bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of exogenous γ-aminobutyric acid (GABA) on hepatic insulin-like growth factor I (IGF-I) and IGF-I binding protein (IGFBP-I) mRNA abundance following partial hepatectomy in rats
Authors: Minuk G. Y. , Kaita K. , Gauthier T. , Dembinski T. , Murphy L. J.
Published: April 2011

Insulin-like growth factor I (IGF-I) and IGF-I binding protein (IGFBP-I) are highly expressed in the liver and may play an important role in enhancing hepatic regeneration following partial hepatectomy in rats. Since hepatic levels of these growth factors are infuenced by pituitary growth hormone release, which in turn is regulated by systemic serum γ-aminobutyric acid (GABA) concentrations, we chose to examine the effects of elevated serum GABA concentrations on hepatic IGF-I and IGFBP-I mRNA abundance following partial hepatectomy in the rat. The results of our experiments revealed that at serum GABA concentrations similar to those associated with liver failure, peak hepatic IGF-I and IGFBP-I mRNA levels were significantly lower in GABA-treated rats compared with saline-treated controls (p < 0.05 and 0.01, respectively). To exclude a direct effect of GABA on hepatocyte IGF-I and IGFBP-I mRNA expression, suspensions of isolated hepatocytes were incubated in the presence and absence of exogenous GABA. In these experiments GABA treatment did not lower either IGF-I or IGFBP-I mRNA or protein levels. These findings suggest that increased concentrations of GABA in the systemic circulation could contribute to the impairment in hepatic regenerative activity that occurs in animals and humans with advanced liver failure.Key words: GABA, insulin-like growth factor, IFG-I, IGF-I binding protein, growth hormone, liver regeneration.
Effects of incremental cortisol and adrenalectomy on plasma corticosteroid binding capacity in fetal sheep
Authors: Jeffray Treena M. , Berdusco Edward T. M. , Challis John R. G. , Wallace Megan , Fowden Abigail
Published: April 2011

The effects of incremental cortisol infusion or fetal adrenalectomy on plasma corticosteroid-binding capacity (CBC) were examined in sheep fetuses during late gestation (term ≈ 150 days). Cortisol, infused from day 120 at 1.5 mg/day for the first 3 days, 2.5 mg/day for the next 5 days, and 3.5 mg/day for the final 2 days, stimulated a significant rise in plasma CBC and immunoreactive corticosteroid binding globulin (CBG). There was a significant positive correlation between individual values for total plasma cortisol concentrations and CBC values. In contrast, fetal adrenalectomy at day 115 prevented the rise in plasma CBC found in intact fetuses at term. These experiments show that exogenous cortisol, given in a manner that mimics the prepartum rise in fetal plasma cortisol, stimulates CBG biosynthesis, whereas abolition of the cortisol rise prevents the increase in CBG. The study provides strong support for the proposal that the prepartum increase in CBG biosynthesis in fetal sheep occurs in response to the progressive rise in adrenal cortisol output by the fetus towards term.Key words: corticosteroid binding globulin, cortisol, adrenalectomy, fetus, sheep.
Hypoxia-induced release of prostaglandins: mechanisms and sources of production in coronary resistance vessels of the isolated rabbit heart
Authors: Nakhostine Nabil , Nadeau Réginald , Laurent Charles E. , Cardinal René , Lamontagne Daniel
Published: April 2011

The mechanism of hypoxia-induced prostacyclin (PGI2) release was studied in isolated, modified Krebs–Henseleit buffer perfused rabbit hearts under constant-flow conditions. The contribution of vascular endothelium and the role of catecholamines and calcium influx through L-type calcium (Ca2+) channels in hypoxic release of PGI2 were investigated. Reduction in the perfusion solution [Formula: see text] (from 476 ± 13 to 127 ± 24 mmHg; 1 mmHg = 133.3 Pa) in the presence of glucose (5 mM) and pyruvate (2 mM) caused a significant release of 6-keto-PGF1α, the stable metabolite of PGI2 (from 3.0 ± 0.4 to 7.3 ± 2.0 pmol ∙ min−1 ∙ g−1, p < 0.05, n = 12), whereas no variation in washout of catecholamines in the perfusate was observed. Electrolysis of the perfusion buffer solution was used to destroy the endothelium. Endothelium impairment by electrolysis almost completely abolished the vasodilation induced by serotonin (5HT) and acetylcholine (ACh), without affecting that caused by papaverine. The basal release of 6-keto-PGF1α was significantly enhanced after electrolysis. However, its release during hypoxia was completely abolished. In a separate group of normal hearts, verapamil (10−7 M) completely blocked the release of 6-keto-PGF1α during hypoxia. Similar results were obtained in 15 mM KCl arrested hearts challenged with hypoxia. Under normoxic conditions, isoproterenol (10−7 M) induced a significant release of 6-keto-PGF1α (from 2.9 ± 0.5 to 5.3 ± 0.8 pmol ∙ min−1 ∙ g−1, p < 0.05, n = 9). To stimulate endogenous catecholamine release, hearts perfused with glucose-free buffer (pyruvate 14.8 mM) were submitted to hypoxia. Under these conditions, hypoxia was accompanied by an enhanced release of noradrenaline (from 1.3 ± 0.5 to 19.7 ± 7.8 pmol ∙ min−1 ∙ g−1). Despite the increased noradrenaline washout in effluent, the hypoxia-induced release of 6-keto-PGF1α, in glucose-free perfused hearts was not enhanced. Our results suggest that endothelial cells are the major site of PGI2 synthesis during hypoxia and that myocardial contractility is a prime factor involved in this process. Verapamil reduction of PGI2 release is most probably through its negative inotropic effect. Although exogenous β-adrenergic stimulation can induce PGI2 release, endogenous catecholamines do not appear to contribute to the hypoxia-induced release of PGI2.Key words: prostacyclin, endothelium, L-type calcium channel blockers, norepinephrine, glucose, hypoxia.
Discrimination by nimodipine, but not by nifedipine, between phasic and tonic contractions of guinea-pig taenia coli induced by K+ depolarization
Authors: Usune Sadaharu , Katsuragi Takeshi , Furukawa Tatsuo
Published: April 2011

