angiotensinogen is a unique substrate of the RAS. This study was performed to examine the regulation of the angiotensinogen gene in cardiac myocytes in response to ANG II and stretch. ANG II and stretch significantly increased the levels of angiotensinogen mRNA in cardiac myocytes. Actinomycin D completely inhibited ANG II- and stretch-mediated increases in angiotensinogen mRNA. Although CV-11974 abolished ANG II-mediated increases in mRNA level and promoter activity of the angiotensinogen gene, the inhibition of stretch-mediated activation by CV-11974 was significant but not complete. These results indicate that ANG II activates transcription of the angiotensinogen gene exclusively via ANG II type 1-receptor pathway and that stretch activates such transcription mainly via the same pathway in cardiac myocytes. Furthermore, factors other than ANG II may also be involved in stretch-mediated activation of the angiotensinogen gene in cardiac myocytes.
Mode of action of OB protein (leptin) on feeding
Authors: Flynn Mark C. , Scott Thomas R. , Pritchard Thomas C. , Plata-Salamán Carlos R.
Published: December 2017

OB protein (leptin) decreases food intake in a variety of species. Here we investigated the effects of the intracerebroventricular administration of recombinant murine OB protein on food consumption and meal parameters in Wistar rats maintained ad libitum. The intracerebroventricular administration of OB protein (0.56–3.5 μg/rat) decreased feeding in a dose-dependent manner. Computer analysis of meal parameters demonstrated that OB protein (3.5 μg/rat, n = 10) decreased nighttime meal size by 42%, whereas meal frequency and meal duration were unaffected. Derived analyses for the nighttime also showed that OB protein decreased the feeding rate (meal size/meal duration) by 30%, whereas the satiety ratio (intermeal intervals/meal size) increased by 100%. A similar profile was observed during the daytime and total daily periods. The intracerebroventricular administration of heat-inactivated OB protein (3.5 μg/rat, n = 10) had no effect on any meal parameter. The results show that OB protein administered intracerebroventricularly inhibits feeding through a specific reduction of meal size.
Chronic administration of OB protein decreases food intake by selectively reducing meal size in male rats
Authors: Kahler Andrea , Geary Nori , Eckel Lisa A. , Campfield L. Arthur , Smith Françoise J. , Langhans Wolfgang
Published: December 2017

The potent hypophagic effect of OB protein (OB) is well established, but the mechanism of this effect is largely unknown. We investigated the effects of chronic administration of a novel modified recombinant human OB (Mod-OB) with a prolonged half-life (>48 h) on ad libitum food intake, spontaneous meal patterns, and body weight in 24 adult, male Sprague-Dawley rats (body weight at study onset: 292 g). Single daily subcutaneous injections of Mod-OB (4 mg/kg daily) for 8 consecutive days significantly reduced ad libitum food intake compared with vehicle injections from injection day 3through postinjection day 3. Mod-OB-injected rats ate between 4.5 and 7.1 g (or 13–20%) per day less than controls, with the reduction primarily occurring during the dark period. Body weight gain was significantly decreased in response to Mod-OB from injection day 8until postinjection day 4, with a maximum difference of 24 g on postinjection day 3. The reduction of food intake by Mod-OB was mainly due to a 21–34% decrease in nocturnal spontaneous meal size. There was no significant effect of Mod-OB on nocturnal meal frequency or duration. Mod-OB also did not reliably affect the size, duration, or frequency of diurnal meals. Mod-OB-injected rats displayed no compensatory hyperphagia after the injection period. These results indicate that chronically administered OB selectively affects the mechanisms controlling meal size in male rats.
Chronic administration of OB protein decreases food intake by selectively reducing meal size in female rats
Authors: Eckel Lisa A. , Langhans Wolfgang , Kahler Andrea , Campfield L. Arthur , Smith Françoise J. , Geary Nori
Published: December 2017

