bluuebunny/crossref_metadata_2025 huggingface dataset:
Cyclosporine attenuates the autonomic modulation of reflex chronotropic responses in conscious rats
Authors: El-Mas Mahmoud M , Afify Elham A , Omar Amal G , Sharabi Fouad M
Published: October 2002

Cyclosporine A (CyA), an immunosuppressant drug, has been shown to attenuate the baroreflex control of heart rate (HR). This study investigated whether or not the CyA-induced baroreflex dysfunction is due to alterations in the autonomic (sympathetic and parasympathetic) control of the heart. We evaluated the effect of muscarinic or beta-adrenergic blockade by atropine and propranolol, respectively, on reflex HR responses in conscious rats treated with CyA (20 mg·kg1·day1 dissolved in sesame oil) for 1113 days or the vehicle. Baroreflex curves relating changes in HR to increases or decreases in blood pressure (BP) evoked by phenylephrine (PE) and sodium nitroprusside (NP), respectively, were constructed and the slopes of the curves were taken as a measure of baroreflex sensitivity (BRSPE and BRSNP). Intravenous administration of PE and NP produced dose-related increases and decreases in BP, respectively, that were associated with reciprocal changes in HR. CyA caused significant (P < 0.05) reductions in reflex HR responses as indicated by the smaller BRSPE (0.97 ± 0.07 versus 1.47 ± 0.10 beats·min1·mmHg1 (1 mmHg = 133.322 Pa)) and BRSNP (2.49 ± 0.29 versus 5.23 ± 0.42 beats·min1·mmHg1) in CyA-treated versus control rats. Vagal withdrawal evoked by muscarinic blockade elicited significantly lesser attenuation of BRSPE in CyA compared with control rats (40.2 ± 8.0 versus 57.7 ± 4.4%) and abolished the BRSPE difference between the two groups, suggesting that CyA reduces vagal activity. CyA also appears to impair cardiac sympathetic control because blockade of beta-adrenergic receptors by propranolol was less effective in reducing reflex tachycardic responses in CyA compared with control rats (41.6 ± 4.2 versus 59.5 ± 4.5%). These findings confirm earlier reports that CyA attenuates the baroreceptor control of HR. More importantly, the study provides the first pharmacological evidence that CyA atten uates reflex chronotropic responses via impairment of the autonomic modulation of the baroreceptor neural pathways.Key words: cyclosporine A, baroreflex sensitivity, autonomic control, atropine, propranolol.
An extracellular source of heme can induce a significant heme oxygenase mediated relaxation in the rat aorta
Authors: Hosein S , Marks G S , Brien J F , McLaughlin B E , Nakatsu K
Published: October 2002

Carbon monoxide has been under active investigation for a role in controlling vascular tone throughout the last decade because of its ability to induce relaxation in blood vessels. The underlying mechanisms of this response are hypothesized to be mediated by soluble guanylyl cyclase (sGC) and, in some instances, KCachannels. The major source of CO in major blood vessels is the catabolic process of heme degradation, which is catalyzed by heme oxygenase (HO). This heme substrate could be derived from heme sources within vascular smooth muscle cells, such as heme proteins, or by uptake from the extracellular milieu. The current study shows that the isolated rat aorta relaxes upon exposure to pharmacological concentrations of heme in the bathing medium. This response was inhibited by an inhibitor of HO (tin protoporphyrin) and sGC (1-H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one). These observations were interpreted to mean that vascular smooth muscle cells are capable of taking up and utilizing heme for the production of CO. Key words: carbon monoxide, heme oxygenase, heme, vascular smooth muscle.
Effects of fast neutrons on chromatin: dependence on chromatin structure
Authors: Radu Liliana , Constantinescu B , Gazdaru Doina
Published: October 2002

The effects of fast neutrons (10100 Gy) on chromatin extracted from normal (liver of Wistar rats) and tumor (Walker carcinosarcoma maintained on Wistar rats) tissues were compared. The spectroscopic assays used were (i) chromatin intrinsic fluorescence, (ii) time-resolved fluorescence of chromatin  proflavine complexes, and (iii) fluorescence resonance energy transfer (FRET) between dansyl chloride and acridine orange coupled to chromatin. For both normal and tumor chromatin, the intensity of intrinsic fluorescence specific for acidic and basic proteins decreased with increasing dose. The relative contributions of the excited-state lifetime of proflavine bound to chromatin were reduced upon fast-neutron irradiation, indicating a decrease in the proportion of chromatin DNA available for ligand binding. The Förster energy transfer efficiencies were also modified by irradiation. These effects were larger for chromatin from tumor tissue. In the range 0100 Gy, fast neutrons induced alterations in DNA and acidic and basic proteins, as well as in global chromatin structure. The radiosensitivity of chromatin extracted from tumor tissue seems to be higher than that of chromatin extracted from normal tissue, probably because of its higher euchromatin (loose)  heterochromatin (compact) ratio.Key words: chromatin structure, normal and tumor tissues, fast neutrons, spectrofluorimetric methods.
Ultrastructural lesions induced by neptunium-237: apoptosis or necrosis?
Authors: Pusset D , Fromm M , Poncy J L , Kantelip B , Galle P , Chambaudet A , Baud M , Boulahdour H
Published: October 2002

