bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of hypothermia on neuronal-vascular function after cerebral ischemia in piglets
Authors: Perciaccante James V. , Domoki Ferenc , Puskar Michelle , Busija David W.
Published: March 2015

We determined whether cerebral arteriolar dilation to N-methyl-d-aspartate (NMDA), a response dependent on stimulation of cortical neurons and inhibited by anoxic stress, would be preserved by hypothermia during and following ischemia. Pial arteriolar diameters in anesthetized piglets were determined via intravital microscopy. Arteriolar responses to NMDA (10, 50, and 100 μmol/l) were measured before and 1 h after 10 min of global ischemia. Piglets were exposed to either total body or selective brain cooling (33–34°C). Arteriolar dilation to lower doses or to 100 μmol/l NMDA was not affected by hypothermia alone (51 ± 3 vs. 46 ± 7%, normothermia vs. hypothermia; n = 7) in nonischemic animals. However, arteriolar responses to 100 μmol/l NMDA were clearly attenuated after ischemia despite body cooling during ischemia (53 ± 3 vs. 32 ± 6%; n = 8), hypothermia during ischemia and early reperfusion (49 ± 10 vs. 20 ± 3%; n = 8), or selective brain cooling (48 ± 5 vs. 20 ± 5%; n = 10). In contrast, pretreatment with indomethacin resulted in complete preservation of NMDA-induced vasodilation after ischemia. Thus, hypothermia fails to protect against neuronal dysfunction during ischemia.
Tumor necrosis factor-α inhibits renin gene expression
Authors: Todorov Vladimir , Müller Markus , Schweda Frank , Kurtz Armin
Published: March 2015

Renin, produced in renal juxtaglomerular (JG) cells, is a fundamental regulator of blood pressure. Accumulating evidence suggests that cytokines may directly influence renin production in the JG cells. TNF-α, which is one of the key mediators in immunity and inflammation, is known to participate in the control of vascular proliferation and contraction and hence in the pathogenesis of cardiovascular diseases. Thus TNF-α may exert its effects on the cardiovascular system through modulation of renal renin synthesis. Therefore we have tested the effect of TNF-α on renin transcription in As4.1 cells, which represent transformed mouse JG cells, and in native mouse JG cells in culture. Renin gene expression was also determined in mice lacking the gene for TNF-α (TNF-α knockout mice). TNF-α inhibited renin gene expression via an inhibition of the transcriptional activity, targeting the proximal 4.1 kb of the renin promoter in As4.1 cells. TNF-α also attenuated forskolin-stimulated renin gene expression in primary cultures of mouse JG cells. Mice lacking the TNF-α gene had almost threefold higher basal renal renin mRNA abundance relative to the control strain. The general physiological regulation of renin expression by salt was not disturbed in TNF-α knockout mice. Our data suggest that TNF-α inhibits renin gene transcription at the cellular level and thus may act as a modulator of renin synthesis in (physio)pathological situations.
Decompensated hemorrhage activates serotonergic neurons in the subependymal parapyramidal region of the rat medulla
Authors: Pelaez Nicole M. , Schreihofer Ann M. , Guyenet Patrice G.
Published: March 2015

According to prior evidence opioid and serotonin release by lower brain stem neurons may contribute to hemorrhage-induced sympathoinhibition (HISI). Here we seek direct evidence for the activation of opioidergic, GABAergic, or serotonergic neurons by severe hemorrhage in the medulla oblongata. Blood was withdrawn from awake rats (40–50% total volume) causing hypotension and profound initial bradycardia. Other rats received the vasodilator hydralazine, causing tachycardia and hypotension. Neuronal activation was gauged by the presence of Fos-immunoreactive (ir) nuclei after 2 h. Serotonergic, enkephalinergic, and GABAergic neurons were identified by the presence of a diagnostic enzyme or mRNA. Hemorrhaged rats had 30% fewer non-GABAergic Fos-ir neurons in the rostral ventrolateral medulla (RVLM) than hydralazine-treated rats, but they had six times more Fos-ir neurons within the subependymal parapyramidal nucleus (SEPPN). Fos-labeled SEPPN neurons were serotonergic (40–60%), GABAergic (31%), enkephalinergic (15%), or had mixed phenotypes. The data suggest that a reduced sympathoexcitatory drive from RVLM may contribute to HISI. SEPPN neuronal activation may also contribute to HISI or could mediate defensive thermoregulatory mechanisms triggered by hemorrhage-induced hypothermia.
Interactions of dietary fat and 2,5-anhydro-d-mannitol on energy metabolism in isolated rat hepatocytes
Authors: Ji Hong , Graczyk-Milbrandt Grazyna , Osbakken Mary D. , Friedman Mark I.
Published: March 2015

The fructose analog 2,5-anhydro-d-mannitol (2,5-AM) stimulates feeding in rats by reducing ATP content in the liver. These behavioral and metabolic effects occur with rats fed a high-carbohydrate/low-fat (HC/LF) diet, but they are prevented or attenuated when the animals eat high-fat/low-carbohydrate (HF/LC) food. To examine the metabolic bases for this effect of diet, we assessed the actions of 2,5-AM on ATP content, oxygen consumption, and substrate oxidation in isolated hepatocytes from rats fed one of the two diets. Compared with cells from rats fed the HC/LF diet (“HC/LF” cells), cells from rats fed the HF/LC diet (“HF/LC” cells) had similar ATP contents but lower oxygen consumption, decreased fructose, and increased palmitate oxidation. 2,5-AM did not decrease ATP content or oxygen consumption in HF/LC cells as much as it did in HC/LF hepatocytes, and it only affected fructose and palmitate oxidation in HC/LF cells.31P-NMR spectroscopy indicated that differences in phosphate trapping accounted for differences in depletion of ATP by 2,5-AM. These results suggest that intake of the HF/LC diet prevents the eating response and attenuates the decline in liver ATP by shifting hepatocyte metabolism to favor fat over carbohydrate as an energy-yielding substrate.
Chronic angiotensin II infusion attenuates the renal sympathoinhibitory response to acute volume expansion
Authors: LaGrange Lila P. , Toney Glenn M. , Bishop Vernon S.
Published: March 2015

