bluuebunny/crossref_metadata_2025 huggingface dataset:
Respective contribution of age, mean arterial pressure, and body weight on central arterial distensibility in SHR
Authors: Labat Carlos , Cunha Roberto S. A. , Challande Pascal , Safar Michel E. , Lacolley Patrick
Published: October 2005

In spontaneously hypertensive rats (SHR), carotid and aortic distensibilities measured at operational blood pressure (BP) are reduced. Increased body weight and mean arterial pressure (MAP) are both known to reduce distensibility independently. However, whether, after adjustment to body weight and mean BP, distensibility remains reduced in SHR has never been investigated. Carotid and abdominal aorta distensibilities were measured under anesthesia in SHR at 5, 12, 52, and 78 wk of age, and measurements were compared with age-matched normotensive Wistar rats. Each age group was composed of 9 or 10 animals. We determined distensibility using echo-tracking techniques of high resolution. Compared with Wistar rats, carotid and aortic distensibilities measured at operational MAP are reduced in SHR. This reduction is accentuated with age, particularly for the carotid artery. After adjustment to body weight and MAP, carotid and aortic distensibilities become identical in Wistar and SHR (or even slightly increased in SHR) but continue to be reduced with age, mainly for the carotid artery. In conclusion, in SHR, age and high BP do not have a parallel and similar influence on the reduction of arterial distensibility. Aging constantly reduces arterial distensibility, whereas MAP levels contribute to maintenance of arterial function.
Plasticity of GABAergic control of hypothalamic presympathetic neurons in hypertension
Authors: Li De-Pei , Pan Hui-Lin
Published: October 2005

Increased sympathetic outflow contributes to the pathogenesis of hypertension. However, the mechanisms of increased sympathetic drive in hypertension remain unclear. We examined the tonic GABAergic inhibition in control of the excitability of paraventricular (PVN) presympathetic neurons in spontaneously hypertensive rats (SHR) and normotensive controls, including Sprague-Dawley (SD) and Wistar-Kyoto (WKY) rats. Whole cell patch-clamp recordings were performed on retrogradely labeled PVN neurons projecting to the rostral ventrolateral medulla (RVLM) in brain slices. The basal firing rate of PVN neurons was significantly decreased in 13-wk-old SD and WKY rats but increased in 13-wk-old SHR, compared with their respective 6-wk-old controls. The GABAA antagonist bicuculline consistently increased the firing of PVN neurons in normotensive controls. Surprisingly, bicuculline either decreased the firing or had no effect in 59.3% of labeled cells in 13-wk-old SHR. In contrast, the GABAB antagonist CGP-55845 had no effect on the firing of PVN neurons in normotensive controls but significantly increased the firing of 75% of cells studied in 13-wk-old SHR. Furthermore, the evoked GABAA current decreased significantly in labeled PVN neurons of 13-wk-old SHR compared with that in normotensive controls. Both the frequency and amplitude of GABAergic spontaneously inhibitory postsynaptic currents were also reduced in 13-wk-old SHR. This study demonstrates an unexpected functional change in GABAA and GABAB receptors in regulation of the firing activity of PVN-RVLM neurons in SHR. This change in GABAA receptor function and GABAergic inputs to PVN output neurons may contribute to increased sympathetic outflow in hypertension.
Transcriptional analysis of doxorubicin-induced cardiotoxicity
Authors: Yi Xiaoming , Bekeredjian Raffi , DeFilippis Nicholas J. , Siddiquee Zakir , Fernandez Eduardo , Shohet Ralph V.
Published: October 2005

Doxorubicin is an effective chemotherapeutic agent against a broad range of tumors. However, a threshold dose of doxorubicin causes an unacceptably high incidence of heart failure and limits its clinical utility. We have established two models of doxorubicin cardiotoxicity in mice: 1) in an acute model, mice are treated with 15 mg/kg of doxorubicin once; and 2) in a chronic model, they receive 3 mg/kg weekly for 12 wk. Using echocardiography, we have monitored left ventricular function during treatment in the chronic model and seen the expected development of dilated cardiomyopathy. Treated mice showed histological abnormalities similar to those seen in patients with doxorubicin cardiomyopathy. To investigate transcriptional regulation in these models, we used a muscle-specific cDNA microarray. We have identified genes that respond to doxorubicin exposure in both models and confirmed these results using real-time PCR. In the acute model, a set of genes is regulated early and rapidly returns to baseline levels, consistent with the half-life of doxorubicin. In the chronic model, which mimics the clinical situation much more closely, we identified dysregulated genes that implicate specific mechanisms of cardiac toxicity. These include STARS, a hypertrophy-responsive gene; SNF1-kinase, a potential modulator of ATP levels; and AXUD1, a downstream target of the proapoptotic regulator AXIN1.
Exercise training increases basal tone in arterioles distal to chronic coronary occlusion
Authors: Heaps Cristine L. , Mattox Mildred L. , Kelly Katherine A. , Meininger Cynthia J. , Parker Janet L.
Published: October 2005