In this study, we are concerned with the 237 isotope of neptunium (237Np), which is a by-product of uranium in nuclear reactors. To study ultrastructural lesions induced by this element, a group of rats were injected with a solution of 237Np-nitrate once a day for 14 weeks. Lesions observed in liver and kidney are described using electron microscopy. Ultrastructural alterations of cellular membranes and intracellular organelles demonstrated the existence of neptunium toxicity. This toxicity was characterized by various lesions, such as cytoplasmic clarification, disappearance of mitochondrial cristae, swollen mitochondria, abnormal condensation of nuclear chromatin, and nuclear fragmentations. This study demonstrated the probable induction of apoptosis by neptunium both in liver and kidneys.Key words: neptunium, apoptosis, contamination, intracellular concentration.
Effect of pre-exposure to beta rays of tritium on some biochemical parameters measured in organs of rats subsequently irradiated with fast neutrons
Authors: Petcu Ileana , Moisoi Nicoleta , Savu Diana , Constantinescu B
Published: October 2002

The experiment examined biological responses produced by combined sequential exposure to low-level tritium contamination, followed by challenging irradiation with fast neutrons. Modifications of endogenous antioxidant potential of different organs in rats were discussed in relation to tissue radiosensitivity. Rats pre-contaminated to 7 cGy and 35 cGy have been additionally irradiated to 1 Gy with fast neutrons. Lipid peroxide level was determined in liver, kidney, small intestine, spleen, bone marrow, and plasma. Reduced glutathione (GSH) level and glucose-6-phosphate dehydrogenase (G6PDH) activity were determined in erythrocytes. An in vitro thymidine uptake assay was performed in isolated bone marrow cells. The lipid peroxide level decreased significantly only in liver and kidney from rats pre-exposed to 35 cGy. For small intestine and spleen, tissues of comparatively higher radiosensitivity, no induced radioprotection was observed, as reflected in the homeostasis of the lipid peroxides. The same behavior was observed in bone marrow, the most radiosensitive tissue studied. However, the bone marrow thymidine-incorporation assay revealed a possible adaptive-type reaction in rats pre-exposed to 35 cGy. We conclude that for radiosensitive tissues pre-exposure to chronic low doses of low linear energy transfer (LET) irradiation has no protective effect on their antioxidant status, whereas a protective effect is observed in radioresistent tissues.Key words: induced radioprotection, tritium contamination, lipid peroxides, thymidine uptake, tissue radiosensitivity, antioxidant defense.
Thrombopoietin protects mice from mortality and myelosuppression following high-dose irradiation: importance of time scheduling
Authors: Mouthon Marc-André , Van der Meeren Anne , Vandamme Marie , Squiban Claire , Gaugler Marie-Hélène
Published: October 2002

Thrombopoietin is the major regulator of platelet production and a stimulator of multilineage hematopoietic recovery following irradiation. The efficacy of three different schedules of thrombopoietin administration was tested on blood cell counts, hematopoietic bone marrow progenitors, and 30-day animal survival in C57BL6/J mice receiving a total body irradiation, with doses ranging from 7 to 10 Gy. A single dose of murine thrombopoietin was injected 2 h before, 2 h after, or 24 h after irradiation. Thrombopoietin promoted multilineage hematopoietic recovery in comparison to placebo up to 9 Gy at the level of both blood cells and bone marrow progenitors, whatever the schedule of administration. The injection of thrombopoietin 2 h before or 2 h after irradiation equally led to the best results concerning hematopoietic recovery. On the other hand, thrombopoietin administration promoted 30-day survival up to 9 Gy with the highest efficacy obtained when thrombopoietin was injected either 2 h before or 2 h after irradiation. However, when its injection was delayed at 24 h, thrombopoietin had almost no effect on survival of 9 Gy irradiated mice. Altogether, our results show that the time schedule for thrombopoietin injection is of critical importance and when thrombopoietin is administered before or shortly after irradiation, it efficiently promotes mice survival to supra-lethal irradiation (up to 9 Gy) in relation with hematopoietic recovery.Key words: irradiation, thrombopoietin, survival, hematopoiesis.
Potential role of the membrane in the development of intestinal cellular damage after whole-body gamma irradiation of the rat
Authors: Lebrun F , Benderitter M , Berroud A , Voisin P , Griffiths N M
Published: October 2002

Our study emphasizes the effect of gamma irradiation on intestinal cell membrane fluidity and addresses the potential relationships existing between radiation-induced lipoperoxidation, membrane fluidity, and changes in membrane protein activities. Male Wistar rats were exposed to an 8-Gy total body irradiation (60Co source) and studied 1, 4, and 7 days after irradiation (D1, D4, and D7). Membrane enzyme activities and fluorescence anisotropy were determined on small intestinal crude membrane preparations. The supernatants of membrane preparations as well as plasma were used for malonedialdehyde (MDA) quantification. The effect of carbamylcholine on electrical parameters was estimated on distal ileum placed in Ussing chambers. We observed a decrease in fluorescence anisotropy for at least 7 days, an increase in membrane production of MDA at D4, a decrease in membrane enzyme activities at D4, but an amplification of carbamylcholine-induced increase in short-circuit current at D4 and D7. Furthermore, correlations were observed between the 1,6-diphenyl-1,3,5-hexatriene anisotropy coefficient and sucrase activity and between MDA levels and leucine aminopeptidase activity. Thus, total body irradiation induces changes in intestinal membrane fluidity and an increase in lipoperoxidation. These modifications may have an impact on the activity of membrane proteins involved in intestinal function.Key words: irradiation, intestine, membrane, fluidity, function.
Effects of modafinil on heat thermoregulatory responses in humans at rest
Authors: Launay Jean-Claude , Besnard Yves , Guinet Angélique , Bessard Germain , Raphel Christian , Savourey Gustave
Published: October 2002