In this study the hypothesis was tested that chronic infusion of ANG II attenuates acute volume expansion (VE)-induced inhibition of renal sympathetic nerve activity (SNA). Rats received intravenous infusion of either vehicle or ANG II (12 ng · kg−1 · min−1) for 7 days. ANG II-infused animals displayed an increased contribution of SNA to the maintenance of mean arterial pressure (MAP) as indicated by ganglionic blockade, which produced a significantly ( P < 0.01) greater decrease in MAP (75 ± 3 mmHg) than was observed in vehicle-infused (47 ± 8 mmHg) controls. Rats were then anesthetized, and changes in MAP, mean right atrial pressure (MRAP), heart rate (HR), and renal SNA were recorded in response to right atrial infusion of isotonic saline (20% estimated blood volume in 5 min). Baseline MAP, HR, and hematocrit were not different between groups. Likewise, MAP was unchanged by acute VE in vehicle-infused animals, whereas VE induced a significant bradycardia ( P < 0.05) and increase in MRAP ( P < 0.05). MAP, MRAP, and HR responses to VE were not statistically different between animals infused with vehicle vs. ANG II. In contrast, VE significantly ( P < 0.001) reduced renal SNA by 33.5 ± 8% in vehicle-infused animals but was without effect on renal SNA in those infused chronically with ANG II. Acutely administered losartan (3 mg/kg iv) restored VE-induced inhibition of renal SNA ( P < 0.001) in rats chronically infused with ANG II. In contrast, this treatment had no effect in the vehicle-infused group. Therefore, it appears that chronic infusion of ANG II can attenuate VE-induced renal sympathoinhibition through a mechanism requiring AT1 receptor activation. The attenuated sympathoinhibitory response to VE in ANG II-infused animals remained after arterial barodenervation and systemic vasopressin V1receptor antagonism and appeared to depend on ANG II being chronically increased because ANG II given acutely had no effect on VE-induced renal sympathoinhibition.
Brain regions expressing Fos during thermoregulatory behavior in rats
Authors: Maruyama Megumi , Nishi Maiko , Konishi Masahiro , Takashige Yuko , Nagashima Kei , Kiyohara Toshikazu , Kanosue Kazuyuki
Published: March 2015

We surveyed the neural substrata for behavioral thermoregulation with immunohistochemical analysis of the expression of Fos protein in the rat brain. We used an operant system in which a rat exposed to heat (40°C) could get cold air (0°C) for 30 s when it moved into the reward area. Rats moved in and out of the reward area of the system periodically and thus maintained their body temperature at a normal level. In the rats performing heat escape behavior (active group), strong Fos immunoreactivity (Fos-IR) was found in the median preoptic nucleus (MnPO), parastrial nucleus (PS), and dorsomedial hypothalamus (DMH) compared with the controls. Another group of rats (passive group) were given the same temperature changes, regardless of the rat's movement, as those obtained by rats of the active group. Fos-IR in the MnPO was also seen in this group. The present results suggest that the PS and DMH play an important role in the genesis of thermoregulatory behavior, whereas the MnPO may be important for detecting changes in ambient and/or body temperatures.
Artificial selection for high activity favors mighty mini-muscles in house mice
Authors: Houle-Leroy Philippe , Guderley Helga , Swallow John G. , Garland Theodore
Published: March 2015

After 14 generations of selection for voluntary wheel running, mice from the four replicate selected lines ran, on average, twice as many revolutions per day as those from the four unselected control lines. To examine whether the selected lines followed distinct strategies in the correlated responses of the size and metabolic capacities of the hindlimb muscles, we examined mice from selected lines, housed for 8 wk in cages with access to running wheels that were either free to rotate (“wheel access” group) or locked (“sedentary”). Thirteen of twenty individuals in one selected line (line 6) and two of twenty in another (line 3) showed a marked reduction (∼50%) in total hindlimb muscle mass, consistent with the previously described expression of a small-muscle phenotype. Individuals with these “mini-muscles” were not significantly smaller in total body mass compared with line-mates with normal-sized muscles. Access to free wheels did not affect the relative mass of the mini-muscles, but did result in typical mammalian training effects for mitochondrial enzyme activities. Individuals with mini-muscles showed a higher mass-specific muscle aerobic capacity as revealed by the maximal in vitro rates of citrate synthase and cytochrome c oxidase. Moreover, these mice showed the highest activities of hexokinase and carnitine palmitoyl transferase. Females with mini-muscles showed the highest levels of phosphofructokinase, and males with mini-muscles the highest levels of pyruvate dehydrogenase. As shown by total muscle enzyme contents, the increase in mass-specific aerobic capacity almost completely compensated for the reduction caused by the “loss” of muscle mass. Moreover, the mini-muscle mice exhibited the lowest contents of lactate dehydrogenase and glycogen phosphorylase. Interestingly, metabolic capacities of mini-muscled mice resemble those of muscles after endurance training. Overall, our results demonstrate that during selection for voluntary wheel running, distinct adaptive paths that differentially exploit the genetic variation in morphological and physiological traits have been followed.
Glucose acts in the CNS to regulate gastric motility during hypoglycemia
Authors: Shi Min , Jones Allison R. , Niedringhaus Mark S. , Pearson Rebecca J. , Biehl Ann M. , Ferreira Manuel , Sahibzada Niaz , Verbalis Joseph G. , Gillis Richard A.
Published: March 2015

