bluuebunny/crossref_metadata_2025 huggingface dataset:
Normalization of impaired glucose tolerance by the short-acting hypoglycemic agent calcium (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate dihydrate (KAD-1229) in non-insulin-dependent diabetes mellitus rats
Authors: Ohnota Hideki , Koizumi Takashi , Kobayashi Miho , Sato Fumiyasu , Momose Yasunori
Published: April 2011

We have investigated the hypoglycemic effects of the newly synthesized short-acting nonsulphonylurea hypoglycemic agent calcium (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinyicarbonyl)-propionate dihydrate (KAD-1229) in non-insulin-dependent diabetes mellitus (NIDDM) rats. NIDDM rats that were given a neonatal injection of 60 mg/kg streptozotocin showed a dose-dependent but attenuated response to oral administration of KAD-1229 and gliclazide, and their impaired glucose tolerance was improved but not normalized. We next produced, using a neonatal injection of 30 mg/kg streptozotocin, a mild type of NIDDM rat with less impaired glucose tolerance. These rats responded well to these insulinotropic hypoglycemic agents. Their impaired glucose and meal tolerance were completely normalized by oral administration of 3 mg/kg KAD-1229. The efficacy of KAD-1229 in this NIDDM rat model 1–3 h after oral glucose administration was comparable with similar doses of gliclazide, despite its shorter hypoglycemic action (compared with gliclazide), in fasting normal rats. In meal tolerance tests (20 kcal/kg; 1 cal = 4.2 J), KAD-1229 reduced abnormally enhanced plasma glucose levels 1–3 h after administration. This effect disappeared by 5 h. In contrast, gliclazide showed sustained hypoglycemic effects until 5 h after oral administration, with a lower postprandial (0.5–1 h) effect. These data indicated that the rapid- and short-acting efficacy of KAD-1229 would be beneficial and sufficient to control postprandial plasma glucose in NIDDM rats.Key words: KAD-1229, hypoglycemic agent, streptozotocin-induced non-insulin-dependent diabetes mellitus rats.
Patch-clamp recording from identified rat ciliary ganglion neurons in primary culture
Authors: Kelly M. E. M. , Johnson K. K. , Jackson P. C.
Published: April 2011

Adult rat parasympathetic ciliary ganglion (CG) neurons were retrogradely labelled by intraocular injection of the carbocyanine fluorescent dye 1,1-dioleyl-3,3,3′,3′-tetramethylindocarbocyanine methanesulfonate (DiI). Whole-cell and nystatin perforated patch recording techniques were then used to examine the electrophysiological properties of labelled CG neurons growing in primary culture. The resting membrane potential of CG neurons in dissociated cell culture was −50 ± 8 mV, and isolated neurons fired overshooting action potentials in response to depolarizing current injection. Voltage-clamp recordings of membrane currents revealed a transient tetrodotoxin-sensitive Na+ inward current and both sustained and transient outward K+ currents. Sustained outward K+ current was reduced (55–77%) by 5 mM tetraethylammonium and to a lesser extent (42–46%) by superfusion with nominally Ca2+ free external solution. Transient outward current was blocked by 100 μm 4-aminopyridine and exhibited steady-state inactivation at potentials depolarized to −50 mV. These data demonstrate that identified adult mammalian CG neurons can be successfully maintained in culture. Cultured CG neurons retain electrical excitability, with voltage-sensitive Na+ and K+ currents giving rise to action potentials.Key words: fluorescent tracer, patch clamp, neuron, ciliary ganglion.
Contribution of proprioception for calibrating and updating the motor space
Authors: Bard Chantal , Fleury Michelle , Teasdale Normand , Paillard Jacques , Nougier Vincent
Published: April 2011

The absence of muscular proprioception, whether at a segmental or at a central level, impairs performance in several ways. The contribution of proprioception to movement control and learning is not easily dissociated from that of other sources of sensory information (e.g., vision). Therefore, the rare clinical cases of extensive neuropathy, depriving the brain massively and permanently of its presumed main sources of dynamogenic information from skin and muscles, are of very special interest. Two such patients and controls were tested in experiments investigating (i) force production, (ii) amplitude coding, (iii) spatial reference frames in pointing, and (iv) prismatic adaptation. Overall, our results highlight the key role of proprioceptive afferents for calibrating the spatial motor frame of reference, and the powerful substitutive properties of the central nervous system.Key words: proprioception, deafferentation, space calibration, motor control.
Proprioceptive control of interjoint coordination
Authors: Ghez Claude , Sainburg Robert
Published: April 2011

