bluuebunny/crossref_metadata_2025 huggingface dataset:
Kinetic profile of the rat CYP4A isoforms: arachidonic acid metabolism and isoform-specific inhibitors
Authors: Nguyen Xuandai , Wang Mong-Heng , Reddy Komandla M. , Falck John R. , Schwartzman Michal Laniado
Published: December 2017

20-Hydroxyeicosatetraenoic acid (HETE), the cytochrome P-450 (CYP) 4A ω-hydroxylation product of arachidonic acid, has potent biological effects on renal tubular and vascular functions and on the control of arterial pressure. We have expressed high levels of the rat CYP4A1, -4A2, -4A3, and -4A8 cDNAs, using baculovirus and Sf 9 insect cells. Arachidonic acid ω- and ω-1-hydroxylations were catalyzed by three of the CYP4A isoforms; the highest catalytic efficiency of 947 nM−1⋅ min−1for CYP4A1 was followed by 72 and 22 nM−1⋅ min−1for CYP4A2 and CYP4A3, respectively. CYP4A2 and CYP4A3 exhibited an additional arachidonate 11,12-epoxidation activity, whereas CYP4A1 operated solely as an ω-hydroxylase. CYP4A8 did not catalyze arachidonic or linoleic acid but did have a detectable lauric acid ω-hydroxylation activity. The inhibitory activity of various acetylenic and olefinic fatty acid analogs revealed differences and indicated isoform-specific inhibition. These studies suggest that CYP4A1, despite its low expression in extrahepatic tissues, may constitute the major source of 20-HETE synthesis. Moreover, the ability of CYP4A2 and -4A3 to catalyze the formation of two opposing biologically active metabolites, 20-HETE and 11,12-epoxyeicosatrienoic acid, may be of great significance to the regulation of vascular tone.
Conditioned immunosuppression makes subtherapeutic cyclosporin effective via splenic innervation
Authors: Exton Michael S. , Schult Marc , Donath Stefan , Strubel Tim , Bode Ulrike , del Rey Adriana , Westermann Jürgen , Schedlowski Manfred
Published: December 2017

The present study investigated the mechanisms by which conditioned immunosuppression enhances the effectiveness of cyclosporin A (CsA) treatment in prolonging heart allograft survival. Dark Agouti rats that were administered subtherapeutic CsA (7 × 2 mg/kg on alternate days) rejected heart allografts at the same time as non-CsA-treated rats. The addition of a behavioral conditioning regimen (conditioned stimulus, saccharin; unconditioned stimulus, 20 mg/kg CsA) to the subtherapeutic CsA protocol produced a significant prolongation of graft survival, including long-term survival (>100 days) in 20% of the animals. Prior sympathetic denervation of the spleen completely blocked this effect. In nontransplanted rats both conditioning and CsA treatment reduce interleukin-2 and interferon (IFN)-γ in the supernatant of proliferating splenocytes. Additionally, therapeutic CsA treatment decreased the number of IFN-γ-producing CD4+naive and memory T cells in the spleen. In contrast, behavioral conditioning increased that number. These data indicate that behavioral conditioning prolongs heart allograft survival by inhibiting the release of these cytokines in the spleen via sympathetic innervation, supplementing the inhibited cytokine production induced by CsA treatment.
Aging and spectral characteristics of the nonharmonic component of 24-h heart rate variability
Authors: Sakata Seiichiro , Hayano Junichiro , Mukai Seiji , Okada Akiyoshi , Fujinami Takao
Published: December 2017

To examine whether heart rate variability (HRV) during daily life shows power law behavior independently of age and interindividual difference in the total power, log-log scaled coarse-graining spectra of the nonharmonic component of 24-h HRV were studied in 62 healthy men (age 21–79 yr). The spectra declined with increasing frequency in all subjects, but they appeared as broken lines slightly bending downward, particularly in young subjects with a large total power. Regression of the spectrum by a broken line with a single break point revealed that the spectral exponent (β) was greater in the region below than above the break point (1.63 ± 0.23 vs. 0.96 ± 0.21, P < 0.001). The break point frequency increased with age ( r = 0.51, P < 0.001) and β correlated with age negatively below the break point ( r = 0.39) and positively above the break point ( r = 0.70). The contribution to interindividual difference in total power was greater from the differences in the power spectral density at frequencies closer to both ends of the frequency axis and minimal from that at −3.25 log(Hz), suggesting hingelike movement of the spectral shape at this frequency with the difference in total power. These characteristics of the 24-h HRV spectrum were simulated by an artificial signal generated by adding two noises with different β values. Given that the power law assumption is fundamental to the analysis of dynamics through the log-log scaled spectrum, our observations are substantial for physiological and clinical studies of the heartbeat dynamic during daily life and suggest that the nonharmonic component of HRV in normal subjects during daily life may include at least two 1/ f β fluctuations that differ in dynamics and age dependency.
Visceral afferent activation-induced changes in sympathetic nerve activity and baroreflex sensitivity
Authors: Saleh Tarek M. , Connell Barry J. , Allen Gary V.
Published: December 2017

The following experiments were done to determine whether changes in baroreflex sensitivity evoked by cervical vagus nerve stimulation are due to sympathoexcitation mediated by the parabrachial nucleus. The relative contribution of cardiopulmonary and general gastric afferents within the cervical vagus nerve to the depression in baroreflex sensitivity are also investigated. Male Sprague-Dawley rats anesthetized with thiobutabarbital sodium (50 mg/kg) were instrumented to measure blood pressure and heart rate or for the continuous monitoring of renal sympathetic nerve activity. Baroreflex sensitivity was measured using bolus injections of phenylephrine. Electrical stimulation of the cervical vagus (with or without the aortic depressor nerve) or the abdominal vagus nerve produced a significant increase in renal nerve activity and a decrease in baroreflex sensitivity. Both of these effects were blocked after the microinjection of lidocaine into the parabrachial nucleus before nerve stimulation. Therefore, we conclude that an increase in the activity of cardiac, pulmonary, or general gastric afferents mediated the increased sympathetic output and decreased baroreflex sensitivity via a pathway involving the parabrachial nucleus.
Metabolic and cardiorespiratory responses to hypoxia in fetal sheep: adenosine receptor blockade
Authors: Chau Andrew , Koos Brian J.
Published: December 2017