The effects of modafinil on heat thermoregulatory responses were studied in 10 male subjects submitted to a sweating test after taking 200 mg of modafinil or placebo. Sweating tests were performed in a hot climatic chamber (45°C, relative humidity <15%, wind speed = 0.8 m·s1, duration 1.5 h). Body temperatures (rectal (Tre) and 10 skin temperatures (Tsk)), sweat rate, and metabolic heat production (Mdot) were studied as well as heart rate (HR). Results showed that modafinil induced at the end of the sweating test higher body temperatures increases (0.50 ± 0.04 versus 0.24 ± 0.05°C (P < 0.01) for deltaTre and 3.64 ± 0.16 versus 3.32 ± 0.16°C (P < 0.05) for deltaTbarsk (mean skin temperature)) and a decrease in sweating rate throughout the heat exposure (P < 0.05) without change in Mdot, leading to a higher body heat storage (P < 0.05). DeltaHR was also increased, especially at the end of the sweating test (17.95 ± 1.49 versus 12.52 ± 1.24 beats/min (P < 0.01)). In conclusion, modafinil induced a slight hyperthermic effect during passive dry heat exposure related to a lower sweat rate, probably by its action on the central nervous system, and this could impair heat tolerance. Key words: modafinil, heat, human, thermoregulation.
Mouse one-cell embryos undergoing a radiation-induced G2 arrest may re-enter S-phase in the absence of cytokinesis
Authors: Jacquet P , Buset J , Vankerkom J , Baatout S , de Saint-Georges L , Schoonjans W , Desaintes C
Published: October 2002

PCC (premature chromosome condensation) can be used for visualizing and scoring damage induced by radiation in the chromatin of cells undergoing a G1 or G2 arrest. A method involving the fusion of irradiated single embryonic cells with single MI oocytes was used to induce PCC in mouse zygotes of the BALB/c strain, which suffer a drastic G2 arrest after X-irradiation (dose used 2.5 Gy). Other G2-arrested embryos were exposed in vitro to the phosphatase inhibitor calyculin A. Both methods furnished excellent chromosome preparations of the G2-arrested embryos. The mean number of chromosome fragments did not change significantly during G2 arrest, suggesting that zygotes of this strain are unable to repair DNA damage leading to such aberrations. Forty to fifty percent of the irradiated embryos were unable to cleave after G2 arrest and remained blocked at the one-cell stage for a few days before dying. PCC preparations obtained from such embryos suggested that about 30% of them had undergone a late mitosis not followed by cytokinesis and had entered a new DNA synthesis. These results are discussed in the light of recent observations in irradiated human cells deficient in the p53/14-3-3sigma pathway.Key words: PCC, embryo, oocyte, calyculin A, G2 arrest, cytokinesis.
Réacteur Silene: outil adapté aux études appliquées à l'effet des moyennes et fortes doses
Authors: Verrey B , Leo Y , Fouillaud P
Published: October 2002

Designed in 1974 to study the phenomenology and consequences of a criticality accident, the SILENE experimental reactor, an intense source of mixed neutron and gamma radiation, is also suited to radiobiological studies.Key words: radiation, neutron, gamma, SILENE.
L'aplasie médullaire secondaire à un accident d'irradiation: options thérapeutiques et évolution des concepts
Authors: de Revel T , Fagot T , Souleau B , Dormont D , Nedellec G
Published: October 2002

Bone marrow grafting following accidental irradiation exposure should be viewed in the perspective of a severe myeloablative syndrome linked to high medullary damage for a dose range higher than 68 Gy, resulting in very late or no recovery. Prognosis will depend on the presence or absence of radio-combined injuries, the toxicity of the transplant procedure, and the risk of rejection induced by insufficient percritical immunosuppression. It is in this context that new cell therapy modalities, which combine enhanced peripheral hematopoietic cell engraftment and high immunosuppressive conditioning regimen with low extrahematological toxicity, inducing early and stable mixed lymphomyeloid chimerism with minimal morbidity, can be considered. Such an approach is being evaluated in the treatment of patients with hematological malignancies at high risk of transplant-related mortality using conventional bone marrow methods. Key words: medullary aplasia, irradiation, hematopoiesis, bone marrow, grafting.[Journal translation]
Méthodes de mesure du transfert cutané des radionucléides au travers d'un épiderme intact ou lésé, application à la radiotoxicologie
Authors: Tymen H , Rateau G , Guillet K , Ramounet-Le Gall B , Gérasimo P , Fritsch P
Published: October 2002

Although skin contamination by radionuclides is the most common cause of nuclear workers accidents, few studies dealing with the penetration of radioactive contamination through the skin are available. This work is a review of experimental methods that allow to assess transfer of radionuclides through the skin in occupational conditions, with or without skin trauma. The first section describes the different methods applied for skin transfer assessment of chemicals used in pharmacology. Major radionuclide contamination accidents can be associated with skin traumas. Thus, the second section describes the adaptation of these methods to radiotoxicology. Finally, the third section is an in vivo investigation of cobalt transfer (57CoCl2) through undamaged and damaged skin which simulates different industrial accident conditions (excoriation, acid or alcalin burn, scalding, branding).Key words: skin lesion, cobalt, percutaneous absorption, skin radiocontamination, Franz's cell.
Mécanismes de l'apoptose radio-induite
Authors: Baatout Sarah , Derradji Hanane , Petitfour Olivier , Suchodoletz Hanna von , Mergeay Max
Published: October 2002