This paper reviews a series of experiments comparing intact controls with functionally deafferented patients to determine the role of proprioception in controlling dynamic interactions between limb segments during movement. We examine the control of hand path in a planar movement-reversal task and in a familiar three-dimensional gesture with similar biomechanical characteristics. In the planar task subjects had to move their hand out and back along a series of straight-line segments in the horizontal plane without visual feedback. The lengths and directions of the target line segments were chosen to require different amounts of shoulder motion while requiring the same elbow excursion. In controls, hand paths were, as required, straight with sharp bends at the outermost point. In patients, however, distinctive errors appeared at movement reversals, consisting of widened hand paths resulting from desynchronization in the reversals of elbow and shoulder motions. These errors reflected an inability to program elbow muscle contractions in accord with interaction torques produced at the elbow by variations in acceleration of the shoulder. The reversal errors were substantially reduced after patients had practiced for a few trials while visually monitoring movements of their arm. The improvement was not limited to the direction where they had practiced with vision, but also extended to other directions in which the elbow torques were different. This suggests that practice with vision of the arm served to improve the general rules that subjects used to plan movement, rather than simply improving the performance of a specific response. Similar to their performance on the planar task, the patients made errors in interjoint coordination during unconstrained three-dimensional gestures with movement reversals. We conclude (i) that both the planning and the learning of movement required an internal model of the dynamic properties of the limb that takes account of interaction torques acting at different joints; (ii) that this internal model is normally established and updated using proprioceptive information; but (iii) that when proprioception is lacking, vision of the limb in motion partially substitutes for proprioception.Key words: proprioception, multijoint coordination, limb movement, multijoint dynamics, deafferentation.
Control variables and proprioceptive feedback in fast single-joint movement
Authors: Levin M. F , Lamarre Y. , Feldman A. G.
Published: April 2011

Sensorimotor mechanisms were studied on the basis of kinematic and electromyographic data as well as the static torque developed by the muscles as a function of joint angle. The latter relationship is known as the torque/angle characteristic. Fast single-joint movement may result from a shift in this characteristic and a change in its slope. Such movements were studied at the wrist in 9 normal and 1 deafferented subject. After training to flex the wrist to a target, subjects repeated the same movements but in random test trials movements were opposed by the load generated by linear position feedback to a torque motor. At the end of the loaded trials, the load was suddenly removed. In the second experiment, subjects made wrist movements to the target that were opposed by the load and, on random test trials, the movements were not loaded. In these test trials, the wrist arrived in a static position outside the target zone. In both experiments, subjects were instructed not to correct errors. The final torque/angle characteristics specified in the movements were reconstructed on the basis of the static wrist positions and torques before and after unloading. Normal subjects made movements by shifting the position of the torque/angle characteristic and by increasing its slope. If subjects indeed maintained the same pattern of control variables (descending commands), the same final position of the characteristic would be reproduced from trial to trial regardless of load perturbations. This assumption of equifinality was tested by comparing the final position of the wrist in nonloaded movements with that after removal of the load in loaded movements. Equifinality was observed in normal subjects. Movements in the deafferented subject were also associated with a shift of the torque/angle characteristic and a change in its slope. However, she was unable to consistently reproduce its final position. In spite of muscle coactivation, her maximal stiffness was lower than in normal subjects. In the absence of vision, the subject made movements with the load by increasing the slope of the characteristic instead of by shifting its position far enough. Load perturbation affected her final wrist position (inequifinality), which may reflect the presence of a significant hysteresis of the characteristic as a result of the absence of stretch reflexes. The deficits following deafferentation presumably result from the destruction of biomechanical and sensorimotor mechanisms including the ability of control variables to specify the positional frame of reference for afferent and descending systems.Key words: sensorimotor integration, positional frames of reference, deafferentation, wrist stiffness, equilibrium-point hypothesis.
Body temperature regulation in rats near term of pregnancy
Authors: Fewell James E.
Published: April 2011

Experiments were carried out to define the effects of pregnancy on body tempreature (Tb) regulation in rats. Tb was measured by biotelemetry in six animals from day 10 of pregnancy (term day 21) to postpartum day 10. Average 24-h Tb decreased from day 15 of gestation to the time of parturition. Furthermore, there was a loss of the normal circadian variation of Tb late in gestation, which was again present by postpartum day 2. The decrease in 24-h Tb on day 15 of gestation resulted from this loss of circadian variation, as Tb did not increase during the dark period. The further decrease in Tb on day 20 of gestation resulted from an overall decrease in Tb during the light and dark periods as well as from a loss of the circadian variation in Tb. Tb increased dramatically within 4 h of birth of the first pup, which always occurred on day 21 during the light period. The mechanisms responsible for these dramatic changes in thermoregulation during late gestation and around the time of parturition are presently unknown.Key words: body temperature, circadian, parturition, pregnancy, rat, thermoregulation.
Differential effects of a flexor nerve input on the human soleus H-reflex during standing versus walking
Authors: Capaday C. , Lavoie B. A. , Comeau F.
Published: April 2011

A conditioning (C) stimulus at group I strength was delivered during standing to the common peroneal (CP) nerve before a test (T) stimulus at several C–T intervals ranging from 0 to 150 ms. At sufficiently long C–T intervals (100–120 ms) the soleus H-reflex was strongly inhibited despite little, or no change, in the background level of EMG activity. This finding indicates that a significant portion of the inhibition occurs at a premotoneuronal level, likely via presynaptic inhibition of the Ia-afferent terminals. During standing, at C–T intervals of 100–120 ms (optimal C–T interval) a conditioning stimulus to the CP nerve of 1.5 times motor threshold (MT) intensity reduced the soleus H-reflex by an average of 45.8% (n = 14 subjects). The conditioning stimulus always produced a clear inhibition of the H-reflex during standing at these C–T intervals. The effects of this conditioning stimulus on the soleus H-reflex were then determined in the early part of the stance phase of walking. In contrast to standing, the conditioning stimulus produced little or no inhibition during the early part of the stance phase of walking (average inhibition 45.8 vs. 11.6%, n = 14 subjects). The soleus background EMG, and the soleus and tibialis anterior M-waves were essentially the same during standing and walking. Furthermore, there was no shift of the optimal C–T interval during walking. The difference in the effects of the conditioning stimulus was not due to differences in the size of the test H-reflex in each task. It appears to be due to a genuine task-dependent change in the input–output properties of the underlying spinal cord circuits. There are at least two, mutually compatible, explanations of these results. Firstly, during walking the intraspinal terminals of the afferent fibres (group Ia and Ib) conducting the conditioning volley may be presynaptically inhibited, or their input gated at the interneuronal level. Secondly, on the assumption that the conditioning stimulus is acting via the presynaptic inhibitory network in the spinal cord, it is possible that during walking this network is saturated as a result of increased central or peripheral synaptic inputs. Finally, it seems unlikely that differences in the refractoriness of the CP nerve between the tasks may be involved; the reasons for this are presented in the discussion.Key words: Ia afferents, motoneurons, presynaptic inhibition, EMG, posture, locomotion, spinal cord.
Site-specific effects of sympathectomy on the adrenergic control of lipolysis in hamster fat cells
Authors: Robidoux Jacques , Pirouzi Peivand , Lafond Julie , Savard Roland
Published: April 2011