Our purposes were to 1) develop an animal model where intravenously (iv) administered d-glucose consistently inhibited antral motility, and 2) use this model to assess whether iv glucose acts to inhibit motility from a peripheral or a central nervous system site and to elucidate the factor(s) that determine(s) whether stomach motor function is sensitive to changes in blood glucose. Rats were anesthetized with α-chloralose-urethane, and antral motility was measured by a strain-gauge force transducer sutured to the antrum. In some cases, antral motility and gastric tone were measured by monitoring intragastric balloon pressure. Increases in blood glucose were produced by continuous iv infusion of 25% d-glucose at 2 ml/h. Inhibition of antral motility and gastric tone was observed when gastric contractions were induced by hypoglycemia (subcutaneously administered insulin, 2.5 IU/animal). In contrast, no inhibition of gastric motor function was observed when glucose infusion was tested on gastric contractions that were 1) spontaneously occurring, 2) evoked by iv administered bethanechol in vagotomized animals, and 3) evoked by the TRH analog RX77368, microinjected into the dorsal motor nucleus of the vagus. Using the model of insulin-induced hypoglycemia to increase gastric motor activity, we found that neither sectioning the hepatic branch of the vagus ( n = 5), nor treating animals with capsaicin to destroy sensory vagal afferent nerves ( n = 5) affected the ability of iv d-glucose to inhibit gastric motor function. Our results indicate that an important factor determining whether stomach motor function will be sensitive to changes in blood glucose is the method used to stimulate gastric contractions, and that the primary site of the inhibitory action of iv glucose on gastric motility is the central nervous system rather than the periphery.
Changes of carp FoF1-ATPase in association with temperature acclimation
Authors: Itoi Shiro , Kinoshita Shigeharu , Kikuchi Kiyoshi , Watabe Shugo
Published: March 2015

Previously we have shown, using two-dimensional electrophoresis, that mitochondrial ATP synthase (FoF1-ATPase) β-subunit is the 55-kDa protein increased in cold-acclimated carp Cyprinus carpio (Kikuchi K, Itoi S, and Watabe S. Fisheries Sci 65: 629–636, 1999). To clarify the coordinate expression in various subunits of carp FoF1-ATPase with temperature acclimation, we examined the differences in mRNA levels of mitochondrial proteins encoded by both nuclear and mitochondrial genes in fast muscle of carp acclimated to 10 and 30°C. The mRNA levels of nuclear genes per unit weight of total RNA were nearly twofold higher in the 10°C- than 30°C-acclimated carp. However, the transcripts of mitochondrial genes for the 10°C-acclimated carp in terms of the same comparing unit were six to seven times as much as those for the 30°C-acclimated carp. The FoF1-ATPase activities measured at 10, 25, and 30°C were nearly twofold higher for the cold-acclimated fish than their warm-acclimated counterparts. Such quantitative and qualitative changes in carp FoF1-ATPase may contribute to extra ATP production required to compensate for energy balance at suboptimal temperatures.
Physiological control of pituitary hormone secretory-burst mass, frequency, and waveform: a statistical formulation and analysis
Authors: Keenan Daniel M. , Roelfsema Ferdinand , Biermasz Nienke , Veldhuis Johannes D.
Published: March 2015

The present study investigates the time-varying control of pituitary hormone secretion over the day and night (D/N). To this end, we implemented an analytical platform designed to reconstruct simultaneously 1) basal (nonpulsatile) secretion, 2) single or dual secretory-burst waveforms, 3) random effects on burst amplitude, 4) stochastic pulse-renewal properties, 5) biexponential elimination kinetics, and 6) experimental uncertainty. The statistical solution is conditioned on a priori pulse-onset times, which are estimated in the first stage. Primary data composed of thyrotropin (TSH) concentrations were monitored over 24 h in 27 healthy adults. According to statistical criteria, 21/27 profiles favored a dual compared with single secretory-burst waveform. An objectively defined waveform change point (D/N boundary) emerged at 2046 (±23 min), after which 1) the mass of TSH released per burst increases by 2.1-fold ( P < 0.001), 2) TSH secretory-burst frequency rises by 1.2-fold ( P < 0.001), 3) the latency to maximal TSH secretion within a burst decreases by 67% ( P < 0.001), 4) variability in secretory-burst shape diminishes by 50% ( P < 0.001), and 5) basal TSH secretion declines by 17% ( P < 0.002). In contrast, the regularity of successive burst times and the slow-phase half-life are stable. In conclusion, nycthemeral mechanisms govern TSH secretory-burst mass, frequency, waveform, and variability but not evidently TSH elimination kinetics or the pulse-timing process. Further studies will be required to assess the generality of the foregoing distinctive control mechanisms in other hypothalamo-pituitary axes.
Effects of sodium intake on cardiovascular variables in humans during posture changes and ambulatory conditions
Authors: Damgaard Morten , Gabrielsen Anders , Heer Martina , Warberg Jørgen , Bie Peter , Christensen Niels Juel , Norsk Peter
Published: March 2015

