bluuebunny/crossref_metadata_2025 huggingface dataset:
Postural adjustments associated with different unloadings of the forearm: effects of proprioceptive and cutaneous afferent deprivation
Authors: Forget Robert , Lamarre Yves
Published: April 2011

Postural adjustments to imposed (passive) and voluntary (active) unloading conditions of the forearm were studied in normal subjects and a deafferented patient. The latency of the postural behaviour (deactivation of the biceps supporting the weight) was linearly related to the displacement amplitude of the unloaded forearm, independent of the unloading conditions. The postural behaviour consisted of an anticipatory postural adjustment (APA) occurring prior to active unloading (in both normals and the patient) and conversely in an unloading reflex response following passive unloading (only in the normals). In both the deafferented and the normal subjects, the amplitudes of the displacement during active unloadings were much smaller (3×) than in the passive conditions and an APA was present in both the deafferented and the normal subjects. The APA could not be triggered by some types of active movement and was absent when the movement was not directly producing the unloading. The EMG latencies of the APA and of the contralateral muscles used to unload were tightly coupled. However, the latency would sometimes be decoupled, particularly when a temporal delay was introduced between the active movement and the unloading in normal subjects. In contrast to the normal subjects, who were able to adapt quickly to an unusual unloading condition (produced by voluntary knee flexion), the deafferented patient did not show an APA in this task. It was concluded that, although the APA is of central origin, it cannot be generated only on the basis of internal timing cues and must rely on afferent information for its generation during unfamiliar unloading conditions.Key words: posture, bimanual coordination, deafferentation, open-loop control.
Cardiovascular effects of N-methyl leukotriene C4, a nonmetabolizable leukotriene C4 analogue, and the antagonism of leukotriene-induced hypotension by Ro 23-3544, in the American bullfrog, Rana catesbeiana
Authors: Sun Jimin , Herman Cell A.
Published: April 2011

Although some leukotriene antagonists have been reported to block leukotriene (LT) C4 responses in vivo, it is difficult to determine whether those antagonists block the effect of LTC4 directly or act via blocking the action of LTD4, as LTC4 is metabolized to LTD4 rapidly in vivo. In this study, the dose–response curves of N-methyl LTC4 (NMLTC4), the nonmetabolizable LTC4 analogue, and the peptidoleukotrienes (LTC4, LTD4, and LTE4) were obtained in the absence and presence of the leukotriene antagonist Ro 23-3544 in cannulated frogs. The more potent effect of NMLTC4 suggests that receptors that preferentially bind LTC4 exist in frog vascular smooth muscle and the previously reported LTC4 effect is a combination of LTC4 and its less potent metabolite LTD4. The NMLTC4- and LTC4-induced hypotensive effects were antagonized by Ro 23-3544. Ro 23-3544 also antagonized the effects induced by high doses of LTD4 and LTE4. Ro 23-3544 had no effect on duration of response and did not affect heart rate responses to LTC4 at low dose of the antagonist. The data suggest that receptors that preferentially bind LTC4 in bullfrog vascular smooth muscle regulate the hypotensive effect and that they can be antagonized by Ro 23-3544.Key words: leukotriene receptors, N-methyl LTC4, Ro 23-3544, cardiovascular, bullfrog.
Endothelin-1 expression in blood vessels of DOCA-salt hypertensive rats treated with the combined ETA/ETB endothelin receptor antagonist bosentan
Authors: Larivière Richard , Sventek Pavol , Thibault Gaétan , Schiffrin Ernesto L.
Published: April 2011

In previous studies it has been shown that blood vessels of deoxycorticosterone acetate (DOCA) salt hypertensive rats present significantly higher immunoreactive ET-1 (ir-ET-1) content and increased ET-1 gene expression. DOCA-salt hypertensive rats respond to treatment with the combined ETA/ETB endotheiin receptor antagonist bosentan with lowering of blood pressure. In the present study, we investigated the ir-ET-1 levels and the expression of the ET-1 gene in blood vessels of DOCA-salt hypertensive rats treated or not treated with bosentan. Blood pressure was significantly lower in bosentan-treated rats (185 ± 6 mmHg; 1 mmHg = 133.3 Pa) compared with DOCA-salt hypertensive rats (203 ± 4 mmHg; p < 0.01). Plasma ir-ET-1 concentration was slightly but significantly elevated (p < 0.01) in DOCA-salt hypertensive rats compared with uninephrectomized control rats, and was further increased (p < 0.01) in bosentan-treated rats. The tissue wet weight and ir-ET-1 content of segments of thoracic aorta were significantly increased (p < 0.01) in DOCA-salt hypertensive rats in comparison with control rats, but were similar in bosentan-treated DOCA-salt rats. The abundance of ET-1 mRNA measured by Northern blot analysis in thoracic aorta and the ir-ET-1 content were attenuated by bosentan treatment. Tissue wet weight and ir-ET-1 content in the mesenteric vascular bed were similar in bosentan-treated and -untreated DOCA-salt rats, and were significantly higher in both groups than in control rats (p < 0.01). ET-1 mRNA levels were increased in mesenteric arteries of DOCA-salt hypertensive rats and were further enhanced by bosentan treatment. These data suggest that inhibition of ETA and ETB receptor mediated ET-1 responses by bosentan has a slight but beneficial effect on blood pressure of DOCA-salt hypertensive rats. Chronic blockade of both ET receptors results in increased circulating levels of ET-1 and attenuated ET-1 expression and vascular hypertrophy in aorta but not in the mesenteric vasculature. ET-1 may be involved in the maintenance of elevated blood pressure in DOCA-salt hypertension and perhaps other experimental models of hypertension in the rat in part through a vascular hypertrophic effect.Key words: endothelin-1, endothelin receptor antagonist, aorta, mesenteric arteries, immunoreactive ET-1, preproET-1 mRNA, gene expression.
Neurophysiological consequences of nitroxide antioxidants
Authors: Hahn Stephen M. , DeLuca Anne Marie , Mitchell James B. , Lepinski Dennis L. , Pellmar Terry C.
Published: April 2011