Regional variations in the response of adipose tissue to lipolytic stimuli have been suggested to be involved in the development of visceral adiposity-related morbidity and mortality. Moreover, studies in humans and in laboratory rodents such as hamsters have shown that the response of adipocytes to catecholamines depends on their anatomical origin. The aim of the present study was to investigate the relative involvement of the adrenal medulla and of the sympathetic nervous system on regional differences in the adrenergic control of lipolysis in isolated adipocytes from inguinal and epididymal adipose tissues. For this purpose, we carried out adrenal demedullation or chemical sympathectomy in hamsters. The results confirmed that epididymal adipocytes were significantly more responsive to a β-adrenergic stimulation than inguinal adipocytes (p ≤ 0.05). This site specificity could originate at a step distal to receptors since tissues exhibited a similar number of binding sites for [125I]cyanopindolol. No significant regional differences were observed in the α2-adrenergic antilipolytic response, with the exception of the clonidine EC50. A 14-day sympathectomy significantly increased the β-adrenergic lipolytic response only in inguinal adipocytes (p < 0.05), and increased the α2_adrenergic response only in epididymal adipocytes (p < 0.05). On the other hand, adrenal demedullation had no effect on both adrenergic pathways. These results suggest that the sympathetic tone of adipose tissues could be involved in the α2- and β-adrenergic site-specific response in hamster fat cells. The 33% increase of the β-response in inguinal fat cells and the 38% increase of the α2-response in epididymal fat cells also suggest that the sympathetic pathway favors the lipolytic activation of the epididymal adipose tissue.Key words: white adipose tissue, adrenal demedullation, α2-adrenergic receptors, β-adrenergic receptors.
The hypercholesterolemic effect of cod protein is reduced in the presence of high dietary calcium
Authors: Jacques Hélène , Lavigne Charles , Desrosiers Thérèse , Giroux Isabelle , Hurley Christine
Published: April 2011

To determine the respective and interactive effects of dietary protein source and calcium level on serum, hepatic, and fecal lipid levels, 48 male New Zealand rabbits were fed purified diets varying in the source of dietary protein, namely casein, cod protein, or soy protein, at an adequate (7 mg Ca/g diet) or a high (14 mg Ca/g diet) concentration of calcium in a 3 × 2 factorial design for 28 days. Dietary proteins interacted with dietary calcium to modulate serum and low density lipoprotein (LDL) cholesterol. When combined with the adequate-calcium diet, cod protein induced higher levels of serum and LDL cholesterol than casein and soy protein. When calcium was increased in the diet, cod protein, in contrast to casein and soy protein, induced lower serum and LDL cholesterol than when associated with an adequate concentration of calcium. These results indicate that the hypercholesterolemic effect of cod protein is reduced in the presence of high dietary calcium. Moreover, fecal lipid content was inversely correlated with serum total (p = 0.06) and LDL (p = 0.04) cholesterol in rabbits fed cod protein diets only. An increased formation of insoluble calcium phosphate in the intestine, which may result in lower fat intestinal absorption and serum cholesterol levels, may have been responsible for the decrease in serum and LDL cholesterol in rabbits fed cod protein with high dietary calcium.Key words: dietary protein, dietary calcium, serum cholesterol, lipoproteins, fat excretion.
Metabolic adaptations to short-term training are expressed early in submaximal exercise
Authors: Green H. J. , Ball-Burnett M. , Jamieson G. , Cadefau J. , Cussó R.
Published: April 2011

In previous studies we have been able to demonstrate tighter metabolic control of muscle metabolism during prolonged steady-state exercise 5 to 6 days after the initiation of training and well before changes in oxidative potential. To examine whether the metabolic adaptations are manifested during the non-steady-state adjustment to submaximal exercise, 11 male subjects ([Formula: see text] peak, 45 ± 2.4 mL∙kg−1∙min−1, [Formula: see text]) performed 98 min of cycle exercise at 67% of [Formula: see text] peak prior to and following 3 to 4 days of training for 2 h per day. Analysis of lactate concentration (mmol/kg dry weight) in samples rapidly extracted from vastus lateralis indicated reductions (p < 0.05) of 44% at 3 min (42.1 ± 7.1 vs. 23.6 ± 7.7), 29% at 15 min (35.4 ± 6.4 vs. 25.0 ± 6.0), and 32% at 98 min (22.9 ± 6.9 vs. 15.6 ± 3.2) with training. Training also resulted in higher phosphocreatine and lower creatine and Pivalues that were not specific to any exercise time point. In addition, [Formula: see text] was not altered either during the non-steady state or during the steady-state phases of exercise. These results suggest that at least part of the tightening of the metabolic control and the apparent reduction in glycogenolysis and glycolysis in response to short-term training occurs during the adjustment phase to steady-state exercise.Key words: training, metabolic control, nonsteady state.
Roles of peptides and other substances in cotransmission from vascular autonomic and sensory neurons
Authors: Morris J. L. , Gibbins I. L. , Kadowitz P. J. , Herzog H. , Kreulen D. L. , Toda N. , Claing A.
Published: April 2011