Endurance exercise training increases basal active tone in coronary arteries and enhances myogenic tone in coronary arterioles of control animals. Paradoxically, exercise training has also been shown to augment nitric oxide production and nitric oxide-mediated relaxation in coronary arterioles. The purpose of the present study was to examine the effect of exercise training on basal active tone of arterioles (∼150 μm ID) isolated from the collateral-dependent region of hearts exposed to chronic coronary occlusion. Ameroid occluders were surgically placed around the proximal left circumflex coronary artery of miniature swine. Arterioles were isolated from both the collateral-dependent and nonoccluded myocardial regions of sedentary (pen confined) and exercise-trained (treadmill run; 14 wk) pigs. Coronary tone was studied in isolated arterioles using microvessel myographs and standard isometric techniques. Exposure to nominally Ca2+-free external solution reduced resting tension in all arterioles; decreases were most profound ( P < 0.05) in arterioles from the collateral-dependent region of exercise-trained animals. Furthermore, nitric oxide synthase (NOS) inhibition ( Nω-nitro-l-arginine methyl ester; 100 μM) unmasked markedly increased nitric oxide-sensitive tone in arterioles from the collateral-dependent region of exercise-trained swine. Blockade of K+ channels revealed significantly enhanced K+ channel contribution to basal tone in collateral-dependent arterioles of exercise-trained pigs. Protein content of endothelial NOS (eNOS) and phosphorylated eNOS (pS1179), determined by immunoblot, was elevated in arterioles from exercise-trained animals with the greatest effect in collateral-dependent vasculature. Taken together, we demonstrate the interaction of opposing exercise training-enhanced arteriolar basal active tone, nitric oxide production, and K+ channel activity in chronic coronary occlusion, potentially enhancing the capacity to regulate blood flow to collateral-dependent myocardium.
Thromboxane A2induces airway constriction through an M3muscarinic acetylcholine receptor-dependent mechanism
Authors: Allen Irving C. , Hartney John M. , Coffman Thomas M. , Penn Raymond B. , Wess Jürgen , Koller Beverly H.
Published: October 2005

Thromboxane A2(TXA2) is a potent lipid mediator released by platelets and inflammatory cells and is capable of inducing vasoconstriction and bronchoconstriction. In the airways, it has been postulated that TXA2causes airway constriction by direct activation of thromboxane prostanoid (TP) receptors on airway smooth muscle cells. Here we demonstrate that although TXA2can mediate a dramatic increase in airway smooth muscle constriction and lung resistance, this response is largely dependent on vagal innervation of the airways and is highly sensitive to muscarinic acetylcholine receptor (mAChR) antagonists. Further analyses employing pharmacological and genetic strategies demonstrate that TP-dependent changes in lung resistance and airway smooth muscle tension require expression of the M3mAChR subtype. These results raise the possibility that some of the beneficial actions of anticholinergic agents used in the treatment of asthma and chronic obstructive pulmonary disease result from limiting physiological changes mediated through the TP receptor. Furthermore, these findings demonstrate a unique pathway for TP regulation of homeostatic mechanisms in the airway and suggest a paradigm for the role of TXA2in other organ systems.
Evidence of differential control of renal and lumbar sympathetic nerve activity in conscious rabbits
Authors: Ramchandra Rohit , Barrett Carolyn J. , Guild Sarah-Jane , Malpas Simon C.
Published: October 2005

We have explored the possibility that renal sympathetic nerve activity (RSNA) and vasomotor sympathetic nerve activity are differentially regulated. We measured sympathetic nerve activity (SNA) to the kidney and the hind limb vasculature in seven conscious rabbits 6–8 days after the implantation of recording electrodes. Acute infusion of NG-nitro-l-arginine methyl ester (l-NAME) (6 mg·kg−1·min−1 for 5 min) led to an increase in blood pressure (from 66 ± 1 to 82 ± 3 mmHg) and a decrease in heart rate (from 214 ± 15 to 160 ± 13 bpm). l-NAME administration caused a significantly greater decrease in RSNA than lumbar sympathetic nerve activity (LSNA) (to 68 ± 14% vs. 84 ± 4% of control values, respectively). Volume expansion (1.5 ml·kg−1·min−1) resulted in a significant decrease in RSNA to 66 ± 7% of control levels but no change in LSNA (127 ± 20%). There was no difference in the gain of the baroreflex curves between the LSNA and RSNA [maximum gain of −7.6 ± 0.4 normalized units (nu)/mmHg for LSNA vs. −7.9 ± 0.75 nu/mmHg for RSNA]. A hypoxic stimulus (10% O2 and 3% CO2) led to identical increases in both RSNA and LSNA (195 ± 40% and 158 ± 21% of control values, respectively). Our results indicate tailored differential control of RSNA and LSNA in response to acute stimuli.
Resetting of the hamster circadian system by dark pulses
Authors: Canal M. M. , Piggins H. D.
Published: October 2005

Circadian rhythms of animals are reset by exposure to light as well as dark; however, although the parameters of photic entrainment are well characterized, the phase-shifting actions of dark pulses are poorly understood. Here, we determined the tonic and phasic effects of short (0.25 h), moderate (3 h), and long (6–9 h) duration dark pulses on the wheel-running rhythms of hamsters in constant light. Moderate- and long-duration dark pulses phase dependently reset behavioral rhythms, and the magnitude of these phase shifts increased as a function of the duration of the dark pulse. In contrast, the 0.25-h dark pulses failed to evoke consistent effects at any circadian phase tested. Interestingly, moderate- and long-dark pulses elevated locomotor activity (wheel-running) on the day of treatment. This induced wheel-running was highly correlated with phase shift magnitude when the pulse was given during the subjective day. This, together with the finding that animals pulsed during the subjective day are behaviorally active throughout the pulse, suggests that both locomotor activity and behavioral activation play an important role in the phase-resetting actions of dark pulses. We also found that the robustness of the wheel-running rhythm was weakened, and the amount of wheel-running decreased on the days after exposure to dark pulses; these effects were dependent on pulse duration. In summary, similarly to light, the resetting actions of dark pulses are dependent on both circadian phase and stimulus duration. However, dark pulses appear more complex stimuli, with both photic and nonphotic resetting properties.
An enteric signal regulates putative gastrointestinal presympathetic vasomotor neurons in rats
Authors: Sartor Daniela M. , Shulkes Arthur , Verberne Anthony J. M.
Published: October 2005