Nitroxides are antioxidant compounds that have been shown to provide radioprotection in vivo and in vitro. Radioprotection in vivo is limited by toxicity, which appears to be neurologic in nature. To further evaluate the toxicity of these compounds, three representative nitroxides, Tempol, Tempamine, and Tempo, were examined in slices of guinea pig hippocampus. Each nitroxide increased the population spike and caused potentiation of excitatory postsynaptic potential – spike coupling. Repetitive activity and epileptiform activity were observed at the highest concentrations of Tempo and Tempamine. Tempol was the least toxic compound in this system, followed by Tempamine and Tempo. Additional studies are necessary to further define the effects of nitroxides on the central nervous system and to develop strategies to mitigate these effects.Key words: nitroxides, brain, neurophysiology, toxicity, antioxidants.
Endothelium derived relaxing factor release from canine coronary artery by leukocytes
Authors: Kleha Joseph F. , Devesly Pierre , Johns Anthony
Published: April 2011

Lectins, known to recognize endothelial cell adhesion molecules, have been shown to release endothelium-derived relaxing factor (EDRF) from blood vessels. We investigated the effects of different leukocyte-type cells to determine if these cells, by interacting with the endothelium, could release EDRF from the circumflex branch of the canine coronary artery. The following cells were investigated: human promyelocytic leukemia (HL-60), human monocyte (THP-1), and human Burkitt lymphoma (DAUDI). All of these cells produced a significant endothelium-dependent relaxation of the dog coronary artery in the presence of ibuprofen. The endothelium-dependent relaxations were reversed by hemoglobin (10 μM), methylene blue (3 μM), 6-anilino-5,8-quinolinedione (LY 83583, 30 μM), and NG-nitro-L-arginine methyl ester (L-NAME, 1 mM). HL-60 cells grown in the presence of 1 mM L-NAME retained their ability to cause endothelium-dependent relaxation of the canine coronary artery, suggesting that the source of the NO was the endothelium and not the HL-60 cells. The cell-induced vascular relaxation could be obtained in the absence of extracellular calcium. It is suggested that HL-60, THP-1, and DAUDI cells interact with a specific receptor on the endothelial cell and as a result of this interaction the endothelial cells are stimulated to release EDRF.Key words: endothelium-derived relaxing factor, nitric oxide, endothelium, HL-60, DAUDI, THP-1, smooth muscle, calcium, contraction, canine coronary artery.
Is there facilitated uptake of fatty acids by the liver? Interpretation and analysis of experimental data
Authors: Burczynski F. J. , Luxon B. A.
Published: April 2011

Uptake of hydrophobic organic anions that are extensively bound to serum proteins has been a controversial issue for over 30 years. It is known that steady-state uptake is lower in the presence of binding proteins, but it is much higher than predicted on the basis of protein–ligand binding equilibrium. Several theories have been postulated to account for this observation. Recent work has shown how binding proteins are capable of enhancing the uptake rate of long-chain fatty acids by decreasing the diffusional resistance of the unstirred fluid layer. The enhanced transport via codiffusion is especially important for tightly bound ligands like long-chain fatty acids. Whether this model accounts for all experimental data or whether hepatocytes facilitate the uptake of protein-bound ligands, by for example mediating the protein–ligand dissociation rate, is not clear. We review the published reports to gain an understanding into the potential mechanism for the extraction of long-chain fatty acids. Understanding the uptake mechanism of these important metabolic substrates is vitally important in determining their overall utilization in a variety of clinical disorders as diverse as gallstones, obesity, and atherosclerosis.Key words: surface charge, pI, albumin, lysozyme, orosmucoid, α1-acid glycoprotein, protein binding, palmitate, organic anion, uptake, hepatocytes, facilitation, diffusion, unstirred fluid layer, myocytes, long-chain fatty acids, fatty acids.
Muscarinic and ganglionic blocking properties of atropine compounds in vivo and in vitro: time dependence and heart rate effects
Authors: Vicenzi M. N. , Woehick H. J. , Boban M. , McCallum B. , Atlee J. L. , Bosnjak Z. J.
Published: April 2011

High doses (3 mg/kg) of methylatropine nitrate have been used in vivo to produce long-lasting muscarinic blockade during physiologic experiments. At these levels, the possibility exists that ganglionic blockade may also be responsible for some heart rate effects. Therefore, the effects of methylatropine nitrate (0.0012–2.4 mg∙kg−1) and atropine sulfate (0.0036–0.060 mg∙kg−1) were evaluated in vivo using conscious dogs and in vitro using canine right atria and isolated stellate ganglia. The lowest doses of either agent given in vivo caused bradycardia, while intermediate doses induced excess tachycardia. High doses of methylatropine nitrate transiently decreased the heart rate, followed by slow recovery. In vitro using the canine right atria, neither drug caused pacemaker shifts nor directly altered the atrial rate, but postvagal tachycardia occurred with acetylcholine challenge and was prevented by metoprolol or 6-hydroxydopamine. In vitro studies using the canine stellate ganglia indicate that both agents depressed postganglionic compound action potentials at high doses. In conclusion, with high-dose methylatropine nitrate, ganglionic blockade yields the mechanism for a reduction of excess tachycardia as well as a likely explanation for opposing chronotropic effects in conscious and anesthetized dogs. In experimental studies where high doses of atropine compounds are used for long-term muscarinic blockade, it is possible that ganglionic blocking effects may also be produced.Key words: atropine sulfate, methylatropine nitrate, dominant and subsidiary atrial pacemakers, atrial dysrhythmias, excess tachycardia, postvagal tachycardia.
Heme oxygenase activity in the adult rat aorta and liver as measured by carbon monoxide formation
Authors: Cook Michael N. , Nakatsu Kanji , Marks Gerald S. , McLaughlin Brian E. , Vreman Hendrik J. , Stevenson David K. , Brien James F.
Published: April 2011

