bluuebunny/crossref_metadata_2025 huggingface dataset:
Interleukin-1 receptor antagonist: effectiveness against interleokin-1 fever
Authors: Coceani Flavio , Lees Jodi , Redford Jane , Bishai Isis
Published: April 2011

Conscious cats were used to examine the effectiveness of the interleukin-1 receptor antagonist against the fever induced by interleukin-1 and endotoxin. Although inactive by itself, the antagonist (three 1-μg bolus injections at 10-min intervals), injected into the third ventricle, attenuated the febrile response to a subsequent intracerebroventricular bolus of interleukin-1. The rise in prostaglandin E2 levels in cerebrospinal fluid, which is a characteristic feature of fever, was curtailed as well. The interleukin-1 antagonist had little or no inhibitory effect on the response to an intracerebroventricular bolus of endotoxin, even though a higher dose was employed (2-μg bolus injections given three times at 10-min intervals and six times at 30-min intervals, respectively, before and after endotoxin administration). At either dosage, the intracerebroventricular antagonist was completely ineffective against an intravenous bolus injection of interleukin-1 or endotoxin and both fever and prostaglandin E2 elevation developed unabated. We conclude that brain receptors mediating the pyrogenic action of centrally injected interleukin-1 are susceptible to the antagonist. The same receptors, however, are seemingly not activated by systemic pyrogens. Our findings are consistent with the concept of circulating interleukin-1 acting outside the blood–brain barrier in the normal sequence of fever.Key words: interleukin-1, interleukin-1 receptor antagonist, endotoxin, prostaglandin E2, fever mechanism.
Energy-dependent transport of digoxin across renal tubular cell monolayers (LLC-PK1)
Authors: Ito Shinya , Koren Gideon , Harper Patricia A. , Silverman Melvin
Published: April 2011

Digoxin secretory transport across renal tubular cell monolayers (LLC-PK1) grown on permeable filters was characterized. Metabolic inhibitors reduced total and specific basolateral to apical (B–A) flux of digoxin and conversely increased the apical to basolateral (A–B) flux. The specific transport of digoxin from the basolateral to the apical compartment was saturable, with a maximum velocity of transport of 184.5 ± 38.0 pmol∙cm−2∙h−1 and a Michaelis–Menten constant (Km) of 14.1 ± 1.6 μM. In addition, B–A flux of digoxin resulted in accumulation of digoxin in the apical compartment against the concentration gradient. P-Glycoprotein inhibitors such as quinidine, verapamil, vincristine, and cyclosporine increased the net A–B flux and inhibited the total B–A flux without affecting the nonspecific flux significantly. Tetraethylammonium, a prototype substrate for an organic cation transport system, had no such effect. Our results suggest that digoxin undergoes transepithelial secretion by an energy-dependent, carrier-mediated process in renal tubules, a process that seems to be distinct from the tetraethylammonium transport system.Key words: renal tubular secretion of digoxin, quinidine, tetraethylammonium, verapamil, vincristine, cyclosporine, P-glycoprotein.
General anesthetics inhibit cytochrome P450 monooxygenases and arachidonic acid metabolism
Authors: LaBella Frank S. , Queen Gary
Published: April 2011

Identification of a specific biomolecular target appropriately sensitive to a wide array of anesthetics has been elusive. At concentrations close to their respective ED50's for anesthesia in man or other species, 18 compounds, differing in potencies up to 66 000 fold, inhibited cytochrome P450 mediated metabolism of aminopyrine, a synthetic substrate, and arachidonic acid (AA), an endogenous substrate, in isolated liver microsomes. There was a highly significant correlation for both substrates between the absolute concentrations required for anesthesia (EC50) and for inhibition of P450 activity (Ki or IC50). The mean Ki/EC50 ratio was 0.97 for inhibition of aminopyrine demethylase. The mean IC50/EC50 ratios were 0.42 and 0.64 for inhibition of two AA-derived products and 2.8 for a third; a mean ratio of 1.4 for inhibition of overall AA metabolism suggests interaction of general anesthetics with a composite of P450 isozymes. The universal cytochrome P450 monooxygenases, in conjunction with other lipid oxygenases (cyclooxygenases and lipoxygenases) participate in the second messenger AA cascade. In nerve cells the sensitivity of these enzymes to hydrophobic neurodepressant drugs may underlie the state of general anesthesia: reversible disruption of intracellular and intercellular signalling without impairment of enzymes vital to cell respiration.Key words: anesthetics, general anesthesia, cytochrome P450, arachidonic acid, liver microsomes.
Endothelial adhesion molecules and their role in inflammation
Authors: Smith C. Wayne
Published: April 2011

The emigration of leukocytes such as neutrophils into inflammatory sites requires adhesion to the endothelium of small venules. The initial adhesive event is margination characterized by rolling of neutrophils along the luminal surface of the endothelium. Each member of the selectin family of adhesion molecules has been shown to support neutrophil rolling under conditions of flow. E-selectin is synthesized by endothelial cells following cytokine stimulation, P-selectin is rapidly mobilized from Weibel–Palade bodies to the endothelial cell surface following stimulation with agents such as histamine, and L-selectin is constitutively expressed on the surface of leukocytes. Each selectin functions primarily as a lectin, recognizing carbohydrate structures on the leukocyte or endothelial cell surface. Once the marginated neutrophil forms a stationary adhesion with endothelial cells, it is stimulated by chemotactic factors to downregulate the selectin-based adhesion and upregulate adherence dependent on β2-integrins, principally CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1). These adhesion molecules interact with intercellular adhesion molecule 1 (ICAM-1) and possibly other structures on the endothelial cell, and the leukocyte rapidly emigrates into surrounding tissue. Transendothelial migration in vitro is markedly inhibited by monoclonal antibodies against CD18 integrins or ICAM-1. Monoclonal antibodies against the selectins, CD18, CD11a, CD11b, and ICAM-1 have all been shown to significantly reduce the influx of neutrophils into sites of inflammation in various animal models.Key words: adhesion, integrins, selectins, leukocytes, endothelial cells.
Hepatic blood flow distribution: consideration of gravity, liver surface, and norepinephrine on regional heterogeneity
Authors: Lautt W. Wayne , Schafer Joshua , Legare Dallas J.
Published: April 2011

