bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurokinin receptor mediated plasma extravasation in guinea pig and rat airways: comparison of 125I-labelled human fibrinogen and 99mTc-labelIed human serum albumin as markers of leakage
Authors: Tousignant Christine , Chan Chi-Chung , Young Donna , Guevremont Diane , Rodger Ian W.
Published: April 2011

In the present study we have characterized NK-1 and NK-2 receptor induced microvascular leakage in guinea pig and rat airways, using 125I-labelled human fibrinogen ([125I]FN) versus 99mTc-labelled human serum albumin ([99mTc]HSA) as markers for plasma protein extravasation. Intravenous administration of the selective NK-1 agonist [Sar9, Met(O2)11]SP (1 nmol kg−1) caused a dose-dependent increase of [125I]FN extravasation in guinea pig trachea, main bronchi, secondary bronchi, and intraparenchymal airways. Extravasation of [125I]FN increased by up to 192 (trachea), 284 (main bronchi), 368 (secondary bronchi), and 271% (intraparenchymal bronchi) over control levels in these regions of the airways. Pretreatment of the animals with CP 99,994 and RP 67,580, two NK-1 nonpeptide antagonists, caused a dose-dependent inhibition of [Sar9, Met(O2)11]SP-induced leakage of [125I]FN. [Sar9, Met(O2)11]SP (1 nmol kg−1) did not induce specific leakage of [99mTc]HSA in the intraparenchymal bronchi. Specific NK-2 receptor induced leakage was detected in the lower airways but only when using [125I]FN as a marker. We have also compared the ability of CP 99,994 and RP 67,580 to inhibit [Sar9, Met(O2)11]SP induced extravasation of [125I]FN in rat airways. CP 99,994 was 40–50 (tracheobronchial region) to 75 (lower airways) times more potent in the guinea pig than the rat airways. In contrast, RP 67,580 had higher affinity for rat airways compared with guinea pig airways. The results of this study highlight the superiority of [125I]FN as a sensitive marker of plasma extravasation over [99mTc]HSA. Furthermore, the results strongly suggest that both NK-1 and NK-2 receptors mediate plasma extravasation in the guinea pig lower airways and that NK-1 receptors are different in guinea pig and rat airways.Key words: Leakage, tachykinins, NK-1 and NK-2 receptors, airway, asthma.
Effect of temperature on glyceryl trinitrate induced relaxation of rabbit aorta
Authors: Booth Brian P. , Brien James F. , Marks Gerald S. , Nakatsu Kanji
Published: April 2011

It has previously been shown that the vasodilatory response to glyceryl trinitrate (GTN) was decreased during hypothermic cardiopulmonary bypass. The purpose of these experiments was to determine the effect of temperature on GTN-induced relaxation and on GTN biotransformation in rabbit aorta. It was determined that the EC50 of GTN on rabbit aortic rings (RARs) was increased significantly from 1.8 × 10−8 M at 37 °C to 3.4 × 10−8 M at 27 °C (p < 0.05). The production of NO by rabbit aortic strips (RASs) was significantly less at 27 °C compared with 37 °C after 80 min, being 9.62 × 10−11 ± 13.2 × 10−11 mol NO/g wet wt. RASs compared with 5.71 × 10−10 ± 9.43 × 10−11 mol NO/g wet wt. RASs, respectively (p < 0.05), after 80 min incubation. There was no difference in the amount of glyceryl-1,2-dinitrate (1,2-GDN) produced from GTN at the two temperatures. The ED20 for NO-induced relaxation of RARs increased from 3.46 × 10−10 ± 2.24 × 10−10 mol at 37 °C to 1.01 × 10−9 ± 4.51 × 10−10 mol at 27 °C (p < 0.05). These data indicate that the biotransformation of GTN and the release of NO were impaired by hypothermia, and that this, as well as a decrease in the tissue response to NO at 27 °C, explains the decrease in GTN activity at reduced body temperatures.Key words: glyceryl trinitrate, nitric oxide, temperature, rabbit aorta, vasodilation.
Expression of histamine H1 receptors in autoimmune myocarditis mice
Authors: Goren Nora , Leiros Claudia Perez , Sterin-Borda Leonor , Borda Enri
Published: April 2011

Two populations of histaminergic H1 receptors with distinct high and low affinity binding sites were characterized by the specific H1 receptor antagonist [3H]mepyramine in autoimmune myocardium. No saturable binding of the radiolabelled H1 antagonist was observed in normal myocardium. Reaction of autoimmune myocardium with specific H1 agonist (2-thiazolyl-ethylamine (ThEA)) triggered positive inotropy and negative chronotropy, which were inhibited by mepyramine. Inhibitors of phospholipase C and protein kinase C attenuated both the inotropic and chronotropic effects of ThEA, suggesting the participation of phosphoinositide hydrolysis in this phenomenon. The latter was verified by measurement of polyphosphoinositide hydrolysis in autoimmune myocardium following the reaction of ThEA with histaminergic H1 receptors. We conclude that functional H1 histaminergic receptors could involve a distinctive mechanism operating in autoimmune myocardium as a result of cardiac antigen immunization.Key words: histamine, H1 receptors, myocarditis, autoimmunity.
Essential fatty acids in fish physiology
Authors: March B. E.
Published: April 2011

