bluuebunny/crossref_metadata_2025 huggingface dataset:
Ontogeny of positive inotropic responses to sympathomimetic agents and of myocardial adrenoceptors in rats
Authors: Inayatulla Arjumand , Li Ding-You , Chemtob Sylvain , Varma Daya R.
Published: April 2011

Positive inotropic efficacies (maximal increase in contractile force) and potencies of the α-adrenoceptor agonist methoxamine and β-adrenoceptor agonist isoprenaline were determined on electrically driven (1 Hz) ventricular strips from rats aged 0.5, 1, 2, 3, 6, and 10 (adult) weeks. The inotropic response to methoxamine significantly decreased after 2 weeks of age. The inotropic potency of isoprenaline was slightly but significantly lower at all ages than at 0.5 weeks of age. Up to 2 weeks of age, the maximal inotropic effect of methoxamine was comparable with that of isoprenaline, thereafter it was but markedly less. Phenylephrine behaved like methoxamine, and noradrenaline like isoprenaline. The effect of methoxamine was antagonized by prazosin but not by propranolol; the reverse was true for isoprenaline. Injections at birth of triiodothyronine and dexamethasone exerted minimal effects on the inotropic responses to methoxamine and isoprenaline. Chemical sympathectomy with 6-hydroxydopamine caused supersensitivity to the inotropic effects of isoprenaline but produced subsensitivity to responses to methoxamine at 1 week; effects of methoxamine at 3 and 6 weeks of age were not altered by sympathectomy. No significant differences in α1 or β1-adrenoceptor densities or affinities in ventricular membranes from 7-day-old and adult rats were found. It is concluded that the positive inotropic responses to sympathomimetic amines decline with age, the decline is most marked in the case of α1-adrenoreceptor-mediated effects, and these changes do not appear to be due to a decrease in the number or affinity of α1- and β1-adrenoceptors.Key words: myocardial adrenocepters, methoxamine, isoprenaline, phenylephrine, noradrenaline, ontogeny, inotropic responses.
Mechanism-based inactivation of hepatic cytochrome P450 2C6 and P450 3A1 following in vivo administration of 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine to rats: differences from previously observed in vitro results
Authors: Kimmett S. M. , McNamee J. P. , Marks G. S.
Published: April 2011

Using progesterone 21-hydroxylase as a selective substrate for P450 2C6 in phenobarbital-treated male rats, and androstenedione and progesterone 6β-hydroxylases as well as erythromycin N-demethylase as selective markers for P450 3A1 in dexamethasone-treated female rats, we have shown that these P450 isozymes undergo mechanism-based inactivation after in vivo administration of 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine (4-ethyl DDC). These results differ from our previous studies where no inactivation was observed after in vitro administration of 4-ethyl DDC to rat hepatic microsomes. We show that the differences between the in vivo and in vitro effects of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) analogues are due to the presence of residual 4-ethyl DDC in the in vitro experiments causing time-independent competitive inhibition and obscuring observation of mechanism-based inactivation.Key words: 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine, cytochrome P450, steroid hydroxylation, rat hepatic microsomes.
The Adaptive Control of Prehension
Authors: Lederman Susan J.
Published: April 2011

This paper provides a brief overview of the adaptive control of prehension. Several primary issues for research in the field are considered. One pertains to the stages of prehensile activity, with particular concern for the kinematic control of pre-contact phases, and the coordination of load and grip forces following contact. Others relate to the basis of anticipatory and sensory-guided (via visual, proprioceptive, tactile, and haptic feedback) control of prehension. The nature of internal representations of actions is also briefly considered.Key words: grasp, prehension, adaptive control, kinematic control, force control.
Catching a ball: contributions of intrinsic muscle stiffness, reflexes, and higher order responses
Authors: Bennett David J. , Gorassini Monica , Prochazka Arthur
Published: April 2011

In three sets of experiments in nine normal subjects and a patient with a percutaneous wrist-stabilizing splint, we quantified the open-loop gain (OLG) of the stretch reflex acting about the elbow. The subjects exerted a steady mean flexing force and were instructed not to intervene (i.e., not to resist actively) when force or displacement perturbations were imposed on the forearm. The method was either to reconstruct transmission around the entire loop in a two-part experiment, or to use the attenuation of external perturbations in normal and electrically stimulated muscle to compute gain. Across all experiments, the mean magnitude of stretch reflex OLG was close to unity in the frequency range 1–2 Hz, and declined at higher frequencies, as required to ensure stability, given that the phase lag approached 180° at 5 Hz. Inherent muscle stiffness was approximately equal to reflex stiffness. In functional terms, an OLG of 1 means that the yield caused by a force perturbation is approximately halved by reflex action (prevailing inherent muscle stiffness is doubled). Automatic scaling of reflex transmission at Ia/α-motoneuronal synapses ensures that the OLG remains close to unity as inherent stiffness increases. Trials in the patient with the wrist fixator gave similar results, indicating that the reflexes were proprioceptively mediated. In a fourth experiment in which the task was to catch a heavy ball, we compared the efficacy of inherent muscle stiffness and reflexes alone, with the subject's intentional reactions, which included predictive and voluntary components of response. The latter were far more effective in maintaining the position of the hand after the ball was caught than inherent and reflex stiffnesses alone. We conclude that stability requirements limit the extent to which stretch reflexes can augment inherent muscle stiffness. When inherent muscle stiffness is low, such as in our ball-catching task, the reflex stiffness is also low, and predictive and pre-programmed reactions predominate in load compensation, thus shifting the emphasis from automatic servo or equilibrium-point behaviour to higher order control.Key words: reflexes, muscle stiffness, motor control.
Representation of tactile roughness in thalamus and somatosensory cortex
Authors: Burton Harold , Sinclair Robert J.
Published: April 2011