Blood flow distribution within the livers of cats and dogs was assessed using 15-μm microspheres injected into the hepatic artery and portal vein. Representative vertical core samples (n = 11–18) were taken from the thickest part of each liver. Heterogeneity was assessed in several ways. The difference in total flow to different lobes was greater in dogs than in cats, and in dogs, those lobes with highest portal venous flow had lowest hepatic arterial flow. Overall flow variance was very high in both species, with adjacent surface samples in a single lobe showing variance of 15–22% for both vessels. The ratio of highest to lowest flow within core samples averaged 2.1–3.4 for both vessels in both species. The hepatic arterial flow was highest to the surface 2 mm of the liver. Portal flow most often (31% of all samples) showed a pattern of highest flow to the top, graduating down to lowest flow to the bottom (dorsal side) of the vertical cores. However, this pattern appeared much more frequently in the most ventral liver lobes and very seldom in the lobes lying beneath the liver mass. Norepinephrine reduced heterogeneity. Hepatic arterial occlusion for 10 min produced minor and inconsistent reduction of heterogeneity. Rotating cats from back to front and again to back disrupted patterns of distribution but not in a way that could be interpreted as due to effects of gravity. Flow patterns changed with time. The heterogeneity of perfusion appears to be under dynamic and multiple interacting forces.Key words: blood flow distribution, blood flow heterogeneity, hepatic artery, portal vein, liver.
Effect of inhibitors of glutathione S-transferase on glyceryl trinitrate activity in isolated rat aorta
Authors: Nigam Rita , Whiting Tracy , Bennett Brian M.
Published: April 2011

We investigated the role of glutathione S-transferases (enzymes known to biotransform organic nitrates) in the vascular action of glyceryl trinitrate (GTN). Relaxation of phenylephrine-contracted rat aortic strips was assessed in the presence or absence of the glutathione S-transferase inhibitors Basilen Blue, bromosulfophthalein, Rose Bengal, hematin, chlorotriphenyltin, and (octyloxy)benzoylvinylglutathione. Whereas none of the inhibitors increased the EC50 for GTN relaxation, glutathione S-transferase activity in the 100 000 × g supernatant fraction of rat aorta was inhibited markedly by most of the inhibitors. In addition, GTN-stimulated activation of aortic guanylyl cyclase in broken-cell preparations was attenuated by all of the glutathione S-transferase inhibitors, suggesting a direct inhibitory action on guanylyl cyclase. In other experiments using aortic strips preexposed to phenylephrine, the inhibitors had no effect on GTN-induced cyclic GMP accumulation or on vascular biotransformation of GTN. In contrast, both Basilen Blue and bromosulfophthalein significantly inhibited GTN-induced relaxation of K+-contracted aortic strips, and Basilen Blue significantly inhibited GTN biotransformation in aortic strips preexposed to 25 mM K+. This may be due to a more favourable electrochemical gradient for entry of the inhibitors into membrane-depolarized tissues. We conclude that vascular glutathione S-transferases play a role in mediating the vasodilator actions of GTN in intact tissues in vitro, but that this appears to depend upon the nature of the contractile agent used in such studies.Key words: glyceryl trinitrate, glutathione S-transferase, cyclic GMP, vascular smooth muscle, biotransformation.
Hepatic cytochrome P450 and related drug biotransformation during an outbreak of mouse hepatitis virus in a colony of Swiss BALB/c mice
Authors: Armstrong Steven , Renton Kenneth W.
Published: April 2011

Mouse hepatitis is a common highly infectious virus of the Coronaviridae family that commonly infects laboratory colonies of BALB/c mice. In a natural outbreak of this disease in our institution we demonstrated that mouse hepatitis virus appears to have little or no effect on the levels of cytochrome P450 or on the activities of ethoxyresorufin O-dealkylase and benzyloxy resorufin O-dealkylase in hepatic microsomes. Antibody titers for the virus were elevated in ail mice tested and were negative in a control uninfected group. In a number of studies carried out over a period of months during the active outbreak we did not observe lower levels of cytochrome P450 in comparison with infectious free periods. Although the activation of host defence mechanisms and infections are well known to diminish the cytochrome P450 enzyme system in the liver, these results indicate that during a period of confirmed active infection with mouse hepatitis virus there was no evidence of an impairment in drug biotransformation enzymes.Key words: cytochrome P450, mouse hepatitis, infection, drug metabolism.
Effects of medial prefrontal cortex stimulation on the spontaneous activity of the ventral pallidal neurons in the rat
Authors: Delgado-Martínez A. D. , Vives F.
Published: April 2011