The hypothesis was tested that cardiac output (CO) and stroke volume (SV) are increased by a moderate physiological elevation in sodium intake with a more pronounced effect in the ambulatory upright seated than supine position. Fourteen healthy males were investigated during ambulatory and controlled laboratory conditions at the end of two consecutive 5-day periods with sodium intakes of 70 (low) and 250 (high) mmol/24 h or vice versa, respectively. Comparing high and low sodium intake, plasma volume and plasma protein concentrations were 9 and 8% higher in the seated and the supine position, respectively. When seated during laboratory conditions, CO was 5.3 ± 0.2 l/min on the high sodium intake vs. 4.8 ± 0.2 l/min on the low ( P < 0.05), and SV was 81 ± 3 vs. 68 ± 3 ml ( P< 0.05). In the supine position, SV was 107 ± 3 ml on the high vs. 99 ± 3 ml ( P < 0.05) on the low sodium intake, while CO remained unchanged. The difference in CO and SV induced by the change in sodium intake was significantly higher in the seated than in the supine position ( P < 0.05). During upright ambulatory conditions, CO was 5.9 ± 0.2 l/min during the high and 5.2 ± 0.2 l/min during the low sodium intake ( P < 0.05), and SV was 84 ± 3 and 69 ± 3 ml ( P < 0.05), respectively. Mean arterial pressure was unchanged by the variations in sodium intake. In conclusion, increments in sodium intake within the normal physiological range increase CO and SV and more so in the seated vs. the supine position. These changes are readily detectable during upright, ambulatory conditions. The results indicate that the higher SV and CO could constitute an arterial baroreflex stimulus for the augmented renal sodium excretion.
Reduced feeding during water deprivation depends on hydration of the gut
Authors: Schoorlemmer Guus H. M. , Evered Mark D.
Published: March 2015

Removal of drinking water at the start of the dark period reduced food intake in freely feeding rats within 45 min. Both first and later meals were smaller during 7.5 h of water deprivation, but meal frequency did not change. Ingestion of a normal-sized meal (3 g) rapidly increased plasma tonicity when drinking water was withheld, but intravenous infusions of hypertonic NaCl causing similar increases in plasma tonicity did not reduce feeding. Feeding during 6 h of water deprivation was restored by slowly infusing the volume of water normally drunk into the stomach, jejunum, or cecum, but not in the vena cava or hepatic portal vein. The infusions did not alter water or electrolyte excretion or affect food intake in rats allowed to drink. We conclude that the inhibition of feeding seen during water deprivation is mediated by a sensor that is located in the gastrointestinal tract or perhaps in the mesenteric veins draining the gut, but not the hepatic portal vein or the liver. In the absence of drinking water, signals from this sensor provoke the early termination of a meal.
Hypertension alters GABA receptor-mediated inhibition of neurons in the nucleus of the solitary tract
Authors: Mei Lin , Zhang Jing , Mifflin Steve
Published: March 2015

Previous studies have demonstrated that microinjection of baclofen, a GABAB receptor agonist, into the nucleus of the solitary tract (NTS) results in an enhanced pressor response in hypertensive (HT) rats compared with normotensive (NT) rats, suggesting a possible alteration in the responses of neurons in this area to activation of GABAB receptors. The following studies were designed to determine whether HT alters the sensitivity of neurons in the NTS to GABA receptor agonists. Sham-operated NT and unilateral nephrectomized, renal-wrap HT Sprague-Dawley rats were anesthetized, and the responses of NTS neurons receiving aortic nerve (AN) afferent inputs to iontophoretic application of GABA, the GABAA receptor agonist muscimol, and the GABAB agonist baclofen were examined. The AN input was classified as monosynaptic (MSN) if the cell responded to each of two stimuli separated by 5 ms with an action potential. If the cell did not respond, the input was considered polysynaptic (PSN). In MSNs, inhibition of AN-evoked discharge by GABA was not altered in 1 wk of HT but was reduced in 4 wk of HT, whereas in PSNs, sensitivity to GABA was reduced at 1 and 4 wk of HT. In HT rats, inhibition of AN-evoked discharge by baclofen was enhanced in MSNs, but not in PSNs, after 1 and 4 wk of HT, whereas inhibition by muscimol was reduced in MSNs and PSNs at 1 and 4 wk of HT. Changes in sensitivity to muscimol and baclofen within MSNs were the same whether the MSN received a slowly or a rapidly conducted AN afferent input. The results demonstrate that early in HT the sensitivity of NTS neurons to inhibitory amino acids is altered and that these changes are maintained for ≥4 wk. The alterations are dependent on the subtype of GABA receptor being activated and whether the neuron receives a mono- or polysynaptic baroreceptor afferent input.
Ontogeny of central CO2chemoreception: chemosensitivity in the ventral medulla of developing bullfrogs
Authors: Taylor Barbara E. , Harris Michael B. , Leiter J. C. , Gdovin Matthew J.
Published: March 2015

Sites of central CO2chemosensitivity were investigated in isolated brain stems from Rana catesbeiana tadpoles and frogs. Respiratory neurograms were made from cranial nerve (CN) 7 and spinal nerve 2. Superfusion of the brain stem with hypercapnic artificial cerebrospinal fluid elicited increased fictive lung ventilation. The effect of focal perfusion of hypercapnic artificial cerebrospinal fluid on discrete areas of the ventral medulla was assessed. Sites of chemosensitivity, which are active continuously throughout development, were identified adjacent to CN 5 and CN 10 on the ventral surface of the medulla. In early- and middle-stage tadpoles and frogs, unilateral stimulation within either site was sufficient to elicit the hypercapnic response, but simultaneous stimulation within both sites was required in late-stage tadpoles. The chemosensitive sites were individually disrupted by unilateral application of 1 mg/ml protease, and the sensitivity to bath application or focal perfusion of hypercapnia was reassessed. Protease lesions at CN 10 abolished the entire hypercapnic response, but lesions at CN 5 affected only the hypercapnic response originating from the CN 5 site. Neurons within the chemosensitive sites were also destroyed by unilateral application of 1 mM kainic acid, and the sensitivity to bath or focal application of hypercapnia was reassessed. Kainic acid lesions within either site abolished the hypercapnic response. Using a vital dye, we determined that kainic acid destroyed neurons by only within 100 μm of the ventral medullary surface. Thus, regardless of developmental stage, neurons necessary for CO2sensitivity are located in the ventral medulla adjacent to CN 5 and 10.
Angiotensin II regulates oxygen consumption
Authors: Cassis Lisa , Helton Marc , English Vicki , Burke Gerome
Published: March 2015