8-Phenyltheophylline (PT), a potent and specific inhibitor of adenosine receptors, was infused intra-arterially into unanesthetized fetal sheep to determine the role of adenosine in hypoxic inhibition of fetal breathing. PT in normoxic fetuses increased heart rate and the incidence of low-voltage electrocortical activity, rapid eye movements (REM), and breathing. Mean breath amplitude increased by 44%. Hypoxia (preductal arterial[Formula: see text] = 14 Torr) induced a metabolic acidemia, a transient bradycardia, and hypertension while virtually eliminating REM and breathing. PT administration during hypoxia enhanced the metabolic acidemia, blocked the bradycardia and hypertension, increased the incidence of REM and breathing, and elevated mean breath amplitude. The results indicate that 1) adenosine is involved in fetal glycolytic and cardiovascular responses to hypoxia, 2) activation of central adenosine receptors mediates about one-half the inhibitory effects of hypoxia on REM and breathing, and 3) the depression of breathing may critically depend on a hypoxia-induced reduction in phasic REM sleep.
Role of angiotensin II in modulating the hemodynamic effects of nitric oxide synthesis inhibition
Authors: Hernández Isabel , Carbonell Luis F. , Quesada Tomas , Fenoy Francisco J.
Published: December 2017

This study examined the role of ANG II in modulating the increase of hematocrit and vascular permeability that follows nitric oxide (NO) synthesis blockade, that are contributing to the decrease in cardiac index (CI) in conscious, chronically catheterized rats. Pretreatment with losartan attenuated the Nω-nitro-l-arginine methyl ester (l-NAME)-induced increase in total peripheral resistance by 26% and also blunted the fall in CI (28%) and stroke volume. l-NAME produced an increase in hematocrit (4.5%) and in125I-labeled albumin content in the heart and small intestine in untreated rats, but the increase was prevented in rats pretreated with losartan. Furthermore, l-NAME induced a transient increase of plasma protein concentration and tissue intestinal blood flow, which was abolished in rats given losartan. The results of the present study indicate that the systemic hemodynamic responses, the fall in plasma volume, and the increase in albumin escape observed after inhibition of NO synthesis are in part the consequence of unmasking the actions of endogenous ANG II. These data suggest a physiological role for NO by restraint of the vascular actions of the renin-angiotensin system.
Neuronal uptake affects dynamic characteristics of heart rate response to sympathetic stimulation
Authors: Nakahara Tsutomu , Kawada Toru , Sugimachi Masaru , Miyano Hiroshi , Sato Takayuki , Shishido Toshiaki , Yoshimura Ryoichi , Miyashita Hiroshi , Inagaki Masashi , Alexander Joe , Sunagawa Kenji
Published: December 2017

Recently, studies in our laboratory involving the use of a Gaussian white noise technique demonstrated that the transfer function from sympathetic stimulation frequency to heart rate (HR) response showed dynamic characteristics of a second-order low-pass filter. However, determinants for the characteristics remain to be established. We examined the effect of an increase in mean sympathetic stimulation frequency and that of a blockade of the neuronal uptake mechanism on the transfer function in anesthetized rabbits. We found that increasing mean sympathetic stimulation frequency from 1 to 4 Hz significantly ( P < 0.01) decreased the dynamic gain of the transfer function without affecting other parameters, such as the natural frequency, lag time, or damping coefficient. In contrast, the administration of desipramine (0.3 mg/kg iv), a neuronal uptake blocking agent, significantly ( P < 0.01) decreased both the dynamic gain and the natural frequency and prolonged the lag time. These results suggest that the removal rate of norepinephrine at the neuroeffector junction, rather than the amount of available norepinephrine, plays an important role in determining the low-pass filter characteristics of the HR response to sympathetic stimulation.
Intracerebroventricular infusion of angiotensin II increases water and ethanol intake in rats
Authors: Weisinger R. S. , Blair-West J. R. , Burns P. , Denton D. A.
Published: December 2017

The influence of prolonged ingestion of ethanol on stimulation of water or ethanol intake by intracerebroventricular infusion of ANG II was evaluated in rats. Animals were maintained for 5–6 mo with either 10% ethanol solution or water as their only source of fluid. In both groups of rats, infusion of ANG II caused a large increase in water intake (7-fold) and a lesser increase in 10% ethanol intake (2-fold). The effect of ANG II on the volume of ethanol solution ingested, however, was inversely related to the concentration of the ethanol solution. As the concentration of ethanol solution was decreased, frequency and duration of drinking bouts increased. The intake of sweetened 10% ethanol solution or commercially produced wine during infusion of ANG II was similar to the intake of 10% ethanol and not related to taste preference. In conclusion, chronic consumption of ethanol solution did not appear to adversely effect ANG II stimulation of water intake. The intake of ethanol solution during infusion of ANG II was inhibited by a direct effect of ingested ethanol and/or by indirect effect from metabolized ethanol.
Nitric oxide differentially attenuates microvessel response to hypoxia and hypercapnia in injured lungs
Authors: Naoki Katsuhiko , Yamaguchi Kazuhiro , Suzuki Koichi , Kudo Hiroyasu , Nishio Kazumi , Sato Nagato , Takeshita Kei , Suzuki Yukio , Tsumura Harukuni
Published: December 2017