Ingestion of a meal results in gastrointestinal (GI) hyperemia and is associated with systemic and paracrine release of a number of peptide hormones, including cholecystokinin (CCK) and 5-hydroxytryptamine (5-HT). Systemic administration of CCK octapeptide inhibits a subset of presympathetic neurons of the rostroventrolateral medulla (RVLM) that may be responsible for driving the sympathetic vasomotor tone to the GI viscera. The aim of this study was to determine whether endogenous release of CCK and/or 5-HT also inhibits CCK-sensitive RVLM neurons. The effects of intraduodenal administration of the secretagogues sodium oleate (SO) and soybean trypsin inhibitor (SBTI) on circulating levels of CCK and 5-HT were examined. In separate experiments, the discharge rates of barosensitive, medullospinal, CCK-sensitive RVLM presympathetic vasomotor neurons were recorded after rapid intraduodenal infusion of SO-SBTI or water. Alternatively, animals were pretreated with the CCK1receptor antagonists devazepide and lorglumide or the 5-HT3antagonist MDL-72222 before SO-SBTI administration. Secretagogue infusion significantly increased the level of circulating CCK, but not 5-HT. SO-SBTI significantly decreased (58%) the neuronal firing rate of CCK-sensitive RVLM neurons compared with water (5%). CCK1receptor antagonists did not reverse SO-SBTI-induced neuronal inhibition (58%), whereas the 5-HT3antagonist significantly attenuated the effect (22%). This study demonstrates a functional relation between a subset of RVLM presympathetic vasomotor neurons and meal-related signals arising from the GI tract. It is likely that endogenously released 5-HT acts in a paracrine fashion on GI 5-HT3receptors to initiate reflex inhibition of these neurons, resulting in GI vasodilatation by withdrawal of sympathetic tone.
l-NAME- and ADMA-induced sympathetic neural activation in conscious rats
Authors: Augustyniak Robert A. , Victor Ronald G. , Morgan Donald A. , Zhang Weiguo
Published: October 2005

Although studies in anesthetized, sino-aortic denervated animals indicate that inhibition of central nitric oxide (NO) causes an excitatory influence on efferent sympathetic nerve activity (SNA) that is normally offset by baroreflex activation, studies in conscious animals have not provided clear-cut evidence for a sympathoexcitatory effect of Nω-nitro-l-arginine methyl ester (l-NAME) or the endogenous circulating NO synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA). Thus our goals were to 1) use surgical sino-aortic denervation to test for a sympathoexcititatory effect of intravenous l-NAME in conscious rats, and 2) to determine whether SNA responses to intravenous l-NAME can be extrapolated directly to intravenous ADMA. We recorded mean arterial blood pressure and renal SNA in both intact and sino-aortic-denervated conscious rats during 3 h of continuous intravenous infusion with either l-NAME or ADMA. When we eliminated the confounding influence of the sino-aortic baroreceptors, l-NAME produced a progressive increase in SNA with the peak response exceeding the baseline level of nerve firing by 150%. The same type of frank sympathetic activation was observed with intravenous ADMA. Taken together, these data offer straightforward evidence for l-NAME, as well as ADMA-induced sympathetic activation with direct recordings of SNA in conscious animals. These data confirm and extend the concept that circulating endogenous NOS inhibitors can constitute an excitatory signal to SNA.
Tubular mitochondrial alterations in neonatal rats subjected to RAS inhibition
Authors: Lasaitiene Daina , Chen Yun , Mildaziene Vida , Nauciene Zita , Sundelin Birgitta , Johansson Bengt R. , Yano Masato , Friberg Peter
Published: October 2005

Pharmacological interruption of the angiotensin II (ANG II) type 1 receptor signaling during nephrogenesis in rats perturbs renal tubular development. This study aimed to further investigate tubular developmental defects in neonatal rats subjected to ANG II inhibition with enalapril. We evaluated tubular ultrastructural changes using electron microscopy and estimated spectrophotometrically activity or concentrations of succinate dehydrogenase (SDH), cytochromes a and c, which are components of mitochondrial respiratory chain, on postnatal days 2 and 9 (PD2 and PD9). Renal expression of sodium-potassium adenosinetriphosphatase (Na+-K+-ATPase) and two reflectors of mitochondrial biogenesis [mitochondrial transcription factor A (TFAM) and translocase of outer mitochondrial membrane 20 (TOM20)] also were studied using Western immunoblotting and immunohistochemistry. Enalapril disrupted inner mitochondrial membranes of developing cortical and medullary tubular cells on PD2 and PD9. These findings were paralleled by impaired mitochondrial respiratory function, as revealed from the changes in components of the mitochondrial respiratory chain, such as decreased cytochrome c level in the cortex and medulla on PD2 and PD9, decreased cytochrome a level in the cortex and medulla on PD2, and diminished cortical SDH activity on PD2 and PD9. Moreover, tubular expression of the most active energy-consuming pump Na+-K+-ATPase was decreased by enalapril treatment. Renal expression of TFAM and TOM20 was not altered by neonatal enalapril treatment. Because nephrogenesis is a highly energy-demanding biological process, with the energy being utilized for renal growth and transport activities, the structural-functional alterations of the mitochondria induced by neonatal enalapril treatment may provide the propensity for the tubular developmental defect.
Angiotensin II stimulation of VEGF mRNA translation requires production of reactive oxygen species
Authors: Feliers Denis , Gorin Yves , Ghosh-Choudhury Goutam , Abboud Hanna E. , Kasinath Balakuntalam S.
Published: October 2005