Effects of Ca2+ channel blockers, such as nifedipine, nimodipine, gallopamil, verapamil, diltiazem, loperamide, Mn2+ and Ni2+, and papaverine, on contractile responses to K+ depolarization were evaluated in longitudinal muscles of taenia coli isolated from guinea-pig. Depolarization with high K+ solution (K+, 40 mM) produced a biphasic (phasic and tonic) contraction, which was inhibited by the above blockers in a concentration-dependent manner. Ratios of IC50 for the phasic contraction to IC50 for the tonic contraction of nimodipine, verapamil, gallopamil, nifedipine, loperamide, diltiazem, papaverine, Ni2+, and Mn2+ were 516.1, 73.7, 22.0, 6.4, 5.3, 4.9, 1.2, 0.7, and 0.1, respectively, indicating that nimodipine suppressed the tonic contraction more effectively than the phasic contraction. In a fluorescence study with fura 2, K+ depolarization elicited an increase in intracellular free Ca2+, [Ca2+]i, which was coupled with the phasic and tonic contraction. The increases in [Ca2+]i coupled with both types of the contraction were abolished by exposure to Ca2+-free solution. In addition, the increase of [Ca2+]i coupled with the phasic contraction was abolished by nifedipine, 10−7 M, but not by nimodipine, 10−7 M, whereas the increase with the tonic contraction was suppressed by both nifedipine and nimodipine. These findings suggest that the phasic and tonic contractions evoked by K+ depolarization are due to increases in [Ca2+]i via activation of respective nimodipine-resistant and nimodipine-sensitive Ca2+ channels in the longitudinal muscles of the taenia coli. Accordingly, nimodipine, but not nifedipine, appears to be a useful tool for distinguishing between the phasic and tonic contractions.Key words: guinea-pig taenia coli, phasic contraction, tonic contraction, nimodipine, nifedipine, intracellular free Ca2+.
Stimulation of brown adipose tissue activity in tumor-bearing rats
Authors: Oudart Hugues , Calgari Christiane , Andriamampandry Margaret , Maho Yvon Le , Malan André
Published: April 2011

Despite anorexia, cancer development is frequently accompanied by an increase of energy expenditure. Considering the pivotal role played by brown adipose tissue (BAT) in the energy metabolism of small mammals, we investigated the functional and compositional modification in BAT of anorexic tumor-bearing (Yoshida sarcoma) and pair-fed control rats. BAT thermogenic activity (assessed by maximal mitochondrial GDP binding) was 1.8-fold greater in tumor-bearing rats than in controls, while the thermogenic capacity (assessed by measurement of uncoupling protein) was unchanged. This suggests that tumor bearing had induced an unmasking of uncoupling protein sites. BAT hypertrophy and hyperplasia, characteristic of full-fledged BAT activation, did not occur. The mitochondrial oxidative capacity of BAT (assessed by cytochrome c oxidase activity) was 1.6-fold lower in tumor-bearing than in control rats. The main compositional modification observed in BAT of tumor-bearing rats was an increase in the saturation of cardiolipin fatty acids. These results suggest that the BAT stimulation induced by tumor bearing after 10 days is almost exclusively functional and that the tissue development is limited, probably by anorexia. However, a suppressive effect of anorexia inhibition by tumor bearing cannot be excluded.Key words: cancer cachexia, nonshivering thermogenesis, brown adipose tissue cardiolipins.
Thromboxane A2 does not act at the carotid sinus to mediate cardiovascular, adrenocorticotropin, cortisol, or blood gas responses
Authors: Cudd Timothy A
Published: April 2011

Thromboxane A2 (TxA2), well known as a vasoconstrictor and activator of platelets, also stimulates reflex cardiovascular, pituitary, adrenocortical, and blood gas responses, although the site of action is unknown. Previously we determined that the site of these actions is perfused by the carotid vasculature. The purpose of the present study was to test the hypothesis that TxA2 stimulates these responses by acting at the carotid sinus. The TxA2 mimetic U46619 (1 µg ·kg-1 ·min-1) or saline was infused into the carotid artery (CA) or vena cava in conscious, chronically instrumented carotid sinus denervated (CSD) or sham-operated sheep. Mean arterial pressure increased in all groups receiving U46619. Heart rate increased only in the CSD group receiving CA infusions of U46619. Adrenocorticotropic hormone (ACTH) and cortisol increased in the sham and CSD groups receiving CA U46619, and responses were not different between sham and CSD groups. PaCO2 values were higher in all CSD treatment groups compared with sham treatment groups. Arterial pH increased and PaCO2 decreased in both the sham and CSD groups in response to CA U46619. Although PaCO2 values were higher overall in the CSD group, the magnitude of change in response to U46619 infusions was similar in sham and CSD animals. There was no difference in pHa between CSD and sham groups. Hematocrit and PaO2 did not change. We conclude that TxA2 does not act at the carotid sinus, as responses to U46619 infusions in CSD animals were not different in the cases of ACTH, cortisol, and blood gases, or were enhanced rather than diminished in the case of heart rate. These findings support a hypothesis that TxA2 acts at the brain to mediate cardiovascular, pituitary, adrenocortical, and blood gas responses.Key words: ACTH, thromboxane A2, blood pressure, heart rate, prostaglandins, U46619.
Vascular wall reactivity in conductance and resistance arteries: differential effects of insulin resistance
Authors: O'Brien Sheila F , McKendrick Joyce D , Radomski Marek W , Davidge Sandra T , Russell James C
Published: April 2011