A general overview of the activation mechanisms of programmed cell death or apoptosis following an irradiation is given in this review. First, are summarized the main induction pathways of radiation-induced apoptosis by which extracellular (tumor necrosis factor (TNF), Fas ligand, TNF-related apoptosis-inducing ligand (TRAIL)) and intracellular (mitochondria and caspases) signals are integrated. A second part is then devoted to the importance of p53 and of its regulators (ATR, ATM, DNA-PKcs) in the process of radiation-induced apoptosis. Thereafter, signal transduction pathways and more specially the role of some protein kinases (MEKK, SAPK/JNK, p38-MAPK) is treated. At last, a chapter concerns the clinical interest of radiation-induced apoptosis and the implication of apoptosis in the treatment of certain diseases.Key words: apoptosis, radiation, caspase, p53, mitochondria.
Influence de la distribution de dose sur le risque d'apparition de cancers pulmonaires après inhalation d'oxydes d'actinides
Authors: Fritsch P , Dudoignon N , Guillet K , Rateau G , Delforge J
Published: October 2002

The aim of this work was to estimate risk of lung tumour occurrence after inhalation of actinide oxides from published studies and rat studies in progress. For the same delivered dose, the risk increases when homogeneity of irradiation increases, i.e., the number of particles deposited after inhalation increases (small particles and (or) low specific alpha activity). The doseeffect relationships reported appear linear up to a few gray, depending on the aerosol considered, and then the slope decreases. This slope, which corresponds with the risk, can vary over one order of magnitude depending on the aerosol used. An effective threshold at about 1 Gy was not observed for the most homogeneous dose distributions. A dosimetric and biological approach is proposed to provide a more realistic risk estimate.Key words: actinide oxides, inhalation, lung tumour, alpha irradiation, dosimetry.
Retinoic acid suppression of endothelial nitric oxide synthase in porcine oocyte
Authors: Hattori Masa-aki , Kato Yukio , Fujihara Noboru
Published: October 2002

The presence of endothelial nitric oxide synthase (eNOS) has been found in porcine oocytes, but its mRNA and protein levels remain relatively constant during hormonal stimulation. The present study was designed to determine the effect of retinoic acid on eNOS regulation in porcine oocytes during follicle-stimulating hormone (FSH) stimulation. Cumulusoocyte complexes (COCs), prepared from small antral follicles of immature porcine ovaries, were cultured for 15 h and treated with FSH for an additional 48 h. eNOS mRNA and its protein were analyzed by reverse transcription  polymerase chain reaction and Western blotting, respectively. Retinoic acid had an inhibitory effect on the level of oocyte eNOS mRNA in a dose-dependent manner if COCs were exposed to retinoic acid before FSH stimulation. The inhibition of FSH action was reflected in a decrease in expression of c-fos mRNA. eNOS protein also decreased to approximately 50% of the control after exposure to 10 μM retinoic acid. However, the ability of NO synthesis was abolished in the oocytes prepared from retinoic acid pretreated COCs. These results suggest that retinoic acid has a strong inhibitory action on eNOS mRNA level and NO synthesis in the porcine oocyte.Key words: oocyte, retinoic acid, NO synthesis, eNOS, RTPCR.
Growth factor stimulated cell proliferation is accompanied by an elevated labile intracellular pool of zinc in 3T3 cells
Authors: Paski Shirley C , Xu Zhaoming
Published: October 2002

Growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and insulin-like growth factor-I (IGF-I) are required for quiescent 3T3 cells to proliferate, but zinc deprivation impairs IGF-I-induced DNA synthesis. We recently showed that labile intracellular pool of zinc is involved in cell proliferation. Our objective was to determine whether the labile intracellular pool of zinc plays a role in growth factor (PDGF, EGF, and IGF-I) - stimulated proliferation of 3T3 cells. Quiescent 3T3 cells were cultured in DMEM with or without growth factors. Labile intracellular pool of zinc, DNA synthesis, and cell proliferation were assessed using fluorescence microscopy, 3H-thymidine incorporation, and total cell number counts, respectively. After 24 h, growth factors stimulated DNA synthesis (24%) but not cell proliferation. After 48 h, growth factors stimulated both DNA synthesis (37%) and cell proliferation (89%). In response to growth factor stimulation, the labile intracellular pool of zinc was also elevated after 24 or 48 h of treatment. In summary, growth factor (PDGF, EGF, and IGF-I) - stimulated increase in DNA synthesis and cell proliferation were accompanied by an elevated labile intracellular pool of zinc in 3T3 cells. Since elevation of the labile intracellular pool of zinc occurred along with increased DNA synthesis, but cell proliferation remained unchanged, the elevation of the labile intracellular pool of zinc likely occurred during the S phase to provide the zinc needed to support DNA synthesis and ultimately cell proliferation.Key words: PDGF, EGF, IGF-I, labile intracellular pool of zinc, cell proliferation, DNA synthesis, 3T3 cells.
Comparison of the rapid insulin sensitivity test (RIST), the insulin tolerance test (ITT), and the hyperinsulinemic euglycemic clamp (HIEC) to measure insulin action in rats
Authors: Reid Maria A.G , Latour Martin G , Legare Dallas J , Rong Na , Lautt W Wayne
Published: October 2002

The objective was to compare the ability of the rapid insulin sensitivity test (RIST), the hyperinsulinemic euglycemic clamp (HIEC), and the insulin tolerance test (ITT) to detect hepatic insulin sensitizing substance (HISS) dependent insulin action. HISS action was augmented by feeding and inhibited by fasting, blockade of hepatic nitric oxide synthase, or blockade of hepatic muscarinic cholinergic receptors. A significant correlation was found between the RIST index and ITT nadir (r2= 0.84) but not between the glucose infusion rate of the HIEC and RIST index. There was, however, a relationship between the RIST index and the initial response during the HIEC. Use of the HIEC resulted in HISS-dependent insulin resistance in both conscious and anesthetized animals. We concluded that since the RIST and ITT were comparable in quantifying both HISS-dependent and HISS-independent insulin action, the RIST was validated against this standard. The observation that the HIEC is capable of detecting HISS action in the first rising slope of the test but not at the end of the test and that HISS release is fully blocked after the conclusion of the HIEC raises concerns about the use of the commonly used HIEC.Key words: HISS, insulin resistance, insulin sensitivity tests.
Increases in myocardial cyclic GMP attenuate contractile delay in myocardial stunning
Authors: Huang Mark W , Scholz Peter M , Weiss Harvey R
Published: October 2002