This paper emphasizes those aspects of fatty acid research in fish that have relevance to the investigation of the functions of essential fatty acids in other species. Lipid requirements of fish came under investigation only in the 1960s. The most significant finding has been the requirement for n − 3 fatty acids. The dietary ratio of (n − 3):(n − 6) is critical if the essential requirement is met by C18 fatty acids because of competition between fatty acids for the enzymes involved in elongation and desaturation to produce the physiologically essential long-chain fatty acids. The fatty acid composition of fish lipids varies according to the fatty acid profile of the dietary lipid. The fatty acid composition of fish also responds to temperature changes in an adaptive mechanism for maintenance of membrane homeoviscosity and physiological function over a range of temperatures. The dietary intake of essential fatty acids by brood stock must be adequate for ova formation and for embryonic development, with the latter requirement being more critical for reproductive success. Absolute requirements of fish for essential fatty acids are difficult to define and may vary depending upon the dietary ratio of (n − 3) to (n − 6) fatty acids.Key words: essential fatty acids, nutritive requirements, fish.
Ferritin and ceruloplasmin in oxidative damage: review and recent findings
Authors: Silva D. M. de , Aust S. D.
Published: April 2011

The oxidation of biomolecules such as lipid, protein, and DNA is associated with a variety of toxicities and pathologies. In an all-encompassing definition these oxidative processes have been referred to as "oxidative stress." Although the direct reaction between molecular oxygen and most biomolecules is spin forbidden, this reaction can be efficiently catalyzed by transition metals such as iron and copper. Iron especially has been demonstrated to be a potent catalyst of biological oxidations. This review focuses on the relationship between iron and copper with respect to the copper protein ceruloplasmin, which may play a role in iron homeostasis by catalyzing the oxidation of iron as it is placed in ferritin.Key words: iron, copper, ferritin, ceruloplasmin.
Putative anticarcinogenic actions of carotenoids: nutritional implications
Authors: Davison Allan , Rousseau Eunice , Dunn Bruce
Published: April 2011

This review provides an update on nutritional aspects of carotenoids (as distinct from retinoids), with specific relevance to anticarcinogenesis. Critical gaps remain in our knowledge of the nutritional functions of carotenoids despite an overwhelming accumulation of research data in areas tangential to human nutrition. In addition to their roles as precursors of retinol and retinoids, carotenoids have distinct functions of their own in animals and humans. In vitro they are antioxidants with a broad range of potencies. In vivo, they protect porphyries against sunlight. The evidence for anticarcinogenic actions of β-carotene in certain specified test situations is persuasive. Nevertheless, despite a large number of studies demonstrating protection by carotenoids, the characteristics that render a given carotenoid effective and the relative efficacy of the individual carotenoids are not known. Moreover, dose–response and pharmacokinetic relationships remain virtually unexplored. Research to uncover mechanisms of protection by carotenoids is, for technical reasons, painfully slow. Epidemiological studies reveal associations but not cause and effect. To explore cause and effect, intervention trials are underway, hampered by the paucity of data regarding optimal choice of carotenoid, dosage, and regimen. The in vitro test systems that would provide this information are not available because the molecular sites relevant to the chemopreventive action of carotenoids are obscure. Each of these problems has a solution, but not a simple one. Until these are resolved, blanket recommendations regarding supplementation will remain problematic. To this point, health authorities have not recommended dietary supplementation with carotenoids. Instead, they recommend increased consumption of yellow and dark green carotenoid-rich vegetables. In the future, an individual at risk for a particular carcinogenic process may be recommended a supplement of the most appropriate anticarcinogen, specific to their individual endowment of genetic and environmental risk factors. This review emphasizes not only what is known but also what is not known. Consequently we identify priorities for research that, if undertaken, will allow such recommendations to be made or discounted with more confidence.Key words: β-carotene, carotenoids, free radicals, antioxidants, carcinogenesis, chemoprevention.
Does endogenous zinc protoporphyrin modulate carbon monoxide formation from heme? Implications for long-term potentiation, memory, and cognitive function
Authors: Marks Gerald S. , Nakatsu Kanji , Brien James F.
Published: April 2011

Carbon monoxide, which is formed endogenously from heme catabolism catalyzed by heme oxygenase and shares some of the chemical and biological properties of nitric oxide, may play a similar role as a widespread signal transduction mechanism for the regulation of cell function and communication. Zinc protoporphyrin, an inhibitor of heme oxygenase, prevents induction of long-term potentiation. Zinc protoporphyrin is an endogenous substance and we suggest that it has a physiological role, by modulating heme oxygenase activity and, therefore, formation of carbon monoxide from heme. This in turn would modulate long-term potentiation, memory, and cognitive function.Key words: zinc protoporphyrin, carbon monoxide, heme oxygenase, long-term potentiation.
Ethanol neuro–behavioural teratogenesis in the guinea pig: behavioural dysfunction and hippocampal morphologic change
Authors: Abdollah Shirin , Catlin Michelle C. , Brien James F.
Published: April 2011