Rat aorta was homogenized and the 13 000 × g supernatant fraction was tested for heme oxygenase (HO) activity by using a sensitive gas chromatographic method to measure carbon monoxide (CO), one of the products of the HO reaction. The rate of NADPH-dependent CO formation, an index of HO activity, was 1.41 ± 0.40 nmol CO∙mg−1protein∙h−1in the rat aorta supernatant fraction and 2.05 ± 0.55 nmol CO∙mg−1protein∙h−1in the rat liver 13 000 × g supernatant fraction, a tissue known to contain HO activity. Chromium mesoporphyrin (0.05 mM), an inhibitor of rat liver HO, significantly decreased HO activity by 26% in the aorta supernatant fraction and 50% in the liver supernatant fraction. On the basis of the results of this study, which demonstrated HO-catalyzed CO formation in aortic tissue, and previous observations that CO relaxes vascular smooth muscle, we suggest that a physiological role for CO in vascular smooth muscle relaxation should be further investigated.Key words: carbon monoxide, heme oxygenase, vascular smooth muscle, liver, gas chromatographic analysis.
Regulation of vascular tone: cross-talk between sarcoplasmic reticulum and plasmalemma
Authors: Daniel Edwin E. , Breemen Casey van , Schilling William P. , Kwan C.-Y.
Published: April 2011

Selected topics on the roles of sarcoplasmic reticulum (SR) in the control of vascular smooth muscle (VSM) tone are briefly reviewed with particular reference to the regulation of cytosolic concentration of free calcium ions, [Ca2+]i. Although morphological evidence and subcellular membrane studies indicate a relatively meager quantity of SR in VSM and of endoplasmic reticulum (ER) in endothelial cells (ECs) compared with skeletal muscle and cardiac muscle, contractility studies suggest that vascular tone is, to a large extent, regulated by the intracellular Ca2+stores in smooth muscle and endothelial cells. Cytosolic Ca2+levels control myosin light chain phosphorylation and contraction in VSM and activation of NO synthase and phospholipase A2in ECs to regulate nitric oxide (NO) and prostaglandin I2formation. Understanding of the importance of SR or ER in modulating the [Ca2+]iin VSM and ECs has been further advanced as a result of the new development and refinement of biophysical techniques in the measurement of cellular Ca2+concentrations and ion currents, such as fluorescent Ca2+indicators and patch-clamp techniques. Experimental evidence has accumulated in support of the existence of cross-talk between SR–ER and the plasma membrane (PM). Novel pharmacological tool drugs selective for the SR–ER Ca2+pump, such as thapsigargin and cyclopiazonic acid, as well as for SR–ER Ca2+channels, such as ryanodine (for the Ca2+-induced Ca2+release channel) and inositol polyphosphates and heparin (for the inositol-1,4,5-trisphosphate activated Ca2+channel), together with the use of blockers for selective PM Ca2+channels have enabled better formulation and elucidation of the mechanisms of cross-talk between SR–ER and PM. It appears that SR has multiple roles in maintaining the homeostasis of cytosolic Ca2+, which controls the VSM tone directly or indirectly via ECs. These roles include (i) activation of phasic contraction of VSM by opening of the Ca2+release channels, (ii) acting as a sink for entering Ca2+when the Ca2+stores are depleted, extruding Ca2+when the Ca2+stores are refilled, and (iii) signalling and regulating the amount of Ca2+entry in relation to the degree of filling of the store. This symposium concensus paper reflects current thoughts on the above roles of SR–ER in the control of cytosolic Ca2+concentration, and thus the regulation of vascular tone.Key words: calcium channels, calcium pumps, sarcoplasmic reticulum, plasma membranes, vascular smooth muscle, endothelial cell.
Intracellular mechanisms involved in the regulation of vascular smooth muscle tone
Authors: Walsh Michael P. , Kargacin Gary J. , Kendrick-Jones John , Lincoln Thomas M.
Published: April 2011

Vascular smooth muscle contraction is thought to occur by a mechanism similar to that described for striated muscles, i.e., via a cross-bridge cycling – sliding filament mechanism. This symposium focused on Ca2+signalling and the role of intracellular free Ca2+concentration, [Ca2+]i, in regulating vascular tone: how contractile stimuli leading to an increase in [Ca2+]itrigger vasoconstriction and how relaxant signals reduce [Ca2+]icausing vasodilation. M.P. Walsh opened the symposium with an overview emphasizing the central role of myosin phosphorylation–dephosphorylation in the regulation of vascular tone and identifying recent developments concerning regulation of [Ca2+]i, Ca2+sensitization and desensitization of the contractile response, Ca2+-independent protein kinase C induced contraction, and direct regulation of cross-bridge cycling by the thin filament associated proteins caldesmon and calponin. The remainder of the symposium focused on three specific areas related to the regulation of vascular tone: Ca2+signalling in relation to smooth muscle structure, structure–function relations of myosin, and the role of cyclic GMP (cGMP) dependent protein kinase. G.J. Kargacin described how smooth muscle cells are structured and how second messenger signals such as Ca2+might be modified or influenced by this structure. J. Kendrick-Jones then discussed the results of mutagenesis studies aimed at understanding how the myosin light chains, particularly the phosphorylatable (Ca2+–calmodulin dependent) regulatory light chains, control myosin. The vasorelaxant effects of signalling molecules such as β-adrenergic agents and nitrovasodilators are mediated by cyclic nucleotide dependent protein kinases, leading principally to a reduction in [Ca2+]i. T.M. Lincoln described the roles of cyclic nucleotide dependent protein kinases, in particular cyclic GMP dependent protein kinase, in vasodilation.Key words: vascular smooth muscle, regulation of contraction, smooth muscle structure, calcium, cyclic GMP, myosin.
Benefits and risks of traditional food for Indigenous Peoples: focus on dietary intakes of Arctic men
Authors: Kuhnlein Harriet V.
Published: April 2011