The issue of whether the acinar microvessel response to alveolar hypoxia and hypercapnia is impaired in injured lungs has not been vigorously addressed, despite the importance of knowing whether it is or not when treating patients with serious lung injury in terms of permissive hypercapnia. Applying a real-time laser confocal luminescence microscope, we studied hypoxia- and hypercapnia-induced changes in the diameter of the intra-acinar arterioles, venules, and capillaries of isolated rat lungs harvested from animals exposed for 48 h to 21% O2 ( group N) or 90% O2 ( group H). Measurements were made with and without inhibition of nitric oxide (NO) synthase (NOS) by N ω-nitro-l-arginine methyl ester or of cyclooxygenase (COX) by indomethacin at different basal vascular tones evoked by thromboxane A2(TXA2) analog. Hypoxia in the absence of TXA2 contracted arterioles in group N but not in group H. Attenuated hypoxia-induced arteriole constriction was restored almost fully by inhibiting NOS and partially by inhibiting COX. Hypercapnia induced venule dilation in group N, but did not dilate venules in group H, irrespective of TXA2. NOS inhibition in hypercapnia unexpectedly enhanced venule and arteriole dilation in group H. These responses no longer occurred when NOS and COX were inhibited simultaneously. In conclusion, microvessel reactions to hypoxia and hypercapnia are abnormal in hyperoxia-injured acini, in which NO directly attenuates hypoxia-induced arteriole constriction, whereas COX inhibited by excessive NO impedes hypercapnia-induced microvessel dilation.
Transmural pressure inhibits prorenin processing in juxtaglomerular cell
Authors: Ichihara Atsuhiro , Suzuki Hiromichi , Miyashita Yutaka , Naitoh Mareo , Hayashi Matsuhiko , Saruta Takao
Published: December 2017

Pressure control of renin secretion involves a complex integration of shear stress, stretch, and transmural pressure (TP). This study was designed to delineate TP control of renin secretion with minimal influence of shear stress or stretch and to determine its mechanism. Rat juxtaglomerular (JG) cells were applied to a TP-loading apparatus for 12 h. In cells conditioned with atmospheric pressure or atmospheric pressure + 40 mmHg, renin secretion rate (RSR) averaged 29.6 ± 3.7 and 14.5 ± 3.3% ( P < 0.05, n = 8 cultures), respectively, and active renin content (ARC) averaged 47.3 ± 4.6 and 38.4 ± 3.4 ng of ANG I ⋅ h−1⋅ million cells−1( P < 0.05, n = 10 cultures), respectively. Total renin content and renin mRNA levels were unaffected by TP. The TP-induced decrease in RSR was prevented by Ca2+-free medium and the Ca2+channel blocker verapamil and was attenuated by thapsigargin and caffeine, which deplete intracellular Ca2+stores. Thapsigargin and caffeine, but not Ca2+-free medium or verapamil, prevented TP-induced decreases in ARC. The adenylate cyclase activator forskolin did not modulate TP-induced decreases in RSR or ARC. These findings suggest that TP not only stimulates Ca2+influx but also inhibits prorenin processing through an intracellular Ca2+store-dependent mechanism and thus inhibits active renin secretion by JG cells.
Regulatory response of intramembranous absorption of amniotic fluid to infusion of exogenous fluid in sheep
Authors: Faber J. Job , Anderson Debra F.
Published: December 2017

Six fetal sheep were operated on at 118 to 121 days of gestation. The pulmonary end of the trachea was connected to the gastric end of the esophagus with a section of tubing. This left urine as the only source of amniotic fluid and intramembranous absorption as sole exit. Multiple indwelling fetal vascular, intra-amniotic, allantoic, and a fetal bladder catheter were placed. Beginning 5 days after surgery, all urine was drained from the bladder and immediately reinfused into the amniotic sac to monitor urine production rate. After 4 days of urine infusion alone, the urine infusion was augmented for 6 days with an intra-amniotic infusion of Ringer solution. Amniotic and allantoic fluid volumes were measured at autopsy. During the period of Ringer infusion, intramembranous absorption of amniotic fluid increased by more than 1,191 ± 186 (SE) ml/day ( P < 0.002) and the rates of Na+ and Cl− absorption increased to more than five times ( P < 0.005) and eight times ( P < 0.005) their initial values. Only one of six fetuses had polyhydramnios. It is concluded that intramembranous absorption of amniotic fluid makes a strong regulatory adjustment in response to an abnormal increase in inflow of exogenous fluid.
Large-magnitude, transient, bradycardic events in rabbits
Authors: Roach Daniel , Thakore Ela , Sheldon Robert S.
Published: December 2017

We propose that heart period sequences are organized similarly to sentences, with a lexicon of recurrent, similarly shaped words. These words should fulfill four criteria: universality, nonrandomness, central statistical tendencies, and specific associated physiology. Here we describe a large-magnitude, transient bradycardia (LMTB) and assess whether it constitutes a word. LMTBs were seen in 11 of 12 adult female rabbits. All shape parameters were different than those of the beat-randomized and phase-randomized surrogate sequences ( P < 0.05–0.001). LMTBs were 8.4 ± 2.9 beats and 2.64 ± 0.87 s long and were characterized by bradycardia of 77 ± 49 ms over 1.09 ± 0.49 s with a recovery to baseline over 1.56 ± 0.61 s. The LMTBs had a slower recovery than onset in 9 of 11 rabbits and were highly peaked in 10 of 11 rabbits ( P< 0.05). Scalar, magnitude, and shape parameters had values with central statistical tendencies. About 76% of LMTBs were accompanied by hypotension (mean −6.1 ± 3.9 mmHg) that lagged 2 beats behind the onset of the bradycardia and that correlated with the bradycardia (−10.5 ± 4.1 ms/mmHg). Thus transient bradycardic events are a distinct “word” in the lexicon of heart rate variability.
Effects of dorsomedial hypothalamic nuclei lesions on intake of an imbalanced amino acid diet
Authors: Bellinger Larry L. , Evans James F. , Tillberg Connie M. , Gietzen Dorothy W.
Published: December 2017