Neuronal responses were recorded in the thalamic ventroposterior lateral nucleus and primary and secondary somatosensory cortical areas of two rhesus monkeys performing a tactile discrimination task. The subjects actively stroked their fingertips over gratings that varied in groove width. Many cells in each location displayed average firing rates that incrementally reflected groove width dimensions (0.5–2.9 mm). Approximately 10% of cortical cells were more active to surfaces with narrower grooves, i.e., had negative graded response functions. All thalamic cells and ~50% of cortical cells with positive graded functions to gratings also showed increased responsiveness to contact force. Some cells also varied their activity with stroke speed. Many thalamic, a few primary somatosensory cortical cells, and no secondary somatosensory cortical cells showed periodic firing patterns that reflected the spatial–temporal frequency of stimulation. Responses to gratings of nearly every cell with negative graded responses and the remaining cortical cells with positive functions were independent of contact force and stroke velocity. The results only partially confirm predictions based on different models of texture perception that propose spatial, intensive, or cross modal neural codes. Negative graded response functions may require a form of spatial convergence across a cell's receptive field that has not previously been discussed by these models.Key words: active touch, roughness perception, somatosensory system, primates.
Force-related neuronal activity in two regions of the primate ventral premotor cortex
Authors: Hepp-Reymond M.-C. , Hüsler E. J. , Maier M. A. , Qi H.-X.
Published: April 2011

Neuronal activity was recorded in the ventral premotor cortex of one monkey (Macaca fascicularis) trained to exert finely graded forces with thumb and index finger on a force sensor in a visuomotor step-tracking paradigm. Trials with two or three consecutive ramp-and-hold force steps were presented randomly. Most neurons displayed similar discharge patterns in the two- and three-step trials and were assigned to one of the following classes: phasic, phasic–tonic, tonic, decreasing, and mixed. For more than 50% of the neurons with tonic activity, positive or negative correlations between firing rate and force were statistically significant. The indices of force sensitivity were on average higher for the two-step than for the three-step trials, indicating that the correlations yielded linearity over only a limited force range. The force-related cells were located in two regions of the ventral premotor cortex. One group was lying rostrally within the inferior limb of the arcuate sulcus, from which microstimulation elicited movements of fingers and hand. In the other more caudal region, adjacent to the finger region of primary motor cortex, microstimulation was rarely effective, but all neurons had clear peripheral receptive fields on finger and hand. The data indicate that two populations of neurons, located in the ventral premotor cortex, are related to movement execution. Effective microstimulation also suggests that one of the populations has fairly direct access to the spinal motor apparatus.Key words: precision grip, isometric force, premotor cortex, alert monkey, single cell activity.
Temporal coordination in bimanual actions
Authors: Wiesendanger Mario , Kaluzny Pawel , Kazennikov Oleg , Palmeri Agostino , Perrig Stephen
Published: April 2011

The issue of bimanual temporal coordination in human subjects is discussed for three selected movement paradigms: (i) simple, symmetric, bimanual finger movements, (ii) bimanual unloading, and (iii) a complex bimanual pull and grasp task. Temporal synchronization was found for all three experiments and was least variable for the first experiment. In the second experiment, synchronization concerned unloading with the index finger of one hand (electromyographic activation of the first dorsal interosseus muscle) and the postural adjustment of the load-bearing index finger of the other hand (electromyographic deactivation of the first dorsal interosseus muscle). In the third experiment, a goal-related temporal invariance was observed, even in the absence of visual guidance. Possible neural mechanisms for the observed temporal coordination of the three types of bimanual movements are discussed, as well as the concepts of goal invariance and motor equivalence.Key words: bimanual coordination, temporal invariance, motor equivalence.
Mechanisms involved in the activation of ischemically sensitive, afferent renal nerve mediated reflex increases in hind-limb vascular resistance in the anesthetized rabbit
Authors: Ashton N. , Clarke C. G. , Eddy D. E. , Swift F. V.
Published: April 2011

Acute occlusion of the renal circulation in the anesthetized rabbit results in a neurally mediated, reflex increase in hind-limb vascular resistance, which is flow rather than pressure dependent. This suggests that the activating stimulus could be ischemia. In the present study vascularly isolated kidneys were perfused with hypoxemic or hypercapnic blood, and the hind-limb vascular response was measured. Renal perfusion with hypoxemic blood resulted in an increase in femoral perfusion pressure (FPP), which was negatively correlated with the oxygen tension of the blood. At a [Formula: see text] of 36.4 ± 0.9 mmHg (1 mmHg = 133.3 Pa), FPP rose by 34.4 ± 5.7 mmHg. Renal denervation abolished this effect. Renal perfusion with hypercapnic blood had no effect on FPP. Prostaglandin E2, bradykinin, and adenosine are released during renal ischemia and have been implicated in the mediation of afferent renal nerve activity; intrarenal administration (prostaglandin E2, 10 μg; bradykinin, 5 μg; adenosine, 20 μg; as a 1-mL bolus) during renal perfusion with normoxemic blood elicited increases in FPP of 32.4 ± 13.2, 19.2 ± 3.7, and 55.6 ± 17.8 mmHg, respectively. Intrarenal indomethacin, aprotonin, and aminophylline all inhibited the increase in FPP observed during renal perfusion with hypoxemic blood. These data indicate that renal hypoxemia stimulates an afferent renal nerve mediated increase in FPP and suggest that prostaglandin E2, bradykinin, and adenosine may all be involved in the activation of ischemically sensitive R1 chemoreceptors.Key words: renal ischemia, chemoreceptor, prostaglandins, bradykinin, adenosine.
Myocardial β-adrenoceptors in pacing-induced heart failure: regulation by enalapril?
Authors: Forster Christine , Naik George O. A. , Larosa Giulia
Published: April 2011