A variety of community and external pressures on Indigenous Peoples are leading to increased use of food that is available through industrialization and market economies; food in traditional food systems derived from local, natural environments is declining in use. This report focusses on dietary intake of Arctic men. While nutrient density of Arctic traditional food systems is superior to that of the composite of market food consumed in the North, the percentage of men's daily energy derived from market food is more than double that from traditional food in some communities. Older members of communities consume more traditional food than younger members; men consume more traditional food than do women. In addition to providing excellent nutrition and opportunities for physical exercise, Indigenous Peoples identify many sociocultural benefits to the harvest and use of traditional food. Evaluation of environmental accumulation of organochlorines in wildlife animal food species shows that risk of organochlorine consumption is higher in food systems containing sea mammals, and that tolerance levels for some organochlorines may be exceeded.Key words: Indigenous Peoples, traditional food, contaminants, nutrition.
Pharmacology and structure – activity relationships of the nonpeptide bradykinin receptor antagonist WIN 64338
Authors: Sawutz David G. , Salvino Joseph M. , Dolle Ronald E. , Seoane Peter R. , Farmer Stephen G.
Published: April 2011

A series of competitive, nonpeptide bradykinin receptor antagonists based on an α-amino acid scaffold have been developed and biologically characterized. The lead compound in the series, WIN 64338, demonstrates competitive inhibition of bradykinin-mediated functional responses through B2 receptors in a variety of tissues and species. WIN 64338 is specific for the bradykinin B2 receptor; it is inactive at both the B1and B3 kinin receptors. In conscious guinea pigs, WIN 64338 inhibits kinin-mediated bronchoconstriction but does not attenuate a similar response to acetylcholine. A series of WIN 64338 analogues display a well-defined structure–activity relationship, strongly suggesting binding in a specific manner to the B2 receptor. Structure–activity data suggest that a hydrophobic binding pocket that prefers large aromatic groups in a specific conformational orientation exists in the receptor ligand binding domain. This class of nonpeptide bradykinin receptor antagonists may lead to the design of other compounds with enhanced receptor affinity and optimal in vivo biological activity.Key words: bradykinin, antagonists, nonpeptide.
New aspects on the role of kinins in neurogenic inflammation
Authors: Geppetti Pierangelo , Bertrand Claude , Ricciardolo Fabio M. L. , Nadei Jay A.
Published: April 2011

The inflammatory response to injury consists of the activation of several protective mechanisms involving different cellular systems. Among the mechanisms and systems that exert their effects rapidly, peptide transmitters released from peripheral endings of primary sensory neurons (evoking neurogenic inflammation) play a major role in the response to tissue injury. Noxious stimuli may directly activate sensory nerves to release proinflammatory neuropeptides. More recently, evidence has accumulated suggesting that indirect mechanisms leading to sensory neuropeptide release are also activated in relevant models of pathophysiological conditions. Tachykinin NK1 and NK2 receptor antagonists reduced the plasma extravasation in the trachea and nasal mucosa and the bronchoconstriction caused by antigen challenge in sensitized guinea-pigs. Blockade of kinin B2 receptors with the selective antagonist HOE-140 had a similar inhibitory effect. The magnitude of the inhibition observed with the kinin receptor antagonist alone was similar to that caused by a combination a tachykinin and kinin receptor antagonists. This suggests activation of a common final pathway by these two groups of mediators. Pharmacological and biochemical evidence suggests that in the airways of sensitized guinea-pigs, kinins released by the anaphylactic reaction stimulate the release of tachykinins from sensory nerves, thus contributing to their proinflammatory action.Key words: kinins, tachykinins, neurogenic inflammation, antigen challenge, airways, nitric oxide.
Mechanisms of the antihypertensive effects of dietary calcium and role of calcitonin gene related peptide in hypertension
Authors: Wimalawansa Sunil J. , Supowit Scott C. , DiPette Donald J.
Published: April 2011

Alterations in calcium metabolism and calcium-regulating hormones have been described in essential hypertension. However, the mechanisms that mediate these responses are unknown. In previous studies, using the genetically spontaneously hypertensive rat and the mineralocorticoid-salt (DOC-salt) hypertensive rat model, we and others have observed that oral calcium supplementation attenuates the associated increase in peripheral vascular resistance and consequently lowers blood pressure (BP). When hypertensive patients (n = 8, diastolic BP 90–95 mmHg (1 mmHg = 133.3 Pa)) were given daily oral calcium supplementation (1.4 g elemental calcium), both systolic and diastolic BP were decreased (5–10 mmHg, p < 0.01). The only biochemical variables significantly changed were serum ionized calcium and intact parathyroid hormone (PTH, 1–84) (p < 0.05); furthermore, the levels of calcitonin gene related peptide (CGRP), measured by both radioimmunoassay and radioreceptor assay, showed a marked 75% increase (p < 0.001). The antihypertensive effects of Ca2+ and the increased levels of CGRP in the circulation returned to baseline levels immediately following cessation of calcium supplementation, suggesting that the effects of calcium on BP and CGRP are specific. On the basis of these observations we propose that the antihypertensive effect of dietary calcium supplementation, at least in part, is mediated through CGRP.Key words: calcium, calcitonin gene related peptide, human hypertension, mineralocorticoid-salt hypertension.
Modulation of the release and activity of neuropeptides in the microcirculation
Authors: Brain S. D. , Newbold P. , Kajekar R.
Published: April 2011