The neural connections from the medial prefrontal cortex to the ventral pallidum were investigated in urethane-anesthetized rats. Extracellular recordings were made from 124 spontaneously firing neurons in the ventral pallidum while the medial prefrontal cortex was electrically stimulated. The most frequent response to prefrontal cortex stimulation was inhibition of the firing rate of 72.3% of the neurons with orthodromic response (mean latency: 14.4 ± 1.6 ms). Excitatory responses were found in 27.7% of the neurons with orthodromic response (mean latency: 8.5 ± 1.4 ms). Frequency histograms of latencies were unimodal in both types of responses. Fifty-nine neurons (47.6% of the total tested) showed no change in spontaneous firing after medial prefrontal cortex stimulation. The electrophysiological results support previous anatomical findings of connections between the medial prefrontal cortex and the ventral pallidum. These projections play a predominantly inhibitory role in the spontaneous activity of ventropallidal neurons, and show topographical organization. This inhibition may modulate the motor performance of motivated behaviors.Key words: ventral pallidum, medial prefrontal cortex, electrophysiology.
Effects of amphetamine on the release of excitatory amino acid neurotransmitters in the basal ganglia of the conscious rat
Authors: Mora Francisco , Porras Alberto
Published: April 2011

The effects of systemic injections of amphetamine sulfate on the release of aspartic acid, glutamic acid, and glutamine were studied using a push–pull perfusion system in the conscious rat. Amphetamine produced a dose-related increase of the extracellular levels of aspartic acid and glutamic acid. The mean time effect of amphetamine was 40 min, followed by a recovery to baseline levels. The mean percentage increase in amino acids released by the highest dose of amphetamine (5 mg/kg) was as follows: Asp, 334.6%; Glu, 224.5%; and Gln, 317.6%. All these effects were blocked by the dopamine D1–D2 receptor blocker haloperidol. It is suggested that dopamine, released by amphetamine, induces the release of amino acid neurotransmitters in the neostriatum. In addition, it is proposed that dopamine could mediate the neurotoxic effects produced by amphetamines through their secondary action on the release of excitatory amino acids.Key words: amphetamine, dopamine, excitatory amino acids, neostriatum, conscious rat.
Increased extracellular dopamine in the nucleus accumbens of the rat elicited by a conditional stimulus for food: an electrochemical study
Authors: Phillips A. G. , Atkinson L. J. , Blackburn J. R. , Blaha C. D.
Published: April 2011

Stearate-modified graphite paste electrodes were implanted chronically into dopamine terminal regions in the nucleus accumbens or caudate nucleus of the rat. Reverse dialysis was used to demonstrate a selective response of these electrodes to dopamine, but not 3,4-dihydroxyphenylacetic acid or ascorbic acid. In a separate behavioural experiment, a significant increase in the chronoamperometric response was observed during presentation of a conditional stimulus predictive of food, and the electrochemical response remained elevated during and following consumption of the meal. Similar trends were observed from electrodes in the caudate nucleus. These data confirm the activation of mesolimbic dopamine neurons by incentive stimuli predictive of food and possibly by consumption of food. Together with other recent data on sex- and thirst-related increases in dopamine levels in the nucleus accumbens, these findings are consistent with a role for the nucleus accumbens as an interface between motivation and activation of the motor system.Key words: dopamine, nucleus accumbens, electrochemistry, feeding, conditional response.
Contractile responses and signal transduction of endothelin-1 in aorta and mesenteric vasculature of adult spontaneously hypertensive rats
Authors: Nguyen Paul V. , Yang Xiao-Ping , Li Guo , Deng Li Yuan , Flückiger Jean-Pierre , Schiffrin Ernesto L.
Published: April 2011

The contractile responses and generation of intracellular second messengers in response to endothelin-1 (ET-1), a potent vasoconstrictor peptide released locally by endothelial cells and involved in the regulation of vascular tone, were investigated in different segments of the vascular tree of adult 18-week-old spontaneously hypertensive rats (SHR) as compared with age-matched Wistar–Kyoto (WKY) rats. Aorta rings of SHR showed lower maximum response to ET-1 in comparison with WKY rats. Rings of the main superior mesenteric artery of SHR and WKY showed similar responses to ET-1. Small mesenteric resistance arteries of SHR, mounted on a wire myograph, developed similar tension to those of WKY rats in response to ET-1. The dose–response of inositol phosphates to ET-1 was significantly blunted in thoracic aorta of SHR compared with WKY rats, whereas it was similar in the mesenteric arterial bed. Baseline 1,2-diacylglycerol content was higher in thoracic aorta of SHR than WKY, while it was similar in the mesenteric arterial bed of the two strains. The response of 1,2-diacylglycerol to ET-1 was blunted in aorta of SHR, whereas no significant differences in diacylglycerol accumulation could be found in mesenteric vessels between SHR and WKY. In small mesenteric arteries, the dose–response to ET-1 of cytosolic free calcium, measured with the fluorescent dye Fura 2-AM, was similar in the two groups of rats. We conclude that in the aorta of 18-week-old SHR there is reduced generation of second messengers (inositol phosphates and diacylglycerol), which underlies its decreased response to ET-1 In mesenteric vessels (both proximal and distal) signal transduction is similar in SHR and WKY, and as a result contractile responses in both species are comparable. The responses to ET-1 of the arterial tree in terms of contractility and second messenger generation may reflect the adaptive processes taking place as a consequence of elevated blood pressure within the arterial wall of different segments of the vasculature of SHR.Key words: inositol phosphate, phospholipids, diacylglycerol, cytosolic calcium, second messengers, conduit and resistance arteries, Wistar–Kyoto rats.
Activation of Cl− currents by intracellular chloride in fibroblasts stably expressing the human cystic fibrosis transmembrane conductance regulator
Authors: Wang Xiaodong , Marunaka Yoshinori , Fedorko Ludwik , Dho Sascha , Foskett J. Kevin , O'Brodovich Hugh
Published: April 2011