Previous studies demonstrated that angiotensin II (ANG II) decreases body weight. This study examined whether ANG II regulates body weight through energy expenditure. Acute ANG II administration decreased oxygen consumption. To determine whether this effect was maintained, rats were infused with ANG II or saline for 14 days. Oxygen consumption was transiently decreased on day 1 of ANG II infusion; however, body weight and food intake were reduced for 14 days. In pair-feeding studies, reductions in food intake accounted for 63% of the effect of ANG II on body weight but did not influence systolic pressure, water intake, or oxygen consumption. With 28 days of ANG II infusion, differences in body weight between ANG II and control rats were of greater magnitude. An initial decrease in oxygen consumption was followed by a rebound increase. Coadministration of losartan prevented the effect of ANG II on body weight, food intake, blood pressure, and water intake. However, losartan only partially prevented ANG II reductions in oxygen consumption. These results demonstrate that ANG II transiently decreases oxygen consumption through mechanisms unrelated to food intake. With chronic ANG II exposure, energy expenditure may contribute to sustained reductions in body weight.
Effects of different angiotensins during acute, double blockade of the renin system in conscious dogs
Authors: Wamberg Christian , Plovsing Ronni R. , Sandgaard Niels C. F. , Bie Peter
Published: March 2015

Evidence of biological activity of fragments of ANG II is accumulating. Fragments considered being inactive degradation products might mediate actions previously attributed to ANG II. The study aimed to determine whether angiotensin fragments exert biological activity when administered in amounts equimolar to physiological doses of ANG II. Cardiovascular, endocrine, and renal effects of ANG II, ANG III, ANG IV, and ANG-(1-7) (6 pmol·kg-1·min-1) were investigated in conscious dogs during acute inhibition of angiotensin I-converting enzyme (enalaprilate) and aldosterone (canrenoate). Furthermore, ANG III was investigated by step-up infusion (30 and 150 pmol·kg-1·min-1). Arterial plasma concentrations [ANG immunoreactivity (IR)] were determined by an ANG II antibody cross-reacting with ANG III and ANG IV. Metabolic clearance rates were higher for ANG III and ANG IV (391 ± 19 and 274 ± 13 ml·kg-1·min-1, respectively) than for ANG II (107 ± 13 ml·kg-1·min-1). ANG II increased ANG IR by 60 ± 7 pmol/ml, blood pressure by 30%, increased plasma aldosterone markedly (to 345 ± 72 pg/ml), and plasma vasopressin transiently, while reducing glomerular filtration rate (40 ± 2 to 33 ± 2 ml/min), sodium excretion (50 ± 7 to 16 ± 4 μmol/min), and urine flow. Equimolar amounts of ANG III induced similar antinatriuresis (57 ± 8 to 19 ± 3 μmol/min) and aldosterone secretion (to 268 ± 71 pg/ml) at much lower ANG IR increments (∼1/7) without affecting blood pressure, vasopressin, or glomerular filtration rate. The effects of ANG III exhibited complex dose-response relations. ANG IV and ANG-(1-7) were ineffective. It is concluded that 1) plasma clearances of ANG III and ANG IV are higher than those of ANG II; 2) ANG III is more potent than ANG II in eliciting immediate sodium and potassium retention, as well as aldosterone secretion, particularly at low concentrations; and 3) the complexity of the ANG III dose-response relationships provides indirect evidence that several effector mechanisms are involved.
Regulation of SGLT1 expression in response to Na+ intake
Authors: Barfull Anna , Garriga Carles , Tauler Albert , Planas Joana M.
Published: March 2015

In the chicken intestine, the reduction in Na+ intake led to a decrease in the transport of α-methyl-d-glucoside in the ileum (reduction of 42%) and in the rectum (51%). These reductions were reversed within 24 h after resalination and were inversely correlated to the changes in aldosterone plasma concentration. The reduction in intestinal hexose transport in the low Na+-fed animals was due to a decrease in the number of Na+-dependent d-glucose cotransporters (SGLT1) in the rectum (46%) and in the ileum (38%). Northern blot analysis showed that specific SGLT1 mRNA was expressed in the jejunum, ileum, and rectum. The amount of SGLT1 mRNA was the same in all intestinal regions and was not affected by Na+ intake, supporting the view that the effects of dietary Na+ on intestinal hexose transport involve posttranscriptional regulation of SGLT1. This study suggests that changes in SGLT1 expression may be involved in the homeostasis of Na+.
Thyroxine-induced cardiac hypertrophy: influence of adrenergic nervous system versus renin-angiotensin system on myocyte remodeling
Authors: Hu L. W. , Benvenuti L. A. , Liberti E. A. , Carneiro-Ramos M. S. , Barreto-Chaves M. L. M.
Published: March 2015