Electrical stimulation of the sensory saphenous nerve leads to neurogenic edema formation in the innervated area of the paw of the anesthetized rat. Evidence suggests that the edema formation is the result of increased microvascular permeability mediated via neurokinin NK1 receptors and increased blood flow mediated via calcitonin gene related peptide CGRP1 receptors. Results indicate that selective receptor antagonists will only inhibit the response mediated by the specific receptor they antagonise. In the case of neurogenic inflammation, where it is common for more than one biologically active neuropeptide to be released concomitantly, it may be more sensible to develop agents that inhibit neuropeptide release. The effects of some agents suggested to affect neurogenic responses are presented. The anti-inflammatory steroid dexamethasone (1 mg/kg subcutaneously, −4 h) significantly (p < 0.01) inhibited edema formation, but the mechanism of action is likely to be related to the general anti-edema effect of dexamethasone. In contrast the anti-asthma agent nedocromil sodium (up to 10 mg/kg intravenously, −15 min) and the histamine H3 agonist (R)-α-methyl histamine (1–10 mg/kg intravenously, −5 min) both failed to inhibit saphenous nerve induced edema formation, despite positive results in other sensory nerve systems. The results are discussed in the context of evidence obtained using other agents in skin.Key words: neurogenic inflammation, substance P, calcitonin gene related peptide, edema.
Calcitonin gene related peptide gene expression in collagen-induced arthritis
Authors: Weihe Eberhard , Nohr Donatus , Schäfer Martin K.-H. , Persson Stefan , Källström Johanna , Nyberg Fred , Ekström Gunilla , Post Claes
Published: April 2011

Changes in calcitonin gene related peptide (CGRP) gene expression in spinal motoneurons and dorsal root ganglia (DRG) of rats subjected to collagen II induced arthritis (CIA) were evaluated by semiquantitative in situ hybridization. The effects of systemic treatment with the corticosteroid budesonide on basal CGRP expression and on changes under inflammatory conditions were examined. CIA caused a significant increase in CGRP mRNA levels in DRG. Budesonide reduced the constitutive CGRP mRNA levels in DRG, compared with untreated control rats, and reversed the CIA-induced increase. In contrast, CIA caused a marked decrease of CGRP mRNA levels in motoneurons. Budesonide had no effect on constitutive CGRP mRNA levels in motoneurons and attenuated the decrease in CGRP mRNA levels in motoneurons of rats subjected to CIA. Thus, peripheral inflammation and systemic corticosteroids have differential effects on CGRP expression in sensory and motor neurons. This may be relevant for the pathophysiology and pharmacotherapy of chronic inflammatory pain and motor dysfunction in chronic arthritis.Key words: calcitonin gene related peptide, neuropeptides, sensory, spinal motoneuron, arthritis, glucocorticoids, pain.
Astrocytes and microglia as potential targets for calcitonin gene related peptide in the central nervous system
Authors: Reddington Martin , Priller Josef , Treichel Julia , Haas Carola , Kreutzberg George W.
Published: April 2011

Injury of peripheral motoneurons leads to the activation of astrocytes and microglia in the vicinity of the damaged neurons in the central nervous system. It has been proposed that neuropeptides such as the calcitonin gene related peptide (CGRP), which show an increased expression in motoneurons following axotomy, play a role as signalling molecules mediating the interactions between the damaged neurons and surrounding glial cells. Evidence supporting this hypothesis is provided by in vitro investigations of the actions of neuropeptides on glial cells. CGRP induces activation of both astrocytes and microglia at the transcriptional level, as seen by the stimulation of mRNA for the immediate early gene, c-fos, in these cells in culture. In addition to its stimulation of immediate early gene expression, treatment of astrocyte cultures with CGRP stimulated release of the tissue plasminogen activator and led to the accumulation of mRNAs for tissue plasminogen activator and the plasminogen activator inhibitor 1. These components of the plasminogen activator system, which has been implicated in processes of tissue remodelling, are upregulated in astrocytes in the facial nucleus in vivo after facial nerve axotomy. The data suggest a role for CGRP as a mediator of glial cell activation following motoneuron injury.Key words: calcitonin gene related peptide, plasminogen activator, immediate early genes, astrocytes, microglia.
Rat adrenomedullin induces a selective arterial vasodilation via CGRP1 receptors in the double-perfused mesenteric bed of the rat
Authors: Berthiaume Nathalie , Claing Audrey , Cadieux Alain , D'Orléans-Juste Pedro , Lippton Howard
Published: April 2011