Blood vessels may be innervated by up to three major classes of neurons: sympathetic vasoconstrictor neurons; sympathetic or parasympathetic vasodilator neurons; and peripheral fibres of small diameter sensory neurons, which can mediate vasodilation. Most vascular neurons utilise multiple transmitters, including neuropeptides and small nonpeptides such as ATP or nitric oxide, often in addition to noradrenaline or acetylcholine. Subpopulations of each major class of vascular neurons innervating different vascular segments may contain different combinations of neurotransmitters. Furthermore, the same population of neurons can release different cotransmitters in response to different patterns of stimulation. In general, peptides mediate slower and more long lasting changes in vascular resistance than do nonpeptides. Thus, autonomic and sensory neurons are well adapted to produce qualitatively different vascular effects in response to different types of afferent input. The major challenge for the future is to develop new antagonists for many of the substances colocalised in vascular neurons, particularly neuropeptides. These agents will allow us to precisely determine the relative roles of multiple cotransmitters, and are likely to provide therapeutic agents that can be targeted to specific regions of the vasculature.Key words: neurotransmission, blood vessels, neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), calcitonin gene related peptide (CGRP), pituitary adenylate cyclase activating peptide (PACAP), adenosine 5′-triphosphate, nitric oxide.
Vascular α-adrenoceptors: from the gene to the human
Authors: Bylund David B. , Regan John W. , Faber James E. , Hieble J. Paul , Triggle Christopher R. , Ruffolo Jr. Robert R.
Published: April 2011

Adrenoceptors can be subdivided into three major types, the α1-, α2-, and β-adrenoceptors. Each of these types can be further subdivided into three subtypes, based on pharmacological characteristics. Molecular cloning techniques have supported this subclassification. Recent data now suggest that α-adrenoceptor subtypes identified by pharmacological and molecular techniques correspond well, although species orthologs of several adrenoceptor subtypes have been identified. The secondary structure of the adrenoceptors has been elucidated and correlated with their interaction with second messenger molecules. α1-Adrenoceptors, β-adrenoceptors, and α2-adrenoceptors mediate their actions through stimulation of inositol phosphate release, stimulation of adenylate cyclase, and inhibition of adenylate cyclase, respectively. Site-directed mutagenesis and the preparation of chimeric receptors have located the site of receptor – second messenger interaction to the third intracellular loop for each of these adrenoceptors. While subtypes of each of these classes all interact with the same second messenger, studies with recombinant α2-adrenoceptors show subtype-related differences in receptor – second messenger interaction. Multiple α-adrenoceptor subtypes are expressed in vascular smooth muscle and are involved in various aspects of blood vessel function, including contraction, cellular growth, and proliferation. Various physiological factors can selectively influence responses to a particular subtype, and the relative roles of each subtype can vary between vascular beds and along an individual blood vessel as its caliber changes. Functional studies in blood vessels suggest the presence of additional α-adrenoceptor subtypes not yet identified via molecular techniques. Optimization of the therapeutic profile of an α-adrenoceptor antagonist may be possible via enhancement of selectivity for a particular subtype or by design of a specific profile of affinity for the individual subtypes.Key words: adrenoceptor subclassification, second messenger, G-proteins, vasoconstriction, smooth muscle proliferation.
Actions of diazoxide on CA1 neurons in hippoeampal slices from rats
Authors: Erdemli G. , Krnjević K.
Published: April 2011

Membrane effects of diazoxide (DZX) were examined in CA1 pyramidal neurons, mainly by whole-cell recording in slices kept at 33 °C (from Sprague–Dawley rats). Bath applications of DZX (0.65 mM) did not significantly change the resting input conductance; but instantaneous inward rectification was reduced by 47 ± 14% (near –110 mV). There was a similar depression of a large, sustained voltage-dependent outward current (by 44 ± 11% near 0 mV). A nearly identical reduction of the outward current recorded in a Ca current suppressing medium (but not in 30 mM tetraethylammonium) indicated that the DZX-sensitive current includes the delayed rectifier. In Mn, low-Ca medium containing tetraethylammonium and carbachol, DZX potentiated (by 43 ± 12%) the D-type slowly decaying outward current seen after hyperpolarizing pulses at a holding potential of ≈ −50 mV. DZX abolished or depressed slow inward currents, such as the tetrodotoxin-sensitive persistent Na current, high voltage activated Ca currents (IC50 = 0.47 mM), and the Q current. In 6 of 13 cells recorded with electrodes containing either guanosine or adenosine diphosphate, DZX potentiated the voitage-dependent outward current, but input conductances were reduced. In conclusion, although there was little indication that it activates classical KATP channels in CA1 neurons, DZX strongly depresses several voltage-dependent, slowly inactivating outward and inward currents, which are important modulators of cell excitability.Key words: KATP channels, persistent Na current, high voltage activated Ca currents, delayed rectifier, D current, sulphonylureas, nucleotide diphosphates.
Characteristics of tetanic contractions in caffeine-treated rat myocardium
Authors: Leite C. M. , Vassallo D. V. , Mill J. G.
Published: April 2011