In heart failure, both the sympathetic nervous system and the renin angiotensin system play important pathophysiological roles, and the two systems may interact with each other, e.g., angiotensin II facilitating noradrenaline release. An abnormality in β-adrenoceptor density (i.e., a decrease) occurs in clinical and pacing-induced heart failure. This observation together with the therapeutic effectiveness of converting-enzyme inhibitors in the management of patients with heart failure led to the current investigation. The aim was to explore the impact of chronic enalapril treatment on the status of myocardial β-adrenoceptors in dogs paced (250 beats∙min−1) to end-stage heart failure. Placebo or enalapril treatment (5 mg b.i.d.) commenced 1 week after the onset of ventricular pacing and continued until end-stage heart failure was reached. Myocardial β-adrenoceptor density and affinity were assessed by radioligand binding with [125I]iodocyanopindolol. Left ventricular angiotensin II formation and noradrenaline concentration were measured. In addition, plasma renin activity and plasma noradrenaline levels were determined. The results showed that there was a significant increase in β-adrenoceptor density following enalapril treatment compared with placebo in the heart-failure group. Enalapril did not change the β-adrenoceptor density in the control animals. However, in both heart failure and control animals, enalapril caused an unexpected increase in Kd. Furthermore, in heart failure, enalapril caused a significant increase in myocardial angiotensin II formation. We conclude that enalapril prevents or reverses the myocardial β-adrenoceptor abnormality seen in heart failure and promotes angiotensin II formation.Key words: congestive heart failure, enalapril, cardiac β-adrenoceptors, angiotensin II formation.
Relation of glycosylated hemoglobin to in vivo cardiac function in response to dobutamine in spontaneously diabetic BB Wor rats
Authors: Broderick Tom L. , Kopp Stephen J. , Daar June T. , Romano Fred D. , Paulson Dennis J.
Published: April 2011

The contribution of metabolic control to in vivo myocardial contractile function in response to β1-adrenergic stimulation was determined in the spontaneously diabetic BB Wor rat. The study involved a group of insulin-dependent BB Wor rats showing marked variations in metabolic control, assessed by the level of glycosylated hemoglobin (gHb). These diabetic BB rats were divided into moderate and severe (%gHb > 14) diabetic groups. A group of Wistar rats and diabetes-resistant BB Wor rats served as controls. In vivo myocardial contractile function was measured under basal conditions and after i.v. dobutamine infusions in anesthetized rats, using a catheter-tip pressure transducer inserted into the left ventricle. No dramatic differences in heart rate with dobutamine stimulation were observed between the moderate, severe diabetic, and diabetes-resistant groups. However, heart rate was lower in Wistar control rats compared with these groups. Systolic left ventricular pressure was depressed in severe diabetic rats compared with Wistar controls. In addition, positive dP/dt was significantly less in the severe diabetic group at the highest doses of stimulation, whereas negative dP/dt was depressed under basal conditions and remained so with increasing doses of dobutamine. In the diabetic group maximal systolic left ventricular pressure, rate–pressure product, and negative dP/dt responses to dobutamine were all inversely correlated with gHb. These results indicate that changes in metabolic control of the insulin-dependent BB diabetic rat can contribute to a depressed myocardial contractile function.Key words: glycosylated hemoglobin, cardiac function, dobutamine, BB rat.
Inhibition of nitrovasodilators by pyocyanin and methylene blue is dissociated from nitric oxide formation
Authors: Bozinovski Jovan , Brien James F. , Marks Gerald S. , Nakatsu Kanji
Published: April 2011

The phenazine pigment pyocyanin (Pyo), like methylene blue (MB), inhibits vascular relaxation induced by organic nitrates. These nitrovasodilators are pro-drugs that have in common the ability to generate nitric oxide (NO). In this study, we characterized responses of rabbit isolated aortic ring to 3-morpholinosydnonimine (SIN-1), S-nitroso-N-acetylpenicillamine (SNAP), sodium nitroprusside, glyceryl trinitrate (GTN), and isosorbide dinitrate in the presence and absence of 10 μM Pyo. We also examined the effect of Pyo (1 and 10 μM) and MB (1 and 10 μM) on vasorelaxation induced by authentic NO, and finally we tested the effects of Pyo and MB on the tissue-independent formation of NO from SIN-1, SNAP, and sodium nitroprusside, using die chemiluminescence – headspace gas method. Pyo (10 μM) surmountably inhibited aortic responses to GTN, isosorbide dinitrate, SIN-1, and SNAP with a characteristic rightward shift of the dose–response curve; the apparent EC50 of these drugs for relaxation of phenylephrine-contracted aorta was increased 18-, 4-, 13-, and 15-fold, respectively. Pyo (1 and 10 μM) and MB (10 μM) inhibited NO-induced vasorelaxation at the EC50 of NO by 35, 72, and 56%. In contrast, Pyo did not inhibit sodium nitroprusside induced vasodilation. For a 10-min incubation, 10 μM Pyo or MB increased NO production from SNAP 1.8- and 2.9-fold, respectively, and increased NO production from SIN-1 by 3.8- and 7.1-fold, respectively. Neither Pyo nor MB enhanced NO formation from sodium nitroprusside. These data indicate that Pyo and MB inhibit nitrovasodilator-induced relaxation of aortic ring by interfering with the action of NO, subsequent to its formation.Key words: pyocyanin, nitric oxide, methylene blue, nitrovasodilators, rabbit aorta.
Effect of vanadium compounds on calmodulin activity in experimental diabetes in rats
Authors: Aktan Fügen , Nebioglu Serpil
Published: April 2011