Ethanol neuro–behavioural teratogenesis was studied in the guinea pig because of its extensive prenatal brain development, Our objective was to study, in the offspring of the guinea pig, behavioural and hippocampal morphologic effects produced by chronic maternal administration of 3 and 4 g ethanol kg body weight−1∙day−1. Pregnant guinea pigs received one of the following chronic treatments via intubation into the oral cavity: 3 or 4 g ethanol∙kg−1∙day−1 as two equally divided doses 2 h apart; isocaloric sucrose and pair feeding; or water. Five litters were obtained for each treatment. Locomotor activity rate was determined on postnatal days 10, 20, and 60, and testing of the spontaneous alternation task was conducted beginning on postnatal days 22 and 62. After behavioural testing, the hippocampus of the brain of randomly selected guinea pig offspring of each treatment group was assessed histologically by light microscopic examination of cresyl violet stained coronal sections. The 3 and 4 g ethanol∙kg−1∙day−1 regimens did not restrict maternal body weight gain or growth of the offspring. Both regimens increased locomotor activity rate in the offspring, which persisted into adulthood for the 4 g ethanol∙kg−1∙day−1 regimen. Neither ethanol regimen impaired spontaneous alternation, but the 4 g ethanol∙kg−1∙day−1 regimen increased the percent completed trials. Only the 4 g ethanol∙kg−1∙day−1 regimen produced structural injury in the hippocampus, consisting of a 25% decrease in the number of CA1 pyramidal neurons. The data demonstrate that the 4 g ethanol∙kg−1∙day−1 regimen produces more behavioural dysfunction and hippocampal morphologic change compared with the 3 g ethanol∙kg−1∙day−1 regimen.Key words: ethanol, teratogenesis, guinea pig, locomotor activity, spontaneous alternation, hippocampus, CA1 pyramidal neurons.
Effects of pertussis and cholera toxins on α-adrenoceptor function in rat tail artery: differences in hypertension
Authors: Li Xiao-Fang , Triggle Christopher R.
Published: April 2011

The α1- and α2-adrenoceptor-stimulated contractile responses of rat tail artery rings were compared in Sprague–Dawley (SD), spontaneously hypertensive (SHR), and Wistar–Kyoto (WKY) rats that were untreated, treated with pertussis toxin, or treated with cholera toxin. The maximal responses, expressed as milligrams of tension, induced by clonidine (an α2-adrenoceptor agonist) and cirazoline (a selective (α1-adrenoceptor agonist) were significantly greater in SHR than in SD or WKY, and the tissues were more sensitive to the agonists in SHR or SD than in WKY. Yohimbine (0.1 μM), a selective α2-adrenoceptor antagonist, shifted the dose–response curves for clonidine to the right. The effects of yohimbine were greater in SD than in WKY or SHR, but not different between WKY and SHR. Prazosin (0.05 μM), a selective α1-adrenoceptor antagonist, shifted the dose–response curves of cirazoline to the right, but the effects of prazosin were not different among these three strains of rats. Nifedipine (0.05 μM) completely blocked the response to clonidine in SD and WKY; however, in SHR, approximately one-third of the response to clonidine was resistant to nifedipine. Nifedipine, at 0.05 μM, only partially inhibited responses to cirazoline in SD, SHR, and WKY, and no differences were noted between the strains. Pertussis toxin pretreatment (50 μg/kg, 3 days before experiment) almost completely blocked the responses to clonidine, but only partially inhibited those to cirazoline. After pertussis toxin pretreatment, the responses (maximal effects and EC50s) to clonidine and cirazoline were not significantly different in arteries from the three strains of rats. A combination of pertussis toxin and nifedipine resulted in an additive inhibition of the responses induced by cirazoline. cholera toxin pretreatment (0.3 mg/kg, 3 days before experiment), however, had no effects on the contractile responses induced by either clonidine or cirazoline, or on the inhibitory effects of nifedipine in SHR, SD, and WKY. These results indicate that (i) the maximal responses to α1- and α2-adrenoceptor agonists are enhanced in rat tail artery rings from SHR; (ii) tissues from SH and SD rats are also more sensitive to cirazoline and clonidine than are tissues from WKY; (iii) responses to clonidine, but not cirazoline, in tissues from the SHR are less sensitive to nifedipine than tissues from SD and WKY; (iv) a G-protein sensitive to pertussis but not cholera toxin is involved in the regulation of both α1 and α2-adrenoceptor signal transduction processes in rat tail artery smooth muscle; and (v) pretreatment with pertussis toxin reduces the enhanced response levels of SHR tissues so that the maximal contractile responses to both α1- and α2-adrenoceptor agonists are equivalent in arteries from the three strains of rats.Key words: pertussis toxin, cholera toxin, α1-adrenoceptor, α2-adrenoceptor, rat tail artery ring.
Myocardial response to regional ischemia and reperfusion in vivo in rat heart
Authors: Ji L. L. , Fu R. G. , Waldrop T. G. , Liu K. J. , Swartz H. M.
Published: April 2011

Ischemia–reperfusion-induced myocardial oxidative changes were investigated in open-chest hearts of anesthetized rats. Surgical occlusion of the left anterior descending coronary artery for 30 min followed by 15 min reperfusion resulted in a significant decrease of reduced glutathione, an increase in glutathione disulfide, and an enhanced lipid peroxidation in rapidly frozen left ventricular tissues. Direct electron paramagnetic resonance spectroscopy revealed an increase in free radical concentration in ischemic cardiac tissues reperfused for 45 s, but the increase diminished at 15 min. These alterations were associated with decreased activities of myocardial glutathione peroxidase, glutathione reductase, and catalase. Ischemia resulted in a significant reduction of high-energy phosphate compounds and an accumulation of nucleotide degradation products, particularly adenosine, in the myocardium. Deterioration of cardiovascular function in reperfused animals was also evident. It is concluded that regional ischemia followed by reperfusion in situ can produce biochemical and physiological alterations consistent with free radical injury in rat hearts, and that an increased purine nucleotide degradation and a decreased antioxidant defense may be responsible for the observed changes.Key words: ischemia–reperfusion, myocardium, oxidative damage, glutathione, antioxidant enzyme.
Role of gastric acid secretion and blood flow in the development of vagal stimulation induced gastric mucosal damage
Authors: Hierlihy Lynn E. , Wallace John L. , Ferguson Alastair V.
Published: April 2011