Within 3 h of ingesting an imbalanced amino acid diet (Imb), rats show attenuated intake, which can be ameliorated by prior administration of the serotonin receptor antagonist tropisetron (Trop). Earlier work in which the dorsomedial hypothalamic nucleus (DMN) was electrolytically lesioned (DMNL) determined that this structure plays a role in the early detection of and subsequent adaptation to Imb. However, that study did not address whether cell bodies in the DMN, fibers of passage, or both were involved in the DMNL response to Imb. In the present investigation in experiment 1, rats were given electrolytic DMNL or a sham operation (Sham). The rats were injected with saline (Sal) or Trop just before introduction of Imb. By 3 h Sal-DMNL rats consumed more Imb than did the Sal-Sham rats; intake was normal by 12 h. Trop enhanced Imb intake, with Trop and DMNL being additive. By day 4the DMNL rats were eating and gaining weight less than were Sham rats. In experiment 2, DMN cell bodies were destroyed by ibotenic acid (Ibo). Sal-injected Ibo-lesioned and Sham rats showed similar food intake depression on Imb; Trop similarly increased Imb intake in both groups. By day 4 both Ibo-L rats were eating and gaining weight less than were Sham rats. In experiment 3, groups of rats were given knife cuts posterior, lateral, ventral, dorsal, or anterior to the DMN. During the first 3 h of consuming Imb, all cuts except posterior enhanced the intake of Imb. Over the next 24 h the anterior cut group continued to eat more Imb than did the Sham rats. In experiment 4 DMNL rats were given novel diets; the DMNL rats did not display a neophilic response. The data suggest that fiber tracts that pass through the DMN may be involved in the early detection of Imb. DMN cell bodies, or fibers of passage, are not involved in the Trop effect. Finally, DMN cell bodies are necessary for proper long-term adaptation to Imb.
Myocardial blood flow and coronary reserve in chronically anemic fetal lambs
Authors: Davis Lowell E. , Hohimer A. Roger , Morton Mark J.
Published: December 2017

Chronic fetal anemia produces large compensatory increases in coronary blood flow in the near-term fetal lamb. To determine if increased coronary flow in anemic fetuses is associated with decreased coronary flow reserve or, alternatively, an increase in coronary conductance, we measured maximal coronary artery conductance during adenosine infusion before and during anemia. Isovolemic hemorrhage over 7 days reduced hematocrit from 30.6 ± 2.7 to 15.8 ± 2.4% ( P < 0.02) and the oxygen content from 7.3 ± 1.4 to 2.6 ± 0.4 ml/dl ( P < 0.001). Coronary blood flow increased from control (202 ± 60) to 664 ± 208 ml ⋅ min−1⋅ 100 g−1with adenosine to 726 ± 169 ml ⋅ min−1⋅ 100 g−1during anemia and to 1,162 ± 250 ml ⋅ min−1⋅ 100 g−1(left ventricle) during anemia with adenosine infusion (all P< 0.001). Coronary conductance, determined during maximal vasodilation, was 18.2 ± 7.7 before and 32.8 ± 11.9 ml ⋅ min−1⋅ 100 g−1⋅ mmHg−1during anemia ( P < 0.001). Coronary reserve, the difference between resting and maximal myocardial blood flow interpolated at 40 mmHg, was unchanged in control and anemic fetuses (368 ± 142 and 372 ± 201 ml/min). Because hematocrit affects viscosity, anemic fetuses were transfused with blood to acutely increase the hematocrit back to control, and conductance was remeasured. Coronary blood flow decreased 57.3 ± 18.9% but was still 42.6 ± 18.9% greater than control. We conclude that in chronically anemic fetal sheep coronary conductance is increased and coronary reserve is maintained, and this is attributed in part to angiogenesis as well as changes in viscosity.
Hemodynamic responses to electrical stimulation of the aortic depressor nerve in awake rats
Authors: Paula Patrícia M. De , Castania Jaci A. , Bonagamba Leni G. H. , Salgado Hélio C. , Machado Benedito H.
Published: December 2017

Changes in mean arterial pressure (MAP), heart rate (HR), and vascular resistance (hindquarter and mesenteric territories) in response to electrical stimulation (ES) of the aortic depressor nerve (ADN) were evaluated in conscious freely moving rats. Platinum electrodes were implanted into the ADN of all rats studied, and some of these animals were also implanted with miniaturized Doppler probes around the superior mesenteric artery and inferior abdominal aorta (hindquarter). In both groups, the femoral artery and vein were catheterized one day before the experiments. In the first group of rats ( n = 7), the control ES of the ADN in the range from 0.5 to 3.0 V (50 Hz, 10 ms) produced bradycardia and hypotension in an intensity-dependent manner, and treatment with methylatropine (intravenously) blocked the bradycardia but produced no significant changes in the hypotensive response. In a second group ( n = 6), ES of the ADN was performed with the intensity fixed at 3 V and the frequency of the stimuli varying from 10 to 50 Hz. In this group, the hypotensive response was frequency dependent, whereas the bradycardic response was not. In a third group of rats ( n = 6), ES of the ADN (2.5 V) produced hypotension (−35 ± 4 mmHg), minor changes in the mesenteric (+5 ± 14%), and vasodilation in hindquarter (−32 ± 6%) vascular beds. The data show that 1) ES of the ADN produces a fall in pressure, bradycardia, vasodilation in the hindquarter, and no changes in the mesenteric vascular resistance, 2) methylatropine blocked the bradycardia and produced no effect on the hypotensive response to ES of the ADN, and 3) the baroreceptor afferent fibers involved in the hypotensive response to ES of ADN are sensitive to the variation of the frequency of the stimuli, whereas the fibers involved in the bradycardic response are not.
Effects on regional brain metabolism of high-altitude hypoxia: a study of six US marines
Authors: Hochachka P. W. , Clark C. M. , Matheson G. O. , Brown W. D. , Stone C. K. , Nickles R. J. , Holden J. E.
Published: December 2017