Vanadate and vanadyl have been reported to have insulin-like properties and have recently been demonstrated to be beneficial in the treatment of diabetic animals. In this study, we determined whether vanadium ions mimic the effect of insulin on calmodulin activity of liver and adipose tissues in streptozotocin-induced diabetic rats and examined their effect with respect to concentration and time. Calmodulin activities in the hormone-sensitive tissues decreased in diabetes and returned to normal after sodium metavanadate or vanadyl sulfate treatment for 3 weeks (0.2, 0.4, and 0.8 mg/mL in drinking water). These results demonstrate that V5+ and V4+ forms of vanadium can restore the activity of calmodulin in experimental diabetes induced by streptozotocin.Key words: calmodulin, vanadium, cyclic-AMP phosphodiesterase, diabetes.
Renal perfusion pressure and renin secretion in bilaterally renal denervated sheep
Authors: Fan L. , Mukaddam-Daher S. , Gutkowska J. , Nuwayhid B. S. , Quillen Jr. E. W.
Published: April 2011

To further investigate the influence of renal nerves on renin secretion, the renin secretion responses to step reductions of renal perfusion pressure (RPP) were studied in conscious sheep with innervated kidneys (n = 5) and with bilaterally denervated kidneys (n = 5). The average basal level of RPP in sheep with denervated kidneys (82 ± 4 mmHg; 1 mmHg = 133.3 Pa) was similar to that in sheep with innervated kidneys (83 ± 3 mmHg). RPP was reduced in four sequential 15-min steps, to a final level of 54 ± 2 mmHg in sheep with innervated kidneys and to 57 ± 1 mmHg in denervated sheep. The renin secretion rate was increased as RPP was reduced in sheep with innervated kidneys. Baseline peripheral plasma renin activity was reduced and there was almost no response of renin secretion rate to reduction of RPP in sheep with denervated kidneys. Also, baseline renal blood flow, urine flow rate, sodium excretion rate, and potassium excretion rate were higher in sheep with denervated kidneys than those with innervated kidneys. Baseline plasma angiotensin II was similar in both groups of sheep. As RPP was decreased, plasma angiotensin II was increased in sheep with innervated kidneys, but was not significantly altered in sheep with denervated kidneys. Plasma atrial natriuretic factor was unaltered by either reduction of RPP or renal denervation. In conclusion, hormonal factors, such as angiotensin II and atrial natriuretic factor, do not account for the dramatic suppression of renin secretion in response to the reduction of RPP in sheep with bilateral renal denervation. Renal nerves are a necessary component in the control of renin secretion during reduction of RPP and may contribute to the regulation of baseline plasma renin activity and sodium excretion rate in conscious ewes.Key words: renin secretion, renal perfusion pressure, renal nerves, denervation, sheep.
Effect of torbafylline on muscle blood flow, performance, and capillary supply in ischemic muscles subjected to varying levels of activity
Authors: Hudlicka O. , Egginton S. , Brown M. D. , Okyayuz-Baklouti I.
Published: April 2011

Torbafylline, a novel xanthine derivative, was given to rats by gavage (2 × 25 mg∙kg−1∙day−1, morning and evening) to study its effect upon fast muscles (tibialis anterior and extensor digitorum longus) made ischemic by unilateral ligation of the common iliac artery and subjected to two types of activity imposed by chronic electrical stimulation at 10 Hz: (i) strenuous, 6 h∙day−1 as 3 × 2 h with 90- to 120-min intervals or (ii) mild, 105 min∙day−1 as 7 × 10–15 min with 90- or 85-min intervals for 12–14 days. Some of the deleterious effects on ischemic muscles of strenuous activity (reduced blood flow during contractions, less resistance to fatigue) were remedied by torbafylline treatment, and values normalized. Most notably, torbafylline significantly reduced the degree of capillary endothelial cell swelling. In addition, the degree of atrophy was reduced and fatigue resistance improved in muscles contralateral to ischemic, which had been impaired with the strenuous regime. Torbafylline treatment had little further effect on ischemic muscles subjected to mild stimulation, which on its own improved functional hyperemia, resistance to fatigue, and the capillaries per fibre ratio in tibialis anterior, although it did significantly increase the capillary per fibre ratio in extensor digitorum longus. These data indicate a possible role for torbafylline as an adjunct to exercise therapy for chronic muscle ischemia.Key words: ischemia, muscle stimulation, methylxanthine, blood flow, fatiguability, capillarity.
Enhanced metabolism of glucose and glutamine in mesenteric lymph node lymphocytes from spontaneously diabetic BB rats
Authors: Field Catherine J. , Wu Guoyao , Marliss Errol B.
Published: April 2011