Vagal stimulation has been shown to result in the development of gastric mucosal erosions in the rat, although the mechanisms underlying the development of such erosions are not known. The effects of vagal stimulation on gastric acid secretion and mucosal blood flow were examined in urethane-anesthetized male Sprague–Dawley rats to determine whether changes in these factors correlate with the mucosal damage in response to vagal stimulation. Electrical stimulation (5 Hz, 5 V, 1 ms for 60 min) of afferent or efferent components of the vagi was not found to induce any significant increase in the mean acid secretory rate compared with control animals (p > 0.05). In contrast, stimulation of intact vagus nerves induced a significant increase in the mean acid secretory rate compared with control and efferent- and afferent-stimulated groups (p < 0.01). Measurement of gastric blood flow with laser-Doppler flowmetry demonstrated intact vagal stimulation to have no significant effect on gastric blood flow. These data suggest that such vagal stimulation induced increases in acid secretion in urethane-anesthetized animals may represent a part of the integrated physiological response to such stimulation which leads to the development of gastric mucosal erosions within 60 min. Pretreatment with antisecretory agents such as cimetidine and inter-leukin-1β significantly reduce the gastric mucosal injury compared with untreated animals (p < 0.05), emphasizing the important role of acid secretion in the development of vagal-induced gastric damage.Key words: vagus, acid secretion, blood flow, gastric.
Luminal nutrients alter tight-junction permeability in the rat jejunum: an in vivo perfusion model
Authors: Sadowski D. C. , Meddings J. B.
Published: April 2011

The regulation of tight-junction permeability between enterocytes has been studied using in vitro perfused loops, Ussing chambers, and cultured cell monolayers. In this communication we demonstrate the ability of an in vivo perfusion model to monitor tight-junction permeability and respond appropriately to physiological luminal stimuli. By using the highly charged anionic ferrocyanide molecule, water flux could be accurately assessed in the rat, and the luminal clearance of high molecular weight dextrans could be used to probe the opening and closing of the paracellular pathway. By utilizing two different molecular weight dextrans markers simultaneously, each conjugated with a different fluorophore, we were able to calculate luminal clearances of these compounds by fluorometric techniques in the presence of luminal nutrients that have previously been demonstrated to open intercellular tight junctions. In the absence of luminal nutrients or the presence of a non-nutrient sugar such as mannitol, clearance of these compounds was negligible. However, with the addition of either D-glucose or L-alanine, clearance of both high molecular weight markers increased dramatically. Thus, opening of tight junctions between enterocytes appears to be a physiological event that occurs in vivo under conditions likely to be found in the lumen. Polyethylene glycol 400 (PEG-400) clearance did not correlate well with the clearance of either dextran marker, suggesting that this probe utilizes a different permeation pathway and may not be appropriate to quantify the nutrient-regulatable pathway observed with the former probes.Key words: intestinal permeability, glucose transport, paracellular transport.
Effects of the liver on circulating adenosine in blood
Authors: Zhang Yong , Lautt W. Wayne
Published: April 2011

The effects of the liver on circulating adenosine in vivo were examined by monitoring plasma adenosine levels in hepatic afferent and efferent blood during intraportal venous (i.p.v.) and intravenous (i.v.) infusions of adenosine (0.04–1 mg∙kg−1∙min−1). Dilazep, a blocker of nucleoside uptake, was also used for studying the uptake of adenosine into the liver and extrahepatic sites. Basal levels of plasma adenosine in portal venous, arterial, and hepatic venous blood were similar. However, increased adenosine levels during infusions were significantly cleared by a single passage through the liver, suggesting that the liver is a potent organ for eliminating the increased adenosine in circulation. Dilazep inhibits extrahepatic elimination but does not affect hepatic extraction of circulating adenosine. Subtypes of nucleoside uptake are suggested to exist between the liver and other cell types, such as red blood cells.Key words: liver, adenosine, dilazep, subtype of nucleoside uptake.
Components of postprandial thermogenesis in relation to meal frequency in humans
Authors: LeBlanc J. , Mercier I. , Nadeau A.
Published: April 2011

Experiments on dogs have shown that the size of the meal has no effect on the early cephalic postprandial thermogenesis, and that four small meals are more thermogenic than a larger meal with the same total caloric content as the four meals. A study was repeated on human subjects who were fed during alternating weeks either one large meal (653 kcal (1 kcal = 4.1855 kJ)) or four small meals (163 kcal) at 40-min intervals. Oxygen consumption and respiratory exchange ratio determinations indicated (i) larger overall increase in postprandial thermogenesis with the four meals than with one meal and (ii) an enhancement of glucose utilization with the large meal compared with greater lipid utilization with the four meals. On the basis of indirect evidence from previous investigations it is suggested that the enhanced thermogenesis observed in the four-meal experiment is due to lipid mobilization caused by repeated stimulation of the sympathetic nervous system with palatable food. Blood analysis indicated a reduced elevation of plasma glucose in the four-meal experiment. The variations of insulin and C-peptide exactly paralleled those observed for glucose. It is concluded that the increased frequency of feeding significantly reduces insulin secretion in subjects fed a relatively high carbohydrate meal. In addition to this beneficial effect, increasing the number of meals increased thermogenesis and fat utilization.Key words: feeding thermogenesis, insulin secretion, meal frequency, lipid oxidation.
Glucose-dependent insulinotropic polypeptide stimulated insulin release from a tumor-derived β-cell line (βTC3)
Authors: Kieffer Tim J. , Verchere C. Bruce , Fell Charlene D. , Huang Zhongxian , Brown John C. , Pederson Raymond A.
Published: April 2011