ANG II, a mediator of renal injury in diabetic renal disease, promotes vascular endothelial growth factor (VEGF) mRNA translation in proximal tubular epithelial (MCT) cells (Feliers D, Duraisamy S, Barnes JL, Ghosh-Choudhury G, and Kasimath BS. Am J Physiol Renal Physiol 288: F521–F529, 2005). The mechanism by which ANG II elicits this effect is not known. ANG II is known to induce oxidative stress and the rapidity of the effect suggested a role for reactive oxygen species (ROS). The aim of this study is to test the hypothesis that ANG II regulates VEGF mRNA translation in MCT cells through ROS production. In MCT cells exposed to 1 nM ANG II, ROS production was increased in a time-dependent manner. Inhibition of ROS production by N-acetylcysteine (NAC), a precursor of glutathione, and diphenyleneiodonium (DPI), an inhibitor of flavoproteins that include NAD(P)H oxidase, prevented ANG II-stimulated VEGF protein expression. NAC and DPI also inhibited phosphorylation of 4E-BP1 on Thr46 and association of eIF4E with eIF4G, steps that are important in the initiation phase of mRNA translation. NAC and DPI also blocked Akt activation which is required for 4E-BP1 phosphorylation. LY-294002, a selective phosphatidylinositol (PI 3-kinase) inhibitor, did not prevent ROS accumulation in response to ANG II, whereas DPI blocked ANG II activation of PI 3-kinase, demonstrating that ROS production is upstream of the PI 3-kinase signaling pathway. Preincubation with catalase abolished ANG II stimulation of VEGF expression and mRNA translation, suggesting involvement of hydrogen peroxide (H2O2). H2O2reproduced the effects of ANG II on VEGF expression and aforementioned parameters of mRNA translation. Finally, neither preincubation of MCT cells with specific inhibitors of the mitochondrial respiratory chain nor inactivation of the mitochondrial respiratory chain in MCT cells prevented ANG II stimulation of VEGF expression. Inhibition of nitric oxide synthase by l-NAME had no effect on ANG II stimulation of VEGF expression. These data show that ROS, generated probably through activation of an NAD(P)H oxidase, mediate ANG II stimulation of VEGF mRNA translation.
Relationship between ventilatory response and body temperature during prolonged submaximal exercise
Authors: Hayashi Keiji , Honda Yasushi , Ogawa Takeshi , Kondo Narihiko , Nishiyasu Takeshi
Published: October 2005

We examined whether an increase in skin temperature or the rate of increase in core body temperature influences the relationship between minute ventilation (V̇e) and core temperature during prolonged exercise in the heat. Thirteen subjects exercised for 60 min on a cycle ergometer at 50% of peak oxygen uptake while wearing a suit perfused with water at 10°C (T10), 35°C (T35), or 45°C (T45). During the exercise, esophageal temperature (Tes), skin temperature, heart rate (HR), V̇e, tidal volume, respiratory frequency (f), respiratory gases, blood pressure (BP), and blood lactate were all measured. We found that oxygen uptake, carbon dioxide output, BP, and blood lactate did not differ among the sessions. Tes, HR, V̇e, and f remained nearly constant from minute 10 onward in the T10 session, but all of these parameters progressively increased in the T35 and T45 sessions, and significantly higher levels were seen in the T45 than the T35 session. For all but two subjects in the T35 and T45 sessions, plotting V̇e as a function of Tesrevealed no threshold for hyperventilation; instead, increases in V̇e were linearly related to Tes, and there were no significant differences in the slopes or intercepts between the T35 and T45 sessions. Thus, during prolonged submaximal exercise in the heat, V̇e increases with core temperature, and the influences of skin temperature and the rate of increase in Teson the relationship between V̇e and Tesare apparently small.
Explanation of the bilateral deficit in human vertical squat jumping
Authors: Bobbert Maarten F. , de Graaf Wendy W. , Jonk Jan N. , Casius L. J. Richard
Published: October 2005

In the literature, it has been reported that the mechanical output per leg is less in two-leg jumps than in one-leg jumps. This so-called bilateral deficit has been attributed to a reduced neural drive to muscles in two-leg jumps. The purpose of the present study was to investigate the possible contribution of nonneural factors to the bilateral deficit in jumping. We collected kinematics, ground reaction forces, and electromyograms of eight human subjects performing two-leg and one-leg (right leg) squat jumps and calculated mechanical output per leg. We also used a model of the human musculoskeletal system to simulate two-leg and one-leg jumps, starting from the initial position observed in the subjects. The model had muscle stimulation as input, which was optimized using jump height as performance criterion. The model did not incorporate a reduced maximal neural drive in the two-leg jump. Both in the subjects and in the model, the work of the right leg was more than 20% less in the two-leg jump than in the one-leg jump. Peak electromyogram levels in the two-leg jump were reduced on average by 5%, but the reduction was only statistically significant in m. rectus femoris. In the model, ∼75% of the bilateral deficit in work per leg was explained by higher shortening velocities in the two-leg jump, and the remainder was explained by lower active state of muscles. It was concluded that the bilateral deficit in jumping is primarily caused by the force-velocity relationship rather than by a reduction of neural drive.
Deceleration time of systolic pulmonary venous flow: a new clinical marker of left atrial pressure and compliance
Authors: Hunderi J. O. , Thompson C. R. , Smiseth O. A.
Published: October 2005