Increased energy substrate metabolism accompanies the functional activation of extrathymic immunocytes in the autoimmune BB diabetic rat, but the specific cells responsible have not been identified. To determine the possible contribution of lymphocytes to the elevated metabolism of glucose and glutamine, mesenteric lymph node cells were selected because they contain few macrophages or natural killer (NK) cells. Results from diabetic (BBd, n = 7) and non-diabetes-prone (BBn, n = 7) rats were compared with those from streptozotocin-induced diabetic (STZ-BBn, n = 6) rats. In BBd cells, all measured metabolites of glutamine (CO2, glutamate, aspartate, and NH3) in the presence of 5 mM glucose were elevated (1.5- to 2.5-fold) compared with BBn. In contrast, the only product of glucose metabolism (in the presence of 2 mM glutamine) that was increased was pyruvate (1.6-fold). All measured products of glucose metabolism were significantly lower in cells from STZ-BBn than from BBn rats. Products from glutamine did not differ. Calculated potential ATP production was greater (p < 0.05) in BBd than in BBn and STZ-BBn cells (86 ± 5 vs. 65 ± 2 and 53 ± 5 nmol∙2 h−1∙10−6 cells, respectively). However, in BBn and STZ-BBn rats, about three quarters of the cells were T (CD5+) cells and one quarter were B (MARK-1+) cells, whereas in BBd three quarters of the cells were MARK-1+. Therefore, to distinguish the role of T- versus B-cells, enriched T-lymphocyte (CD5+) preparations were studied: glutamate (5.3-fold) and NH3 (4.2-fold) production from glutamine and lactate (1.7-fold) production from glucose were greater (p < 0.05) in cells from BBd rats. This establishes that in BBd cells (i) lymphocytes (especially CD4+) contribute to the increased metabolism, (ii) T-lymphocytes are especially active in glutamine metabolism, but because of their reduced numbers, this cannot fully account for the increase in the unfractionated population, and therefore (iii) B-lymphocytes probably also contribute, and (iv) the altered metabolism of these cells is not a result of the diabetic state. These findings are consistent with activation of immunocytes of multiple lineages in this autoimmune syndrome.Key words: glutamine, glucose, lymphocytes, BB rat.
Effects of essential amino acids on food and water intake of rats
Authors: Anderson G. Harvey , Luo Shuqin , Trigazis Leonidas , Kubis Greta , Li Edmund T. S.
Published: April 2011

This study examined the effects of selected groups of essential amino acids (EAAs), given by gavage, on short-term food and water intake. Amino acid groups were selected on the basis of their common physiologic functions in relation to current hypotheses on the role of amino acids in food intake control, and the quantities given were based on the proportions in 1.5 g of the EAA content of albumin. The complete EAA mixture (1.5 g) suppressed food intake by an average of 60 and 37% during the 1st and 2nd h of feeding, respectively, but had no influence on feeding in the subsequent 12 h. Total daily (14 h) intake was decreased by 9%. With the exception of the aromatic amino acid (Phe + Tyr + Trp, 0.34 g) group, all groups significantly decreased food intake by a comparable magnitude (32%) during the 1st h. In this time period, rats given the EAAs, Arg + Met + Val (0.38 g), and Arg + His + Lys (0.44 g) mixtures increased their water intake, whereas intake by rats given the Phe + Tyr + Trp + Thr (0.46 g) and Ile + Leu + Val (0.45 g) mixtures was unchanged. Thus, the food intake suppression caused by EAAs was not accounted for by an equal effect of its component amino acid groups. As well, food intake suppression by amino acid groups was not explained by increased water consumption, nor was it simply related to the quantity of nitrogen provided by the treatment.Key words: food intake, water intake, essential amino acids.
Pharmacological but not physiological modulation of cortical acetylcholine release by cholinergic mechanisms in the nucleus basalis magnocellularis
Authors: Szerb J. C. , Clow K. , Rasmusson D. D.
Published: April 2011

The role of muscarinic transmission in the activation of cholinergic neurons ascending to the neocortex from the nucleus basalis magnocellularis (NBM) was investigated. The release of acetylcholine (ACh) from the neocortex of urethane-anesthetized rats was measured using microdialysis, and a second microdialysis probe was inserted into the NBM to apply drugs to the NBM and to measure ACh release from this area. Cholinergic neurons in the NBM were activated synaptically by stimulating the pedunculopontine tegmentum (PPT). Systemically administered scopolamine greatly increased the PPT stimulation evoked cortical release of ACh when the cortical probe was perfused with the cholinesterase inhibitor neostigmine. PPT stimulation evoked release was also high when the cortical probe was perfused with atropine plus neostigmine, but it was not increased any further by systemic scopolamine or by scopolamine perfused through the NBM probe. When neostigmine was perfused through the NBM probe, PPT stimulation evoked cortical ACh release was halved, but the release was restored when the NBM solution also contained scopolamine. The resting release of ACh within the NBM was increased by local neostigmine, but evoked release in the NBM was large only in the presence of local scopolamine. Both of these increases were blocked by perfusion of the NBM with tetrodotoxin. These results suggest that muscarinic transmission within the NBM does not control the activation of cholinergic neurons under physiological conditions, when the diffusion of ACh is limited by its hydrolysis. However, when ACh is allowed to diffuse to a wider area, it may inhibit the release of an excitatory transmitter, probably glutamate, via presynaptic muscarinic receptors.Key words: acetylcholine release, nucleus basalis magnocellularis, pedunculopontine tegmentum, presynaptic muscarinic receptors, microdialysis.
Excitability of human motor cortex during hyperventilation and hypercapnia
Authors: Kong K. , Ukachoke C. , Ashby P. , Chapman K. R.
Published: April 2011