The Cl− conductance of a mouse fibroblast cell line (LTK− cells) that was stably transfected with the human CFTR (cystic fibrosis transmembrane conductance regulator) complementary DNA was studied. Single Cl− channel activity was observed only after treatment of the cells with forskolin, the single-channel conductance being 6.2 ± 0.2 pS with a linear current–voltage relationship. In CFTR+ cells, the whole-cell current at +90 mV increased from 7.3 ± 2.7 pA/pF (n = 12) to 46.1 ± 11.2 pA/pF (n = 5) after addition of dibutyryl-cyclic AMP (10−4 M) to the bath. Increasing the intracellular Cl− concentration to 150 mM activated linear Cl− currents in the absence of cyclic AMP in CFTR+ (n = 42) but not in CFTR− cells (n = 4). Similar Cl− current was also activated by high intracellular I− concentration. These results indicate that the CFTR-induced Cl− conductance in LTK− cells can be activated by either cyclic AMP or high intracellular halide concentrations.Key words: cystic fibrosis transmembrane conductance regulator (CFTR), chloride channel, cyclic AMP, whole-cell patch clamp, single-channel patch clamp.
Development of portacaval shunts in portal-stenotic cats
Authors: Inglés Andres C. , Légaré Dallas J. , Lautt W. Wayne
Published: April 2011

The goal of the present study was to investigate the formation of portacaval shunts in a new experimental model of chronic portal hypertension, portal vein stenosis in the cat. The procedure gradually occluded the portal vein by use of an Ameroid constrictor around the portal vein. After 4 weeks, the portal vein was completely occluded and portal venous pressure was elevated to 15.6 ± 0.3 mmHg (1 mmHg = 133.3 Pa) (n = 8). The hemodynamic changes did not affect the functional capacity of the liver. Latex injection was used to study the shunts. This revealed the spontaneous development of porta-systemic collaterals in all hypertensive cats, mainly between the gastrosplenic and right gastroepiploic veins and the left renal vein. Fine small branches also drained directly into the cava. The left renal vein was markedly dilated in all cats. Collateral circulation also developed between the inferior vena cava and the inferior mesenteric vein through both left internal testicular and iliolumbar veins. Some branches of the inferior mesenteric vein were connected directly to the cava. Esophageal varices in the mucosa or submucosa were not demonstrated. However, the presence of latex in the pulmonary veins and the visualization of periesophageal collaterals suggest the opening of porta-pulmonary shunts. A constant feature in all cats was the presence of a dilated azygos vein, which drained collaterals retroperitoneally and from the abdominal wall. In conclusion, an experimental model of prehepatic portal hypertension of gradual onset has been developed in cats. The formation of the porta-systemic shunts mimics other animal models and the human form of the disease. It is a homogeneous model and easily reproducible.Key words: portal hypertension, porta-systemic shunts, portal stenosis, Ameroid constrictor, cat.
Controversy in fatty acid balance
Authors: Aerde John E. Van , Clandinin M. T.
Published: April 2011

It is uncertain whether preterm infants can synthesize C20 and C22 (ω−6) and (ω−3) fatty acids required for structural lipids. Dietary intake of CI8:2ω−6 and C18:3ω−3 in formulae lacking long-chain polyunsaturated fatty acids can result in reduced levels of C20 and C22 homologues in membrane phospholipids as compared with breast-fed infants. Supplementation of fish oil has been shown to alleviate this problem in part only, as synthesis and incorporation of arachidonic acid into membrane phospholipids is reduced. Presently, infant formulae do not contain C20 and C22 fatty acids. Feeding an experimental infant formula with a balance between C20 and C22 (ω−6) and (ω−3) fatty acids within the range of human milk results in plasma phospholipid levels of C20 and C22 long-chain polyunsaturated (ω−6) and (ω−3) fatty acids similar to those in breast-fed infants. On the basis of clinical studies and evolutionary data, an increase of the linolenic and a decrease of the linoleic acid content in infant formula are suggested. Balanced incorporation of both (ω−6) and (ω−3) long-chain polyunsaturated fatty acids seems advisable in view of the lack of knowledge concerning the neonate's ability to chain elongate and desaturate essential fatty acids. Recommendations for the essential fatty acid content of preterm infant formula are suggested.Key words: essential fatty acids, long-chain polyunsaturated fatty acids, infant formula, fish oil, desaturation.
Effects of slaframine and 4-diphenylacetoxy-N-methylpiperidine methiodide (4DAMP) on pancreatic exocrine secretion in the bovine
Authors: Walker J. A. , Krehbiel C. R. , Harmon D. L. , St. Jean G. , Croom Jr. W. J. , Hagler Jr. W. M.
Published: April 2011