Insulin resistance is associated with an increased risk of cardiovascular disease that is probably related to abnormalities of vascular wall function. The JCR:LA-cp rat is a unique animal model of human vascular disease that exhibits a profound insulin resistance, vasculopathy, and cardiovascular disease, and allows study of the relationships between insulin resistance and vascular function. Conductance and resistance arteries serve different functions, thus vascular disease may affect these types of artery differently. Concentration-response curves to norepinephrine, phenylephrine, and acetylcholine were studied in conductance vessels (aortic rings) and resistance vessels (mesenteric arteries) from 12-week-old male obese and lean JCR:LA-cp rats. The aortic rings and mesenteric arteries from obese rats showed increased maximal response to phenylephrine compared with those from lean rats, whereas only the mesenteric arteries from obese rats showed increased maximal response to norepinephrine. In aortic rings, relaxation to acetylcholine was similar for both genotypes, but the mesenteric arteries of obese rats showed impaired relaxation to acetylcholine. We conclude that the sensitivity to vasoconstriction is enhanced in aortic rings and mesenteric arteries of obese male JCR:LA-cp rats, but endothelial function is impaired only in the mesenteric resistance arteries of these animals. Hence functional aberrations in the obese, insulin-resistant state are more pronounced in mesenteric resistance arteries than in a major conductance artery.Key words: insulin resistance, arterial contraction and relaxation, resistance vessels, JCR:LA-cp rat, smooth muscle cells,endothelium.
Analysis of effects of bosentan (Ro 47-0203), a nonpeptide endothelin ETA/ETB receptor antagonist, in the hind-limb vascular bed of the cat
Authors: Champion Hunter C , Estrada Lance S , Estrada Leslie N , Filep Janos G , Kadowitz Philip J
Published: April 2011

The effects of bosentan (Ro 47-0203), an endothelin A and B receptor antagonist, on responses to endothelin-1, sarafotoxin 6c, angiotensin II, and arginine vasopressin were investigated in the hind-limb vascular bed of the cat. Under constant-flow conditions, intraarterial injections of endothelin-1 and sarafotoxin 6c induced biphasic changes in hind-limb perfusion pressure characterized by an initial decrease followed by a secondary increase in perfusion pressure. The vasodilator and vasoconstrictor components of the biphasic responses to endothelin-1 and sarafotoxin 6c were reduced by bosentan, and the endothelin receptor antagonist reduced baseline systemic arterial and hind-limb perfusion pressures. Bosentan decreased vasoconstrictor responses to lower doses of angiotensin II, whereas responses to higher doses of angiotensin II and responses to vasopressin, U46619, BAY K8644, norepinephrine, acetylcholine, bradykinin, levcromakalim, PGE1, adrenomedullin, and calcitonin gene-related peptide were not altered. Vasoconstrictor responses to ET-1 were not altered by the angiotensin AT1 receptor antagonist DuP 532 or the AT2 receptor antagonist PD123,319. The results of the present study show that bosentan attenuates vasodilator and vasoconstrictor responses to endothelin-1 and sarafotoxin 6c and vasoconstrictor responses to lower doses of angiotensin II in the hind-limb vascular bed of the cat. These results suggest that endothelin may be involved in mediating responses to lower doses of angiotensin II and in the maintenance of baseline tone in the systemic vascular bed of the cat.Key words: angiotensin II, bosentan (Ro 47-0203), endothelin, regional vascular bed, endothelial-derived peptide.
Synaptic activity, induced rhythmic discharge patterns, and receptor subtypes in enriched primary cultures of embryonic rat motoneurones
Authors: Wallis D I , Elliott P , Foster G A , Stringer BMJ
Published: April 2011

Long-term cultures of ventral horn neurones from embryonic rat spinal cord were established, after enrichment using density gradient centrifugation, to give a high proportion of cells (>82%) with motoneurone characteristics. Neurones were grown on spinal cord glial monolayers for 4-83 days and investigated using whole-cell patch clamp. Synaptic activity interrupted by periods of quiescence increased in frequency with culture age and was suppressed by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and strychnine. However, strychnine (10 µM) or bicuculline (10-30 µM) or removal of Mg2+ alone induced patterned rhythmic bursting. Glutamate (3-300 µM), alpha -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA, 0.3-30 µM), and kainate (1-300 µM) evoked inward currents, as did N-methyl-D-aspartic acid (NMDA, 100 µM) in the absence of Mg2+ and presence of glycine (3-10 µM). Inward currents carried by Cl- were elicited by glycine (10-300 µM) and GABA (1-300 µM), while adenosine (1-10 µM) and cyclopentyladenosine (10 nM - 1 µM) evoked a K+-dependent hyperpolarization. 5-HT, GABAB, purine A, and metabotropic glutamate receptors modulated synaptic excitation of presumed motoneurones. The results suggest that long-term cultures, containing more than 82% developing motoneurones, are able to generate rhythmic bursting; they respond to many of the neurotransmitters that are likely to be released onto motoneurones developing in vivo.Key words: embryonic rat motoneurones, culture, amino acid receptors, adenosine, spinal cord.
Relative resistance of functional β2-adrenoceptor-mediated smooth muscle responses to in vitro desensitization
Authors: Martin S W , Broadley Kenneth J
Published: April 2011