Skinned fiber preparations are used to obtain the maximal contractile activation of isolated myocardial preparations. Tetanic contractions elicited in the presence of sarcoplasmic reticulum inhibitors have also been used as an alternative method to produce maximal active tension in the intact myocardium. In this work our purpose was to define the best conditions to obtain tetanic contractions in the rat myocardium and to compare the influence of muscle length and inotropic interventions (Ca2+ and Bay K8644) in the tension produced in twitches and tetanic contractures. Papillary muscles were mounted in a perfusion chamber to record isometric force. Tetanic contractions were elicited by using suprathreshold stimulation with rectangular pulses (10 ms duration) at 5 Hz in the presence of 2.5 mM caffeine. Caffeine depressed the twitch tension but the tetanic tension was similar to that produced under steady-state stimulation (0.5 Hz) in control conditions. Tetanic and twitch tensions were similar along the whole extension of the length–tension curve and under the positive inotropic effects produced by Ca2+ (0.25 to 3.75 mM) or by the Ca2+-channel agonist Bay K8644 (1 μM). During long tetanic stimuli (60 s) a time-dependent tension decay was observed. This decay was prolonged by reducing the extracellular K+ from 5.4 to 1.0 mM, suggesting that Ca2+ extrusion through the Na–Ca exchanger seems to occur during tetanic stimulation. Since tetanic tension was never higher than the tension obtained in twitches elicited at the same Ca2+ concentration (0.5 Hz), we conclude that tetanic contractures represent a useful tool to investigate the contractile response of intact myocardial preparations with a nonfunctional sarcoplasmic reticulum. However, our results indicate that the maximal activation of the contractile machinery in the rat myocardium seems to be only achieved in twitches elicited in high extracellular Ca2+ concentrations and with a functional sarcoplasmic reticulum.Key words: cardiac muscle, excitation–contraction coupling, sarcoplasmic reticulum, tetanic contracture, Na–Ca exchange.
The 1994 Stevenson Award Lecture. Follicle-stimulating hormone and luteinizing hormone: a tale of two gonadotropins
Authors: Schwartz Neena B.
Published: April 2011

Although most gonadotropes synthesize both luteinizing hormone and follicle-stimulating hormone, the transcription, content, and secretion rates of the two gonadotropins can be separated. The signals external to the gonadotropic cells that appear to be important in the differential regulation are gonadotropin-releasing hormone pulse frequency (high pulse frequency favors luteinizing hormone), steroid feedback (works on both but induces a more powerful negative feedback on luteinizing hormone), and gonadal peptide feedback (activin increases follicle-stimulating hormone; inhibin and follistatin decrease it). We know very little about the pathways within the gonadotropes that favor one gonadotropin rather than another. It is expected that the cloning of the genes for both gonadotropins and the use of specific cell lines and transfections will lead to elucidation of these pathways.Key words: luteinizing hormone, follicle-stimulating hormone, gonadotropin-releasing hormone, inhibin, anterior pituitary, gonads.
Role of nitric oxide and prostaglandins in the regulation of blood pressure in conscious rats
Authors: Inglés Andrés C. , Ruiz Francisco J. , Salom Miguel G. , Quesada Tomás , Carbonell Luis F.
Published: April 2011

The present study was designed to investigate the possible role of endothelium-derived vasodilators, nitric oxide and prostaglandins, in the regulation of blood pressure during the presence and absence of the major pressor systems. Conscious rats were infused with a cocktail of inhibitors of the sympathetic nervous system, renin–angiotensin system, and V1 vascular receptor to vasopressin (achieved with hexamethonium, captopril, phentolamine, propranolol, and the V1 vasopressin (AVP) antagonist des-(CH2)5Tyr(Me)-AVP). The cocktail of vasoconstrictor inhibitors induced a marked fall of mean arterial pressure (MAP) from 109 ± 2 to 52 ± 2 mmHg (1 mmHg = 133.3 Pa) (n = 24). In animals with blockade, the specific inhibitor of nitric oxide synthesis, NG-nitro-L-arginine methyl ester (L-NAME), induced a significant increase of MAP from 51 ± 1 to 84 ± 2 mmHg (n = 6). In the presence of indomethacin, a cyclooxygenase inhibitor, the pressor response to L-NAME was from 52 ± 2 to 126 ± 4 mmHg (n = 6). Neither indomethacin (n = 6) nor vehicle (n = 6) alone altered MAP. In intact animals without blockade, L-NAME caused a similar increase of MAP when it was injected alone (from 107 ± 3 to 144 ± 4 mmHg, n = 7) or with indomethacin (from 113 ± 3 to 144 ± 3, n = 6). Indomethacin alone (n = 8) did not change MAP. In conclusion, in the absence of the major pressor systems, the pressor effect of the inhibition of the production of endogenous nitric oxide and vasodilator prostanoid synthesis appears to be synergistic. These results suggest that these two endogenous vasodilators are involved in the maintenance of blood pressure.Key words: nitric oxide, NG-nitro-L-arginine methyl ester, prostaglandins, blood pressure.
Ethics for working with communities of Indigenous Peoples
Authors: Scott Kim , Receveur Olivier
Published: April 2011