The mechanisms by which OB protein controls food intake and energy balance are unknown. Therefore, we investigated the effects of a novel modified human recombinant OB protein (Mod-OB) on spontaneous feeding patterns, body weight, running wheel activity, and ovarian cycling in female rats. Mod-OB or vehicle was injected (4 mg ⋅ kg−1 ⋅ day−1sc) for 2 ovarian cycles (8 days) using a within-subjects design. Observations were continued for five ovarian cycles after injections; treatments were then reversed. Mod-OB reduced food intake ∼20% from injection day 1 to postinjection day 2. Body weight was reduced from injection day 3 to postinjection day 15 (maximum decrease, 25 ± 4 g, postinjection days 3 and 4). Food intake was reduced due to decreases in nocturnal meal size, which appeared to be superimposed on the normal pattern of spontaneous feeding (i.e., reductions in meal size at estrus). Mod-OB did not significantly affect diurnal food intake or meal patterns, failed to alter wheel running, and did not disrupt the rats’ ovarian cycles. We conclude that chronically administered Mod-OB reduces food intake in female rats by selectively affecting the mechanisms controlling meal size.
Primary structure, distribution, and effects on motility of CGRP in the intestine of the cod Gadus morhua
Authors: Shahbazi Fatemeh , Karila Paul , Olsson Catharina , Holmgren Susanne , Conlon J. Michael , Jensen Jörgen
Published: December 2017

Calcitonin gene-related peptide (CGRP) was isolated from an extract of the intestine of the cod Gadus morhua. The primary structure of this 37-amino acid peptide was established as follows: ACNTA TCVTH RLADF LSRSG GIGNS NFVPT NVGSK AF-NH2. The peptide shows close structural similarities to other nonmammalian (3–4 amino acid substitutions) and mammalian (5–8 amino acid substitutions) CGRPs, and it contains the two residues Asp14 and Phe15 that seem to be characteristic for CGRP in nonmammalian vertebrates. Cod CGRP (10−9–10−7M) inhibited the motility of spontaneously active ring preparations from the cod intestine and was significantly ( P < 0.05) more potent than rat α-CGRP. Neither prostaglandins nor nitric oxide is involved in the inhibitory response produced by cod CGRP, and the lack of effect of tetrodotoxin suggests an action of CGRP on receptors on the intestinal smooth muscle cells. The competitive CGRP antagonist human α-CGRP-(8—37) significantly ( P < 0.05) reduced the response to cod CGRP. Immunohistochemistry demonstrated CGRP-immunoreactive neurons intrinsic to the intestine, and a dense innervation with immunoreactive nerve fibers was observed in the myenteric plexus and the circular muscle layer. Myotomy studies show that CGRP-containing nerves project orally and anally in the myenteric plexus, whereas nerve fibers in the circular muscle layer project mainly anally, indicating a role for CGRP in descending inhibitory pathways of the cod intestine.
Expression of α2-macroglobulin by the interaction between hepatocytes and endothelial cells in coculture
Authors: Talamini Mark A. , McCluskey Michael P. , Buchman Timothy G. , De Maio Antonio
Published: December 2017

The interaction between distinct cell types within the liver seems to be important in regulating hepatic function. However, these interactions have not been well characterized because of difficulty in reproducing the hepatic environment in an ex vivo model. In the present study a coculture system of hepatocytes and endothelial cells was established to investigate the communication between parenchymal and nonparenchymal cells. Freshly isolated rat hepatocytes were placed onto a monolayer of primary aortic rat endothelial cells. Analysis of the proteins secreted into the extracellular medium after pulse labeling with radioactive amino acids revealed the presence of a 180,000-apparent molecular weight glycoprotein, BBB-180, which was not detected in the extracellular medium of hepatocytes or endothelial cells when they were cultured separately. This glycoprotein was identified as α2-macroglobulin after sequencing of the proteolytic peptides derived from the purified protein. This finding was confirmed by Northern and Western blotting, immunoprecipitation, and RT-PCR. The expression of α2-macroglobulin required direct contact between hepatocytes and viable endothelial cells. These findings suggest that endothelial cells modulate hepatocyte gene expression by direct cellular interactions.
Nitric oxide in the ventrolateral medulla regulates sympathetic responses to systemic hypoxia in pigs
Authors: Zanzinger Johannes , Czachurski Jürgen , Seller Horst
Published: December 2017