The effects of in vitro incubation of rat isolated left atria, pulmonary artery rings, and aortic rings with isoprenaline (10-6M for 6 h) were examined to compare the degree of desensitization of β1- and β2-adrenoceptor-mediated functional responses. The experimental protocols were carefully controlled to exclude influence from persistence of agonist in the tissues after the prolonged exposures, time-dependent changes in tissue sensitivity, and the methods of plotting the data. Concentration-response curves for isoprenaline were constructed before incubation with isoprenaline and, after washout during 1 h, a second curve was obtained. Two protocols were employed: firstly, the preincubation curve was constructed to ensure that a maximum response was obtained (>10-6M) and, secondly, the preincubation curve was constructed to a maximum isoprenaline concentration of 10-6M. Preincubation curves were corrected for time-dependent changes in sensitivity from sham-incubation control experiments. There was significant desensitization of the β1-adrenoceptor-mediated positive inotropic responses of the left atria, using both protocols, seen as rightward shifts (dose ratios: 4.48 ± 1.12 and 8.39 ± 2.3) of the concentration-response curves and depression of the maximum responses (77.0 ± 3.2 and 60.8 ± 5.5%). In contrast, the β2-adrenoceptor-mediated relaxations of the noradrenaline-constricted pulmonary artery and aorta did not display a significant loss of sensitivity. When the relaxation responses were plotted as a percentage of the noradrenaline-induced tone, there was no significant rightward shift of the concentration-response curves in the pulmonary artery (dose ratios: 2.82 ± 1.33 and 2.24 ± 0.62) or aorta (dose ratios: 1.43 ± 0.62 and 1.31 ± 0.27) and thus no desensitization.Key words: rat atria, pulmonary artery, aorta, β-adrenoceptors, desensitization.
Glutaminergic and adrenergic receptors expressed on adult guinea pig Schwann cells in vitro
Authors: Fink T , Davey D F , Ansselin A D
Published: April 2011

We have investigated the responsiveness of adult guinea pig Schwann cells to a range of neuroligands, using ratiometric calcium imaging. The majority of cells responded to ATP (90 ± 4%), adrenaline (57 ± 5%), and noradrenaline (61 ± 5%), as well as glutamate (60 ± 5%). The number of cells responding to glutamate increased significantly (90 ± 4%; p < 0.01) when the cells were grown in excitatory amino acid (EAA) free medium, indicating EAA-induced downregulation. Only a small number of cells (9 ± 2%) responded to acetylcholine. Agonist and antagonist experiments show that these adult Schwann cells predominantly express ionotropic glutaminergic receptors (N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isooxazolepropionic acid (AMPA), and kainate) as well as α1-, α2-, and β-adrenoreceptors. We conclude that Schwann cells derived from adult guinea pigs express a variety of neuroligand receptors when established in culture and are particularly rich in glutamate receptors. This probably reflects a de-differentiated state important to development and regeneration.Key words: glia, neuroligands, calcium imaging, ATP, acetylcholine, cell culture.
Arterial versus venous changes in vascular capacitance during nitroprusside infusion: a vascular modelling study
Authors: Wang Steven Y , Scott-Douglas Nairne W , Manyari Dante E , Tyberg John V
Published: April 2011

The distributions of nitroprusside (NP) induced changes in vascular capacitance, arterial versus venous, are unknown. We measured canine ileal arterial and venous pressures and total (isolated loop) vascular volumes (scintigraphy), before and during NP infusion. NP sufficient to decrease perfusion pressure by 30% increased total vascular volume to 111 ± 3% (± SEM) of control (p < 0.01). Increasing flow to restore perfusion pressure increased volume 4% more (p < 0.01). Assuming a two-compartment model and on the basis of the literature data, changes in venous capacitance were estimated and compared with arterial capacitance. During constant-flow perfusion, NP increased venous volume by 10.0% (vs. 18.1%, arterial). When flow was increased to restore pressure, venous volume increased by another 3.7% (vs. 2.6%, arterial). Assuming an original arterial to venous volume ratio of 133/1033, the final, constant-pressure increase in venous volume was almost 4 times the arterial increase. In conclusion, the increase in vascular volume during NP infusion was due primarily to similar-magnitude, active increases in venous and arterial capacitances (i.e., rightward shifts in pressure-volume relations). However, as venous volume is so much larger than arterial, the NP-induced increase in venous volume was greater.Key words: blood volume distribution, pressure-volume relations, veins, arteries.
Activation of bulbospinal serotonergic neurons during cold exposure
Authors: Passerin Alicia M , Bellush Linda L , Henley William N
Published: April 2011

In a four-part study, we expand on our previous report that bulbospinal serotonin (5HT) neuronal activation occurs with 24 h of cold exposure. To characterize temporal aspects, rats were exposed to 3°C or were maintained at 22°C for 2, 8, 48, or 96 h (experiment 1) or for 15, 30, or 60 min (experiment 2). To ensure that cold-induced changes in 5HT activity were not due to disturbances in diurnal pattern, rats in experiment 3 were exposed to cold (8 h) during the dark cycle. To explore the hypothesis that cold-induced 5HT activation is part of a broad metabolic response that includes activation of the sympathetic nervous system, metabolically impaired (hypothyroid) rats were exposed to 8°C in experiment 4. Significant increments in 5-hydroxyindoleacetic acid (5HIAA) concentration were evident by 60 min of cold exposure and existed at all later time points measured. These findings were most robust in spinal cord and rostral brainstem. Activation in spinal cord was also found when rats were exposed to 8 h of cold during the dark cycle, the active period for rats. In experiment 4, hypothyroid rats exhibited significantly greater norepinephrine excretion compared with control rats exposed to the same cold stimulus; this finding was accompanied by significantly greater increments in 5HIAA concentration in rostral brainstem and spinal cord of hypothyroid rats. In addition, significant elevations in tryptophan concentration were noted throughout the brainstem and spinal cord of cold-exposed, hypothyroid rats relative to room temperature, hypothyroid rats. This finding suggested that elevations in 5HIAA concentration in these rats were due to increases in precursor availability. The implications of these findings relative to autonomic and metabolic control are discussed.Key words: serotonin, spinal cord, raphe, cold, sympathetic nervous system.
Nonpeptide endothelin receptor antagonists attenuate the pressor effect of diaspirin-crosslinked hemoglobin in rat
Authors: Rioux Francis , Harvey Nathalie , Moisan Steve , Larivière Richard , Lebel Marcel , Grose John H , Burhop Kenneth
Published: April 2011