Specific ethical guidelines for working with Indigenous Peoples have been adopted by several research institutions. Ethical principles aim at promoting cooperation and mutual respect between researchers and communities of Indigenous Peoples. These principles are meant to be continually assessed. This article reports on the content and format of current ethical guidelines and highlights directions for further development.Key words: ethical guidelines, Indigenous Peoples, research agreement, collaborative studies.
Bradykinin B2 receptor antagonists: development and applications
Authors: Stewart John M.
Published: April 2011

Most physiological and pathophysiological responses to bradykinin are mediated by G-protein-coupled receptors designated B2 receptors. Discovery of antagonists for these receptors has brought about a revolution in research in the kinin field. The chemistry and development of antagonists for B2 kinin receptors are discussed. Uses of the antagonists in biomedical research and potential clinical applications are presented.Key words: bradykinin antagonists, bradykinin inflammation, bradykinin receptors.
Kinin receptor antagonists: unique probes in basic and clinical research
Authors: Wirth Klaus J. , Heitsch Hoiger , Schöikens Bernward A.
Published: April 2011

The availability of potent and stable bradykinin antagonists has had a tremendous impact on kinin research. This article reviews the current status of research on kinin antagonists, describes their chemical properties, and delineates recent advances that have occurred with the advent of the second generation of kinin antagonists. The data collected with these antagonists support the assumption that kinins are implicated in inflammation and tissue injury as endogenous agents. Their importance, however, is not limited to the role as mediators of tissue injury and inflammation, as kinin antagonists have enabled the identification of kinins as potential endogenous cardioprotective substances, also contributing to the effects of angiotensin converting enzyme inhibitors. Clinical studies are currently being performed in asthma, postoperative pain, anaphlyactoid reactions during low density lipoprotein apheresis, systemic inflammatory response syndrome, and suspected sepsis, head injury, and hantavirus infections to investigate the utility of kinin antagonists as therapeutic agents.Key words: bradykinin antagonists, chemistry, pharmacology, basic studies, clinical studies.
Comparison of B1and B2receptor activation on intracellular calcium, cell proliferation, and extracellular collagen secretion in mesangial cells from normal and diabetic rats
Authors: Girolami J. P. , Ouardani M. , Bascands J. L. , Pécher C. , Bompart Guy , Leung-Tack J.
Published: April 2011

The mesangial cell is a contractile secreting cell found in a key position in the renal glomerulus. Several kidney and systemic diseases are associated with dysfunctions of the mesangial cells. We compared the effects of bradykinin (BK; B2agonist) and des-Arg9-bradykinin (DBK; B1agonist) on intracellular calcium mobilization, cell proliferation, and collagen secretion of mesangial cells from normal and streptozotocin-induced diabetic rats. Stimulation of mesangial cells with BK and DBK caused an increase in intracellular calcium (Ca2+). However, the patterns of the Ca2+increases induced by BK and DBK were different, indicating that DBK induced a major Ca2+influx, whereas BK preferentially released Ca2+from intracellular pools. Stimulation with BK and DBK did not show any heterologous desensitization, thus indicating the presence of two distinct binding sites. In normal cells, DBK stimulated cell proliferation more than BK, and this action was potentiated by insulin. No effect of BK or DBK was found in cells harvested from diabetic rats. The proliferation effect of BK and DBK was restored by insulin. DBK stimulated more collagen synthesis than BK in normal cells. In cells harvested from diabetic rats the collagen secretion was increased, but BK and DBK no longer had any effect. Insulin reduced basal collagen secretion in normal cells and cells harvested from diabetic rats. Insulin also blunted stimulation by BK and DBK in normal cells but did not restore the response to BK and DBK in cells harvested from diabetic rats. Our results show that the sensitivity to DBK and BK decreases during the course of insulin-dependent diabetes, indicating modulation by insulin.Key words: bradykinin, des-Arg9-bradykinin, mesangial cell, diabetes, cell proliferation, calcium mobilization, collagen production.
Mutational analysis of neurokinin receptor function
Authors: Fong Tung Ming , Huang Ruey-Ruey C. , Yu Hong , Underwood Dennis , Cascieri Margaret A. , Strader Catherine D. , Swain Christopher J.
Published: April 2011

The interactions of the NK1receptor with peptide agonists or nonpeptide antagonists have been investigated by site-directed mutagenesis and computer modeling. At least 10 residues in the extracellular and transmembrane regions of the receptor are required for the binding of many peptide agonists. The C-terminal amide of peptide agonists is likely to be bound near Asn-85. Residues likely to be involved in the subsequent receptor activation include Glu-78 and Tyr-205. The binding site for nonpeptide antagonists can be defined by at least five residues in transmembrane helices 4–7, and primary contacts between key residues and quinuclidine antagonists have been assigned based on CP-96,345 and its analogs. Analyses of the wild-type and mutant NK1and NK2receptors, intact and truncated peptides, and various antagonists suggest that the agonist and antagonist binding sites overlap spatially, even though agonists and antagonists do not interact with the same set of residues on the receptor. Mapping the ligand binding site not only allows us to better understand the ligand–receptor interaction and antagonism but also leads to a refined three-dimensional model of the NK1receptor.Key words: receptor, substance P, agonist, antagonist, mutagenesis.
Neurokinin receptor gene expression in substantia nigra: localization, regulation, and potential physiological significance
Authors: Bannon Michael J. , Whitty Christopher J.
Published: April 2011