The role of nitric oxide (NO) in the regulation of sympathetic activity during hypoxia was studied in anesthetized pigs ( n = 21). Hypoxia (fractional concentration of O2 in inspired air = 0.1) increased pulmonary arterial pressure and decreased arterial blood pressure and peripheral vascular resistance. Renal sympathetic nerve activity (RSNA) was moderately increased during hypoxia but decreased instantaneously on reoxygenation. Blockade of NO synthesis by N G-nitro-l-arginine (l-NNA, 0.3 mmol/l) administered to the ventral surface of the medulla oblongata (VLM) significantly enhanced RSNA increases induced by hypoxia and abolished the RSNA response to reoxygenation. Furthermore,l-NNA significantly reduced peripheral hypoxic vasodilation but did not affect pulmonary vasoconstriction. The inactive enantiomerd-NNA had no measurable effects at the same concentration. Actions ofl-NNA were effectively counteracted by the NO donor S-nitroso- N-acetyl-penicillamine (0.1 mmol/l). Deafferentiation (carotid sinus and vagal nerves cut) abolished sympathetic responses to hypoxia and their modulation by NO. The results suggest that activation of peripheral chemoreceptors induces NO release in the VLM that buffers sympathoexcitation during hypoxia and contributes to sympathoinhibition during reoxygenation.
Methodology of fever research: why are polyphasic fevers often thought to be biphasic?
Authors: Romanovsky Andrej A. , Kulchitsky Vladimir A. , Simons Christopher T. , Sugimoto Naotoshi
Published: December 2017

This study explains why the recently described triphasic lipopolysaccharide (LPS) fevers have been repeatedly mistaken for biphasic fevers. Experiments were performed in loosely restrained male Wistar rats with a catheter implanted into the right jugular vein. Each animal was injected with Escherichia coli LPS, and its colonic (Tc) and tail skin temperatures were monitored. The results are presented as time graphs and phase-plane plots; in the latter case the rate of change of Tc is plotted against Tc. At an ambient temperature (Ta) of 30.0°C, the response to the 10 μg/kg dose of LPS was triphasic, as is obvious from time graphs of Tc (3 peaks), time graphs of effector activity (3 waves of tail skin vasoconstriction), and phase-plane plots (3 complete loops). When the Ta was below neutral (22.0°C) or the LPS dose was higher (100 or 1,000 μg/kg), the time graph of Tc did not allow for the reliable detection of all three febrile phases, but the phase-plane plot and time graph of effector activity clearly revealed the triphasic pattern. In a separate experiment, LPS (10 μg/kg) or saline was injected via one of two different procedures: in the first group the injection was performed through the jugular catheter, from outside the experimental chamber; in the second group the same nonstressing injection was combined with opening the chamber and pricking the animal in its lower abdomen with a needle. In the first group the febrile response was obviously triphasic, and none of the phases was due to the procedure of injection per se (injection of saline did not affect Tc). In the second group the fever similarly consisted of three Tc rises, but it might have been readily mistaken for biphasic because the first rise was indistinguishable from stress hyperthermia occurring in the saline-injected (and needle-pricked) controls. We conclude that several methodological factors (dose of LPS, procedure of its injection, and Ta) have contributed, although each in a different way, to the common misbelief that there are only two febrile phases.
Single-breath CO diffusing capacity influenced by initial alveolar partial pressure of CO
Authors: Heller Hartmut , Schuster Klaus-Dieter
Published: December 2017

The purpose of this study was to assess the influence of incorrect determinations of the initial alveolar partial pressure of carbon monoxide (CO) at the beginning of breath holding (Pia CO) on the pulmonary CO diffusing capacity of the lung (Dl CO). Single-breath maneuvers were performed on 14 anesthetized and artificially ventilated rabbits, using 0.2% CO in nitrogen as the indicator gas mixture. Inflation and deflation procedures were carried out in an identical manner on each animal, with inflation always starting from residual volume. End-tidal partial pressure of CO was determined by respiratory mass spectrometry and was used to calculate Dl CO values with the application of the three-equation ( method 1), as well as the conventional ( method 2), solution. In each rabbit, method 2 caused Dl CO values to be overestimated when compared with method 1, and this overestimation decreased with increasing time intervals of CO uptake. Because we were able to recalculate this deviation using Pia COvalues that were obtained by taking the diffusive removal of CO during inflation into account, we concluded that errors in estimating Pia CO by applying method 2 significantly contribute to the discrepancy between both methods.
Vasodilation elicited by liposomal VIP is unimpeded by anti-VIP antibody in hamster cheek pouch
Authors: Ikezaki Hiroyuki , Paul Sudhir , Alkan-Önyüksel Hayat , Patel Manisha , Gao Xiao-Pei , Rubinstein Israel
Published: December 2017