The present study assessed the possible involvement of the renin-angiotensin system (RAS) and the sympathetic nervous system (SNS) in thyroxine (T4)-induced cardiac hypertrophy. Hemodynamic parameters, heart weight (HW), ratio of HW to body weight (HW/BW), and myocyte width were evaluated in absence of thyroid hormone (hypothyroidism) and after T4 administration. Male Wistar rats were used. Some were subjected to thyroidectomies, whereas hyperthyroidism was induced in others via daily intraperitoneal injection of T4 (25 or 100 μg · 100 g BW-1 · day-1) for 7 days. In some cases, T4 administration was combined with the angiotensin I-converting enzyme inhibitor enalapril (Ena), with the angiotensin type 1 (AT1) receptor blocker losartan (Los) or with the β-adrenergic blocker propanolol (Prop). Hemodynamics and morphology were then evaluated. Systolic blood pressure (SBP) was not altered by administration of either T4 alone or T4 in combination with the specific inhibitors. However, SBP decreased significantly in hypothyroid rats. An increased heart rate was seen after administration of either T4 alone or T4 in combination with either Los or Ena. Although the higher dose of T4 significantly increased HW, HW/BW increased in both T4-treated groups. Ena and Prop inhibited the increase in HW or HW/BW in hyperthyroid rats. Morphologically, both T4 dose levels significantly increased myocyte width, an occurrence prevented by RAS or SNS blockers. There was a good correlation between changes in HW/BW and myocyte width. These results indicate that T4-induced cardiac hypertrophy is associated with both the SNS and the RAS.
Reduced endothelial NO-cGMP vascular relaxation pathway during TNF-α-induced hypertension in pregnant rats
Authors: Davis Justin R. , Giardina Jena B. , Green Gachavis M. , Alexander Barbara T. , Granger Joey P. , Khalil Raouf A.
Published: March 2015

Placental ischemia during pregnancy is thought to release cytokines such as tumor necrosis factor-α (TNF-α), which may contribute to the increased vascular resistance associated with pregnancy-induced hypertension. We have reported that a chronic twofold elevation in plasma TNF-α increases blood pressure in pregnant but not in virgin rats; however, the vascular mechanisms are unclear. We tested the hypothesis that increasing plasma TNF-α during pregnancy impairs endothelium-dependent vascular relaxation and enhances vascular reactivity. Active stress was measured in aortic strips of virgin and late-pregnant Sprague-Dawley rats untreated or infused with TNF-α (200 ng · kg−1 · day−1 for 5 days) to increase plasma level twofold. Phenylephrine (Phe) increased active stress to a maximum of 4.2 ± 0.4 × 103and 9.9 ± 0.7 × 103 N/m2 in control pregnant and TNF-α-infused pregnant rats, respectively. Removal of the endothelium enhanced Phe-induced stress in control but not in TNF-α-infused pregnant rats. In endothelium-intact strips, ACh caused greater relaxation of Phe contraction in control than in TNF-α-infused pregnant rats. Basal and ACh-induced nitrite/nitrate production was less in TNF-α-infused than in control pregnant rats. Pretreatment of vascular strips with 100 μM N G-nitro-l-arginine methyl ester, to inhibit nitric oxide (NO) synthase, or 1 μM 1 H-[1,2,4]oxadiazolo[4,3-]quinoxalin-1-one, to inhibit cGMP production in smooth muscle, inhibited ACh-induced relaxation and enhanced Phe-induced stress in control but not in TNF-α-infused pregnant rats. Phe contraction and ACh relaxation were not significantly different between control and TNF-α-infused virgin rats. Thus an endothelium-dependent NO-cGMP-mediated vascular relaxation pathway is inhibited in late-pregnant rats infused with TNF-α. The results support a role for TNF-α as one possible mediator of the increased vascular resistance associated with pregnancy-induced hypertension.
A farnesyltransferase inhibitor attenuated β-adrenergic receptor downregulation in rat skeletal muscle
Authors: Lavoie Julie L. , Calderone Angelino , Béliveau Louise
Published: March 2015

Farnesylation represents an essential posttranslational modification of several well-defined proteins implicated in the homologous desensitization of the β-adrenergic receptor (β-ADR). The following study examined the effect of a novel farnesyltransferase inhibitor, BMS-191563, on agonist-mediated β-ADR downregulation in skeletal muscle. Female Sprague-Dawley rats were treated for 12 days with the β2-adrenergic agonist clenbuterol (4 mg/kg) with or without the concurrent administration of BMS-191563 (2 mg · kg−1· day−1). Clenbuterol promoted gastrocnemius muscle hypertrophy, whereas the soleus muscle was unaffected. Total β-ADR density was decreased by 45 and 40% in the soleus and medial gastrocnemius (MG), respectively, after clenbuterol treatment. BMS-191563 treatment did not prevent clenbuterol-stimulated MG hypertrophy, but markedly attenuated β-ADR downregulation in both muscle types. This latter effect in the soleus muscle was not associated with the inhibition of Ras farnesylation. Likewise, in rat cardiac fibroblasts, isoproterenol-mediated decrease of total β-ADR density was abrogated by the prior treatment with BMS-191563. Collectively, these data demonstrate that the mechanism(s) implicated in agonist-mediated β-ADR downregulation was sensitive to BMS-191563, thereby suggesting the involvement of farnesylated proteins.
Dynamics of cerebral blood flow regulation explained using a lumped parameter model
Authors: Olufsen Mette S. , Nadim Ali , Lipsitz Lewis A.
Published: March 2015

The dynamic cerebral blood flow response to sudden hypotension during posture change is poorly understood. To better understand the cardiovascular response to hypotension, we used a windkessel model with two resistors and a capacitor to reproduce beat-to-beat changes in middle cerebral artery blood flow velocity (transcranial Doppler measurements) in response to arterial pressure changes measured in the finger (Finapres). The resistors represent lumped systemic and peripheral resistances in the cerebral vasculature, whereas the capacitor represents a lumped systemic compliance. Ten healthy young subjects were studied during posture change from sitting to standing. Dynamic variations of the peripheral and systemic resistances were extracted from the data on a beat-to-beat basis. The model shows an initial increase, followed approximately 10 s later by a decline in cerebrovascular resistance. The model also suggests that the initial increase in cerebrovascular resistance can explain the widening of the cerebral blood flow pulse observed in young subjects. This biphasic change in cerebrovascular resistance is consistent with an initial vasoconstriction, followed by cerebral autoregulatory vasodilation.
Water deprivation-induced sodium appetite: humoral and cardiovascular mediators and immediate early genes
Authors: De Luca Laurival A. , Xu Zhice , Schoorlemmer Guus H. M. , Thunhorst Robert L. , Beltz Terry G. , Menani José V. , Johnson Alan Kim
Published: March 2015