We tested the hypothesis that the effects of myocardial stunning would be reduced by cyclic GMP in rabbit hearts. In three groups of anesthetized open-chest New Zealand white rabbits, myocardial stunning was produced by 15 min of occlusion of the left anterior descending coronary artery followed by 15 min of reperfusion repeated twice. Either control vehicle (saline plus 1% dimethyl sulfoxide) or 8-bromo-cyclic GMP (8-Br-cGMP (104and 103M)) was topically applied to the left ventricular surface. Hemodynamic (left ventricular and aortic pressures) and functional parameters (wall thickening, delay in onset of wall thickening, and rate of wall thickening) were determined. Coronary blood flow (microspheres) and O2extraction (microspectrophotometry) were used to determine myocardial O2consumption (VO2). Myocardial stunning was observed in the control group through an increased delay in onset of myocardial wall thickening (29 ± 7 versus 55 ± 16 ms) and decreased maximal rate of wall thickening (20 ± 8 versus 11 ± 3 mm·s1). After treatment with 8-Br-cGMP 104and 103M, stunning did not increase the delay (37 ± 5 versus 39 ± 7 and 39 ± 7 versus 28 ± 8 ms). Myocardial stunning did not significantly alter V02. 8-Br-cGMP 103M significantly decreased subepicardial V02(6.2 ± 0.8 versus 3.7 ± 0.6 mL O2·min1·100 g1) and insignificantly decreased subendocardial V02(8.6 ± 0.9 versus 6.3 ± 1.2 mL O2·min1·100 g1) when compared with the vehicle-treated rabbits. We conclude that increasing cyclic GMP reduced the effects of myocardial stunning in the rabbit heart by ameliorating the delay in onset of wall thickening and decreasing the local O2costs in the stunned region. Key words: cyclic GMP, myocardial stunning, O2consumption, ischemia, reperfusion, wall thickening, rabbit.
Subsensitivity to insulin in adipocytes from rats submitted to foot-shock stress
Authors: Farias-Silva Elisângela , Sampaio-Barros Marília M , Amaral Maria EC , Carneiro Everardo M , Boschero Antonio C , Grassi-Kassisse Dora M , Spadari-Bratfisch Regina C
Published: October 2002

We examined the effect of three daily foot-shock stress sessions on glucose homeostasis, insulin secretion by isolated pancreatic islets, insulin sensitivity of white adipocytes, and glycogen stores in the liver and soleus muscle of rats. Stressed rats had plasma glucose (128.3 ± 22.9 mg/dL) and insulin (1.09 ± 0.33 ng/mL) levels higher than the controls (glucose, 73.8 ± 3.5 mg/dL; insulin, 0.53 ± 0.11 ng/mL, ANOVA plus Fisher's test; p < 0.05). After a glucose overload, the plasma glucose, but not insulin, levels remained higher (area under the curve 8.19 ± 1.03 vs. 4.84 ± 1.33 g/dL 30 min and 102.7 ± 12.2 vs. 93.2 ± 16.1 ng/mL 30 min, respectively). Although, the area under the insulin curve was higher in stressed (72.8 ± 9.8 ng/mL) rats than in control rats (34.9 ± 6.9 ng/mL) in the initial 10 min after glucose overload. The insulin release stimulated by glucose in pancreatic islets was not modified after stress. Adipocytes basal lipolysis was higher (stressed, 1.03 ± 0.14; control, 0.69 ± 0.11 µmol of glycerol in 60 min/100 mg of total lipids) but maximal lipolysis stimulated by norepinephrine was not different (stressed, 1.82 ± 0.35; control, 1.46 ± 0.09 µmol of glycerol in 60 min/100 mg of total lipids) after stress. Insulin dose-dependently inhibited the lipolytic response to norepinephrine by up to 35% in adipocytes from control rats but had no effect on adipocytes from stressed rats. The liver glycogen content was unaltered by stress, but was lower in soleus muscle from stressed rats than in control rats (0.45 ± 0.04 vs. 0.35 ± 0.04 mg/100 mg of wet tissue). These results suggest that rats submitted to foot-shock stress develop hyperglycemia along with hyperinsulinemia as a consequence of insulin subsensitivity in adipose tissue, with no alteration in the pancreatic sensitivity to glucose. Foot-shock stress may therefore provide a useful short-term model of insulin subsensitivity.Key words: glucose tolerance test, white adipocytes, lipolysis, pancreatic islets, insulin release, soleus muscle, liver glycogen.
Cerebral blood flow responses to changes in oxygen and carbon dioxide in humans
Authors: Vovk Andrea , Cunningham David A , Kowalchuk John M , Paterson Donald H , Duffin James
Published: October 2002