The βTC3 tumor cell line was examined for the presence of functional glucose-dependent insulinotropic polypeptide (GIP) receptors. Increasing amounts of natural porcine GIP decreased the binding of HPLC-purified [125I]GIP to βTC3 cells in a concentration-dependent manner. Displacement of GIP was significant at concentrations as low as 500 pM, and the radioligand was fully displaced at 100 nM. GIP(1–30) produced a displacement of [125I]GIP comparable with that produced by GIP(1–42), and glucagon yielded 20% displacement at a concentration of 1 μM but was without effect at 100 nM. Incubation of βTC3 cells in the presence of glucose concentrations of 2–20 mM yielded a concentration-dependent stimulation of immunoreactive insulin (IRI) release. GIP and glucagon-like peptide-I(7–36) amide (tGLP-I) at concentrations of 1 nM or greater significantly stimulated IRI release in the presence of 2 mM glucose. The threshold glucose concentration for GIP-stimulated IRI release from βTC3 cells was 0.5 mM, and maximal potentiation of IRI release by GIP occurred at 5 mM glucose. Somatostatin significantly inhibited GIP-stimulated IRI release in the presence of 5 mM glucose. It is concluded that βTC3 cells have functional GIP receptors and may provide a useful model for the study of IRI secretion at the cellular level.Key words: insulin, βTC3, glucose-dependent insulinotropic polypeptide.
Comparison of the cardiac pumping capability and cardiac pumping reserve in double-muscled and conventional calves
Authors: Amory H. , McEntee K. , Linden A. S. , Desmecht D. J. M. , Beduin J. M. L. , D'Orio V. , Lekeux P. M.
Published: April 2011

Hereditary muscular hypertrophy is a character that has been selected in several animal species for industrial meat production. The selection of this character in cattle produces animals of exceptional commercial value but ones with a lower aerobic capacity than that of conventional cattle. The purpose of this work was to study the role of cardiac function as a potential limiting factor of aerobic capacity in double-muscled calves. Two groups of healthy calves were studied, one consisting of nine calves of conventional conformation and the other of nine double-muscled calves. Pulmonary arterial and capillary wedge, central venous, and systemic arterial pressures were measured by fluid-filled catheters and recorded together with the electrocardiogram. Cardiac output was measured by the thermodilution technique. From these measurements, the heart rate, the cardiac and the stroke indices, the pulmonary and the systemic vascular resistances, and the cardiac power output were calculated. The parameters were recorded under basal resting conditions and during incremental dobutamine challenge, which allowed determination of the resting cardiac power output, the cardiac pumping capability, and the cardiac reserve. Dobutamine challenge induced a significant rise in cardiac and stroke indices, heart rate, and cardiac power output, a significant decrease in pulmonary and systemic vascular resistances, and no change in systemic and pulmonary arterial pressures. The cardiac reserve obtained in the present study was low in comparison with those previously reported in humans, dogs, and horses. This may be related to the poor running capability of bovine species relative to that of the former species. The double-muscled calves had significantly lower cardiac and stroke indices, resting cardiac power output, cardiac pumping capability, and cardiac reserve than did conventional calves. Therefore, the cardiac performance, capability, and reserve were reduced in double-muscled calves. It was concluded that cardiac performance is a critical step in the oxygen-transport pathway in double-muscled cattle.Key words: cattle, hereditary muscular hypertrophy, oxygen consumption, cardiovascular system, cardiac power output.
Inhibition of mouse embryonic, yolk sac, and limb-bud functions by the methyl isocyanate metabolite S-(N-methylcarbamoyl)glutathione
Authors: Guest Ian , Varma Daya R.
Published: April 2011

We previously reported that S-(N-methylcarbamoyl)glutathione (SMG), a conjugate formed by the reversible reaction between methyl isocyanate and glutathione, inhibited the development of mouse embryos in culture. The present study was done to determine whether SMG produced embryotoxicity by inhibiting yolk sac functions. For this purpose we determined the effects of an embryotoxic concentration of SMG on mouse yolk sac uptake mechanisms and lysosomal proteolysis as well as on the incorporation of [3H]leucine in mouse embryonic and limb-bud proteins. After 5 h of culture, SMG inhibited the uptake of [14C]sucrose and 125I-labelled bovine serum albumin in isolated day 15 yolk sacs to 62 and 77% of control, respectively. Lysosomal proteolysis was not inhibited, as judged by the release of trichloroacetic acid soluble radioactivity into the culture media. Uptake and incorporation of [3H]leucine from free [3H]leucine or from [3H]leucine-labelled protein in SMG-treated day 9 embryos were inhibited, respectively, to 61 and 25% of the control uptake during a 16-h labelling period. SMG also inhibited the incorporation of free [3H]leucine into limb-bud proteins. SMG-induced inhibition of 125I-labelled bovine serum albumin uptake by yolk sacs was partially prevented by the thiol donors N-acetylcysteine and glutathione but not by acivicin (γ-glutamyl transpeptidase inhibitor) and aminooxyacetic acid (cysteine conjugate β-lyase inhibitor). These data suggest that SMG suppresses embryonic growth primarily by an inhibition of nutrient uptake by the yolk sac. We postulate that this inhibition is due to tissue carbamoylation by methyl isocyanate released from SMG.Key words: yolk sac functions, methyl isocyanate, glutathione conjugate, embryo toxicity, pinocytosis, embryo culture, limb bud.
Evaluation of the rat embryo culture system as a predictive test for human teratogens
Authors: Guest Ian , Buttar Harpal S. , Smith Susan , Varma Daya R.
Published: April 2011