The curvilinearity of the atrial pressure-volume curve implies that atrial compliance decreases progressively with increasing left atrial (LA) pressure (LAP). We predicted that reduced LA compliance leads to more rapid deceleration of systolic pulmonary venous (PV) flow. With this rationale, we investigated whether the deceleration time ( tdec) of PV systolic flow velocity reflects mean LAP. In eight patients during coronary surgery, before extracorporeal circulation, PV flow by ultrasonic transit time and invasive LAP were recorded during stepwise volume loading. The tdec was calculated using two methods: by drawing a tangent through peak deceleration and by drawing a line from peak systolic flow through the nadir between the systolic and early diastolic flow waves. LA compliance was calculated as the systolic PV flow integral divided by LAP increment. Volume loading increased mean LAP from 11 ± 3 to 20 ± 5 mmHg ( P < 0.001) ( n = 40), reduced LA compliance from 1.16 ± 0.42 to 0.72 ± 0.40 ml/mmHg ( P < 0.004) ( n = 40), and reduced tdec from 320 ± 50 to 170 ± 40 ms ( P < 0.0005) ( n = 40). Mean LAP correlated well with tdec ( r = 0.84, P < 0.0005) ( n = 40) and LA compliance ( r = 0.79, P < 0.0005) ( n = 40). Elevated LAP caused a decrease in LA compliance and therefore more rapid deceleration of systolic PV flow. The tdec has potential to become a semiquantitative marker of LAP and an index of LA passive elastic properties.
Faster lactate transport across red blood cell membrane in sickle cell trait carriers
Authors: Fagnété Sara , Philippe Connes , Olivier Hue , Mona Montout-Hedreville , Maryse Etienne-Julan , Marie-Dominique Hardy-Dessources
Published: October 2005

The physical and physiological behavior of sickle cell trait carriers (AS) is somewhat equivocal under strenuous conditions, although this genetic abnormality is generally considered to be a benign disorder. The occurrence of incidents and severe injuries in AS during exercise might be explained, in part, by the lactic acidosis due to a greater lactate influx into AS red blood cells (RBCs). In the present study, the RBC lactate transport activity via the different pathways was compared between AS and individuals with normal hemoglobin (AA). Sixteen Caribbean students, nine AS and seven AA, performed a progressive and maximal exercise test to determine maximal oxygen consumption. Blood samples were obtained at rest to assess haematological parameters and RBC lactate transport activity. Lactate influxes [total lactate influx and monocarboxylate transporter (MCT-1)-mediated lactate influx] into erythrocytes were measured at four external [14C]-labeled lactate concentrations (1.6, 8.1, 41, and 81.1 mM). The two groups had similar maximal oxygen consumption. Total lactate influx and lactate influx via the MCT-1 pathway were significantly higher in AS compared with AA at 1.6, 41, and 81.1 mM. The maximal lactate transport capacity for MCT-1 was higher in AS than in AA. Although AS and AA had the same maximal aerobic physical fitness, the RBCs from the sickle cell trait carriers took up more lactate at low and high concentrations than the RBCs from AA individuals. The higher MCT-1 maximal lactate transport capacity found in AS suggests greater content or greater activity of MCT-1 in AS RBC membranes.
The kinetics of transdermal ethanol exchange
Authors: Anderson Joseph C. , Hlastala Michael P.
Published: October 2005

The kinetics of ethanol transport from the blood to the skin surface are incompletely understood. We present a mathematical model to predict the transient exchange of ethanol across the skin while it is being absorbed from the gut and eliminated from the body. The model simulates the behavior of a commercial device that is used to estimate the blood alcohol concentration (BAC). During the elimination phase, the stratum corneum of the skin has a higher ethanol concentration than the blood. We studied the effect of varying the maximum BAC and the absorption rate from the gut on the relationship between BAC and equivalent concentration in the gas phase above the skin. The results showed that the ethanol concentration in the gas compartment always took longer to reach its maximum, had a lower maximum, and had a slower apparent elimination rate than the BAC. These effects increased as the maximum BAC increased. Our model's predictions are consistent with experimental data from the literature. We performed a sensitivity analysis (using Latin hypercube sampling) to identify and rank the importance of parameters. The analysis showed that outputs were sensitive to solubility and diffusivity within the stratum corneum, to stratum corneum thickness, and to the volume of gas in the sampling chamber above the skin. We conclude that ethanol transport through the skin is primarily governed by the washin and washout of ethanol through the stratum corneum. The dynamics can be highly variable from subject to subject because of variability in the physical properties of the stratum corneum.
Serum erythropoietin levels in healthy humans after a short period of normobaric and hyperbaric oxygen breathing: the “normobaric oxygen paradox”
Authors: Balestra Costantino , Germonpré Peter , Poortmans Jacques R. , Marroni Alessandro
Published: October 2005

Renal (peritubular) tissue hypoxia is a well-known physiological trigger for erythropoietin (EPO) production. We investigated the effect of rebound relative hypoxia after hyperoxia obtained under normo- and hyperbaric oxygen breathing conditions. A group of 16 healthy volunteers were investigated before and after a period of breathing 100% normobaric oxygen for 2 h and a period of breathing 100% oxygen at 2.5 ATA for 90 min (hyperbaric oxygen). Serum EPO concentration was measured using a radioimmunoassay at various time points during 24–36 h. A 60% increase ( P < 0.001) in serum EPO was observed 36 h after normobaric oxygen. In contrast, a 53% decrease in serum EPO was observed at 24 h after hyperbaric oxygen. Those changes were not related to the circadian rhythm of serum EPO of the subjects. These results indicate that a sudden and sustained decrease in tissue oxygen tension, even above hypoxia thresholds (e.g., after a period of normobaric oxygen breathing), may act as a trigger for EPO serum level. This EPO trigger, the “normobaric oxygen paradox,” does not appear to be present after hyperbaric oxygen breathing.
Time course of cytokine, corticosterone, and tissue injury responses in mice during heat strain recovery
Authors: Leon Lisa R. , Blaha Michael D. , DuBose David A.
Published: October 2005