The present work was undertaken to study the effect of rat adrenomedullin (rADM (1–50) and its C-terminal fragment (11–50)) in the endothelium-intact arterial and venous vasculatures of the rat perfused mesenteric bed. rADM (1–50) and the fragment rADM (11–50) (1–1000 pmol) induced a dose-dependent and endothelium-independent vasodilation on the arterial mesenteric vasculature. However, both peptides were inactive on the venous side of this vascular bed. The CGRP1 receptor antagonist, hCGRP8–37 (1 μM), markedly reduced the vasodilation caused by rADM (1–50) in the arterial mesenteric vasculature. Thus, our results show that rADM (1–50) and its C-terminal fragment rADM (11–50) share properties similar to those of hCGRP. The blocking effect of hCGRP8–37 supports a role for CGRP1 receptor activation by adrenomedullin in this vascular preparation.Key words: adrenomedullin (1–50), adrenomedullin (11–50), CGRP1 receptors, rat mesenteric bed, vasodilation.
Comparative study of sodium nitroprusside induced vasodilation of human placental veins from premature and full-term normotensive and preeclamptic pregnancy
Authors: Bobier Harold S. , Brien James F. , Smith Graeme N. , Pancham Sonilal R.
Published: April 2011

The objective of this study was to determine whether nitrovasodilator (nitric oxide donor) drug induced relaxation is different between preeclamptic and normotensive pregnancy. Human placental veins were collected at the time of delivery from normotensive (n = 6 premature, n = 6 full term) and preeclamptic (n = 6 premature, n = 3 lull term) women and cut into rings. Cumulative concentration–response curves were performed on 5-hydroxytryptamine-contracted rings for the nitrovasodilator agent, sodium nitroprusside (SNP). The EC50 values were determined from the SNP concentration–response curves of the individual subjects, and were compared across gestational age and between preeclamptic and normotensive pregnancy by two-way ANOVA. There was no difference in the SNP EC50 values for normotensive and preeclamptic human placental veins in either the premature or full-term study groups. However, for both normotensive and preeclamptic pregnancy, the SNP EC50 value for full-term placental vein was greater than that for premature tissue. The sensitivity of human placental veins to SNP is similar between preeclamptic and normotensive pregnancy at similar gestational ages, but is increased in premature compared with full-term pregnancy in both preeclamptic and normotensive pregnant women.Key words: preeclampsia, nitric oxide, gestational age, pregnancy, vascular tone.
In vivo murine studies on the biochemical mechanism of acetaminophen cataractogenicity
Authors: Wells Peter G. , Wilson Barry , Winn Louise M. , Lubek Barry M.
Published: April 2011

C57BL/6 and DBA/2 mice are, respectively, susceptible and resistant both to the induction of aryl hydrocarbon hydroxylase (cytochrome P450 1A1, or CYP1A1) and to the cataractogenicity of acetaminophen, which may involve its bioactivation to a toxic reactive intermediate, catalysed by P450 and (or) prostaglandin H synthase (PHS). Following induction of P450 using β-naphthoflavone, the cataractogenicity of acetaminophen (400 mg/kg ip) in C57BL/6 mice was reduced by pretreatment with the P450 inhibitors SKF 525A and metyrapone, the glutathione precursor N-acetylcysteine, the antioxidant vitamin E, and the free radical spin trapping agent α-phenyl-N-t-butylnitrone (p < 0.05). Acetaminophen (200 mg/kg) cataractogenicity was enhanced by pretreatment with the glutathione depletor diethyl maleate (DEM) and the γ-glutamylcysteine synthetase inhibitor buthionine sulfoximine (BSO) (p < 0.05). No significant effect on acetaminophen cataractogenicity was observed using the PHS cyclooxygenase inhibitors aspirin or naproxen, or the glutathione reductase inhibitor 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Accordingly, acetaminophen cataractogenicity in C57BL/6 mice does not appear to be dependent upon bioactivation by PHS. In DBA/2 mice treated with β-naphthoflavone, a high dose of acetaminophen (750 mg/kg ip) was not cataractogenic, even after pretreatment with DEM, BSO, or BCNU. The resistance of DBA/2 mice to acetaminophen cataractogenesis, despite concomitant pretreatments with an inducer of P450 and several agents that interfere with glutathione-dependent detoxifying pathways, suggests differences in this strain involving cytoprotective pathways subsequent to acetaminophen bioactivation and detoxification of the cataractogenic reactive intermediate. These results indicate that acetaminophen cataractogenicity in C57BL/6 mice results from P450-catalysed bioactivation of acetaminophen to a reactive intermediate, possibly a benzoquinone imine and (or) a free radical, the toxicity of which is reduced by glutathione-dependent reactions.Key words: cataracts, acetaminophen, genetic susceptibility, acetaminophen cataractogenesis.
Thermogenesis during rest and exercise in cold air
Authors: Paolone Vincent J. , Paolone Albert M.
Published: April 2011

Nine non-cold-acclimated subjects (5 female, 4 male, mean age 22.5 years) were studied to determine whether nonshivering thermogenesis contributes to cold-induced metabolic heat production during rest (50 min standing) and exercise (40 min treadmill walking) in 5 °C. Propranolol was administered orally (females, 60 mg, 1.12 mg∙kg−1; males, 80 mg, 0.96 mg∙kg−1) to block nonshivering thermogenesis. Measurements were taken at both 25 °C, 13.1 Torr (water vapor pressure; 1 Torr = 133.3 Pa) and 5 °C, 3.6 Torr, with sessions randomly assigned to be drug–neutral (DN), drug–cold (DC), placebo–neutral (PN), and placebo–cold (PC). Body core temperature was not different between any of the experimental conditions. Mean body temperature (5 °C, 32.2 ± 0.20 °C (±SEM); 25 °C, 35.3 ± 0.20 °C) and mean skin temperature (5 °C, 22.4 ± 0.70 °C; 25 °C, 31.4 ± 0.60 °C) were lower (p < 0.05) in the 5 °C than 25 °C environment (rest, exercise, drug (D), placebo (P), combined); while shivering (EMG) was higher (16.5 ± 3.9% above baseline) at 5 °C than 25 °C (15 ± 2.1% below baseline) (p < 0.05). The greater [Formula: see text] in 5 °C compared with 25 °C for the same condition is the thermoregulatory [Formula: see text]. [Formula: see text] (mL∙min−1) was lower (p < 0.05) on the D [Formula: see text] than on the P [Formula: see text] during rest and during exercise (D, 206.1 ± 63.7; P, 338.4 ± 46.7). The EMG was 21% above baseline in the DC, and 12% above baseline for PC (p > 0.05). These results suggest a nonshivering component to heat production during acute cold exposure, which can be blocked with propranolol.Key words: nonshivering thermogenesis, propranolol, β-adrenergic blockade, body temperature, exercise, shivering.
Role of voltage oscillations in the automaticity of sheep cardiac Purkinje fibers
Authors: Spiegler Peter A. , Vassalle Mario
Published: April 2011