This study characterized cerebral blood flow (CBF) responses in the middle cerebral artery to PCO2ranging from 30 to 60 mmHg (1 mmHg = 133.322 Pa) during hypoxia (50 mmHg) and hyperoxia (200 mmHg). Eight subjects (25 ± 3 years) underwent modified Read rebreathing tests in a background of constant hypoxia or hyperoxia. Mean cerebral blood velocity was measured using a transcranial Doppler ultrasound. Ventilation (VE), end-tidal PCO2 (PETCO2), and mean arterial blood pressure (MAP) data were also collected. CBF increased with rising PETCO2 at two rates, 1.63 ± 0.21 and 2.75 ± 0.27 cm·s1·mmHg1 (p < 0.05) during hypoxic and 1.69 ± 0.17 and 2.80 ± 0.14 cm·s1·mmHg1 (p < 0.05) during hyperoxic rebreathing. VE also increased at two rates (5.08 ± 0.67 and 10.89 ± 2.55 L·min1·mmHg1 and 3.31 ± 0.50 and 7.86 ± 1.43 L·min1·mmHg1) during hypoxic and hyperoxic rebreathing. MAP and PETCO2 increased linearly during both hypoxic and hyperoxic rebreathing. The breakpoint separating the two-component rise in CBF (42.92 ± 1.29 and 49.00 ± 1.56 mmHg CO2 during hypoxic and hyperoxic rebreathing) was likely not due to PCO2 or perfusion pressure, since PETCO2 and MAP increased linearly, but it may be related to VE, since both CBF and VE exhibited similar responses, suggesting that the two responses may be regulated by a common neural linkage. Key words: brain blood flow, middle cerebral artery, ventilation, mean arterial blood pressure.
Tiron exerts effects unrelated to its role as a scavenger of superoxide anion: effects on calcium binding and vascular responses
Authors: Ghosh Mahua , Wang Hui Di , McNeill J Robert
Published: October 2002

The effect of tiron (4,5-dihydroxy-1,3-benzene disulfonic acid) on the binding of Ca2+ and its effect on vascular responses of the rat perfused mesenteric bed was studied at concentrations of tiron that are used widely to scavenge superoxide anion. In competition assays in buffered solutions with no tissue present, tiron decreased the fluorescence ratio of fura-FF, a measure of [Ca2+]: the inhibition constant (Ki) of tiron with Ca2+ was 0.692 ± 0.036 mM. In the mesenteric bed perfused at constant flow and preconstricted with 90 mM KCl, tiron evoked decreases in perfusion pressure of the mesenteric bed in a concentration-dependent manner (Rmax = 43.58 ± 2.6 mmHg; EC50 = 1.46 ± 0.33 mM). This vasodilator effect of tiron was similar in the presence of the superoxide anion scavenger, tempol (Rmax = 46.12 ± 1.87 mmHg; EC50 = 1.34 ± 0.27 mM). In the presence of 90 mM KCl, increasing concentrations of Ca2+ increased perfusion pressure and tiron shifted the concentration-response curve to Ca2+ to the right. In freshly drawn blood from rats, tiron increased clotting time. The data indicate that tiron binds Ca2+ at concentrations at or below those commonly used to scavenge superoxide anion, an action that may be responsible for a variety of biological responses. The interpretation of effects of tiron in previous work on the role of superoxide anion may need to be re-evaluated.Key words: tiron, calcium, mesenteric vascular bed, superoxide anion, tempol.
Marked depression of radiation-induced emesis in frogs following prior exposure to a brief dose of X-rays
Authors: Miyachi Yukihisa , Koike Takahisa , Muroi Kenzo , Kanao Tomoko , Kawamoto Taro , Yamada Takeshi
Published: October 2002

Acute emesis response to harmful doses of X-rays on frogs (Rana porosa porosa) was examined. Results showed that the number of radioemesis events following exposure to 0.85 Gy was slightly higher than in the sham control animals. The increase in emesis action became more pronounced when the total dose of radiation was raised to 2.5 Gy. Only 1 frog out of a total of 12 did not show vomiting following radiation, while no response was observed in sham control animals. Note that animals in which the low dose rate of radiation was applied to whole body did not display any changes in the emesis response relative to control animals. The present studies, and those by others, showed that a brief dose of X-rays prior to a second exposure to a sub-lethal dose might induce a tolerance to radiation. An additional experiment was conducted to examine whether a small conditioning dose could induce a depression of radioemesis (tolerance) following an exposure to high dose X-ray. With prior exposure to 0.3 Gy, only 1 frog out of a total of 5 frogs vomited as a result of radiation exposure. Suppression of the emetic response became significant when the pre-radiation dose was decreased to 0.1 Gy. On the contrary, increasing the small conditioning dose to 0.5 Gy resulted in a remarkable rise of radiation-induced emesis. This results indicate that exposure to the smaller dose of X-rays elicits a tolerance effect to toxic dose level of radiation.Key words: emesis, hormesis, low-dose X-rays, resistance, frog.
Peripheral blood mononuclear cell production of TNF-α in response to North American ginseng stimulation
Authors: Zhou David L , Kitts David D
Published: October 2002

North American ginseng (Panax quinquefolium) root extract (NAGE) with known ginsenosides composition was examined for its affinity to stimulate human tumour necrosis factor α (TNF-α) production in human peripheral blood mononuclear cells. Case studies were conducted in three donors, one that was diagnosed with an atopic allergy and two that were normal, healthy subjects. Cultured mononuclear cells were incubated with varying concentrations of NAGE for up to 72 h and culture media were tested for TNF-α concentration. Direct stimulation of mononuclear cell TNF-α production in vitro by NAGE occurred as early as 6 h with 200 μg NAGE/mL. The stimulation of TNF-α production was confirmed by TNF-α mRNA gene expression. These interesting results show the immunostimulating activity of NAGE components in reference to TNF-α production. This observation requires further investigation with more subjects to determine the affinity of ginseng in stimulating the human immune system. Moreover, the method of evaluating this response is very useful for standardizing ginseng extracts to a known bioactivity.Key words: North American ginseng extract, TNF-α, bioactivity.
Theoretical analysis of the noncardiac limits to maximum exercise
Authors: Magder S
Published: October 2002