Ingestion of the anticonvulsant drag valproic acid and of the angiotensin converting enzyme inhibitor captopril during pregnancy has been associated with abnormal fetal outcome in humans. In contrast, the use of the antiinflammatory drug ibuprofen and the antihistamine diphenhydramine has not been documented to be embryotoxic in humans. We evaluated the rat embryo culture system as a predictive model of teratogenesis, using these four drugs as test agents. Valproic acid, ibuprofen, and diphenhydramine were embryotoxic, inducing concentration-dependent decreases in growth and a significant increase in anomalies. Valproic acid caused an increase in neural tube defects, ibuprofen increased the incidence of abnormal maxillary processes, and diphenhydramine increased the number of embryos with distorted body morphology. These abnormalities were induced at concentrations of valproic acid and diphenhydramine that are used clinically, but ibuprofen only induced toxicity at concentrations greatly exceeding the therapeutic range. Captopril was not embryotoxic up to 5 mM, the highest concentration tested. These results suggest that the rat embryo culture system produces both false positive and false negative data on the teratogenic potential of drugs. Although such an in vitro assay may be suitable to determine the mechanism of teratogenesis, it is not a sensitive indicator of potential human teratogens on its own. These data support the view that in vitro systems can only supplement clinical and epidemiological observations in humans, possibly as a method to determine mechanisms of actions of teratogens.Key words: embryo culture, teratogenesis, valproic acid, captopril, ibuprofen, diphenhydramine.
Effect of extracellular Ca2+ on indomethacin-induced injury to rabbit dispersed gastric mucosal cells
Authors: Tepperman B. L. , Soper B. D.
Published: April 2011

The effects of extracellular Ca2+ on indomethacin-induced disruption to rabbit dispersed gastric mucosal cells have been examined. Fundic mucosal cells were isolated, and cellular viability and disruption were assessed by the release of the lysosomal enzyme acid phosphatase and by trypan blue dye exclusion. Addition of the Ca2+ ionophore A23187 (12.5 and 25 μM) and indomethacin (0.1–10 μM) to the incubation medium induced concentration-dependent increases in enzyme marker release and trypan blue dye uptake in the cells. The resultant cellular disruption in response to incubation of cells with combinations of indomethacin and A23187 was not significantly different from that observed when the agents were administered separately. The degree of cell injury was reduced by removal of Ca2+ from the incubation medium. Similarly preincubation with the Ca2+ channel antagonist verapamil (1 μM) reduced A23187- and indomethacin-induced cell injury. Both A23187 (25 μM) and indomethacin (10 μM) treatments increased cytosolic Ca2+ concentration ([Ca2+]i). Pretreatment of cells with 16,16-dimethylprostaglandin E2 (0.1–10 μM) reduced both indomethacin (10 μM) induced cellular damage and the elevation in [Ca2+]i. These data suggest that indomethacin-induced disruption of gastric mucosal cells is dependent to some extent upon extracellular Ca2+. An inappropriate Ca2+ flux may contribute to indomethacin-induced damage to gastric mucosal cells.Key words: ionophore A23187, indomethacin, prostaglandin, calcium, cell damage.
Canine colonic circular muscle generates action potentials without the pacemaker component
Authors: Liu Louis W. C. , Huizinga Jan D.
Published: April 2011

Two dominant types of action potentials in canine colon are slow wave type action potentials (slow waves) and spike-like action potentials (SLAPs). The slow waves, originating at the submuscular surface where a network of interstitial cells of Cajal (ICCs) is found, possess a pacemaker component. Activation of the pacemaker component is insensitive to voltage changes and L-type calcium channel blockers, and is postulated to involve a metabolic clock sensitive to cyclic AMP. SLAPs are more prominent in the longitudinal muscle. To understand the contribution circular muscle cells make to the generation of these action potentials, a circular muscle preparation (devoid of the submuscular ICC – smooth muscle network, longitudinal muscle, and myenteric plexus) was developed. Circular muscle preparations were spontaneously quiescent, with a resting membrane potential of −62.9 ± 0.6 mV. Ba2+ (0.5 mM) depolarized the cells to −51.8 ± 0.6 mV and induced electrical oscillations with a frequency, duration, amplitude, and rate of rise equal to 6.6 ± 0.4 cpm, 2.2 ± 0.2 s, 19.4 ± 0.9 mV, and 21.8 ± 1.7 mV/s, respectively. In most cases, Ba2+-induced oscillations were preceded by a prepotential of 4.4 ± 0.3 mV, with a rate of rise of 1.1 ± 0.1 mV/s. Ba2+-induced oscillations were abolished by 1 μM D600 as well as by repolarization of 6–12 mV. Addition of 0.1 μM Bay K8644 in the presence of Ba2+ further depolarized circular muscle cells to −42.4 ± 0.8 mV and increased the oscillation frequency to 16.8 ± 1.8 cpm. The electrical oscillations induced in circular muscle preparations by Ba2+ and Bay K8644 were similar to the SLAPs exhibited by the isolated longitudinal muscle layer, indicating that generation of SLAPs is an intrinsic property of smooth muscle cells. Forskolin (1 μM), previously shown to dramatically decrease the frequency but not the amplitude of slow waves in preparations including the submuscular ICC network, decreased the amplitude of the Ba2+-induced oscillations in circular muscle preparations without changing the frequency. These results provide strong evidence for the hypothesis that the submuscular ICC – smooth muscle network is essential for the initiation of the pacemaker component of the colonic slow waves. The mechanism for regulating the frequency of slow waves is different from that responsible for the Ba2+-induced oscillations in circular muscle preparations. Circular muscle cells are shown to be excitable and capable of generating oscillatory activity dominated by L-type calcium channel activity, which is regulated by K+ conductance.Key words: interstitial cells of Cajal, smooth muscle, dog colon, barium chloride, potassium conductance, Bay K8644, pacemaking activity.
Tachykinin-mediated increase in motility acts independently of vasoactive intestinal polypeptide release in the canine ileum
Authors: Watson E. G. , Fox-Threlkeld J. E. T. , Daniel E. E.
Published: April 2011