Endothelin 1 (ET-1) is a potent vasoactive and mitogenic peptide that is thought to participate in the hemodynamic effects elicited by drugs that block the biosynthesis and release of endothelium-derived nitric oxide (NO), such as NO synthase inhibitors. Using the nonpeptide endothelin receptor antagonists bosentan and LU-135252, we tested the hypothesis that endothelins contribute to the pressor activity of diaspirin-crosslinked hemoglobin (DCLHb), a hemoglobin-based oxygen carrier, whose pressor activity in mammals is attributed primarily to a scavenging action towards NO. The NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME), ET-1, and noradrenaline (NA) were used as reference drugs. Bosentan markedly reduced the pressor effects elicited by DCLHb, L-NAME, and ET-1, but not those evoked by NA. LU-135252 attenuated the pressor effect elicited by DCLHb and ET-1, but not that produced by L-NAME or NA. The decreases in heart rate associated with the pressor effect of DCLHb and L-NAME were reduced by LU-135252, whereas only those elicited by DCLHb were attenuated by bosentan. In contrast with bosentan, LU-135252 caused a decrease in the baseline blood pressure and heart rate. These results suggest that endothelins may participate in the pressor activity of DCLHb. They suggest also that nonpeptide endothelin receptor antagonists such as bosentan or LU-135252 may be useful to counteract endothelin-mediated undesirable hemodynamic effects of drugs that inhibit the activity of the NO system.Key words: hemoglobin, endothelin, nitric oxide, blood pressure, diaspirin-crosslinked hemoglobin (DCLHb).
Effects of ethanol and diabetes on galactose oxidative metabolism and elimination in rats
Authors: Mion François , Géloën Alain , Minaire Yves
Published: April 2011

Blood galactose clearance after an intravenous galactose load has been widely used for years as an index of liver function. We developed a noninvasive [13C]galactose breath test, which explores galactose oxidative metabolism; this test is well correlated with liver fibrosis in patients with chronic viral hepatitis. The goal of this study was to evaluate the influence of nonhepatic factors such as diabetes and ethanol on whole-body galactose clearance (measured as the serum galactose elimination capacity test) and oxidative metabolism (measured as the [13C]galactose-induced breath13CO2production) in rats. Acute ethanol administration induced a significant decrease of galactose clearance and13CO2production. There was a significant correlation between the amount of ethanol given and the inhibition of galactose metabolism (R2= 0.72, p < 0.0001). In streptozotocin-induced diabetic rats, the [13C]galactose-induced breath13CO2production was significantly reduced (p < 0.0001) and normalized by insulin treatment. However, diabetes did not decrease whole-body galactose clearance, indicating an isotopic dilution of [13C]glucose produced from [13C]galactose metabolism into the enlarged glucose pool. These results must be taken into account when using the [13C]galactose breath test as a quantitative liver function test.Key words: stable isotopes, carbon 13, liver functions, breath tests.
Lateral hypothalamic serotonergic responsiveness to food intake in rat obesity as measured by microdialysis
Authors: Mori Rosana CT , Guimarães Regina B , Nascimento Cláudia MO , Ribeiro Eliane B
Published: April 2011

The hypothalamic serotonergic system is involved in the regulation of food ingestion and energy metabolism. Since disturbances of both energy intake and expenditure can contribute to obesity, the objective of the present study was to evaluate the serotonergic response stimulated by food ingestion in two different models of obesity: the hyperphagic Zucker and the hypophagic and hypometabolic, monosodium glutamate (MSG) obese Wistar rat. For this we used microdialysis to examine the release of 5-hydroxytryptamine (serotonin, 5HT) and 5-hydroxyindoleacetic acid (5HIAA) in the lateral hypothalamus. Daily intake of MSG-obese rats was 40% lower while that of Zucker obese rats was 60% higher than that of the respective lean controls. In overnight-fasted animals, 20-min microdialysate samples were collected before (basal release) and during a 2-h period of access to a balanced palatable food mash. The animals began to eat during the first 20 min of food access, and food consumption was similar among the four groups in all six individual 20-min periods recorded. Ingestion of food increased 5HT release in all groups. In MSG-obese and lean Wistar rats, 5HT levels were similarly elevated during the whole experimental period. In the Zucker strain, 5HT increments of basal release tended to be higher in obese than in lean rats at 20 and 40 min, and a significantly higher increment was observed at 60 min after food access (40 and 135% for lean and obese, respectively). The area under the curve relating serotonin levels to the 120 min of food availability was significantly higher in Zucker obese (246.7 ± 23.3) than MSG-obese (152.7 ± 13.4), lean Wistar (151.9 ± 11.1), and lean Zucker (173.5 ± 24.0) rats. The present observation, of a food-induced serotonin release in the lateral hypothalamus of lean Wistar and Zucker rats, evidences that 5HT in the lateral hypothalamus is important in the normal response to feeding. In obese animals, the serotonin response was similar to (in the hypophagic-hypometabolic MSG model) or even higher than (in the hyperphagic Zucker model) that seen in the respective lean controls. This result indicates that the energy homeostasis disturbances of both these obesity models may not be ascribed to an impairment of the acute lateral hypothalamic serotonin response to a dietary stimulus.Key words: serotonin, food intake, brain microdialysis, lateral hypothalamus, monosodium glutamate obesity, Zucker obesity.
Resting metabolic rate and thermic effects of a sucrose-sweetened soft drink during the menstrual cycle in young Chinese women
Authors: Li Edmund TS , Tsang Louisa BY , Lui Susan SH
Published: April 2011