We tested the hypothesis that the excitability of corticospinal neurons was altered by changes in [Formula: see text]. Magnetic stimulation was used to excite the neurons in the human motor cortex that give rise to the fast-conducting corticospinal pathway. The characteristics of the composite excitatory postsynaptic potentials (EPSPs) produced in individual spinal motoneurons by cortical stimulation were derived from changes in the firing probability of voluntarily activated motor units. The amplitudes of these composite EPSPs in response to a constant cortical stimulus were assumed to reflect the excitability of cortical neurons. In 10 healthy subjects, we found no statistically significant changes in the excitability of the cortical neurons during normocapnic conditions (mean end-tidal [Formula: see text] 5.1 kPa), during hyperventilation-induced hypocapnia (mean end-tidal [Formula: see text] 2.9 kPa), and during hyperoxic hypercapnia induced by a rebreathing technique (mean end-tidal [Formula: see text] 6.9 kPa). We conclude that the excitability of corticospinal neurons activated by magnetic stimulation is not significantly affected by changes in [Formula: see text].Key words: corticospinal neurons, [Formula: see text], magnetic stimulation.
Intracellular signal transduction for vasoactive peptides in hypertension
Authors: Schiffrin Ernesto L.
Published: April 2011

Increased peripheral resistance is the hallmark of hypertension. It may result in part from exaggerated vascular reactivity of resistance arteries. Some changes in density of surface receptors for different vasoconstrictors and vasorelaxants have been described that could play a role in physiological findings in hypertension. Smooth muscle cells of resistance arteries have increased cytosolic free calcium concentration in some models of experimental hypertension, which may contribute to enhance vascular responses. Exaggerated response of the inositol phosphate – calcium pathway has been demonstrated after stimulation with some vasoconstrictor agents such as norepinephrine, angiotensin II, and vasopressin. In contrast, responses to the potent vasoconstrictor peptide endothelin-1 are either normal (in spontaneously hypertensive rats) or blunted (in deoxycorticosterone-salt hypertension). In the latter case, endothelin receptor density, inositol phosphate and diacylglycerol generation, and cytosolic calcium responses agree with blunted response of blood vessels. Increased basal cytosolic calcium and exaggerated sensitivity of myosin light chain to calcium may be mechanisms underlying increases in sensitivity of signal transduction in smooth muscle in some models of hypertension. However, in general, signal transduction of receptors for vasoconstrictors appears to be blunted rather than exaggerated, except for responses to angiotensin II. Altered structure of resistance arteries (remodeling) may be a mechanism that, even in presence of blunted intracellular signal transduction, may result in enhanced pressor responsiveness of blood vessels in hypertension.Key words: second messengers, phospholipases, inositol phosphates, calcium, magnesium, Na+–H+ exchange, protein kinases, cyclic nucleotides, vascular reactivity.
The 1993 Borden Award Lecture. Fatty acid requirements of the newborn
Authors: Innis Sheila M.
Published: April 2011

Arachidonic acid (20:4ω−6) and docosahexaenoic acid (22:6ω−3) are deposited in large amounts in the nonmyelin membranes of the developing central nervous system (CNS). Inadequate supplies of ω−6 and ω−3 fatty acids during CNS development are of concern because of possible long-term changes in learning ability and reduced visual function. Although all of the ω−6 and ω−3 fatty acids in the CNS are ultimately derived from the diet, the pathways for transport or transfer from the plasma to the CNS are not known. Current evidence suggests that the newborn is able to synthesize 20:4ω−6 and 22:6ω−3 from linoleic acid (18:2ω−6) and linolenic acid (18:3ω−3), respectively; however, it is not yet clear if synthesis occurs in the liver prior to transfer to the CNS, or directly in the CNS. Further understanding of the roles of 20:4ω−6 and 22:6ω−3 in CNS metabolism, pathways of ω−6 and ω−3 fatty acid transport and CNS uptake, and the effects of premature birth on fatty acid metabolism is needed to facilitate future studies on the importance of 20:4ω−6 and 22:6ω−3 in infant nutrition.Key words: brain development, essential fatty acids, docosahexaenoic acid, arachidonic acid, human milk, infant formula.
The 1994 Merck Frosst Award. Mechanisms of nonsteroidal anti-inflammatory drug (NSAID) induced gastrointestinal damage—potential for development of gastrointestinal tract safe NSAIDs
Authors: Wallace John L.
Published: April 2011

Nonsteroidal anti-inflammatory drugs are widely used for the treatment of osteoarthritis and rheumatoid arthritis, but their ability to cause gastrointestinal bleeding is a significant limitation to this use. A better understanding of the pathogenesis of gastric and intestinal injury induced by these agents will permit the rational design of anti-inflammatory drugs that spare the gastrointestinal tract. In this review, the mechanisms through which nonsteroidal anti-inflammatory drugs are believed to cause gastrointestinal ulceration are reviewed. Several strategies that are being employed to develop gastrointestinal-sparing drugs are outlined.Key words: nonsteroidal anti-inflammatory drugs, ulcer, cyclooxygenase, nitric oxide, gastrointestinal, prostaglandins.
Effect of dexamethasone treatment on the biotransformation of glyceryl trinitrate: cytochrome P450 3A1 mediated activation of rat aortic guanylyl cyclase by glyceryl trinitrate
Authors: McDonald Bernard J. , Monkewich Greg J. , Long Patrick G. , Anderson Diane J. , Thomas Paul E. , Bennett Brian M.
Published: April 2011