Three Holstein steers (345 ± 22 kg) surgically fitted with a pancreatic cannula were used in two 3 × 3 Latin square design experiments to examine the effects of slaframine (SF), a muscarinic agonist, or 4-diphenylacetoxy-N-methylpiperidine methiodide (4DAMP), an M3 muscarinic glandular receptor antagonist, on pancreatic exocrine secretion. Pancreatic exocrine secretion was collected for 8 h postdosing at 30-min intervals beginning 1 h postfeeding. In experiment 1, steers were dosed with 0, 25, or 50 μg∙kg−1 body weight (BW) of SF. Secretion of pancreatic juice and the pH of the secreted juice increased linearly (p < 0.05) with SF; however, secretion rate showed a time by treatment interaction (p < 0.05), as treatments converged 7 h postdosing. Trypsin secretion tended (p < 0.10) to show a quadratic response to SF administration, with the 25 μg SF∙kg−1 BW dose having the lowest value. In experiment 2, steers received 50 μg∙kg−1 BW of SF (positive control), 113 μg∙kg−1 BW of 4DAMP (isomolar with SF), or both. SF caused a greater pancreatic fluid secretion (p < 0.10) than 4DAMP, with SF plus 4DAMP intermediate. A time by treatment interaction (p < 0.04) was found, since treatments converged 8 h postdosing. Trypsin secretion was higher (p < 0.05) for SF than the other treatments. Chymotrypsin, α-amylase, and protein secretion were not affected. SF and 4DAMP alter pancreatic fluid secretion in the steer but have minimal effects on enzyme secretions.Key words: slaframine, 4-diphenylacetoxy-N-methylpiperidine methiodide, bovine, pancreatic exocrine secretion.
Noradrenaline biosynthesis and metabolism during development and recovery from pacing-induced heart failure in the dog
Authors: Forster Christine , Naik George , Armstrong Paul W.
Published: April 2011

We have modified an assay utilizing ion-pair high-performance liquid chromatography with electrochemical detection to measure dihydroxyphenylalanine and dyhydroxyphenylglycol simultaneously with noradrenaline. We measured these agents at control, 1 and 3 weeks following the onset of rapid ventricular pacing, as well as 4 weeks after the cessation of a 3-week period of pacing. Our findings were as follows. Plasma noradrenaline increased significantly at 1 week and increased further after 3 weeks of pacing (control, 202 ± 16; 1 week, 528 ± 62; 3 weeks, 750 ± 139 pg∙mL−1). Plasma dihydroxyphenylalanine did not change throughout, while plasma dihydroxyphenylglycol was significantly elevated at 3 weeks (513 ± 48 vs. 388 ± 35 pg∙mL−1 for the control). Four weeks after discontinuation of pacing, all parameters did not differ from the control. These results imply that during the development of heart failure, the rise in circulating noradrenaline does not reflect simply an increase in catecholamine synthesis, but that there are more dynamic changes associated with noradrenaline spillover, uptake, and metabolism.Key words: heart failure, dihydroxyphenylglycol, sympathetic nervous activity, noradrenaline.
Expression of lipoprotein lipase during differentiation of cultured L6 muscle cells
Authors: LaDu Mary Jo , Palmer Warren K.
Published: April 2011

The presence of lipoprotein lipase (LPL) in L6 muscle cells is equivocal. Analysis of a 21-day time course indicates that these cells express both LPL activity and mRNA. Lipase activity peaked at 4 days after plating and decreased to a nadir at day 21 after plating. Characterization of lipase activity at 4 and 19 days after plating, corresponding to myoblasts and myotubes, respectively, indicated that most of the enzyme activity had the properties of LPL, including an alkaline pH optimum, a serum requirement, and inhibition by NaCl. LPL mRNA expression peaked at 7 days after plating and fell slightly (24%) at day 21. The primary LPL mRNA species in these cells is 3.7 kb in length. Lipase activity and LPL mRNA were highly correlated during the time course (r = +0.82), suggesting transcriptional regulation of the enzyme. These data clearly demonstrate that L6 cells express LPL during differentiation.Key words: myoblasts, myotubes, mRNA, total protein, total RNA.
Role of platelets in thrombosis and hemostasis
Authors: Packham Marian A.
Published: April 2011

Platelet aggregates, stabilized by fibrin, rapidly form hemostatic plugs when blood vessels are severed or arterial thrombi at sites of vessel injury, such as ruptured atherosclerotic plaques, or regions where blood flow is disturbed, such as at stenoses. These thrombi cause the thromboembolic complications of atherosclerosis: heart attacks, strokes, and peripheral vascular disease. Platelet adhesion to subendothelial components such as collagen activates signalling pathways that lead to thromboxane A2 formation and secretion of platelet granule contents, including ADP. Both these substances cause platelet aggregation, a process in which the integrin, glycoprotein IIb/IIIa, becomes a receptor for fibrinogen, which forms bridges between adjacent platelets. On the surface of stimulated platelets, coagulation is accelerated and thrombin is generated; it is a potent inducer of platelet aggregation and secretion and also causes fibrin to form around the aggregates, stabilizing them. There are receptors on the platelet surface for thrombin, thromboxane A2, collagen, ADP, platelet-activating factor, fibrinogen, von Willebrand factor, and other ligands. Agents that inhibit platelet aggregation and the signalling pathways that are activated by the various aggregating agents are under intensive investigation in many laboratories.Key words: platelets, hemostasis, arterial thrombosis, thrombin.
Model-based compartmental analyses in nutrition research
Authors: Mazier M. J. Patricia , Jones Peter J. H.
Published: April 2011