The resting metabolic rate (RMR) and thermic effects (TEF) of a sucrose-sweetened soft drink in a group (n = 19) of ovulating young Chinese women were determined by indirect calorimetry in the midfollicular and midluteal phases of the menstrual cycle. Urinary luteinizing hormone surge was used to confirm ovulation. The RMR was measured twice in each phase and found to be similar (F(1,18) = 0.863) across the follicular (5018 kJ/24 h) and the luteal (5098 kJ/24 h) phases. Within each phase and on separate days, subjects were given water (280 mL) or sucrose-sweetened soft drink (539 kJ). Soft drink, but not water, consumption increased energy expenditure over a period of 45 min. Compared with the follicular phase, a small but significant increase in TEF (kJ/45 min) was observed in the luteal phase (t = 2.434, p < 0.05). Energy expenditure after drinking the soft drink, however, was similar in the two phases. RMR was positively correlated with TEF (r = 0.613, p < 0.01) and net TEF (r = 0.648, p < 0.005) in the luteal but not the follicular phase. In ovulating women, the thermic effect of sucrose is influenced by the phase of the menstrual cycle.Key words: menstrual cycle, resting metabolic rate, thermic effect of food, sucrose, Chinese women.
Na+,K+pump and Na+-coupled ion carriers in isolated mammalian kidney epithelial cells: regulation by protein kinase C
Authors: Gagnon France , Hamet Pavel , Orlov Sergei N
Published: April 2011

This review updates our current knowledge on the regulation of Na+/H+exchanger, Na+,K+,Cl-cotransporter, Na+,Picotransporter, and Na+,K+pump in isolated epithelial cells from mammalian kidney by protein kinase C (PKC). In cells derived from different tubule segments, an activator of PKC, 4beta-phorbol 12-myristate 13-acetate (PMA), inhibits apical Na+/H+exchanger (NHE3), Na+,Picotransport, and basolateral Na+,K+cotransport (NKCC1) and augments Na+,K+pump. In PMA-treated proximal tubules, activation of Na+,K+pump probably plays a major role in increased reabsorption of salt and osmotically obliged water. In Madin-Darby canine kidney (MDCK) cells, which are highly abundant with intercalated cells from the collecting duct, PMA completely blocks Na+,K+,Cl-cotransport and decreases the activity of Na+,Picotransport by 30-40%. In these cells, agonists of P2purinoceptors inhibit Na+,K+,Cl-and Na+,Picotransport by 50-70% via a PKC-independent pathway. In contrast with MDCK cells, in epithelial cells derived from proximal and distal tubules of the rabbit kidney, Na+,K+,Cl-cotransport is inhibited by PMA but is insensitive to P2receptor activation. In proximal tubules, PKC-induced inhibition of NHE3 and Na+,Picotransporter can be triggered by parathyroid hormone. Both PKC and cAMP signaling contribute to dopaminergic inhibition of NHE3 and Na+,K+pump. The receptors triggering PKC-mediated activation of Na+,K+pump remain unknown. Recent data suggest that the PKC signaling system is involved in abnormalities of dopaminergic regulation of renal ion transport in hypertension and in the development of diabetic complications. The physiological and pathophysiological implications of PKC-independent regulation of renal ion transporters by P2purinoceptors has not yet been examined.Key words: Na+/H+exchanger, Na+,K+,Cl-and Na+,Picotransporters, Na+,K+pump, protein kinase C, P2purinoceptor.
Increased flow rate and papaverine increase K+ exchange in perfused rat hind-limb skeletal muscle
Authors: Lindinger Michael I , Hawke Thomas J
Published: April 2011

This study tested the hypothesis that increases in perfusate flow rate result in increased rates of unidirectional and net K+ transport in rat hind-limb skeletal muscle at rest. Ten neurally and vascularly isolated hind limbs, with arterial and venous catheters placed proximal to the popliteal region, were perfused for 10-min periods at flow rates (presented in a random order) of 0.27, 0.42, 0.63, 0.84, or 1.05 mL·min-1·g-1. Potassium extraction and unidirectional K+ influx were determined using 42K, and arterial perfusion pressure was measured continuously. Increases in flow rate resulted in decreases in K+ extraction and increases in unidirectional K+ influx, unidirectional K+ efflux, and net K+ efflux. The increases in K+ flux were associated with increases in oxygen uptake, glucose uptake, and lactate release. In separate experiments (n = 5), the vasodilator papaverine (10-4 M) did not further vasodilate the vasculature of resting hind limbs, suggesting that the hind limbs in this preparation were fully vasodilated. Papaverine, at constant flow, resulted in a nearly 1.5-fold increase in K+ extraction, a doubling of unidirectional K+ influx, and increases in unidirectional K+ efflux and net K+ efflux. It is concluded that physiological increases in flow rate result in increases in K+ transport in isolated, perfused rat hind-limb skeletal muscle. Furthermore, papaverine appeared to induce an increase in skeletal muscle membrane permeability to K+.Key words: K+ transport, potassium extraction, Na-K ATPase, sarcolemma, plasma flow, vasodilator, VO2.
Augmentation and suppression of action potentials by estradiol in the myometrium of pregnant rat
Authors: Inoue Yoshihito , Okabe Koji , Soeda Hiroyuki
Published: April 2011