Elevated circulating cytokines are observed in heatstroke patients, suggesting a role for these substances in the pathophysiological responses of this syndrome. Typically, cytokines are determined at end-stage heatstroke such that changes throughout progression of the syndrome are poorly understood. We hypothesized that the cytokine milieu changes during heatstroke progression, correlating with thermoregulatory, hemodynamic, and tissue injury responses to heat exposure in the mouse. We determined plasma IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12p40, IL-12p70, IFN-γ, macrophage inflammatory protein-1α, TNF-α, corticosterone, glucose, hematocrit, and tissue injury during 24 h of recovery. Mice were exposed to ambient temperature of 39.5 ± 0.2°C, without food and water, until maximum core temperature (Tc,Max) of 42.7°C was attained. During recovery, mice displayed hypothermia (29.3 ± 0.4°C) and a feverlike elevation at 24 h (control = 36.2 ± 0.3°C vs. heat stressed = 37.8 ± 0.3°C). Dehydration (∼10%) and hypoglycemia (∼65–75% reduction) occurred from Tc,Max to hypothermia. IL-1α, IL-2, IL-4, IL-12p70, IFN-γ, TNF-α, and macrophage inflammatory protein-1α were undetectable. IL-12p40 was elevated at Tc,Max, whereas IL-1β, IL-6, and IL-10 inversely correlated with core temperature, showing maximum production at hypothermia. IL-6 was elevated, whereas IL-12p40 levels were decreased below baseline at 24 h. Corticosterone positively correlated with IL-6, increasing from Tc,Max to hypothermia, with recovery to baseline by 24 h. Tissue lesions were observed in duodenum, spleen, and kidney at Tc,Max, hypothermia, and 24 h, respectively. These data suggest that the cytokine milieu changes during heat strain recovery with similarities between findings in mice and those described for human heatstroke, supporting the application of our model to the study of cytokine responses in vivo.
Effects of altitude and exercise on pulmonary capillary integrity: evidence for subclinical high-altitude pulmonary edema
Authors: Eldridge Marlowe W. , Braun Ruedi K. , Yoneda Ken Y. , Walby William F.
Published: October 2005

Strenuous exercise may be a significant contributing factor for development of high-altitude pulmonary edema, particularly at low or moderate altitudes. Thus we investigated the effects of heavy cycle ergometer exercise (90% maximal effort) under hypoxic conditions in which the combined effects of a marked increase in pulmonary blood flow and nonuniform hypoxic pulmonary vasoconstriction could add significantly to augment the mechanical stress on the pulmonary microcirculation. We postulated that intense exercise at altitude would result in an augmented permeability edema. We recruited eight endurance athletes and examined their bronchoalveolar lavage fluid (BALF) for red blood cells (RBCs), protein, inflammatory cells, and soluble mediators at 2 and 26 h after intense exercise under normoxic and hypoxic conditions. After heavy exercise, under all conditions, the athletes developed a permeability edema with high BALF RBC and protein concentrations in the absence of inflammation. We found that exercise at altitude (3,810 m) caused significantly greater leakage of RBCs [9.2 (SD 3.1) × 104cells/ml] into the alveolar space than that seen with normoxic exercise [5.4 (SD 1.2) × 104cells/ml]. At altitude, the 26-h postexercise BALF revealed significantly higher RBC and protein concentrations, suggesting an ongoing capillary leak. Interestingly, the BALF profiles following exercise at altitude are similar to that of early high-altitude pulmonary edema. These findings suggest that pulmonary capillary disruption occurs with intense exercise in healthy humans and that hypoxia augments the mechanical stresses on the pulmonary microcirculation.
Changes in lung permeability after chronic pulmonary artery obstruction
Authors: Wagner Elizabeth M. , Karagulova Gulnura , Jenkins John , Bishai John , McClintock Jessica
Published: October 2005

We have shown that left pulmonary artery ligation (LPAL) in mice causes a prompt angiogenic response, with new systemic vessels from intercostal arteries penetrating the pleura within 6 days. Because angiogenic vessels in other organs have been shown to exhibit increased permeability, we studied vascular permeability (Evans blue dye extravasation, lung wet weight-to-dry weight ratio, and lavaged protein) in naive C57BL/6 mice and 4 h, and 14 and 21 days after LPAL (4–6 mice/time point). We also measured radiolabel clearance as an index of functional perfusion after LPAL. Tracer clearance from the left lung was maximal by 6 days after LPAL and not different from right lungs. Thus a functional vasculature is established before 6 days of LPAL that results in normal tracer clearance. By 21 days after LPAL, Evans blue-albumin was significantly increased in the left lung relative to both 4 h (no vasculature) and 14 days after LPAL. Only after 21 days of LPAL was left lung wet weight-to-dry weight ratio significantly different from naive lungs. Additionally, lavaged protein was significantly increased both 4 h and 21 days after LPAL relative to control mice. Thus, using three different methods, results consistently demonstrated increased permeability to protein and water 21 days after LPAL. Although changes in surface area of perfusion might affect the interpretation of these results, blood flow measured with labeled microspheres indicated no change in left lung perfusion between 14 and 21 days of LPAL. Thus the lung vasculature, remodeled as a consequence of chronic pulmonary artery obstruction, demonstrates increased water and protein permeability.
Adult rats prenatally exposed to ethanol have increased gluconeogenesis and impaired insulin response of hepatic gluconeogenic genes
Authors: Yao Xing-Hai , Chen Li , Nyomba B. L. Grégoire
Published: October 2005