The purpose of this study was to determine whether a monoclonal anti-vasoactive intestinal peptide (VIP) antibody, which binds VIP with high affinity and specificity and catalyzes cleavage of the peptide in vitro, attenuates VIP vasorelaxation in vivo and, if so, whether insertion of VIP on the surface of sterically stabilized liposomes (SSL), which protects the peptide from trypsin- and plasma-catalyzed cleavage in vitro, curtails this response. Using intravital microscopy, we found that suffusion of monoclonal anti-VIP antibody (clone c23.5, IgG2ak), but not of nonimmune antibody (myeloma cell line UPC10, IgG2ak) or empty SSL, significantly attenuates VIP-induced vasodilation in the in situ hamster cheek pouch ( P < 0.05). By contrast, anti-VIP antibody has no significant effects on vasodilation elicited by isoproterenol, nitroglycerin, and calcium ionophore A-23187, agonists that activate intracellular effector systems in blood vessels that mediate, in part, VIP vasoreactivity. Suffusion of VIP on SSL, but not of empty SSL, restores the vasorelaxant effects of VIP in the presence of anti-VIP antibody. Collectively, these data suggest that VIP catalysis by high affinity and specific VIP autoantibodies displaying protease-like activity constitutes a novel mechanism whereby VIP vasoreactivity is regulated in vivo.
Signaling the brain in systemic inflammation: which vagal branch is involved in fever genesis?
Authors: Simons Christopher T. , Kulchitsky Vladimir A. , Sugimoto Naotoshi , Homer Louis D. , Székely Miklos , Romanovsky Andrej A.
Published: December 2017

Recent evidence has suggested a role of abdominal vagal afferents in the pathogenesis of the febrile response. The abdominal vagus consists of five main branches (viz., the anterior and posterior celiac branches, anterior and posterior gastric branches, and hepatic branch). The branch responsible for transducing a pyrogenic signal from the periphery to the brain has not as yet been identified. In the present study, we address this issue by testing the febrile responsiveness of male Wistar rats subjected to one of four selective vagotomies: celiac (CBV), gastric (GBV), hepatic (HBV), or sham (SV). In the case of CBV, GBV, and HBV, only the particular vagal branch(es) was cut; for SV, all branches were left intact. After the postsurgical recovery (26–29 days), the rats had a catheter implanted into the jugular vein. On days 29–32, their colonic temperature (Tc) responses to a low dose (1 μg/kg) of Escherichia colilipopolysaccharide (LPS) were studied. Three days later, the animals were subjected to a 24-h food and water deprivation, and the effectiveness of the four vagotomies to induce gastric food retention, pancreatic hypertrophy, and impairment of the portorenal osmotic reflex was assessed by weighing the stomach and pancreas and measuring the specific gravity of bladder urine, respectively. Stomach mass, pancreas mass, and urine density successfully separated the four experimental groups into four distinct clusters, thus confirming that each type of vagotomy had a different effect on the indexes measured. The Tc responses of SV, CBV, and GBV rats to LPS did not differ and were characterized by a latency of ∼40 min and a maximal rise of 0.7 ± 0.1, 0.6 ± 0.1, and 0.9 ± 0.2°C, respectively. The fever response of the HBV rats was different; practically no Tc rise occurred (0.1 ± 0.2°C). The HBV appeared to be the only selective abdominal vagotomy affecting the febrile responsiveness. We conclude, therefore, that the hepatic vagus plays an important role in the transduction of a pyrogenic signal from the periphery to the brain.
Effects of renal medullary infusion of a vasopressin V1 agonist on renal antihypertensive mechanisms in rabbits
Authors: Bergström Göran , Evans Roger G.
Published: December 2017