It is generally accepted that organic nitrates act via vascular biotransformation to an activator of guanylyl cyclase (presumably NO), resulting in increased cyclic GMP accumulation and vascular smooth muscle relaxation. Previously, we have shown that cytochrome P450 can mediate the biotransformation of glyceryl trinitrate (GTN) and that at least a portion of this biotransformation results in the formation of an activator of guanylyl cyclase. To assess the role of the cytochrome P450 3A subfamily in this phenomenon, we treated male and female rats with dexamethasone (DEX) (150 mg/kg, i.p., daily for 3 days). Under anerobic conditions, hepatic microsomal biotransformation of GTN was increased three-fold in DEX-treated male rats compared with all other treatment groups. Incubation of aortic 100 000 × g supernatant fraction from untreated rats (as a source of guanylyl cyclase) with GTN and hepatic microsomes from all groups resulted in concentration-dependent increases in guanylyl cyclase activation. Microsomes from DEX-treated male and female rats demonstrated a significantly greater activation of guanylyl cyclase compared with microsomes from untreated males and females. Furthermore, GTN-induced guanylyl cyclase activation mediated by microsomes from DEX-treated male and female rats was markedly inhibited by a polyclonal antibody raised to rat CYP3A1. Since CYP3A2 is absent or very low in hepatic microsomes from DEX-treated adult female rats, this identifies CYP3A1 as an isoform capable of biotransforming GTN to an activator of guanylyl cyclase. Similarly, CYP2C11 was identified as an isoform capable of biotransforming GTN to an activator of guanylyl cyclase, since monoclonal antibody to CYP2C11 inhibited GTN-induced activation of guanylyl cyclase mediated by microsomes from control male rats. In both male and female rats, DEX treatment had no effect on GTN-induced relaxation of isolated aorta. However, biotransformation of GTN in intact aorta from DEX-treated male rats was decreased. This suggests that DEX treatment affects only the aortic biotransformation of GTN that is not involved in the formation of an activator of guanylyl cyclase.Key words: glyceryl trinitrate, dexamethasone, guanylyl cyclase, cytochrome P450, vasodilation, biotransformation.
Body-core temperature decreases during hypoxic hypoxia in Long–Evans and Brattleboro rats
Authors: Clark Deborah J. , Fewell James E.
Published: April 2011

In newborn mammals, hypoxic hypoxia produces a regulated decrease in body-core temperature, the mechanism of which is unknown. Since plasma and cerebrospinal fluid levels of arginine vasopressin increase during hypoxemia and intracerebroventricular administration of arginine vasopressin decreases body-core temperature, it has been hypothesized that an increase in central arginine vasopressin may mediate this response. Experiments were therefore carried out to test the hypothesis that the body-core temperature response to hypoxic hypoxia would be different in Brattleboro rats (which lack arginine vasopressin containing cells in the central nervous system) compared with that observed in Long–Evans rats (which have arginine vasopressin containing cells in the central nervous system). Both mild (15% oxygen) and severe (10% oxygen) hypoxic hypoxia decreased body-core temperature in both strains of rats, the decrease actually being accentuated in the Brattleboro rats. Thus, our data do not support the hypothesis that an increase in central arginine vasopressin mediates the regulated decrease in body-core temperature during hypoxic hypoxia in rats.Key words: hypoxic hypoxia, thermoregulation, arginine vasopressin, Brattleboro rats, Long–Evans rats.
Positive inotropic effect of adrenaline on potassium contractures in tonic skeletal muscle fibres of the frog
Authors: García M. C. , Escamilla-Sánchez J.
Published: April 2011

K+ contractures were elicited in small bundles of tonic skeletal muscle fibres of the frog. Adrenaline (1 μM) increased the amplitude of K+ contractures in a [K+]o-dependent manner: maximal effects were produced between 20 and 60 mM [K+]o. In contrast, we found no effect of adrenaline on K+ contractures of twitch fibres. The potentiating effect of adrenaline depended on [Ca2+]o. Increasing [Ca2+]o from 1.8 to 10 mM doubled the positive inotropic effect of adrenaline. In a nominally Ca2+ free saline, adrenaline had no potentiating effect. The Ca2+ channel blockers nifedipine (20 μM) and Ni2+ (1.8 mM) reversibly reduced the amplitude of the tonic phase of K+ contractures and blocked the potentiation by adrenaline. The mechanical effects of adrenaline cannot be explained by changes in the membrane potential, as revealed by intracellular recordings at several [K+]o. It Was concluded that the potentiating effect of adrenaline in tonic muscle fibres of the frog may be mediated through Ca2+ channels.Key words: adrenaline, slow muscle, excitation–contraction coupling, potassium contractures.
Inhibition by antidepressants of glibenclamide-sensitive K+ currents in follicle-enclosed Xenopus oocytes
Authors: Sakuta Hidenari
Published: April 2011

Effects of antidepressive drugs on glibenclamide-sensitive K+ currents were investigated using follicle-enclosed Xenopus oocytes. Antidepressive drugs, imipramine, desipramine, and amitriptyline, inhibited the K+ currents with IC50 (μM) values of 35.4, 39.7, and 87.7, respectively. The K+ current blocking actions of antidepressants appear to be associated with their local anesthetic related structures.Key words: K+ currents, glibenclamide, antidepressive drug, Xenopus oocyte.
Integrative aspects of a human model of endotoxemia
Authors: Ottaway C A , Fong I W , da Silva B , Singer W , Karrass L
Published: April 2011