Previous studies of brain glucose metabolism in people indigenous to high-altitude environments uncovered two response patterns: Quechuas native to the high Andes of South America sustained modest hypometabolism in most brain regions interrogated, whereas Sherpas, native to the Himalayas and considered by many biologists to be most effectively high-altitude adapted of all humans, showed brain metabolic patterns similar to lowlanders, with no acclimation effects noted. In the present study, the database was expanded to include hypoxia acclimation effects in lowlanders. Positron emission tomography (PET) and [18F]-2-deoxy-2-fluro- D-glucose (FDG) imaging techniques were used to assess regional cerebral glucose metabolic rates (rCMRglc) in six US marines (Caucasian lineage) before and after a 63-day training program for operations at high altitudes ranging from 10,500 to 20,320 ft. Significant changes in rCMRglcwere found for 7 of 25 brain regions examined. Significant decreases in absolute cerebral glucose metabolism after high-altitude exposure were found in five regions: three frontal, the left occipital lobe, and the right thalamus. In contrast, for the right and left cerebellum significant increases in metabolism were found. The magnitudes of these differences, in terms of absolute metabolism, were large, ranging from 10 to 18%. Although the results may not be solely the result of lower oxygen levels at high altitude, these findings suggest that the brain of healthy human lowlanders responds to chronic hypoxia exposure with precise, region-specific fine tuning of rCMRglc. The observed short-term hypoxia acclimation responses in these lowlanders clearly differ from the long-term hypoxia adaptations found in brain metabolism of people indigenous to high-altitude environments.
ACE inhibition and glucose transport in insulinresistant muscle: roles of bradykinin and nitric oxide
Authors: Henriksen Erik J. , Jacob Stephan , Kinnick Tyson R. , Youngblood Erik B. , Schmit Melanie B. , Dietze Guenther J.
Published: December 2017

Acute administration of the angiotensin-converting enzyme (ACE) inhibitor captopril enhances insulin-stimulated glucose transport activity in skeletal muscle of the insulin-resistant obese Zucker rat. The present study was designed to assess whether this effect is mediated by an increase in the nonapeptide bradykinin (BK), by a decrease in action of ANG II, or both. Obese Zucker rats (8–9 wk old) were treated for 2 h with either captopril (50 mg/kg orally), bradykinin (200 μg/kg ip), or the ANG II receptor (AT1 subtype) antagonist eprosartan (20 mg/kg orally). Captopril treatment enhanced in vitro insulin-stimulated (2 mU/ml) 2-deoxyglucose uptake in the epitrochlearis muscle by 22% (251 ± 7 vs. 205 ± 9 pmol ⋅ mg−1 ⋅ 20 min−1; P < 0.05), whereas BK treatment enhanced this variable by 18% (249 ± 15 vs. 215 ± 7 pmol ⋅ mg−1 ⋅ 20 min−1; P < 0.05). Eprosartan did not significantly modify insulin action. The BK-mediated increase in insulin action was completely abolished by pretreatment with either the specific BK-B2 receptor antagonist HOE 140 (200 μg/kg ip) or the nitric oxide synthase inhibitor N ω-nitro-l-arginine methyl ester (50 mg/kg ip). Collectively, these results indicate that the modulation of insulin action by BK likely underlies the metabolic effects of ACE inhibitors in the insulin-resistant obese Zucker rat. Moreover, this modulation of insulin action by BK is likely mediated through B2 receptors and by an increase in nitric oxide production and/or action in skeletal muscle tissue.
Volume expansion does not activate neuronal projections from the NTS or depressor VLM to the RVLM
Authors: Shafton Anthony D. , Ryan Andrew , McGrath Barry , Badoer Emilio
Published: December 2017

We investigated whether a monosynaptic connection from the nucleus tractus solitarius (NTS) or the depressor ventrolateral medulla (VLM) to the pressor region of the rostral VLM (RVLM) constituted part of the reflex pathway activated by cardiopulmonary baroreceptors. Volume expansion in the conscious rabbit, which elicits renal nerve inhibition predominantly via cardiac mechanoreceptors, was used as the stimulus. The protein Fos was used as a marker of neuronal activation. The retrogradely transported tracer rhodamine-tagged microspheres, previously injected into the pressor region of the RVLM, identified medullary neurons that projected to that region. Volume expansion significantly increased the number of Fos-positive cell nuclei in the NTS and in the depressor VLM. Neurons that projected to the RVLM were found throughout the depressor region of the VLM and in the NTS but were not activated by volume expansion. Thus, although the central reflex pathways activated by volume expansion include the NTS and the depressor region of the VLM, we could not find evidence for a monosynaptic connection between those regions and the RVLM.
Fos-like immunoreactivity in the brain stem following oral quinine stimulation in decerebrate rats
Authors: Travers Joseph B. , Urbanek Kevin , Grill Harvey J.
Published: December 2017