Kinetic tracer studies have been used extensively in understanding digestion, absorption, and whole-body metabolism of nutrients. Optimal interpretation of changes in tracer levels over time and movement across body pools often requires sophisticated data analysis. The use of model-based compartmental analysis (MCA) can yield more detailed quantitative and predictive information concerning system dynamics, compared with direct stochastic approaches. With MCA, tracer and tracee data from both experimental and literature values are fit to a model that best approximates the system on the basis of experimental data at hand. The number of compartments of the model is determined by the shape of the curve fit to the tracee and tracer data and by literature information. On this basis, MCA can yield information about compartment numbers and sizes, fractional and net turnover, as well as catabolic and synthetic rates. PC-based MCA programs are now available. Whereas earlier editions required use of a programming language, the most recent versions being developed are completely menu driven. Model-based compartmental analyses thus represent important biotechnological advances permitting maximal interpretation of kinetic data in nutrition research.Key words: compartmental analysis, model, kinetics.
The development and applications of sucralose, a new high-intensity sweetener
Authors: Knight I.
Published: April 2011

Sucralose is a new sweetener discovered during a collaborative research program between Tate &Lyle and Queen Elizabeth College of the University of London. It is made by selective substitution of sucrose hydroxyl groups by chlorine, resulting in a highly intense (600×) sugarlike sweetness and exceptional stability at both high temperature and low pH. The research leading to the discovery of sweetness in differently halogenated sucrose is described, as well as the development of sucralose and the process of safety testing and government approval. Finally, sucralose properties and applications in Canada's food and beverage industries are discussed.Key words: sucralose, sweetener, stability, halogen, chlorine.
Hypertriglyceridemia in experimental diabetes: relationship to cardiac dysfunction
Authors: Rodrigues Brian , Grassby Paul F. , Battell Mary L. , Lee Stephanie Y. N. , McNeill John H.
Published: April 2011

The incidence of mortality from cardiovascular disease is higher in diabetic patients. The objective of the present investigation was to test die hypothesis that the diabetes-induced depression in cardiac function may be due to hypertriglyceridemia. Hyperlipidemia and a depressed left ventricular developed pressure and rate of increase and decrease of ventricular pressure (±dP/dt) were produced in isolated hearts from rats made diabetic with streptozotocin compared with hearts from control animals. This depressed cardiac performance was successfully prevented by hydralazine treatment (for 3 weeks), which also lowered plasma triglyceride levels and suggested that hyperlipidemia may be important in altering cardiac function in experimental diabetic rats. The beneficial effects of clofibrate, verapamil, prazosin, enalapril, and benazepril administration were then studied in diabetic rats. The treatments (with die exception of enalapril) significantly reduced plasma triglyceride levels but did not prevent die onset of heart dysfunction in chronically diabetic rats. These studies suggest that in the chronically diabetic rat, hypertriglyceridemia may not be as important as previously suggested, in the development of cardiac dysfunction. Since acute dichloroacetate perfusion improves cardiac function in 6 week (but not 24 week) diabetic rats, it appears more likely that improving myocardial glycose utilization is more critical than triglyceride lowering, in preventing cardiac dysfunction in die diabetic rat at this time point.Key words: diabetes, triglycerides, heart function, glucose oxidation.
Peripheral Mechanisms of Touch and Proprioception
Authors: Jones Lynette A.
Published: April 2011

The basic sensory mechanisms involved in transducing information concerning the spatial properties of objects and the movements and forces generated by the hand are briefly reviewed. The contribution of different cutaneous mechanoreceptors to the processing of spatial information is discussed in the context of psychophysical and neurophysiological studies of the tactile sensory system. The specialization of the hand with respect to the sensory mechanisms that contribute to our awareness of finger position, movement, and force is reviewed, and experimental evidence indicating the critical role played by muscle spindle receptors in proprioception is described.Key words: hand, haptics, kinesthesia, proprioception, tactile sensation.
Evaluation of the relative roles of slowly and rapidly adapting afferent fibers in roughness perception
Authors: Johnson Kenneth O. , Hsiao Steven S.
Published: April 2011

Previous studies of the neural mechanisms of roughness perception have provided evidence that the magnitude of perceived roughness depends on spatial variation in the afferent population discharge. This paper reviews those studies and provides new data that appear to show that roughness perception cannot depend on activity in cutaneous rapidly adapting afferent fibers when surface element spacings exceed 1 mm. Finer surfaces have not been studied in combined psychophysical and neurophysiological studies. This paper also reinterprets the data of an earlier study, showing that all within-fiber neural coding mechanisms, which include impulse rate codes and codes based on the temporal structure of the afferent signal, can be rejected as the basis for roughness perception when the finger scans a textured surface.Key words: roughness, texture, somatosensory, psychophysics, neurophysiology.
Norepinephrine and dihydroxyphenylglycol effluxes from sympathetic nerve endings during hypoxia and reoxygenation in the isolated rat heart
Authors: Chahine R. , Nadeau R. , Lamontagne D. , Yamaguchi N. , Champlain J. de
Published: April 2011