Rat offspring exposed to ethanol (EtOH rats) during pregnancy are insulin resistant, but it is unknown whether they have increased gluconeogenesis. To address this issue, we determined blood glucose and liver gluconeogenic genes, proteins, and enzyme activities before and after insulin administration in juvenile and adult EtOH rats and submitted adult EtOH rats to a pyruvate challenge. In juvenile rats, basal glucose; peroxisome proliferator-activated receptor-coactivator-1α protein and mRNA; and phospho enolpyruvate carboxykinase enzyme activity, protein, and mRNA were similar between groups. After insulin injection, these parameters failed to decrease in EtOH rats, but glucose decreased by 30% and gluconeogenic enzymes, proteins, and mRNAs decreased by 50–70% in control rats. In adult offspring, basal peroxisome proliferator-activated receptor-coactivator-1α protein and mRNA levels were 40–80% higher in EtOH rats than in controls. Similarly, basal phospho enolpyruvate carboxykinase activity, protein, and mRNA were ∼1.8-fold greater in EtOH rats than in controls. These parameters decreased by ∼50% after insulin injection in control rats, but they remained unchanged in EtOH rats. After insulin injection in the adult rats, glucose decreased by 60% in controls but did not decrease significantly in EtOH rats. A subset of adult EtOH rats had fasting hyperglycemia and an exaggerated glycemic response to pyruvate compared with controls. The data indicate that, after prenatal EtOH exposure, the expression of gluconeogenic genes is exaggerated in adult rat offspring and is insulin resistant in both juvenile and adult rats, explaining increased gluconeogenesis. These alterations persist through adulthood and may contribute to the pathogenesis of Type 2 diabetes after exposure to EtOH in utero.
Isometric resistance exercise fails to counteract skeletal muscle atrophy processes during the initial stages of unloading
Authors: Haddad F. , Adams G. R. , Bodell P. W. , Baldwin K. M.
Published: October 2005

This study tested the hypothesis that an isometric resistance training paradigm targeting the medial gastrocnemius of adult rodents is effective in preventing muscle atrophy during the early stages of hindlimb unloading by maintaining normal activation of the insulin receptor substrate-1 (IRS-1)/phosphoinositide-3 kinase (PI3K)/Akt signaling pathway. This pathway has been shown to simultaneously create an anabolic response while inhibiting processes upregulating catabolic processes involving expression of key enzymes in the ubiquitination of proteins for degradation. The findings show that during the 5 days of unloading 1) absolute medial gastrocnemius muscle weight reduction occurred by ∼20%, but muscle weight corrected to body weight was not different from normal weight-bearing controls ( P < 0.05); 2) normalized myofibril fraction concentration and content were decreased; and 3) a robust isometric training program, known to induce a hypertrophy response, failed to maintain the myofibril protein content. This response occurred despite fully blunting the increases in the mRNA for of atrogin-1, MURF-1, and myostatin, e.g., sensitive gene markers of an activated catabolic state. Analyses of the IRS-1/PI3K/Akt markers indicated that abundance of IRS-1 and phosphorylation state of Akt and p70S6 kinase were decreased relative to normal control rats, and the resistance training failed to maintain these signaling markers at normal regulatory level. Our findings suggest that to fully prevent muscle atrophy responses affecting the myofibril system during unloading, the volume of mechanical stress must be augmented sufficiently to maintain optimal activity of the IRS-1/PI3K/Akt pathway to provide an effective anabolic stimulus on the muscle.
Functional Properties of Grasping-Related Neurons in the Ventral Premotor Area F5 of the Macaque Monkey
Authors: Raos Vassilis , Umiltá Maria-Alessandra , Murata Akira , Fogassi Leonardo , Gallese Vittorio
Published: October 2005

We investigated the motor and visual properties of F5 grasping neurons, using a controlled paradigm that allows the study of the neuronal discharge during both observation and grasping of many different three-dimensional objects with and without visual guidance. All neurons displayed a preference for grasping of an object or a set of objects. The same preference was maintained when grasping was performed in the dark without visual feedback. In addition to the motor-related discharge, about half of the neurons also responded to the presentation of an object or a set of objects, even when a grasping movement was not required. Often the object evoking the strongest activity during grasping also evoked optimal activity during its visual presentation. Hierarchical cluster analysis indicated that the selectivity of both the motor and the visual discharge of the F5 neurons is determined not by the object shape but by the grip posture used to grasp the object. Because the same paradigm has been used to study the properties of hand-grasping neurons in the dorsal premotor area F2, and in the anterior intraparietal area (AIP), a comparison of the functional properties of grasping-related neurons in the three cortical areas (F5, F2, AIP) is addressed for the first time.
α-Adrenoceptive Dual Modulation of Inhibitory GABAergic Inputs to Purkinje Cells in the Mouse Cerebellum
Authors: Hirono Moritoshi , Obata Kunihiko
Published: October 2005