The present study compared the distribution of Fos-like immunoreactivity (FLI) following intraoral stimulation with quinine monohydrochloride (QHCl) in awake intact rats to the pattern obtained in chronic supracollicular decerebrate (CD) rats. Because the behavioral rejection response to QHCl is evident in the CD rat, it was hypothesized that the pattern of FLI in the lower brain stem should be similar in both groups. Overall, the distribution of FLI in the brain stem was quite similar in both intact and CD groups, and QHCl stimulation increased FLI in the rostral (gustatory) nucleus of the solitary tract, the parabrachial nucleus (PBN), and the lateral reticular formation (RF) compared with an unstimulated control group. The CD group differed from the intact group, however, with a trend toward less FLI in the RF and a shift in the pattern of label away from the external subdivision of the PBN. CD rats also had increased FLI in the caudal nucleus of the solitary tract, with or without intraoral infusions. The distribution of QHCl-induced FLI in the brain stem of intact rats thus indicates both local sensorimotor processing as well as the influence of forebrain structures.
Renal responses to prolonged (48 h) hypoxemia without acidemia in the late-gestation ovine fetus
Authors: Braaksma Margriethe A. , Dassel A. Carin M. , Aarnoudse Jan G.
Published: December 2017

The effect of sustained moderate hypoxia on renal blood flow and renal function was studied in the ovine fetus (123–129 days). The experiments consisted of 48 h of isocapnic hypoxia, not resulting in acidemia, but sufficient to produce redistribution of blood flow in favor of the brain at the expense of the carcass. Hypoxemia was induced by maternal nitrogen inhalation. Fetal arterial O2 saturation and arterial O2 pressure ([Formula: see text]) decreased from, respectively, 50.6 ± 3.0% and 17.2 ± 0.9 mmHg during control to 36.4 ± 2.7% and 13.4 ± 0.7 mmHg on the first and to 32.2 ± 2.2% and 12.4 ± 0.7 mmHg on the second day of hypoxemia. Fetal renal blood flow and urine production rate were continuously measured using ultrasonic flow transducers. Fetal renal blood flow increased during hypoxemia from 11.8 ± 1.6 to 15.6 ± 1.8 ml/min and remained elevated throughout the 48-h hypoxemia period ( P < 0.01). Renal blood flow was inversely correlated with fetal [Formula: see text]( r is −0.69, P < 0.0001). Fetal urine production rate, glomerular filtration rate, filtration factor, osmotic clearance, and free water clearance did not significantly change from control values during hypoxemia or recovery. We conclude that hypoxemia without acidemia results in an immediate and considerable increase in fetal renal blood flow, which remains elevated for the entire hypoxemic period.
Quantification of conversion and degradation of circulating angiotensin in rats
Authors: Bauer Johannes , Berthold Heike , Schaefer Franz , Ehmke Heimo , Parekh Niranjan
Published: December 2017

The aim of the present study was to quantify with a uniform technique the rates of conversion of ANG I to ANG II in the lung and kidney and the degradation of both peptides to biologically inactive products in the pulmonary, renal, and systemic circulation. We infused the peptides intravenously, into the left ventricle, and into the left renal artery of rats and compared their effects on renal blood flow. The measured change in renal blood flow was used as a bioassay parameter to estimate the concentration of circulating ANG II. Mathematical analysis of our data allowed us to calculate conversion and degradation rates. Furthermore, the role of aminopeptidases A (EC 3.4.11.7 ) and N (EC 3.4.11.2 ) in the degradation of the peptides in the kidney was investigated by intrarenal infusion of the inhibitor amastatin. Our results show that the conversion rate of ANG I is 75% in the pulmonary and 21% in the renal circulation. Both peptides are degraded by 5% in the pulmonary, by 67% in the systemic, and by 93% in the renal circulation. Amastatin prevented 60% of the renal degradation of the peptides to inactive products, and this effect could be attributed to inhibition of aminopeptidase N. The results indicate that the converting capacity of the kidney is of minor importance for endocrine generation of ANG II but could be useful for the paracrine production.
Lack of vasopressin-independent upregulation of AQP-2 gene expression in homozygous Brattleboro rats
Authors: Saito Takako , Ishikawa San-E , Sasaki Sei , Higashiyama Minori , Nagasaka Shoichiro , Fujita Nobuya , Fushimi Kiyohide , Marumo Fumiaki , Saito Toshikazu
Published: December 2017

Arginine vasopressin (AVP) plays an important role in the expression of aquaporin (AQP-2) in the collecting duct. The present study was undertaken to determine whether there is an AVP-independent regulation of AQP-2 gene expression in homozygous Brattleboro rats in which endogenous AVP is absent. Exogenous administration of 1-deamino-8-d-AVP produced an antidiuresis and expressed AQP-2 mRNA and AQP-2 protein in the renal medulla of the homozygous Brattleboro rats. Twelve hours of water deprivation produced severe dehydration in the homozygous Brattleboro rats, such that urinary osmolality increased from 200 to 649 mosmol/kgH2O. However, no increase in AQP-2 mRNA expression was observed after this dehydration, and the medullary tissue content and urinary excretion of AQP-2 also remained unchanged. Increases in AQP-2 mRNA expression and AQP-2 protein were evident in Long-Evans rats after 64 h of water deprivation, with a severity of dehydration almost equal to the 12-h dehydrated, homozygous Brattleboro rats. These results indicate the lack of an AVP-independent mechanism for upregulating AQP-2 mRNA expression in renal collecting duct cells.
Modulation of triglyceride metabolism by glucocorticoids in diet-induced obesity
Authors: Mantha Line , Palacios Elena , Deshaies Yves
Published: December 2017