When right atrial pressure (Pra) is greater than zero (atmospheric pressure), cardiac output is determined by the intersection of two functions, cardiac function and return function, which is used here to mean the determinants of venous return. When Pra [Formula: see text] 0, flow is only determined by circuit function. The objective of this analysis was to determine the potential changes in return function that need to occur to allow the maximum cardiac output during exercise when Pra [Formula: see text] 0 or is constant. The analysis expands on the model of Green and Jackman and includes the effects of changes in circuit parameters, including venous resistance, changes in capacitance, and muscle contractions. The analysis is based on the model of the circulation proposed by Permutt and co-workers, which assumes that the systemic circulation has two lumped compliant regions in parallel with independent inflow and outflow resistances. Changes in total flow in this model can come about by changes in the distribution of flow between the regions, recruitment of unstressed vascular volume, and changes in the regional venous resistances. The data for the analysis are from previous animal studies and are normalized to a 70-kg man. The major conclusions are that, to achieve the high cardiac output that occurs at peak exercise, there need to be marked changes in the distribution of blood flow, recruitment of unstressed volume, and the venous resistance draining vascular beds. A consequence of the increase in peripheral flow is a marked increase in pressure in the veins of the working muscle. Muscle contractions are potentially a very important mechanism for transiently decreasing this pressure and preventing excessive filtration of plasma during exercise.Key words: cardiac output, venous return, muscle contractions.
Circadian variation in cell-adhesion molecule expression by normal human leukocytes
Authors: Niehaus Gary D , Ervin Elyce , Patel Amit , Khanna Kamal , Vanek Vincent W , Fagan Diana L
Published: October 2002

Adhesion molecules located on the surface of blood-borne leukocytes permit adherence of leukocytes to the microvascular endothelium, diapedesis of leukocytes across vessel walls, formation of intimate multicell interactions, and enhanced transmembrane signal transduction. Since some leukocyte-mediated immune functions exhibit nocturnal intensification, the current study was conducted to investigate the hypothesis that expression of selected cell adhesion molecules (CAM) varies with circadian periodicity. Blood was collected from normal human donors over a 24-h period and CAM expression by monocytes, neutrophils, and lymphocytes evaluated by monoclonal antibody binding and flow cytometry. All leukocyte classes exhibited significant circadian-like variation (p < 0.05) in CD62L (L-selectin) expression. Similarly, a diurnal variation (p < 0.05) in monocyte and neutrophil CD54 (ICAM-1) was observed. Finally, neutrophils demonstrated a circadian-like variation (p < 0.05) in CD11a (LFA-1a). The rhythmic alterations in CAM expression may be clinically relevant, since changes in CAM expression have the potential to modulate the leukocyte-induced pathogenesis associated with disease progressions such as nocturnal asthma, the nighttime exacerbations of rheumatoid arthritis, and the high nocturnal incidence of cerebrovascular and cardiovascular crisis.Key words: CD11a, CD62L, CD54, leukocytes, circadian rhythm.
Exaggerated coronary reactivity to endothelin-1 in diabetes: reversal with bosentan
Authors: Verma Subodh , Arikawa Emi , Lee Sammy , Dumont Aaron S , Yao Linfu , McNeill John H
Published: October 2002

We previously demonstrated that chronic endothelin receptor blockade (with bosentan) improved functional cardiac performance in streptozotocin-diabetic rats, suggesting a novel role of endothelin-1 (ET-1) in modulating diabetic heart dysfunction. To gain insight into the mechanism(s) underlying this effect, we examined the coronary vascular responses to ET-1 in hearts from diabetic and control rats treated with or without bosentan. Rats were divided into control, control-treated, diabetic, and diabetic-treated groups. The control-treated and diabetic-treated groups received bosentan (100 mg·kg1·d1) for 8 weeks. Following treatment, hearts were isolated and perfused, and coronary reactivity to ET-1 was assessed by measuring the changes in coronary perfusion pressure in response to ET-1 (50 and 100 pM). Additionally, maximal coronary blood flow (assessed with 105M adenosine) was measured in isolated perfused hearts. The key observation is that coronary reactivity to ET-1 was significantly higher in the diabetic than the control rats. This effect was normalized in diabetic rats chronically receiving bosentan. Maximal coronary vasodilation did not differ between the four groups. In conclusion, the reactivity of ET-1 is altered in the isolated perfused coronary vascular bed from diabetic rats, and chronic ET receptor blockade restores this reactivity to control values. These observations provide a possible mechanism for the improvement in diabetic heart function observed after chronic bosentan treatment.Key words: endothelin-1, streptozotocin-induced diabetes, bosentan, endothelin receptor antagonist, coronary artery.
Antisense inhibition of Flk-1 by oligonucleotides composed of 2'-deoxy-2'-fluoro-β-D-arabino- and 2'-deoxy-nucleosides
Authors: Lacombe Julie , Viazovkina Ekaterina , Bernatchez Pascal N , Galarneau Annie , Damha Masad J , Sirois Martin G
Published: October 2002