Noradrenaline (NA) modulates synaptic transmission in various sites of the CNS. In the cerebellar cortex, several studies have revealed that NA enhances inhibitory synaptic transmission by β-adrenoceptor–and cyclic AMP–dependent pathways. However, the effects of α-adrenoceptor activation on cerebellar inhibitory neurotransmission have not yet been fully elucidated. Therefore we investigated the effects of the α1- or α2-adrenoceptor agonist on inhibitory postsynaptic currents (IPSCs) recorded from mouse Purkinje cells (PCs). We found that the nonselective α-adrenoceptor agonist 6-fluoro-norepinephrine increased both the frequency and amplitude of spontaneous IPSCs (sIPSCs). This enhancement was mostly mimicked by the selective α1-adrenoceptor agonist phenylephrine (PE). PE also enhanced the amplitude of evoked IPSCs (eIPSCs) and increased the frequency but not the amplitude of miniature IPSCs (mIPSCs). Moreover, PE decreased the paired-pulse ratio of eIPSCs and did not change γ-aminobutyric acid (GABA) receptor sensitivity in PCs. Conversely, the selective α2-adrenoceptor agonist clonidine significantly reduced both the frequency and the amplitude of sIPSCs. Neither eIPSCs nor mIPSCs were affected by clonidine. Furthermore, presynaptic cell-attached recordings showed that spontaneous activity of GABAergic interneurons was enhanced by PE but reduced by clonidine. These results suggest that NA enhances inhibitory neurotransmitter release by α1-adrenoceptors, which are expressed in presynaptic terminals and somatodendritic domains, whereas NA suppresses the excitability of interneurons by α2-adrenoceptors, which are expressed in presynaptic somatodendritic domains. Thus cerebellar α-adrenoceptors play roles in a presynaptic dual modulation of GABAergic inputs from interneurons to PCs, thereby providing a likely mechanism for the fine-tuning of information flow in the cerebellar cortex.
Anticipatory Activity of Motor Cortex in Relation to Rhythmic Whisking
Authors: Friedman Wendy A. , Jones Lauren M. , Cramer Nathan P. , Kwegyir-Afful Ernest E. , Zeigler H. Philip , Keller Asaf
Published: October 2005

Rats characteristically generate stereotyped exploratory (5–12 Hz) whisker movements, which can also be adaptively modulated. Here we tested the hypothesis that the vibrissal representation in motor cortex (vMCx) initiates and modulates whisking by acting on a subcortical whisking central pattern generator (CPG). We recorded local field potentials (LFPs) in vMCx of behaving Sprague-Dawley rats while monitoring whisking behavior through mystacial electromyograms (EMGs). Recordings were made during free exploration, under body restraint, or in a head-fixed animal. LFP activity increased significantly prior to the onset of a whisking epoch and ended prior to the epoch's termination. In addition, shifts in whisking kinematics within a whisk epoch were often reflected in changes in LFP activity. These data support the hypothesis that vMCx may initiate and modulate whisking behavior through its action on a subcortical CPG.
Gene expression profiling during increased fetal lung expansion identifies genes likely to regulate development of the distal airways
Authors: Sozo Foula , Wallace Megan J. , Zahra Valerie A. , Filby Caitlin E. , Hooper Stuart B.
Published: October 2005

Growth and development of the fetal lungs is critically dependent on the degree to which the lungs are expanded by liquid; increases in fetal lung expansion accelerate lung growth, whereas reductions in lung expansion cause lung growth to cease. The mechanisms mediating expansion-induced lung growth are unknown but likely include alterations in the expression of genes that regulate lung cell proliferation. Our aim was to isolate and identify genes that are up- or downregulated by increased fetal lung expansion. In chronically catheterized fetal sheep at 126 days gestational age (GA), the left lung was expanded for 36 h, while the right lung remained at a control level of expansion. Subtraction hybridization was used to isolate genes differentially expressed between the left and right lungs. Screening of ∼6,000 clones identified 1,138 and 118 cDNA fragments that were up- and downregulated by increased lung expansion, respectively. Northern blot analyses in separate groups of control fetuses and fetuses exposed to increased lung expansion were used to verify differential expression. Increased fetal lung expansion upregulated heat shock protein 47, thrombospondin-1, TROP2, tropoelastin, and tubulin-α3 in fetal lung tissue by ∼200–300%; connective tissue growth factor and cysteine-rich angiogenic inducer 61 were increased by 20–30%. Genes downregulated by increased fetal lung expansion included CCSP-related protein-1, elongation factor-1α and vitamin D3upregulated protein 1. We conclude that an increase in fetal lung expansion differentially regulates the expression of numerous genes in lung tissue, many of which have important putative roles in lung development, while the functions of others are currently unknown.
Genetic background affects cardiovascular responses to obstructive and simulated apnea
Authors: Iiyori Nao , Shirahata Machiko , O’Donnell Christopher P.
Published: October 2005

We have recently demonstrated that genetic background significantly impacts the blood pressure and heart rate response to hypoxia (Campen MJ, Tagaito Y, Li J, Balbir A, Tankersley CG, Smith P, Schwartz A, and O’Donnell CP. Physiol Genomics 20: 15–20, 2005). Because hypoxia is considered a mediator of the acute and chronic cardiovascular complications of obstructive sleep apnea, we investigated whether genetic factors also influence the cardiovascular response to experimentally induced obstructive apnea (OA) and simulated apnea (SA). In three strains of inbred mice (C57BL/6J, DBA/2J, and FVB/J) anesthetized with urethane (1.2 g/kg), apnea was induced at end-expiration for 5- and 10-s periods in spontaneously breathing (OA) and mechanically ventilated (SA; pancuronium, 0.2 mg/kg bolus + 0.003 mg·kg−1·min−1) animals before and after administration of an autonomic ganglionic blocker (hexamethonium, 20 mg/kg). In contrast to our previous findings with hypoxia, OA produced a marked hypertensive response in all three strains. However, strain impacted on the degree of bradycardia during OA, which was large in C57BL/6J and FVB/J mice and effectively absent in DBA/2J mice. In C57BL/6J but not FVB/J mice, the bradycardia was abolished with SA under mechanical ventilation. Cardiovascular responses to SA in all strains were eliminated by autonomic blockade. These data show that 1) DBA/2J mice, in contrast to the previous demonstration of marked bradycardia during hypoxia, unexpectedly do not produce bradycardia during apnea; 2) C57BL/6J mice exhibit a bradycardia that is dependent on input from thoracic afferents; and 3) FVB/J mice exhibit a bradycardia despite the loss of thoracic afferent input, consistent with a potent pressure response eliciting a baroreceptor-mediated bradycardia. Thus genetic background can affect both the pattern and magnitude of the cardiovascular response to apnea.