The purpose of this study was to investigate the actions of estradiol on spontaneous and evoked action potentials in the isolated longitudinal smooth muscle cells of the pregnant rat. Single cells were obtained by enzymatic digestion from pregnant rat longitudinal myometrium. Action potentials and currents were recorded by whole-cell current-clamp and voltage-clamp methods, respectively. The acute effects of 17β-estradiol on action potentials and inward and outward currents were investigated. The following results were obtained. The average resting membrane potential of single myometrial cells was -54 mV (n = 40). In many cells, an electrical stimulation evoked a membrane depolarization, and action potentials were superimposed on the depolarization. In some cells, spontaneous action potentials were observed. Estradiol (30 µM) slightly depolarized the membrane (ca. 5 mV) and attenuated the generation of action potentials by reducing the frequency and amplitude of the spikes. Afterhyperpolarization was also attenuated by estradiol (30 µM). On the other hand, in 5 of 35 cells, estradiol increased the first spike amplitude and action potential duration, while frequency of the spike generation and afterhyperpolarization were inhibited. In voltage-clamped muscle cells, estradiol inhibited both inward and outward currents. Acute inhibition or augmentation of spike generation by estradiol is due to the balance of inhibition of inward and outward currents. Inhibition of both currents also prevented afterhyperpolarization, causing potential-dependent block of Ca spikes.Key words: estradiol, progesterone, rat myometrium, action potential, channel current.
Physiological roles of matrix metalloproteinases: implications for tumor growth and metastasis
Authors: Forget Marie-Annick , Desrosiers Richard R , Béliveau Richard
Published: April 2011

Physiological processes involving remodelling of the extracellular matrix, such as wound healing, embryogenesis, angiogenesis, and the female reproductive cycle, require the activity of matrix metalloproteinases (MMPs). This group of proteases degrades basal membranes and connective tissues and plays an essential role in the homeostasis of the extracellular matrix. An imbalance in the expression or activity of MMPs can have important consequences in diseases such as multiple sclerosis, Alzheimer's disease, or the development of cancers. Because of the pathophysiological importance of MMPs, their activity is highly controlled in order to confine them to specific areas. An activation cascade, initiated by the proteolysis of plasminogen, cleaves proMMPs, and every step is controlled by specific activators or inhibitors. MMPs destabilize the organization of the extracellular matrix and influence the development of cancer by contributing to cell migration, tumor cell proliferation, and angiogenesis. Accordingly, these proteases possess an important role in cell-matrix interactions by affecting fundamental processes such as cell differentiation and proliferation. Therefore, the characterization of MMPs involved in specific types and stages of tumors will significantly improve the diagnosis and treatment of these cancers in humans.Key words: matrix metalloproteinases, physiology, cancer, cell invasion, extracellular matrix.
Taurine attenuates hypertension and improves insulin sensitivity in the fructose-fed rat, an animal model of insulin resistance
Authors: Anuradha C V , Balakrishnan S D
Published: April 2011

Fructose feeding induces moderate increases in blood pressure levels in normal rats, which is associated with hyperinsulinemia, insulin resistance, and impaired glucose tolerance. Increased vascular resistance, sodium retention, and sympathetic overactivity have been proposed to contribute to the blood pressure elevation in this model. Taurine, a sulphur-containing amino acid, has been reported to have antihypertensive and sympatholytic actions. In the present study, the effects of taurine on blood pressure, plasma levels of glucose and insulin, glucose tolerance, and renal function were studied in fructose-fed rats. Fructose-fed rats had higher blood pressure and elevated plasma levels of insulin and glucose. The plasma glucose levels were higher in fructose-fed rats than in controls at 15, 30, and 60 min after the oral glucose load. Treatment with 2% taurine in drinking water prevented the blood pressure elevation and attenuated the hyperinsulinemia in fructose-fed rats. The exaggerated glucose levels in response to the oral glucose load was also prevented by taurine administration. Thus, taurine supplementation could be beneficial in circumventing metabolic alterations in insulin resistance.Key words: fructose feeding, hypertension, hyperinsulinemia, renal function, taurine.
Beneficial effects of combined terlipressin and tetramethylpyrazine administration on portal hypertensive rats
Authors: Chang Fang-Chi , Huang Yi-Tsau , Lin Han-Chieh , Hong Chuang-Ye , Lin Jaung-Geng , Chen Ke-Ji
Published: April 2011