10.1152/ajpregu.00295.2000. Adult rats deprived of water for 24–30 h were allowed to rehydrate by ingesting only water for 1–2 h. Rats were then given access to both water and 1.8% NaCl. This procedure induced a sodium appetite defined by the operational criteria of a significant increase in 1.8% NaCl intake (3.8 ± 0.8 ml/2 h; n = 6). Expression of Fos (as assessed by immunohistochemistry) was increased in the organum vasculosum of the lamina terminalis (OVLT), median preoptic nucleus (MnPO), subfornical organ (SFO), and supraoptic nucleus (SON) after water deprivation. After rehydration with water but before consumption of 1.8% NaCl, Fos expression in the SON disappeared and was partially reduced in the OVLT and MnPO. However, Fos expression did not change in the SFO. Water deprivation also 1) increased plasma renin activity (PRA), osmolality, and plasma Na+; 2) decreased blood volume; and 3) reduced total body Na+; but 4) did not alter arterial blood pressure. Rehydration with water alone caused only plasma osmolality and plasma Na+concentration to revert to euhydrated levels. The changes in Fos expression and PRA are consistent with a proposed role for ANG II in the control of the sodium appetite produced by water deprivation followed by rehydration with only water.
Cortisol feedback state governs adrenocorticotropin secretory-burst shape, frequency, and mass in a dual-waveform construct: time of day-dependent regulation
Authors: Keenan Daniel M. , Veldhuis Johannes D.
Published: March 2015

Quantification of in vivo pituitary hormone secretion requires simultaneous appraisal of implicit 1) secretory-burst waveform, mass, and stochastic pulse timing; 2) basal secretion; 3) biexponential elimination kinetics; and 4) random experimental error (Keenan DM, Licinio J, and Veldhuis JD. Proc Natl Acad Sci USA 98: 4028-4033, 2001). The present study extends this analytic formalism to allow for time of day-dependent waveform adaptation (burst-shape change) at statistically determinable boundary times. Thereby, we test the hypothesis that diurnal mechanisms and glucocorticoid negative feedback jointly govern distinctive facets of the burstlike secretion of ACTH. To this end, we reanalyzed intensively (10 min) sampled 24-h plasma ACTH concentration profiles collected previously under feedback-intact and drug-induced cortisol depletion in nine healthy adults. Akaiki information criterion-based model comparison favored dual (rather than single) secretory-burst representation of 24-h ACTH release in both the intact and low-cortisol setting in eight of nine subjects. Under feedback-intact conditions, analytically predicted waveform changepoints (median clock times 0611 and 1739) flanked an interval of elevated ACTH secretory-burst mass ( P < 10-3). Experimental hypocortisolemia did not alter day/night boundaries, but 1) stimulated day ACTH secretory-burst mass ( P < 10-3); 2) accelerated day ACTH secretory-burst frequency ( P < 10-3); and 3) forced skewness of day ACTH secretory bursts toward more rapid initial release ( P < 0.05). In contrast, the basal ACTH secretion rate and regularity of interpulse-interval lengths were invariant of day/night segmentation and cortisol availability. In conclusion, unknown diurnal factors and systemic cortisol concentrations codetermine ACTH secretory-burst waveform, frequency, and mass, whereas neither mechanism regulates basal ACTH release or regularity of the burst-renewal process.
Pressor response to chemoreflex activation before and after microinjection of glycine into the NTS of awake rats
Authors: Pimentel Franklin F. , Bonagamba Leni G. H. , Machado Benedito H.
Published: March 2015

Microinjection of glycine into the rostral (bilateral) and caudal (midline) commissural nucleus of the solitary tract (NTS) using three guide cannulas implanted in the direction of these sites produced an increase in mean arterial pressure (MAP) and abolished the pressor response to chemoreflex activation [potassium cyanide ( n = 7)]. Strychnine, a glycine receptor antagonist, attenuated the increase in MAP, and in this new experimental condition ( n = 5) the pressor response to chemoreflex activation was not altered. Considering that the effect of glycine on the attenuation of the pressor response to chemoreflex activation could be secondary to the increase in baseline MAP, in a third group of rats ( n = 5) sodium nitroprusside infusion (intravenous) after microinjections of glycine into the NTS normalizes MAP. In this case, the pressor response to chemoreflex activation was similar to the control. These data show that glycine when microinjected bilaterally into the lateral commissural NTS as well as into the medial commissural NTS plays no major inhibitory role in the processing of the neurotransmission of the sympathoexcitatory component of the chemoreflex.
Lipolytic and metabolic response to glucagon in fasting king penguins: phase II vs. phase III
Authors: Bernard Servane F. , Thil Marie-Anne , Groscolas René
Published: March 2015