The involvement of glucocorticoids (GC) in the development of diet-induced obesity and in the concomitant adaptations of triglyceride (TG)-rich lipoprotein metabolism were examined. Rats were fed either rodent chow, which maintains a low lipid flux, or a diet high in sucrose and fat (HSF) that increases lipid flux, leading to metabolic perturbations similar to those that define the plurimetabolic syndrome in humans. The GC status was manipulated through adrenalectomy (ADX) and corticosterone (Cort) replacement. Compared with chow, the HSF diet increased energy intake (17%) and whole body (8%) and adipose tissue (80%) weights. The HSF diet also increased the acute postprandial rise in plasma insulin (4-fold) and TG (3-fold), fasting liver TG content (3-fold), triglyceridemia (54%), and adipose tissue lipoprotein lipase (LPL) activity (2-fold). ADX decreased energy intake and whole body and adipose tissue weights in both dietary cohorts, but more so in HSF-fed than in chow-fed animals. These ADX-induced effects were totally prevented by Cort replacement in rats fed chow, but only partially so in those fed the HSF diet in proportion to the degree of restoration of energy intake. In the chow-fed cohort, the above indexes of TG metabolism remained unaffected by the Cort status, whereas in the HSF-fed cohort, these variables were decreased by ADX to levels of chow-fed animals. Cort replacement in the HSF-fed animals restored indexes of TG metabolism to intact levels and reestablished the diet-related differences observed in intact animals. These findings indicate that GC modulate fasting TG metabolism only minimally when a diet that maintains a low lipid flux is fed. In contrast, their presence is a necessary condition for the development of diet-induced obesity and the concomitant alterations in insulin sensitivity and TG-rich lipoprotein metabolism.
Renal responses of trout to chronic respiratory and metabolic acidoses and metabolic alkalosis
Authors: Wood Chris M. , Milligan C. Louise , Walsh Patrick J.
Published: December 2017

Exposure to hyperoxia (500–600 torr) or low pH (4.5) for 72 h or NaHCO3infusion for 48 h were used to create chronic respiratory (RA) or metabolic acidosis (MA) or metabolic alkalosis in freshwater rainbow trout. During alkalosis, urine pH increased, and [titratable acidity (TA) −[Formula: see text]] and net H+excretion became negative (net base excretion) with unchanged [Formula: see text] efflux. During RA, urine pH did not change, but net H+excretion increased as a result of a modest rise in [Formula: see text] and substantial elevation in [TA −[Formula: see text]] efflux accompanied by a large increase in inorganic phosphate excretion. However, during MA, urine pH fell, and net H+excretion was 3.3-fold greater than during RA, reflecting a similar increase in [TA −[Formula: see text]] and a smaller elevation in phosphate but a sevenfold greater increase in[Formula: see text] efflux. In urine samples of the same pH, [TA − [Formula: see text]] was greater during RA (reflecting phosphate secretion), and[Formula: see text] was greater during MA (reflecting renal ammoniagenesis). Renal activities of potential ammoniagenic enzymes (phosphate-dependent glutaminase, glutamate dehydrogenase, α-ketoglutarate dehydrogenase, alanine aminotransferase, phospho enolpyruvate carboxykinase) and plasma levels of cortisol, phosphate, ammonia, and most amino acids (including glutamine and alanine) increased during MA but not during RA, when only alanine aminotransferase increased. The differential responses to RA vs. MA parallel those in mammals; in fish they may be keyed to activation of phosphate secretion by RA and cortisol mobilization by MA.
Carbon monoxide as a novel mediator of the febrile response in the central nervous system
Authors: Steiner Alexandre A. , Colombari Eduardo , Branco Luiz G. S.
Published: December 2017

Heme oxygenase catalyzes the metabolism of heme to biliverdin, free iron, and carbon monoxide (CO), which has been shown to be an important neuromodulatory agent. Recently, it has been demonstrated that lipopolysaccharide (LPS) can induce the enzyme heme oxygenase in glial cells. Therefore, the present study was designed to test the hypothesis that central CO plays a role in LPS-induced fever. Colonic body temperature (Tb) was measured in awake, unrestrained rats (basal Tb= 36.8 ± 0.2°C). Intracerebroventricular injection of zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG; 75 nmol), a heme oxygenase inhibitor, caused no significant change in Tb, indicating that the central heme oxygenase pathway plays no tonic role in Tbunder the experimental conditions used. Intraperitoneal injections of LPS (50–100 μg/kg) evoked dose-dependent increases in Tb. Intracerebroventricular injection of ZnDPBG in febrile rats attenuated LPS-induced fever (thermal index with ZnDPBG = 1.1 ± 0.2°C, thermal index with vehicle = 2.3 ± 0.4°C), suggesting that the central heme oxygenase pathway plays a role in fever generation. The antipyretic effect of ZnDPBG could be reversed by intracerebroventricular administration of heme-lysinate or CO-saturated saline. Collectively, our data indicate that CO arising from heme oxygenase may play an important role in fever generation by acting on the central nervous system.
Chloride cell subtypes in the gill epithelium of Japanese eelAnguilla japonica
Authors: Wong Chris K. C. , Chan D. K. O.
Published: December 2017

The purpose of the present study was to characterize chloride cell subtypes in the fish gill and to monitor the kinetic change of cell division in the gill epithelia during seawater adaptation. Employing a three-step Percoll gradient method, the gill chloride cells and nonchloride cell population were isolated. The isolated cells were studied using multiparameter flow cytometry, recording the changes in 1) cell size, 2) cellular granularity, and 3) cell autofluorescence. Two chloride cell subtypes were identified in the freshwater eels. Within 2–4 days after entering seawater, new subtypes of transitory chloride cell, with bigger cell size and more intense mitochondria autofluorescence, appeared. After full adaptation, two major seawater chloride cell subtypes were again discerned; their sizes were the largest and their mitochondria autofluorescence was the highest. In the second part of the experiment, cell cycle analysis demonstrated a progressive increase in the percentage of gill cells entering the DNA synthesis phase during seawater adaptation, where a small population of mitotic cells was identified in the nonchloride cell population but not in chloride cells. We hypothesize that the mitotic cells identified are stem cells, which will ultimately differentiate into seawater chloride cells. Our results confirm the existence of heterogeneity of chloride cells. Individual subtypes could be isolated in high purity for further studies to elucidate their respective function in mediating ion transport.
Locomotor and feeding activity rhythms in a light-entrained diurnal rodent, Octodon degus
Authors: García-Allegue R. , Lax P. , Madariaga A. M. , Madrid J. A.
Published: December 2017