Tachykinins induce motor activity in the canine ileum, and their mechanism of excitation may include inhibition of the release of a nonadrenergic, noncholinergic inhibitor, for which vasoactive intestinal polypeptide (VIP) is a candidate. Both substance P and neurokinin A produced a dose-dependent increase in ileal contractility with no significant change in VIP output. The highly selective NK1 agonist [Sar9, Met(O2)11]substance P and the highly selective NK2 agonist [Nle10]neurokinin A (4–10) also increased motor activity in the absence of any change in VIP released. These data suggest that the tachykinins produce motor activity in the canine ileum via a mechanism that does not involve changes in VIP output but may involve excitation through both NK1 and NK2 receptors.Key words: vasoactive intestinal polypeptide, tachykinins, gastrointestinal tract, motility.
Does endogenous adenosine have a role in the cardiac responses to isoprenaline and in the rapid fade of the inotropic response of perfused heart?
Authors: Broadley Kenneth J. , Wilson Andrew N. A.
Published: April 2011

The role of endogenous adenosine during the β-adrenoceptor responses to isoprenaline of guinea-pig isolated cardiac preparations was examined. Insignificant effects of adenosine deaminase (0.3 U∙mL−1) on cumulative concentration–response curves for isoprenaline on isolated left and right atria and papillary muscles indicated a negligible depressant effect of endogenous adenosine during these responses. The increase in force of contraction to an infusion of isoprenaline (14 nM) in perfused spontaneously beating hearts rapidly waned while the infusion continued, whereas the increase in rate of contraction remained constant throughout the infusion. The degree of fade was less in paced preparations (5 Hz), indicating that it was only in part due to the rate increase exerting some mechanical constraint on the force of contraction. The P1-purinoceptor antagonist 8-phenyltheophylline (12 μM) and adenosine deaminase (0.3 U∙mL−1) did not enhance the peak responses to the isoprenaline infusion. The fade of the inotropic response in both spontaneous and paced hearts was also not attenuated by the presence of 8-phenyltheophylline or adenosine deaminase. The fade was not, therefore, due to release of endogenous adenosine exerting a depressant effect. Whether this declining inotropic response represents a form of rapid desensitization remains to be determined.Key words: guinea-pig perfused hearts, left and right atria, papillary muscles, β-adrenoceptor agonist, endogenous adenosine.
Trichloroethylene induces pulmonary fibrosis in mice
Authors: Forkert P. G. , Forkert L.
Published: April 2011

Trichloroethylene elicits acute pulmonary cytotoxicity in mice, which involves Clara cells of bronchioles. In this study, we have examined the effects of an acute dose of trichloroethylene in lungs of mice over 3 months. Pulmonary fibrosis was first detected at 15 days and was progressive with time elapsed after trichloroethylene exposure. Diffuse interstitial fibrosis was observed in the alveolar zone, resulting in thickening of alveolar septa and distortion of lung structure. The fibrosis was most pronounced at 90 days after treatment, resulting in deposition of connective tissue in the alveolar septa. Levels of total lung hydroxyproline were not significantly different in control and treated mice at 30 and 60 days after trichloroethylene treatment, but were significantly increased at 90 days. Proline content remained unchanged during the course of this study. The increase in collagen deposition at 90 days coincided with a signficant increase in lung elastic recoil. Our results show that a single acute dose of trichloroethylene causes structural and functional abnormalities that are progressive for at least 3 months.Key words: trichloroethylene, lung, interstitial fibrosis.
Shivering thermogenesis during acute hypercapnia
Authors: Lun Victor , Sun John C. L. , Giesbrecht Gordon G. , Mekjavić Igor B.
Published: April 2011

The effects of acute hypercapnia on human thermoregulation during cold exposure were investigated by immersion of eight male subjects to the neck in a 15 °C water bath until their core temperatures dropped to 35 °C or until 1 h of immersion had elapsed. Air was inspired throughout each experiment, with the exception of a 15-min period commencing with the attainment of an esophageal temperature (Tes) of 36.5 °C, during which subjects inspired a gas mixture containing 4% CO2, 20% O2, and 76% N2. Oxygen uptake ([Formula: see text], L∙min−1), inspired minute ventilation ([Formula: see text], L∙min−1), esophageal temperature (Tes, °C), rectal temperature (Tre, °C), mean unweighted skin temperature (Tsk, °C), mean heat flux (Q, W∙m−2), and electromyographic activity (EMG, mV) of the trapezius and masseter muscles were recorded continuously. [Formula: see text] and integrated EMG activity (IEMG) were used as the primary indicators of shivering thermogenesis. Shivering EMG was attenuated immediately following the switch of the inhaled gas mixture from air to 4% CO2. For both the massetter and trapezius muscles the IEMG was significantly suppressed (p < 0.05) during the hypercapnic period. The IEMG values preceding the switch to the hypercapnic mixture were 15% greater than those during the CO2 period. Similarly, IEMG values in the post-CO2 period were 55% greater than during the CO2 period. It is concluded that acute periods of hypercapnia during cold exposure may result in transient suppression of shivering tremor, but this does not appear to affect thermal balance, as reflected in the absence of any significant effect on Tes.Key words: temperature regulation, carbon dioxide, hypothermia, diving, cooling, cold water immersion, carbon dioxide retention.
The gut: central organ in nutrient requirements and metabolism
Authors: McBurney Michael L.
Published: April 2011