The role of oscillatory potentials occurring near the threshold for the fast sodium current (ThVos) in the induction of spontaneous and repetitive activity was studied in sheep Purkinje fibers superfused in vitro. In low extracellular potassium concentration, the steepness and amplitude of diastolic depolarization increased and ThVos appeared during quiescence. ThVos amplitude increased progressively until its depolarizing phase reached the threshold potential for the initiation of the action potential. Drive increased the amplitude of diastolic depolarization and of ThVos, and longer drives induced faster and longer-lasting repetitive activity ("overdrive excitation"). In quiescent fibers, barium depolarized the resting membrane and initiated spontaneous discharge through ThVos. Acetylcholine had similar actions. Cesium hyperpolarized the membrane, thereby suppressing ThVos and related spontaneous activity. Tetrodotoxin and lidocaine also suppressed ThVos, but not the driven action potentials. In low extracellular potassium plus high extracellular calcium concentrations, drive induced ThVos as well as the oscillatory potentials related to calcium overload (Vos), but caused overdrive excitation through ThVos, even when caffeine was present. We conclude from our results that in Purkinje "dominant" pacemaker fibers (i) diastolic depolarization initiates spontaneous activity by attaining the threshold for the upstroke of the action potential through the depolarizing phase of a ThVos; (ii) the depolarizing phase of ThVos is caused by a tetrodotoxin-sensitive Na+ component; (iii) ThVos is voltage dependent in that a small depolarization of the resting membrane induces it and a small hyperpolarization suppresses it; (iv) ThVos can induce overdrive excitation; and (v) ThVos occurs in the absence of calcium overload and has distinguishing characteristics from the Vos induced by calcium overload.Key words: automaticity, overdrive excitation, barium, acetylcholine, cesium, tetrodotoxin, lidocaine, high extracellular calcium, low extracellular potassium.
Ethanol neurobehavioural teratogenesis and the role of L-glutamate in the fetal hippocampus
Authors: Reynolds James D. , Brien James F.
Published: April 2011

The purpose of this article is to review the current state of knowledge of ethanol neurobehavioural teratogenesis and its postulated mechanisms. The review comprises an examination of ethanol teratogenesis in the human, including the fetal alcohol syndrome, and in experimental animals. Several current proposed mechanisms of ethanol neurobehavioural teratogenesis are critically assessed, including the role of acetaldehyde as the proximate metabolite of ethanol; fetal hypoxia; placental dysfunction; fetal prostaglandin metabolism; and action of ethanol on developing neurons in the fetal brain, including the hippocampus, one of ethanol's main target sites. The effect of ethanol on the release of L-glutamate, an excitatory amino acid neurotransmitter, in the fetal hippocampus is described, and the role of L-glutamate in ethanol teratogenesis involving the hippocampus is discussed. A novel mechanism for abnormal neuronal development in the fetal hippocampus produced by prenatal ethanol exposure is presented, and future experiments to test this hypothesis are proposed.Key words: ethanol neurobehavioural teratogenesis, fetal alcohol syndrome, hippocampus, L-glutamate.
Norepinephrine induces expression of c-fos mRNA through the α-adrenoceptor in rat aortic rings
Authors: Carcillo Joseph A. , Hough Christopher J.
Published: April 2011

We examined whether norepinephrine at pharmacologically relevant doses induces increased expression of c-fos mRNA in rat aortic rings, c-fos mRNA was expressed at norepinephrine concentrations known to cause minimum and maximum contraction of rat aorta in vitro. At the concentration known to cause maximum contraction, norepinephrine produced a marked and sustained increase of c-fos mRNA expression. Induction of c-fos was blocked completely by the α1-adrenergic antagonist prazosin, partially by the α2-adrenergic antagonist yohimbine, and not at all by the β-adrenergic antagonist propranolol. A prazosin inhibition curve showed that 1 nmol/L prazosin inhibited 10 μmol/L norepinephrine induced c-fos expression by 40%. At the pharmacologic dose known to cause maximum contraction, norepinephrine induces c-fos mRNA expression through the α-adrenoceptor in rat aortic rings.Key words: vascular smooth muscle contraction, rat aorta, norepinephrine, c-fos mRNA expression, adrenergic receptor, catecholamine.
Metabotropic glutamate receptors and visual cortical synaptic plasticity
Authors: Kamishita T. , Haruta H. , Torii N. , Tsumoto T. , Hicks T. P.
Published: April 2011