Neurokinin receptor gene expression within the rat and human substantia nigra was examined in detail. In the rat, the relative abundances of nigral neurokinin receptor mRNAs were neurokinin 3 > neurokinin 1 [Formula: see text] neurokinin 2. High levels of neurokinin 3 mRNA were localized to dopamine neurons, as determined by dopamine cell lesions and colocalization with tyrosine hydroxylase mRNA. Stimulation of nigral neurokinin 3 receptors activated dopamine cells, as evidenced by increases in striatal dopamine metabolism and in a postsynaptic measure of dopamine neurotransmission (i.e., striatal substance P encoding mRNA). These and other anatomical and physiological data suggest that in the rat, substance P (released from striatonigral neurons) may act on nigral nondopamine cells through neurokinin 1 receptors, while the substance P cotransmitter neurokinin A may act preferentially on nigral dopamine neurons through neurokinin 3 receptors. Interestingly, high levels of neurokinin 1 (but not neurokinin 3) receptor mRNA are seen within human substantia nigra dopamine cells. Thus drugs interacting with neurokinin receptors may prove to be of value in the treatment of various neuropsychiatric disorders.Key words: neurokinin receptor, mRNA, dopamine, substantia nigra, human.
Recent developments in tachykinin NK1 receptor antagonists: prospects for the treatment of migraine headache
Authors: Beattie D. T. , Connor H. E. , Hagan R. M.
Published: April 2011

The role of substance P and the influence of neurokinin 1 (NK1) receptor antagonists in the cranial circulation are described in the present review, particularly with respect to the mechanisms involved in the etiology of migraine headache. Substance P is distributed throughout the cranial vasculature, in the trigeminal sensory afferent nerve fibres, and its release can be demonstrated following activation of the trigeminovascular system in animals and humans. Following its release and NK1 receptor activation, dilatation and edema result, two events that are implicated in the pathogenesis of migraine headache. The recently developed selective NK1 receptor antagonists inhibit substance P mediated dilatation and plasma protein extravasation in the cranial circulation, suggesting that they may provide an effective and novel acute treatment for migraine.Key words: substance P, migraine, NK1 receptor antagonists.
Characterization of the tachykinin receptors involved in spinal and supraspinal cardiovascular regulation
Authors: Couture Réjean , Picard Pierre , Poulat Philippe , Prat Alexandre
Published: April 2011

The pharmacological characterization of the tachykinin receptors involved in spinal and supraspinal cardiovascular regulation is reviewed in this report. In conscious rats, substance P (SP), neurokinin A (NKA), neurokinin B (NKB), neuropeptide K (NPK), and neuropeptide γ (NPγ) were injected either intrathecally (i.t.) or intracerebroventricularly (i.c.v.), and their effects were assessed on mean arterial blood pressure (MAP) and heart rate (HR). Moreover, selective antagonists for NK1 ((±)-CP-96345 and RP-67580), NK2 (SR-48968), and NK3 (R-486) receptors were tested against the agonists. I.t. tachykinins elicited dose-dependent increases in MAP and HR (NPK > NPγ > SP > NKA > NKB). The cardiovascular response to i.t. SP, NPK, and NPγ was significantly attenuated by the prior i.t. administration of (±)-CP-96345 and RP-67580 but not by SR-48968 and R-486. By the i.c.v. route, tachykinins also elicited pressor and tachycardiac responses dose dependently (NPK > NPγ > SP > NKA > NKB). Senktide and [MePhe7]NKB, two NK3-selective agonists, were slightly more potent than NKB on both parameters. Whereas the cardiovascular response to NPK was largely blocked by (±)-CP-96345 and RP-67580, that to SP was reduced by 40–50%. This treatment had no effect on the cardiovascular response to NKA and [MePhe7]NKB. Conversely, SR-48968 reduced by 40–50% the NKA-induced cardiovascular changes without affecting the central mediated effects of NPK, SP, and [MePhe7]NKB. However, when coadministered, RP-67580 and SR-48968 abolished the effects to SP and NKA while leaving untouched those induced by [MePhe7]NKB. Finally, the central effects mediated by [MePhe7]NKB, senktide, and NKB were blocked by R-486. These findings suggest that the i.t. action of tachykinins on the rat cardiovascular system is mediated by a NK1 receptor in the spinal cord, while NK1, NK2, and NK3 receptors are likely involved in the supraspinal (hypothalamus) effects of these neuropeptides. It is also concluded that NPK is a pure and powerful NK1 agonist, in contrast to SP and NKA, which are not selective for NK1 or NK2 receptors, respectively.Key words: tachykinins, spinal cord, central cardiovascular control, tachykinin receptor antagonists.
Tachykinin receptors in guinea-pig airways: characterization using selective ligands
Authors: Burcher Elizabeth , Zeng Xiang-Ping , Strigas John , Geraghty Dominic P. , Lavielle Solange
Published: April 2011