The production of tumor necrosis factor (TNF)-alpha is a key step in the response to sepsis and has powerful local and systemic effects on the host. These systemic responses include a complex cascade of centrally mediated endocrine and neural responses. An integrative model of these regulatory cytokine-neuroendocrine interactions in humans is presented. The rapid kinetics of these responses are illustrated by data showing the response of normal human subjects to experimental endotoxemia. Appreciation of the integrative biology of the in vivo response to experimental endotoxemia can provide a framework for the design of experiments aimed at examining the effects of physical training paradigms on particular cytokine and neuroendocrine pathways.Key words: tumor necrosis factor (TNF)-alpha, tumor necrosis factor (TNF)-alpha soluble receptors, hypothalamic-pituitary axis, lipopolysaccharide (LPS), integrative biology of human response to LPS, cytokine-neuroendocrine interactions.
Immune responses to inflammation and trauma: a physical training model
Authors: Shephard Roy J , Shek Pang N
Published: April 2011

Physical activity and training have some potential as tools for examining immune responses to inflammation and trauma. Contributors to the present symposium review various aspects of the inflammatory process, including issues of lymphocyte recirculation and endotoxemia. They examine also the extent and nature of the immune disturbances induced by acute and chronic exercise and consider parallels between such responses and cellular manifestations of clinical sepsis. Factors modulating immune responses during physical activity include changes in the circulating levels of various cytokines, alterations in nutritional status, an altered expression of adhesion molecules, and the possible intervention of reactive species. Factors that can exacerbate exercise-induced changes include exposure to adverse environments, particularly hot conditions, and disturbances of the normal sleep-wakefulness cycle. Current research in exercise immunology finds clinical application in attempts to regulate aging, acute viral infections, and neoplasia.Key words: cold exposure, environmental stress, heat exposure, high altitudes, immunosuppression.
A pharmacological and HPLC analysis of the excitatory transmitter of the cardiac ganglion in the heart of the isopod crustacean Bathynomus doederleini
Authors: Yazawa Toru , Tanaka Kosuke , Yasumatsu Mikinobu , Otokawa Minoru , Aihara Yasutsugu , Ohsuga Kenji , Kuwasawa Kiyoaki
Published: April 2011

In crustacean neurogenic hearts, the myocardium contracts under the tight control of rhythmically active neurons of the cardiac ganglion located inside the heart. We demonstrated that the myocardium of Bathynomus doederleini was sensitive to glutamate, quisqualate, and kainate, and that the tension of myocardial cells developed in a dose-dependent manner. The threshold concentrations were 10-5 M for quisqualate, 10-4 M for glutamate, and 3 × 10-4 M for kainate. Concanavalin A, known to prevent desensitization of glutamate receptors at crustacean neuromuscular junctions, augmented excitatory junctional potentials evoked by the cardiac ganglionic neurons in myocardial cells. Using a high performance liquid chromatography (HPLC), we analyzed glutamate in extracts of the cardiac ganglion and myocardium. We obtained values for glutamate concentrations, 8741.2 ± 184.2 and 678.2 ± 10.7 pmol/mg, respectively. Although we attempted to measure monoamines in the extracts by HPLC, these were not detected at measurable (more than 1 fmol per 10-µL sample) levels. In conclusion, myocardial cells in isopod crustaceans were suggested to receive glutamatergic motor innervation.Key words: HPLC, glutamate, heart, crustacean, neurotransmitter.
Effects of α1-antagonists on production and release of aldosterone and other steroid hormones by porcine adrenocortical cells in vitro
Authors: Jager Lowie P , de Graaf Gerrit J , Widjaja-Greefkes H C. Aura
Published: April 2011

Quinazoline type alpha1-adrenoceptor antagonists (range 10100 µM) inhibited aldosterone release of a cellsuspension of porcine adrenocortical cells, potency order: doxazosin > prazosin > trimazosin. Phenoxybenzamine alsoinhibited the aldosterone release at a concentration of 100 µM. alpha1-Adrenoceptor antagonists from other chemicalclasses had no measurable effect on the aldosterone output from adrenocortical cells in vitro. Agonists selective foreither alpha1- or beta-adrenoceptors did not affect the aldosterone release. The inhibition of the aldosterone release induced byquinazolines was similar with different substrates. The small differences between the drug-induced inhibitions could beranked as corticosterone = progesterone > pregnenolone = deoxycorticosterone. The doxazosin (10 µM)-inducedchanges in the release of nine steroids indicated that quinazoline-type alpha1-antagonists interfere with enzymes of thealdosterone biogenesis pathway involved in C18-oxidation and C21beta-hydroxylation, reducing the release of bothaldosterone and corticosterone. At higher concentrations (100 µM), the C21beta-hydroxylation in the cortisol biogenesispathway is also affected, decreasing the output of cortisol and deoxycortisol, but increasing the output of progesteroneand OH-progesterone. Simultaneously, the C17-oxidation and side-chain cleavage is also inhibited, decreasing theoutput of androstenedione. The rank order of phenoxybenzamine (100 µM)-induced inhibition of the aldosteronerelease with different substrates is pregnenolone > corticosterone = progesterone > deoxycorticosterone. Withpregnenolone as substrate, the output of aldosterone, corticosterone, and cortisol was reduced to the same extent. Thedehydroepiandrosterone, androstenedione, and progesterone release was enhanced. It seems that phenoxybenzamine is arather selective inhibitor of the mitochondrial P45011 beta/18 enzymes.Key words: piperazinyl quinazolines, steroid hormones, porcine adrenocortical cells in vitro, carbadox, prazosin, doxazosin, trimazosin, phenoxybenzamine.