The present experiments were carried out in isolated rat hearts perfused according to the Langendorff method at a constant pressure of 10 kPa. The aim was to measure norepinephrine (NE) overflow and its deaminated metabolite dihydroxyphenyl-glycol (DOPEG) by changing the composition of the buffer perfusing the heart to simulate hypoxia. When aerobic and glycolytic pathways were simultaneously reduced, NE and DOPEG overflow increased 711 and 145%, respectively, after 30 min, compared with control values of 0.45 ± 0.06 and 0.66 ± 0.7 ng∙min−1∙g−1 of heart (n = 8, p < 0.05). Whereas NE leakage decreased sharply after reoxygenation and glucose addition, DOPEG continued to increase up to 260% after 5 min of normal reperfusion. This mechanism was calcium independent and inhibited by 80% with desipramine (1 μM), confirming the role of the uptake I carrier, which reversed its normal transport direction. Neuropeptide Y, a marker of exocytotic release, did not increase in the perfusate with the progression of hypoxia, which supports the hypothesis of a nonexocytotic release. Tyramine (1 μM) significantly enhanced NE outflow by displacing the amine from its storage vesicles through a calcium-independent mechanism, indicating that a pool of NE was still available. In the presence of 1 μM clorgyline (a monoamine oxidase A inhibitor) but not deprenyl (a monoamine oxidase B inhibitor), NE outflow increased 934% and DOPEG only 40% at 30 min (n = 6, p < 0.05 versus control hearts). It is concluded that both oxygen and glucose deprivation are necessary to induce a significant NE release from cardiac sympathetic nerve terminals and mat monoamine oxidase A plays a principal role in NE deamination during hypoxia.Key words: heart, norepinephrine, hypoxia, monoamine oxidase, uptake I carrier.
Competitive binding experiments reveal differential interactions for dihydropyridine calcium channel activators and antagonists at dihydropyridine receptors on mouse brain membranes
Authors: O'Neill Sean K. , Triggle Chris R. , Bolger Gordon T.
Published: April 2011

The binding of the dihydropyridine (±)-202-791 and its corresponding calcium channel activating and calcium channel antagonist enantiomers ((+)-S-202-791 and (−)-R-202-791, respectively) to dihydropyridine receptors on mouse brain membranes was studied through competition for [3H]nitrendipine binding and 3H-labelled (±)-BAY K8644 ((±)-[3H]BAY K8644). Direct binding studies with (±)-[3H]BAY K8644 and [3H]nitrendipine revealed high affinity binding to a homogeneous set of dihydropyridine calcium channel activator and antagonist receptors on mouse brain membranes, (±)-[3H]BAY K8644 binding to approximately one half as many receptors as did [3H]nitrendipine. Competition binding studies revealed a significant discrimination of both high and low affinity receptors for (−)-R-202-791 and a homogeneous set of receptors for (+)-S-202-791 regardless of whether (±)-[3H]BAY K8644 or [3H]nitrendipine was the competing radioligand. Molar ratios (1:1, 5:1, 10:1) of (+)-S-202-792 to (−)-R-202-791 inhibited [3H]nitrendipine binding with displacement binding isotherms substantially different from those predicted on the basis of the binding properties of the individual enantiomers. These data suggest that dihydropyridine calcium channel antagonists and activators bind to different allosterically linked receptors or domains of the dihydropyridine protein associated with the voltage-dependent calcium channels. Furthermore, these results support the concept of multiple binding sites for dihydropyridine ligands.Key words: dihydropyridines, Ca2+ channels, allosteric interactions.
In vitro response of rat renal artery to perfusion pressure
Authors: Ajikobi D. O. , Cupples W. A.
Published: April 2011

Both tubuloglomerular feedback and a myogenic response contribute to autoregulation of renal blood flow. Vascular interaction initiated by tubuloglomerular feedback has been described and prevents definition, in vivo, of the contribution of myogenic responses to autoregulation. Segments of rat renal artery were perfused in vitro at constant flow while upstream and downstream pressures were measured on-line, allowing determination of resistance. Transmural pressure was governed by a downstream resistor. Outside diameter was measured by an ocular micrometer. The segments were bathed in bicarbonate Ringer solution and perfused with Ringer containing 50 g/L bovine serum albumin. Potassium depolarization reduced the diameter and made it more sensitive to perfusion pressure. Serosal norepinephrine, 10−7–10−5 M, caused graded constriction and increased the axial pressure drop due to vessel resistance. Addition to the perfusate of rat red blood cells to hematocrit ≈ 33% significantly reduced arterial diameter and enhanced the increased axial pressure drop induced by 10−6 M norepinephrine. Sequential elevation of perfusion pressure from 50 to 100 mmHg (1 mmHg = 133.3 Pa) increased the diameter significantly. Red cells reduced the slope of the diameter–pressure relationship. In another experiment, norepinephrine reduced the slope of diameter versus perfusion pressure, while 10−4 M papaverine plus norepinephrine increased the slope, compared with norepinephrine alone. Norepinephrine caused a sizable axial pressure drop (15.7 ± 3.7 mmHg), which decayed as perfusion pressure increased; the decay was accentuated by papaverine. The changes in axial pressure drop were linearly related to the inverse 4th power of diameter, indicating that both measurements assessed the same behavior. Several different maneuvers thus affect the relationship between arterial diameter and perfusion pressure, and the relationship between axial pressure drop and perfusion pressure. The results indicate the presence of a myogenic response, which is, however, not strong enough to defend vessel diameter when pressure rises.Key words: blood flow, autoregulation, myogenic response, resistance.
Differential effects of pinacidil and cromakalim on vascular relaxation and sympathetic neurotransmission
Authors: Cai Baiqiang , Hao Qinzhong , Greenberg Stan S. , deBoisblanc Bennett , Gillott Doug , Goharderakhshan Reza , Summer Warren R. , Hyman Al , Lippton Howard
Published: April 2011