The factors responsible for the development of hypertension during chronic activation of intrarenal V1receptors are unknown. We therefore tested whether medullary interstitial infusion of the selective V1-receptor agonist [Phe2,Ile3,Orn8]vasopressin (V1 agonist) influences renal antihypertensive mechanisms initiated by increased renal perfusion pressure (RPP). In intact anesthetized rabbits, the V1 agonist (10 ng ⋅ kg−1 ⋅ min−1) reduced medullary perfusion by 36 ± 7%, whereas cortical perfusion was reduced by only 14 ± 2%. An extracorporeal circuit was used to increase RPP in a stepwise manner from 65 to 85, 110, 130, and 160 mmHg for consecutive 20-min periods. Increased RPP reduced mean arterial pressure by 35 ± 8% in vehicle-treated rabbits, but by only 10 ± 3% in V1agonist-treated rabbits. Simultaneously, pressure-diuresis-natriuresis was induced; urine flow and sodium excretion increased similarly in the two groups of rabbits, but hematocrit did not change. We suggest that the depressor response to increased RPP is mainly due to release of a putative renal medullary depressor hormone (RMDH). Suppression of the release and/or actions of RMDH may therefore contribute to the hypertensive effect of chronic V1receptor activation.
Capsaicin activates heat loss and heat production simultaneously and independently in rats
Authors: Kobayashi Akiko , Osaka Toshimasa , Namba Yoshio , Inoue Shuji , Lee Tai Hee , Kimura Shuichi
Published: December 2017

Subcutaneous administration of capsaicin (5 mg/kg) immediately increased the temperature of the tail skin (Tsk) for 2 h in urethan-anesthetized rats, suggesting an increase in heat loss. O2 consumption, an index of heat production, also immediately increased after the capsaicin injection, and this increase lasted for >10 h. Colonic temperature (Tco) decreased within 1 h after the injection, and this decrease was followed by a long-lasting hyperthermic period. Adrenal demedullation largely attenuated the capsaicin-induced increase in O2consumption, and sympathetic denervation of the interscapular brown adipose tissue partly attenuated the increase in O2 consumption. However, capsaicin-induced heat loss was normal in these rats. In rats with cutaneous vasodilation maximized by warming and administration of hexamethonium, capsaicin did not further increase Tsk but normally induced heat production, and Tco gradually rose without a hypothermic period. Thus capsaicin simultaneously increased heat loss and heat production, and inhibition of one response did not affect the other. These findings suggest that capsaicin simultaneously activates independent networks for heat loss and heat production.
Effects of varied fatigue protocols on sarcoplasmic reticulum calcium uptake and release rates
Authors: Ward Christopher W. , Spangenburg Espen E. , Diss Lilian M. , Williams Jay H.
Published: December 2017

The purpose of this investigation was to examine changes in sarcoplasmic reticulum (SR) function in muscles subjected to different patterns of muscle activity. Frog sartorius muscles were stimulated with tetanic trains (100 ms, 100 Hz) delivered at rates of 2.0, 0.5, and 0.2 trains/s. In one set of experiments, stimulation was continued until force had declined to ∼17% of initial (constant fatigue), whereas in the other set, stimulation was continued for 1 min (constant duration). In the constant-fatigue experiments, Ca2+uptake (1 mM MgATP) and release rates (25 μM AgNO3, 5 mM 4-chloro- m-cresol) were depressed by similar extents following each protocol. This occurred despite 1, 4, and 17 min of stimulation, respectively, used to induce fatigue. In the constant-duration experiments, larger reductions in SR function occurred following the highest frequency stimulation protocol. These data suggest that when muscles are fatigued to similar extents, depressions in SR function are independent of the activity protocol. On the other hand, when a constant duration of activity is imposed, changes in SR function are closely linked to the extent of force reduction.
Regulation of skeletal muscle glycogen phosphorylase and PDH at varying exercise power outputs
Authors: Howlett Richard A. , Parolin Michelle L. , Dyck David J. , Hultman Eric , Jones Norman L. , Heigenhauser George J. F. , Spriet Lawrence L.
Published: December 2017