The purpose of this study was to investigate the therapeutic effects of terlipressin (TP) alone or in combination with tetramethylpyrazine (TMP) on anesthetized portal hypertensive rats. Portal hypertension was induced by either partial portal vein ligation (PVL, without cirrhosis) or bile duct ligation (BDL, with cirrhosis) in Sprague-Dawley rats. Each PVL or BDL rat received only one of the two regimens: vehicle for 3 min followed by TP (0.017 mg·kg-1·min-1 for 3 min) or TMP (10 mg·kg-1·min-1 for 3 min) followed by TP. In PVL rats, infusion of vehicle followed by TP induced significant reduction of portal venous pressure (PVP, -15.0 ± 1.0%) and prominent elevation of mean arterial pressure (MAP, 57.3 ± 8.1%) as well as total peripheral resistance (TPR, 113 ± 11%) from baseline, and there was a cardiodepressant response (cardiac index, CI, -26.3 ± 1.1%). Infusion of TMP followed by TP induced significant reduction of PVP (-20.3 ± 0.4%) and CI (-9.9 ± 1.2%) and significant elevation of MAP (31.3 ± 2.5%) and TPR (46.0 ± 4.1%) from baseline. In BDL rats, infusion of vehicle followed by TP also induced significant reduction of PVP (-13.8 ± 1.7%) but an increase in MAP (57.1 ± 2.2%) and TPR (101 ± 6%) from baseline, and there also was a cardiodepressant response (CI, -21.4 ± 2.3%). Infusion of TMP followed by TP induced significant reduction of PVP (-18.9 ± 1.4%) and CI (-11.9 ± 2.1%), but an increase in MAP (36.2 ± 2.5%) and TPR (55.0 ± 5.2%). Compared with vehicle followed by TP, TMP not only significantly enhanced portal hypotensive (PVP reduction) effects of TP but also attenuated the systemic pressor (MAP and TPR elevation) and cardiodepressant (CI reduction) effects of TP in both PVL and BDL rats. Our results suggest that TP, alone or in combination with TMP, induced portal hypotensive effects in two models of portal hypertensive rats. Combination of TP and TMP was beneficial in enhancing portal hypotensive effects of TP and ameliorating the systemic pressor and cardiodepressant effects of TP.Key words: terlipressin, tetramethylpyrazine, cirrhosis, portal hypertension, hemodynamics.
The HISS story overview: a novel hepatic neurohumoral regulation of peripheral insulin sensitivity in health and diabetes
Authors: Lautt W Wayne
Published: April 2011

Data are reviewed that are consistent with the following working hypothesis that proposes a novel mechanism regulating insulin sensitivity, which when nonfunctional, leads to severe insulin resistance. Postprandial elevation in insulin levels activates a hepatic parasympathetic reflex release of a putative hepatic insulin-sensitizing substance (HISS), which activates glucose uptake at skeletal muscle. Insulin causes HISS release in fed but not fasted animals. The reflex is mediated by acetylcholine and involves release of nitric oxide in the liver. Interruption of the release of HISS is achieved by surgical denervation of the anterior hepatic nerve plexus, muscarinic receptor blockade, or nitric oxide synthase antagonism and leads to immediate severe insulin resistance. The nitric oxide donor, SIN-1, reverses L-NAME-induced insulin resistance. Denervation-induced insulin resistance is reversed by intraportal but not intravenous administration of acetylcholine or SIN-1. Liver disease is often associated with insulin resistance; the bile duct ligation model of liver disease results in parasympathetic neuropathy and insulin resistance that is reversed by intraportal acetylcholine. Possible relevance of this HISS-dependent control of insulin action to insulin resistance in diabetes, liver disease, and obesity is discussed.Key words: insulin resistance, parasympathetic nerves, liver, obesity, nitric oxide.
Amplification of calcium signals at dendritic spines provides a method for CNS quantal analysis
Authors: Wang Sabrina , Prange Oliver , Murphy Timothy H
Published: April 2011

It has been proposed that the small volume of a dendritic spine can amplify Ca2+signals during synaptic transmission. Accordingly, we have performed calculations to determine whether the activation of N-methyl-D-aspartate (NMDA) type glutamate receptors during synaptic transmission results in significant elevation in intracellular Ca2+levels, permitting optical detection of synaptic signals within a single spine. Simple calculations suggest that the opening of even a single NMDA receptor would result in the influx of ~ 310 000 Ca2+ions into the small volume of a spine, producing changes in Ca2+levels that are readily detectable using high affinity Ca2+indicators such as fura-2 or fluo-3. Using fluorescent Ca2+indicators, we have imaged local Ca2+transients mediated by NMDA receptors in spines and dendritic shafts attributed to spontaneous miniature synaptic activity. Detailed analysis of these quantal events suggests that the current triggering these transients is attributed to the activation of <10 NMDA receptors. The frequency of these miniature synaptic Ca2+transients is not randomly distributed across synapses, as some synapses can display a >10-fold higher frequency of transients than others. As expected for events mediated by NMDA receptors, miniature synaptic Ca2+transients were suppressed by extracellular Mg2+at negative membrane potentials; however, the Mg2+block could be removed by depolarization.Key words: miniature release, N-methyl-D-aspartate (NMDA), calcium, glutamate, spine.
Sensing of extracellular calcium by neurones
Authors: Xiong Zhi-Gang , MacDonald J F
Published: April 2011

Transient changes in the intracellular concentration of Ca2+ provide a major signal for the regulation of many ion channels and enzymes in central neurones. In contrast, changes in extracellular Ca2+ are thought to play little or no signaling role. However, concentrations of extracellular calcium in the central nervous system do change dramatically during intense physiological and pathological stimulation, and recent studies have identified a number of membrane proteins that can sense and respond to changes in extracellular Ca2+. These include the recently cloned Ca2+-sensing receptor, hemi-gap-junction channels, and a potential Ca2+-sensing cation channel. Lowering extracellular Ca2+ strongly depolarizes and excites cultured hippocampal neurones. The excitation can be detected with decreases from physiological concentrations of as little as 100 µM. The depolarization results from activation of a nonselective cation current, which is sensitive to block by divalent and polyvalent cations. In outside-out patches, lowering Ca2+ induces a single-channel current with a conductance of 36 pS. Activation of this cation channel, in response to decreases in extracellular Ca2+, likely plays a key role in a positive feedback system of excessive neuronal depolarization, which accompanies intense excitatory activity in the hippocampus.Key words: nonselective cation channel, calcium-sensing receptor, calcium-sensing channel, hemi-gap channels, extracellular calcium.