We tested the hypothesis that pinacidil and cromakalim acted at different sites to relax vascular smooth muscle, in vitro. We compared the effects of pinacidil and cromakalim on tension development in isolated canine and bovine pulmonary artery and vein and canine mesenteric artery and dorsal metatarsal vein, and on the pre- and post-synaptic responses of the canine blood vessels to transmural nerve stimulation. Both pinacidil and cromakalim relaxed bovine and canine blood vessels precontracted to 50% of maximal tension with U46619, prostaglandin F2α, or norepinephrine. Pinacidil- and cromaklim-mediated relaxations of the blood vessels were not mediated by endothelium-derived factors, prostanoids, muscarinic receptors, β-adrenoceptors, or Ca2+-activated or voltage-dependent K+ channels, since they were unaffected by endothelium-rubbing, indomethacin, L-NG-monomethyl-L-arginine, atropine, propranolol, and charybdotoxin. Glibenchlamide, an inhibitor of ATP-activated K+ channels (K+ATP), and KCl (25–60 mM) sufficient to minimize the role of K+ channels almost abolished cromakalim- but not pinacidil-induced relaxation of the blood vessels. Pinacidil inhibited the contractions of the dorsal metatarsal vein and mesenteric artery to norepinephrine and transmural nerve stimulation and the efflux of 2-[14C]norepinephrine during transmural nerve stimulation. In contrast, 1 and 10 nM cromakalim enhanced while 0.1 and 1 μM cromakalim inhibited the contractions of, and 2-[14C]norepinephrine efflux from, the mesenteric artery and dorsal metatarsal vein during transmural nerve stimulation. Thus, pinacidil and cromakalim relax smooth muscle by stimulation of K+ATP channels. Pinacidil also relaxes the blood vessels by a K+ channel independent mechanism. Pinacidil-induced relaxation may also result from presynaptic inhibition of norepinephrine release from the sympathetic neuron.Key words: potassium channels, pulmonary blood vessels, systemic blood vessels, glibenclamide, pinacidil, cromakalim, neurotransmission.
Regulation of vascular smooth muscle tone
Authors: Walsh Michael P.
Published: April 2011

Vascular smooth muscle tone is regulated primarily by the sarcoplasmic free Ca2+ concentration, which determines the level of myosin phosphorylation. Stimulation of the muscle results in an increase in free [Ca2+], whereupon Ca2+ binds to calmodulin, inducing a conformational change enabling calmodulin to interact with and activate myosin light chain kinase. The active Ca2+∙calmodulin∙myosin light chain kinase complex catalyses the phosphorylation of serine-19 of the two 20-kDa light chains of myosin; this triggers cross-bridge cycling and the development of force. Relaxation follows restoration of free [Ca2+] to the resting level, whereupon calmodulin dissociates from myosin light chain kinase, which is thereby inactivated, and myosin is dephosphorylated by myosin light chain phosphatase and remains detached from actin. Overwhelming evidence now exists in favour of the central role of myosin phosphorylation–dephosphorylation in smooth muscle contraction–relaxation. However, considerable evidence supports the existence of additional, secondary mechanisms that can modulate the contractile state of smooth muscle either by altering the Ca2+ sensitivity of the contractile response or otherwise modulating one of the molecular events occurring downstream of the Ca2+ signal, e.g., the interaction of phosphorylated myosin heads with actin. The interplay of several regulatory elements confers on the contractile response of vascular smooth muscle the high degree of flexibility and adaptability required for the effective regulation of blood pressure.Key words: calcium, myosin, protein kinases, protein phosphatases, signal transduction, regulation of contraction, caldesmon, calponin.
Exercise and resistance to neoplasia
Authors: Woods Jeffrey A
Published: April 2011

Epidemiological evidence has revealed an inverse relationship such that increased physical activity as measured directly subjective recall, job classification, former athletic status, or indirectly by physical fitness is associated with decreased incidence and (or) mortality rates for various cancers. The relationship appears strongest for colon cancer and female estrogen-dependent cancers of the breast, ovary, and endometrium. While some epidemiological studies have controlled for numerous confounding variables such as smoking, body mass index, and percent body fat, it is still difficult to ascertain whether physical activity exerts an independent effect on cancer above and beyond that associated with an improved lifestyle and numerous other potential confounding variables. Experimental studies performed in animals suggests that chronic exercise, especially when performed prior to tumorigenesis, can retard, delay, or prevent the incidence, progression, or spread of experimental tumors. There is also limited animal evidence suggesting that exercise may help ameliorate cancer cachexia. Exercise or physical activity may contribute to a reduction in site-specific cancers by different physiological mechanisms. Some purported mechanisms include decreased lifetime exposure to estrogen or other hormones, reduced body fat, enhanced gut motility, improved anti-oxidant defenses, and stimulation of anti-tumor immune defenses. Unfortunately, most animal studies have failed to account for plausible biological mechanisms as to how exercise might influence cancer. In addition, the exercise or activity dosage required to provide optimal protection from cancer is unclear. Interpretation of epidemiological studies is hampered by the numerous and sometimes inaccurate assessments of physical activity. Likewise, many animal studies have utilized unrealistic exercise protocols. Clearly, more research is needed to define appropriate activity or exercise dosages definitively and to explore the mechanism(s) by which exercise helps protect against cancer. Nevertheless, moderate exercise appears to be a safe and effective means of aiding in the prevention of cancer and should be adopted by the public in addition to other prudent behavioral practices such as proper diet. More research needs to be performed regarding the effects of exercise or physical activity on those who already have cancer to determine if exercise improves their prognosis.Key words: exercise, physical activity, cancer, metastasis.