The wheel running (WR) and feeding activity (FA) of Octodon degus, a new laboratory rodent characterized by its diurnal habits, were recorded under different lighting conditions. Under 12:12-h light-dark (LD 12:12) cycles, WR activity exhibited a crepuscular pattern with two peaks, M and E, associated with “dawn” and “dusk,” respectively. In both cases, an anticipatory activity was patent, suggesting that, beside the masking effect of LD transitions, both peaks have an endogenous origin. This pattern, which was also observed under a skeleton photoperiod (LD 0.5:11.5), became unimodal after LD 0.5:23.5 and constant darkness (DD) exposure. Simultaneously, FA showed an arrhythmic pattern in most animals, especially under DD, when none of the animals exhibited a significant circadian rhythm. The existence of two groups of oscillators, or two oscillators, would explain most properties of the WR rhythms noted in this species. Our results show that the degu’s temporal feeding strategy seems mainly arrhythmic, whereas its WR pattern is driven by a strongly circadian bimodal rhythm.
Pressure-dependent renin release: effects of sodium intake and changes of total body sodium
Authors: Seeliger Erdmann , Lohmann Katrin , Nafz Benno , Persson Pontus B. , Reinhardt H. Wolfgang
Published: December 2017

The impact of sodium intake and changes in total body sodium (TBS) for the setting of pressure-dependent renin release (PDRR) was studied in freely moving dogs. An aortic cuff allowed servo control of renal perfusion pressure (RPP) at preset values. Protocols were 1) high sodium intake (HSI), 2) low sodium intake (LSI), 3) TBS moderately increased (+3.1 mmol Na/kg body wt) by 20% reduction of RPP for 2–4 days, 4) large increase of TBS (+8.2) by combining protocol 3 with aldosterone infusion, and 5) TBS reduced (−3.1) by peritoneal dialyses. Twenty-four-hour time courses of arterial plasma renin activity (PRA) revealed that LSI increased PRA for the first 10 h only; afterward PRA did not differ between LSI and HSI. Reduced TBS increased PRA constantly, and the large increase of TBS constantly reduced PRA. PDRR stimulus-response curves (assessed 20 h after last sodium intake) revealed an exponential relationship in each protocol. PDRR was not changed by different sodium intake. Conversely, reduced TBS increased PDRR markedly, whereas the large increase of TBS suppressed it. Thus an inverse relationship between TBS and PRA, i.e., a TBS-dependent renin release, was found. This relationship was enhanced by decreasing RPP. This interplay between TBS-dependent renin release and PDRR allows the organism a differentiated reaction to changes in TBS and arterial pressure.
Glycine-extended gastrin regulates HEK cell growth
Authors: Stepan Vinzenz M. , Krametter Dieter F. , Matsushima Masashi , Todisco Andrea , Delvalle John , Dickinson Chris J.
Published: December 2017

Posttranslational processing of progastrin to a carboxy terminally amidated form (G-NH2) is essential for its effect on gastric acid secretion and other biological effects mediated by gastrin/CCK-B receptors. The immediate biosynthetic precursor of G-NH2, glycine-extended gastrin (G-Gly), does not stimulate gastric acid secretion at physiological concentrations but is found in high concentrations during development. G-NH2and G-Gly have potent growth stimulatory effects on gastrointestinal tissues, and G-NH2can stimulate proliferation of human kidney cells. Thus we sought to explore the actions of G-NH2and G-Gly on the human embryonic kidney cell line HEK 293. HEK 293 cells showed specific binding sites for125I-labeled Leu15-G17-NH2and125I-Leu15-G2—17-Gly. Both G-NH2and G-Gly induced a dose-dependent increase in [3H]thymidine incorporation, and both peptides together significantly increased [3H]thymidine incorporation above the level of either peptide alone. G-NH2and G-Gly were detected by radioimmunoassay in serum-free conditioned media. Antibodies directed against G-NH2and G-Gly lead to a significant reduction in [3H]thymidine incorporation. G-NH2but not G-Gly increased intracellular Ca2+concentration. We conclude that G-NH2and G-Gly act cooperatively via distinct receptors to stimulate the growth of a nongastrointestinal cell line (HEK 293) in an autocrine fashion.
Duodenal loading with glucose induces Fos expression in rat brain: selective blockade by devazepide
Authors: Wang Lixin , Cardin Sylvain , Martínez Vicente , Taché Yvette , Lloyd K. C. Kent
Published: December 2017

The role of CCK in mediating neuronal activity in the brain in response to dietary carbohydrate was measured by detecting Fos immunoreactivity in response to duodenal glucose load in rats after administration of the CCK-A receptor antagonist devazepide. In adult, male Sprague-Dawley rats, infusion for 30 min of 545 mg (2.18 kcal) dextrose through a duodenal cannula induced Fos expression in the nucleus of the solitary tract (NTS), area postrema (AP), lateral division of the central nucleus of the amygdala (CeAL), and the external subnucleus of the lateral parabrachial nucleus (LPBE). Devazepide treatment (1 mg/kg) attenuated Fos expression in the NTS and AP by 81 and 78%, respectively, but not in the CeAL or LPBE. These results indicate that central neuronal activation is elicited by dietary glucose in the intestinal lumen and that activation of neurons in the NTS and AP is mediated by CCK-A receptors.