This study aims to determine how glucagon intervenes in the regulation of fuel metabolism, especially lipolysis, at two stages of a spontaneous long-term fast characterized by marked differences in lipid and protein availability and/or utilization (phases II and III). Changes in the plasma concentration of various metabolites and hormones, and in lipolytic fluxes as determined by continuous infusion of [2-3H]glycerol and [1-14C]palmitate, were examined in vivo in a subantarctic bird (king penguin) before, during, and after a 2-h glucagon infusion. In the two fasting phases, glucagon infusion at a rate of 0.025 μg · kg−1· min−1induced a three- to fourfold increase in the plasma concentration and in the rate of appearance (Ra) of glycerol and nonesterified fatty acids, the percentage of primary reesterification remaining unchanged. Infusion of glucagon also resulted in a progressive elevation of the plasma concentration of glucose and β-hydroxybutyrate and in a twofold higher insulinemia. These changes were not significantly different between the two phases. The plasma concentrations of triacylglycerols and uric acid were unaffected by glucagon infusion, except for a 40% increase in plasma uric acid in phase II birds. Altogether, these results indicate that glucagon in a long-term fasting bird is highly lipolytic, hyperglycemic, ketogenic, and insulinogenic, these effects, however, being similar in phases II and III. The maintenance of the sensitivity of adipose tissue lipolysis to glucagon could suggest that the major role of the increase in basal glucagonemia observed in phase III is to stimulate gluconeogenesis rather than fatty acid delivery.
Conversion of brain angiotensin II to angiotensin III is critical for pressor response in rats
Authors: Wright John W. , Tamura-Myers Elizabeth , Wilson Wendy L. , Roques Bernard P. , Llorens-Cortes Catherine , Speth Robert C. , Harding Joseph W.
Published: March 2015

The present investigation measured the relative pressor potencies of intracerebroventricularly infused ANG II, ANG III, and the metabolically resistant analogsd-Asp1ANG II andd-Arg1ANG III in alert freely moving rats. The stability of these analogs was further facilitated by pretreatment with the specific aminopeptidase A inhibitor EC33 or the aminopeptidase N inhibitor PC18. The results indicate that the maximum elevations in mean arterial pressure (MAP) were very similar for each of these compounds across the dose range 1, 10, and 100 pmol/min during a 5-min infusion period. However, d-Asp1ANG II revealed significantly extended durations of pressor effects before return to base level MAP. Pretreatment intracerebroventricular infusion with EC33 blocked the pressor activity induced by the subsequent infusion of d-Asp1ANG II, whereas EC33 had no effect on the pressor response to subsequent infusion ofd-Arg1ANG III. In contrast, pretreatment infusion with PC18 extended the duration of thed-Asp1ANG II pressor effect by about two to three times and the duration of d-Arg1ANG III's effect by ∼10 to 15 times. Pretreatment with the specific AT1receptor antagonist losartan blocked the pressor responses induced by the subsequent infusion of both analogs indicating that they act via the AT1receptor subtype. These results suggest that the brain AT1receptor may be designed to preferentially respond to ANG III, and ANG III's importance as a centrally active ligand has been underestimated.
RhoA-Rho kinase mediates synergistic ET-1 and phenylephrine contraction of rat corpus cavernosum
Authors: Wingard Christopher J. , Husain Shahid , Williams Jan , James Sharita
Published: March 2015

Maintenance of the detumescent state of the penis is believed to involve the actions of several vasoconstrictors. However, our mechanistic understanding of any synergistic vasoconstrictor influences is extremely limited. We tested the hypothesis that a vasoconstrictor combination of endothelin (ET-1) and phenylephrine (PE) augments the constrictor responses in rat corporal cavernosal tissues by a mechanism involving the RhoA-Rho kinase pathway. Independently, ET-1 (1 nM-30 μM) and PE (100 nM-100 μM) both caused dose-dependent contractions of isolated rat cavernosal tissues. In combination, ET-1 (30 nM) augmented the contractile effect of PE and shifted the calculated EC50 for PE (90 ± 12 to 45 ± 5 μM). The active stress generated by cavernosal strips during the ET-1 + PE combined stimulation (4.9 ± 0.2 mN/mm2) was greater than the combined stress generated with ET-1 (0.4 ± 0.1 mN/mm2) or PE (3.3 ± 0.2 mN/mm2) stimulations alone. Blockade of ETA receptors (30 nM; A-127722) reversed the augmented stress generation and the Rho-kinase inhibitor Y-27632 differentially and dose-dependently relaxed the tissue. The combined constrictor effect was associated with a fourfold increase of RhoA in the membrane faction of the tissue homogenates. We conclude that the ET-1 + PE combination potentiate vasoconstriction through mutual activation of the RhoA-Rho kinase pathway. The interactions of these agonists likely play important roles in the maintenance of the flaccid state and contribute to some forms of erectile dysfunction.
Venous plasma potassium is not associated with maintenance of the exercise pressor reflex in humans
Authors: Daley Joseph C. , Hogeman Cynthia S. , Sinoway Lawrence I.
Published: March 2015

Increases in the concentration of interstitial potassium concentration during exercise may play a role in the modulation of the cardiovascular response to exercise. However, it is not known if changes in potassium correlate with indexes of muscle reflex engagement. Eight healthy subjects performed dynamic [rhythmic handgrip (RHG)] and static handgrip (SHG) exercise at 40% of maximal voluntary contraction. Forearm circulatory arrest was performed to assess the metaboreceptor component of the exercise pressor reflex. Mean arterial pressure (MAP) and muscle sympathetic nerve activity (MSNA) were measured during each exercise paradigm. Venous plasma potassium concentrations ([K+]V) were measured and used as a surrogate marker for interstitial potassium. [K+]V were measured at baseline and at 1-min intervals during dynamic handgrip. During SHG, [K+]V were measured at baseline, 30 and 90 s of exercise, and twice during forearm circulatory arrest. Mean [K+]V was 3.6 mmol/l at rest before both paradigms. During RHG, [K+]V rose by ∼1.0 mmol/l by min 2 and remained constant throughout the rest of handgrip. During SHG, [K+]V rose significantly at 30 s and rose an additional ∼1.0 mmol/l by peak exercise. MAP and MSNA rose during both exercise paradigms. During posthandgrip circulatory arrest (PHG-CA), MSNA and blood pressure remained above baseline. [K+]V and MSNA did not correlate during either exercise paradigm. Moreover, during PHG-CA, there was clear dissociation of MSNA from [K+]V. These data suggest that potassium does not play a direct role in the maintenance of the exercise pressor reflex.