The design of new antisense oligomers with improved binding affinity for targeted RNA, while still activating RNase H, is a major research area in medicinal chemistry. RNase H recognizes the RNADNA duplex and cleaves the complementary mRNA strand, providing the main mechanism by which antisense oligomers elicit their activities. It has been shown that configuration inversion at the C2' position of the DNA sugar moiety (arabinonucleic acid, ANA), combined with the substitution of the 2'OH group by a fluorine atom (2' F-ANA) increases the oligomer's binding affinity for targeted RNA. In the present study, we evaluated the antisense activity of mixed-backbone phosphorothioate oligomers composed of 2'-deoxy-2'-fluoro-β-D-arabinose and 2'-deoxyribose sugars (S-2' F-ANADNA chimeras). We determined their abilities to inhibit the protein expression and phosphorylation of Flk-1, a vascular endothelial growth factor receptor (VEGF), and VEGF biological effects on endothelial cell proliferation, migration, and platelet-activating factor synthesis. Treatment of endothelial cells with chimeric oligonucleotides reduced Flk-1 protein expression and phosphorylation more efficiently than with phosphorothioate antisenses (S-DNA). Nonetheless, these two classes of antisenses inhibited VEGF activities equally. Herein, we also demonstrated the capacity of the chimeric oligomers to elicit RNase H activity and their improved binding affinity for complementary RNA as compared with S-DNA.Key words: antisense DNA, 2' F-ANA nucleosides, mixed-backbone antisense, Flk-1, VEGF.
Effects of age and anesthetic on plasma glucose and insulin levels and insulin sensitivity in spontaneously hypertensive and Wistar rats
Authors: Vera Erika R , Battell Mary L , Bhanot Sanjay , McNeill John H
Published: October 2002

We examined the effects of anesthetic, age, and strain on oral glucose tolerance tests (OGTT, 1 g/kg body weight) and intraperitoneal glucose tolerance tests (IPGTT, 2 g/kg body weight) in spontaneously hypertensive (SH) and Wistar rats. Pentobarbital anesthesia caused an elevation in basal glucose and insulin levels in Wistar rats at 9 and 16 weeks of age and in SH rats at 9 weeks. Anesthesia increased the insulin output during an OGTT in both strains of rats while glucose was unchanged. Anesthesia reduced the insulin sensitivity index calculated from the OGTT but not from the IPGTT data. The age of the rats (911 vs. 1618 weeks) had no effect on the basal glucose or insulin levels, but older Wistar rats had a greater insulin output following oral glucose and older SH rats had a greater insulin output following intraperitoneal glucose. On the basis of the insulin sensitivity index, SH rats were clearly more insulin resistant than age-matched Wistar rats. The SH rats also had higher basal insulin levels, as well as higher insulin output, following both glucose challenges. In summary, SH rats are more insulin resistant than Wistar rats, and anesthesia, which elevated basal glucose and insulin levels and increased the insulin output in response to a glucose challenge, may increase insulin resistance.Key words: spontaneously hypertensive rats, insulin sensitivity index, anesthesia, age.
Restricted ability of human mast cell tryptase to activate proteinase-activated receptor-2 in rat aorta
Authors: Compton Steven J , McGuire John J , Saifeddine Mahmoud , Hollenberg Morley D
Published: October 2002

We investigated the potential of human mast cell tryptase to induce relaxation of rat aorta. Trypsin and the selective PAR2-activating peptide (PAR2-AP) SLIGRL-NH2stimulated robust relaxation of phenylephrine-precontracted rat aortic rings. However, human lung tryptase (1100 nM) either in the presence or absence of heparin failed to induce any significant relaxation. Notwithstanding, incubation of the aorta with tryptase (100 nM), following the addition of a peptide corresponding to the cleavage/activation sequence of rat PAR2(rPAR2), resulted in relaxation of precontracted tissue due to the proteolytic release of the PAR2-AP SLIGRL/ from the parent peptide. Thus, tryptase was enzymatically active in the bioassay system. Preincubation of aorta with neuraminidase to remove cell-surface sialic acid unmasked the ability of tryptase to induce relaxation of the aorta, but had no effect on relaxation induced by trypsin, SLIGRL-NH2, or acetylcholine (Ach). Like trypsin and SLIGRL-NH2, the tryptase-induced relaxation was inhibited by either removal of the endothelium or pretreatment of the tissue with NG-nitro-L-arginine methyl ester (L-NAME), suggesting an endothelium-derived nitric oxide mechanism. Interestingly, tryptase in the presence of heparin failed to induce relaxation of precontracted neuraminidase-treated rat aorta. We conclude that tryptase-induced relaxation of rat aorta, most likely via PAR2, is tightly regulated by heparin and cell-surface sialic acid.Key words: tryptase, PAR2, cardiovascular system, protease.
The effect of strength training combined with bisphosphonate (etidronate) therapy on bone mineral, lean tissue, and fat mass in postmenopausal women
Authors: Chilibeck P D , Davison K S , Whiting S J , Suzuki Y , Janzen C L , Peloso P
Published: October 2002

The combined and separate effects of exercise training and bisphosphonate (etidronate) therapy on bone mineral in postmenopausal women were compared. Forty-eight postmenopausal women were randomly assigned (double blind) to groups that took intermittent cyclical etidronate; performed strength training (3 d/week) and received matched placebo; combined strength training with etidronate; or took placebo and served as nonexercising controls. Bone mineral, lean tissue, and fat mass were assessed by dual-energy X-ray absorptiometry before and after 12 months of intervention. After removal of outlier results, changes in bone mineral density (BMD) of the lumbar spine and bone mineral content (BMC) of the whole body were greater in the subjects given etidronate (+2.5 and +1.4%, respectively) compared with placebo (0.32 and 0%, respectively) (p < 0.05), while exercise had no effect. There was no effect of etidronate or exercise on the proximal femur and there was no interaction between exercise and etidronate at any bone site. Exercise training resulted in significantly greater increases in muscular strength and lean tissue mass and greater loss of fat mass compared with controls. We conclude that etidronate significantly increases lumbar spine BMD and whole-body BMC and that strength training has no additional effect. Strength training favourably affects body composition and muscular strength, which may be important for prevention of falls.Key words: exercise, resistance training, lumbar spine.