This study investigated the transformational and posttransformational control of skeletal muscle glycogen phosphorylase and pyruvate dehydrogenase (PDH) at three exercise power outputs [35, 65, and 90% of maximal oxygen uptake (V˙o2 max)]. Seven untrained subjects cycled at one power output for 10 min on three separate occasions, with muscle biopsies at rest and 1 and 10 min of exercise. Glycogen phosphorylase in the more active ( a) form was not significantly different at any time across power outputs (21.4–29.6%), with the exception of 90%, where it fell significantly to 15.3% at 10 min. PDH transformation increased significantly from rest (average 0.53 mmol ⋅ kg wet muscle−1⋅ min−1) to 1 min of exercise as a function of power output (1.60 ± 0.26, 2.77 ± 0.29, and 3.33 ± 0.31 mmol ⋅ kg wet muscle−1⋅ min−1at 35, 65, and 90%, respectively) with a further significant increase at 10 min (4.45 ± 0.35) at 90%V˙o2 max. Muscle lactate, acetyl-CoA, acetylcarnitine, and free ADP, AMP, and Piwere unchanged from rest at 35% V˙o2 maxbut rose significantly at 65 and 90%, with accumulations at 90% being significantly higher than 65%. The results of this study indicate that glycogen phosphorylase transformation is independent of increasing power outputs, despite increasing glycogenolytic flux, suggesting that flux through glycogen phosphorylase is matched to the demand for energy by posttransformational factors, such as free Piand AMP. Conversely, PDH transformation is directly related to the increasing power output and the calculated flux through the enzyme. The rise in PDH transformation is likely due to increased Ca2+concentration and/or increased pyruvate. These results demonstrate that metabolic signals related to contraction and the energy state of the cell are sensitive to the exercise intensity and coordinate the increase in carbohydrate use with increasing power output.
RT-PCR study of the distribution of connexin 43 mRNA in the glomerulus and renal tubular segments
Authors: Guo Rong , Liu Li , Barajas Luciano
Published: December 2017

An RT-PCR study of the distribution of connexin 43 (Cx43) mRNA in glomeruli and along the rat tubular segments was carried out to establish the differential expression of Cx43 in the different segments of the tubule, in renal regions, in isolated glomerular preparations (IGP), and in microdissected glomeruli. The mRNA level of Cx43 in macrodissected renal regions appeared in the following order: inner papilla > outer papilla and IGP > outer medulla and cortex. Among the microdissected tubules, inner medullary collecting ducts (IMCD) expressed the highest level of Cx43 mRNA, followed by the cortical collecting ducts (CCD). The proximal convoluted tubules and proximal straight tubules expressed significantly less Cx43 than the IMCD, glomeruli, and CCD. Medullary thick ascending limb and distal convoluted tubules showed the lowest level of Cx43 mRNA. The RT-PCR results of the microdissected segments correlate well with those obtained by RT-PCR of the renal regions. The high concentration of Cx43 mRNA in the IMCD together with the observation of abundant punctate immunofluorescence for Cx43 suggests that the IMCD not only expresses Cx43 mRNA but also that the mRNA is translated to Cx43 protein.
Metabolic inhibition increases feeding and brain Fos-like immunoreactivity as a function of diet
Authors: Horn Charles C. , Friedman Mark I.
Published: December 2017