The gut is an important organ, which not only digests and absorbs food but selectively excludes bacteria and toxins from entering the body. It has one of the highest rates of protein turnover of any tissue in the body. Maintenance of epithelial cell proliferation and secretory, digestive, and gut-associated lymphatic tissues (GALT) function requires a constant supply of substrates. A primary feature of the metabolic response to fasting, accidental injury, or surgery is accelerated skeletal muscle proteolysis and translocation of amino acids from the periphery to visceral organs. Nevertheless, the serosal supply of nutrients may be inadequate to maintain normal gut barrier function. The following factors influencing gut nutrient requirements and the effect of the gut on the whole-body metabolism are discussed: (i) diet composition and gut mass, (ii) physiological and pathologic nutrient requirements of epithelial and GALT cells, (iii) route of nutrition (enteral versus parenteral), and (iv) nutrient inadequancy and gut barrier dysfunction (structural or immune mediated).Key words: gastrointestine, metabolism, gut-associated lymph tissue, glutamine, short-chain fatty acids.
Different pharmacological characteristics of structurally similar benzylisoquinoline analogs, papaverine, higenamine, and GS 389, on isolated rat aorta and heart
Authors: Chang Ki Churl , Chong Won Seog , Lee In Je
Published: April 2011

In the present study, we compared the pharmacological properties of structurally similar benzylisoquinoline compounds, papaverine, higenamine, and GS 389, using isolated rat aorta and atrial preparations. The three benzylisoquinoline compounds, concentration dependently, relaxed phenylephrine (3 μM) induced contraction of rat aortic rings, with the rank order of potency being higenamine > papaverine > GS 389. They also relaxed high K+ (60 mM) induced contraction, with the rank order of potency being papaverine > GS 389 [Formula: see text] higenamine. The relaxation was not modified by the presence of endothelium. To assess whether these compounds directly interfere with Ca2+ influx, the effects of these compounds on Ca2+-induced contraction in Ca2+-free media were examined. Among the three compounds, papaverine most strongly inhibited Ca2+-induced contraction of both K+ stimulated and phenylephrine-stimulated aorta. Higenamine was least potent in inhibition of Ca2+-induced contraction in high K+ depolarized aorta. In atrial tissues, lower concentrations of papaverine increased spontaneous beats and isometric tension, whereas above 30 μM its action was reversed. GS 389 decreased heart rate without affecting the contractility. On the other hand, higenamine concentration dependently increased both heart rate and isometric tension, as well as cyclic AMP levels in atrial tissues as a result of β-receptor activation. Cyclic AMP and cyclic GMP dependent phosphodiesterases from rat atrial and ventricular tissue homogenates were inhibited by papaverine and GS 389, but not by higenamine. These results suggest that calcium antagonistic action of these compounds is at least in part responsible for vasodilation action, but not for cardiac action. Dihydroxyl groups attached at C6 and C7 on the isoquinoline backbone appear to be responsible for altering the action of cardiac muscle.Key words: relaxation, Ca2+ antagonist, inotropic and chronotropic action, cyclic nucleotides.
Adrenal medullary counterregulatory response to hypoglycemia in dogs with hepatic cross perfusion
Authors: Yamaguchi Nobuharu , Lamarche Louis
Published: April 2011

The present study was conducted to investigate adrenal medullary responses to cross perfusion of the liver in postabsorptive anesthetized dogs. The liver of the first dog (recipient) was perfused with vena caval and aortic blood of the second dog (donor) through the portal vein and hepatic artery, respectively. Hepatic venous blood was returned to the donor through an intracaval double-lumen hepatic catheter placed in the vena cava of the recipient. A portacaval shunt was made through the right femoral vein in the recipient. Upon the cross perfusion, normoglycemic clamp in the recipient was started to compensate the loss of hepatic glucose input into the systemic circulation. When the glucose infusion was discontinued, aortic glucose level rapidly declined, within 45 min, from 125.2 ± 10.2 to 30.3 ± 4.6 mg% (p < 0.05, n = 6) along with a similarly rapid decline of aortic insulin level. Inversely, both adrenal venous epinephrine and norepinephrine increased significantly (163.2 ± 88.0 vs. 794.9 ± 55.7 ng/mL (p < 0.05) and 36.6 ± 22.4 vs. 119.7 ± 15.3 ng/mL (p < 0.05), respectively; n = 6) during this hypoglycemic period. However, in the donor, glucose level did not change either in aortic or vena caval blood, indicating that the recipient's liver was perfused with normal blood glucose levels. In the control group in which the normoglycemic clamp in the recipient was continued during the cross perfusion, both aortic glucose and adrenal venous catecholamines remained unchanged. The results indicate that the hepatic cross perfusion caused a rapid and severe hypoglycemia, resulting in a significant increase in adrenal medullary secretion, due most probably to the activation of central glucoreceptor-mediated mechanisms. This model may be useful for studying interactions between hepatic and central glucoreceptors implicated in regulatory mechanisms of glucose homeostasis.Key words: catecholamines, counterregulation, cross perfusion, glucoreceptors, liver.