Two forms of use-dependent synaptic plasticity, called long-term potentiation (LTP) and long-term depression (LTD), can be elicited in the visual cortex following different paradigms of electrophysiological stimulation. These neurobiological phenomena often are considered as necessary components of models for the alteration in function of the nervous system that must occur at some level for the establishment and (or) maintenance of memory engrams, for learning processes, or for the consolidation of active neural connections and regression of inactive contacts in the developing brain. It has been postulated that for LTP and LTD to be produced in the hippocampus, activation of a particular subtype of excitatory amino acid receptor, the metabotropic receptor, is a critical requirement. Only recently has it become possible to test this hypothesis directly, as a new compound, (±)-α-methyl-4-carboxyphenylglycine (MCPG), has been introduced and the suggestion made that it selectively antagonizes the metabotropic receptor. This substance has been tested in the present study on responses recorded from slices of rat visual cortex and has been found both to block the activation of the metabotropic receptor and to interfere selectively with the form of synaptic plasticity called LTD. It thus appears from the experiments reported in this paper as though the metabotropic receptor subtype that is blocked by MCPG is required for the expression of LTD but not for the expression of LTP, in the visual cortex of adult rats.Key words: excitatory amino acids, long-term potentiation, long-term depression, visual cortex, (±)-α-methyl-4-carboxyphenylglycine (MCPG).
Abnormal spatial but normal temporal resolution in the Siamese cat: a behavioral correlate of a genetic disorder of the parallel visual pathways
Authors: Girelli M. , Campara D. , Tassinari G. , Marzl C. A.
Published: April 2011

Six ordinary and one Siamese cat were tested for spatial frequency contrast sensitivity and for flicker discrimination thresholds. The Siamese cat was markedly impaired in the former task but performed normally in the latter. This result is consistent with single-cell physiological evidence showing an abnormally high Y/X cell ratio in the area centralis of Siamese cats. Under a more general perspective, this genetically related dissociation of visual impairments confirms the idea of parallel pathways subserving spatial and temporal resolution, respectively.Key words: Siamese cat, spatial resolution, temporal resolution, parallel pathways, albino mutants.
Dissociation of thermogenic and trophic actions of norepinephrine in brown adipocytes of Richardson ground squirrels
Authors: Desautels M. , Beard A. P. , Rawlings N. C.
Published: April 2011

Richardson ground squirrels are hibernators with seasonal changes in the thermogenic capacity of brown adipose tissue (BAT). The objective of this work was to evaluate whether norepinephrine (NE) acts both as a thermogenic and a growth factor in BAT. Brown adipocytes were isolated by collagenase digestion of axillary BAT and kept in a tissue culture incubator in methionine-free Dulbecco's modified Eagle's medium supplemented with albumin, antibiotics, and calf serum with or without NE for up to 24 h. For short-term incubations (<6 h), calf serum was omitted. Freshly isolated brown adipocytes responded to NE with 10- to 20-fold increases in rates of oxygen uptake. This ability to respond calorigenically to NE was maintained over a 24-h period. However, no significant increase in [35S]methionine incorporation into cellular proteins was observed when brown adipocytes were incubated for 1–6 or 24 h with NE. When labelled cell proteins were separated by SDS–PAGE and visualized by autoradiography, no selective change in protein labelling, particularly in the uncoupling protein (32 kDa) region was observed. Likewise, [35S]methionine incorporation into immunoprecipitable uncoupling protein was not affected by the presence of NE. These results suggest a dissociation between the thermogenic and growth effects of NE in BAT of Richardson ground squirrels.Key words: brown fat, uncoupling protein, hibernation, body temperature, body weight, cold acclimation.
Sarcoplasmic reticulum Ca2+uptake is not decreased in aorta from deoxycorticosterone acetate hypertensive rats: functional assessment with cyclopiazonic acid
Authors: Tostes Rita C. A. , Bendhack Lusiane M. , Traub Oren , Webb R. Clinton
Published: April 2011

Ca2+plays a major role in vascular contraction, and a defect in intracellular Ca2+regulation has been associated with increased vascular reactivity in hypertension. To test the hypothesis that the sarcoplasmic reticulum does not adequately buffer Ca2+in deoxycorticosterone acetate (DOCA) hypertension, contractile experiments were performed with a specific inhibitor of the sarcoplasmic reticulum Ca2+ATPase, cyclopiazonic acid (CPA). Contractile force in aortic strips from DOCA and control rats was measured, using standard muscle bath procedures, to evaluate (i) Ca2+handling, assessing caffeine and serotonin (5HT) induced contractions in Ca2+-free buffer and (ii) relaxation rate after 5HT washout. Contractile responses elicited with 5HT (3 × 10−6 mol/L) and caffeine (20 mmol/L) were greater in DOCA than in control arteries. CPA (1 × 10−7to 3 × 10−5 mol/L) reduced phasic contractions to 5HT and caffeine in DOCA and control aorta, and no differences in the IC50values were observed. Aortae from DOCA rats contracted when placed in normal buffer, subsequent to treatment with Ca2+-free buffer, but control aortae did not. CPA potentiated these responses in DOCA aorta and only caused a modest contraction in control aorta. CPA-induced contraction did not occur in Ca2+-free buffer, and it was inhibited by nifedipine (IC50 = 4 × 10−9 mol/L). The relaxation rate, after 5HT washout (3 × 10−6 mol/L), was increased in DOCA aorta (2.6 ± 0.3 min) compared with control (1.7 ± 0.2 min), and CPA (10−5 mol/L) increased the relaxation rate in both groups. The results support the hypothesis of defective Ca2+handling in DOCA hypertension. However, an increased Ca2+influx, and not a decreased buffering ability of the sarcoplasmic reticulum, contributes to the enhanced vascular reactivity observed in DOCA hypertension.Key words: vascular smooth muscle, intracellular calcium mobilization, caffeine, cyclopiazonic acid, sarcoplasmic reticulum, deoxycorticosterone (DOCA) hypertension.