Whether administration of 2,5-anhydro-d-mannitol (2,5-AM) or methyl palmoxirate (MP) elicits eating behavior in rats depends on the composition of the maintenance diet. To assess whether specific brain sites are involved in triggering the eating responses to these metabolic inhibitors, we measured food intake and Fos-like immunoreactivity (Fos-li) in rats maintained on either a low-fat/high-carbohydrate (LF/HC) or high-fat/low-carbohydrate (HF/LC) diet. Rats fed the LF/HC diet increased food intake after administration of 2,5-AM (200 mg/kg ip) but not after treatment with MP (10 mg/kg po), whereas rats maintained on the HF/LC diet increased food intake in response to MP administration but not after 2,5-AM injection. The effects of these inhibitors on brain Fos-li in several specific brain nuclei paralleled those on feeding behavior; that is, the number of cells showing Fos-li increased only under dietary conditions in which 2,5-AM or MP stimulated eating. These results suggest that the eating response to metabolic inhibition is tied to increased neuronal activity in brain regions that process vagal afferent signals.
Cholinesterase affects dynamic transduction properties from vagal stimulation to heart rate
Authors: Nakahara Tsutomu , Kawada Toru , Sugimachi Masaru , Miyano Hiroshi , Sato Takayuki , Shishido Toshiaki , Yoshimura Ryoichi , Miyashita Hiroshi , Sunagawa Kenji
Published: December 2017

Recent investigations in our laboratory using a Gaussian white noise technique showed that the transfer function representing the dynamic properties of transduction from vagus nerve activity to heart rate had characteristics of a first-order low-pass filter. However, the physiological determinants of those characteristics remain to be elucidated. In this study, we stimulated the vagus nerve according to a Gaussian white noise pattern to estimate the transfer function from vagal stimulation to the heart rate response in anesthetized rabbits and examined how changes in acetylcholine kinetics affected the transfer function. We found that although increases in the mean frequency of vagal stimulation from 5 to 10 Hz did not change the characteristics of the transfer function, administration of neostigmine (30 μg ⋅ kg−1 ⋅ h−1iv), a cholinesterase inhibitor, increased the dynamic gain from 8.19 ± 3.66 to 11.7 ± 4.88 beats ⋅ min−1 ⋅ Hz−1( P < 0.05), decreased the corner frequency from 0.12 ± 0.05 to 0.04 ± 0.01 Hz ( P < 0.01), and increased the lag time from 0.17 ± 0.12 to 0.27 ± 0.08 s ( P < 0.05). These results suggest that the rate of acetylcholine degradation at the neuroeffector junction, rather than the amount of available acetylcholine, plays a key role in determining the dynamic properties of transduction from vagus nerve activity to heart rate.
Central losartan blocks natriuretic, vasopressin, and pressor responses to central hypertonic NaCl in sheep
Authors: Mathai Michael L. , Evered Mark D. , McKinley Michael J.
Published: December 2017

This study investigated the effect of intracerebroventricular administration of the angiotensin AT1 receptor antagonist losartan on the natriuresis, pressor effect, and arginine vasopressin (AVP) secretion caused by intracerebroventricular infusion of either ANG II, hypertonic saline, or carbachol. Losartan (1 mg/h) or artificial cerebrospinal fluid (CSF) was infused into the lateral ventricle before, during, and after infusions of either ANG II at 10 μg/h for 1 h, 0.75 mol/l NaCl at 50 μl/min for 20 min, or carbachol at 1.66 μg/min for 15 min. Intracerebroventricular infusions of ANG II, 0.75 mol/l NaCl, or carbachol caused increases in renal Na+ and K+ excretion, arterial pressure, and plasma AVP levels. Increases in arterial pressure, Na+ excretion, and plasma AVP concentration ([AVP]) in response to intracerebroventricular ANG II or intracerebroventricular 0.75 mol/l NaCl were either abolished or attenuated by intracerebroventricular infusion of losartan but not by intracerebroventricular infusion of artificial CSF or intravenous losartan. Intracerebroventricular losartan did not reduce the increase in plasma [AVP] or arterial pressure in response to intracerebroventricular carbachol, but it did attenuate the natriuretic response to intracerebroventricular carbachol. We conclude that an intracerebroventricular dose of losartan (1 mg/h) that inhibits responses to intracerebroventricular ANG II also inhibits vasopressin secretion, natriuresis, and the pressor response to intracerebroventricular hypertonic saline. These results suggest that common neural pathways are involved in the responses induced by intracerebroventricular administration of ANG II and intracerebroventricular hypertonic NaCl. We propose that intracerebroventricular infusion of hypertonic saline activates angiotensinergic pathways in the central nervous system subserving the regulation of fluid and electrolyte balance and arterial pressure in sheep.