Tachykinin receptors in guinea-pig airways were examined using radioligand binding techniques in lung homogenates, and using isolated bronchial segments. Binding of the NK1 selective radioligand 125I-labelled Bolton–Hunter [Sar9,Met(O2)11]substance P ([125I]BHSarSP) was saturable and of high affinity (KD, 0.26 nM). The rank potency order of competitors for [125I]BHSarSP binding was [Pro9]SP > CP 96345 [Formula: see text] septide > [pGlu6]SP(6–11) > RP 67580 ≥ [DPro9, [Formula: see text],Trp11]SP > [DPro9,[Formula: see text],Trp11]physalaemin ≥ GR 82334 ≥ 127I Bolton–Hunter neurokinin A (BHNKA). Septide had higher affinity than expected, and it was the only ligand to bind to two sites. Agonists interacting with NK2 receptors were more potent contractile agents than NK1 receptor agonists. Responses to BHNKA (pD2 8.4) were antagonized by MDL 29913 and MEN 10207, with pKB values 6.42 and 6.79, and also by SR 48968 and GR 94800, although this was not dose dependent. This agonist was also weakly inhibited by CP 96345 and RP 67580. These data demonstrate that BHNKA can interact with both NK1 and NK2 receptors. There was no relationship between the binding affinity of NK1 ligands in lung homogenates, with GR 82334 being notably weak, and their agonist or antagonist potency in bronchial smooth muscle.Key words: tachykinin receptor, radioligand binding, septide, guinea-pig bronchus, 127I Bolton–Hunter neurokinin A.
Neurokinin receptors subserving bronchoconstriction
Authors: Ellis James L.
Published: April 2011

Tachykinin receptor subtypes were initially defined using agonist potency ratios for the endogenous ligands substance P (SP), neurokinin (NK) A, and NKB. On this basis it was suggested that there are three tachykinin receptor subtypes. These subtypes were designated NK1, NK2, and NK3, where SP is most potent at NK1 receptors, NKA is most potent at NK2 receptors, and NKB is most potent at NK3 receptors. Recently analogs of the endogenous ligands that show greater selectivity (about 1000-fold) for the different receptor subtypes have been developed. In addition selective antagonists, which are either nonpeptides or modified peptides, for the receptor subtypes have been developed. This minireview concentrates on the wealth of new knowledge concerning the tachykinin receptor subtypes subserving bronchoconstriction in several mammalian species, including man, provided by the use of these selective agonists and antagonists.Key words: neurokinins, bronchoconstriction, substance P, neurokinin A, receptor subtypes.
Neurokinin receptors subserving plasma extravasation in guinea pig airways
Authors: Rodger Ian W. , Tousignant Christine , Young Donna , Savoie Chantal , Chan Chi-Chung
Published: April 2011

In the respiratory system the tachykinins substance P and neurokinin A exhibit a variety of effects on airway function that include bronchoconstriction, vasodilatation, and plasma extravasation. Increased microvascular permeability with accompanying plasma extravasation is a principal cause of tissue edema observed in asthma. In guinea pig airways it has been suggested that neurogenic plasma extravasation is mediated by tachykinins, released from sensory nerve terminals, acting via neurokinin (NK) receptors. We have characterized NK receptor mediated plasma extravasation in guinea pig airways, using 125I-labelled human fibrinogen as a marker for leakage. Extravasation was induced using selective NK1 and NK2 receptor agonists, capsaicin, or nonadrenergic, noncholinergic nerve stimulation. The inhibitory effects of the selective nonpeptide NK receptor antagonists (CP 99,994 for NK1 and. SR 48,968 for NK2) were also examined. Results from our studies demonstrate conclusively that only NK1 receptors subserve plasma extravasation in the trachea and large airways of the guinea pig. In stark contrast, extravasation in the lower airways (secondary bronchi and intraparenchymal airways) of the guinea pig is mediated by both NK1 and NK2 receptors.Key words: tachykinins, substance P, neurokinin A, plasma extravasation, neurokinin receptors, asthma.
Ultrastructural features of the colocalization of calcitonin gene related peptide with substance P or somatostatin in the dorsal horn of the spinal cord
Authors: Ribeiro-da-Silva A.
Published: April 2011

Calcitonin gene related peptide (CGRP), substance P (SP), and somatostatin (SOM) are probably the three most important sensory neuropeptides. However, in contrast to CGRP immunoreactivity (IR), SP- and SOM-IR occur also in neurons intrinsic to the dorsal horn. Colocalization of either SP- or SOM-IR with CGRP-IR is, therefore, strongly suggestive of a primary sensory origin. In this study, high resolution double-labelling immunocytochemistry was applied to detect CGRP/SP and CGRP/SOM colocalizations in axonal boutons of the rat superficial dorsal horn. Most boutons colocalizing CGRP-IR and SP-IR were not part of synaptic glomeruli. However, 15% of such boutons represented the central varicosities of type I synaptic glomeruli. CGRP-IR was always present in the small proportion of type I glomeruli central boutons that displayed SOM-IR. In a study in the cat combining double-labelling immunocytochemistry with intracellular injection of electrophysiologically characterized neurons, we found that nociceptive neurons received numerous synapses from varicosities colocalizing SP-IR and CGRP-IR. In contrast, non-nociceptive neurons almost completely lacked synaptic input from boutons colocalizing both immunoreactivities. This study confirms that fibres colocalizing SP-IR and CGRP-IR probably play a major role in spinal nociceptive mechanisms.Key words: substantia gelatinosa, sensory systems, immunocytochemistry, nociceptive neurons.