Action Of Catecholamines Research Articles

Dexamphetamine reduces auditory P3 delta power and phase-locking while increasing gamma power

Auditory P3 amplitude reduction is one of the most robust and replicated findings in schizophrenia. Recent evidence suggests that these reductions are due to reductions in both power and phase-locking at delta and theta frequencies. We have previously shown that the auditory, but not visual, P3 is reduced in healthy participants given the catecholamine releasing agent dexamphetamine. Our aim was to determine whether the auditory P3 amplitude reduction induced by dexamphetamine has similar power and phase locking characteristics to that seen in schizophrenia. Forty-four healthy participants were given 0.45mg/kg dexamphetamine and placebo, in a double-blinded, placebo-controlled, cross-over design. The task was a three-stimulus auditory odd-ball task, target stimuli were the major stimuli of interest. Individual target trials underwent wavelet analysis to give power and phase-locking of delta (3Hz), theta (4–7Hz), alpha (8–12Hz), beta (13–30Hz) and gamma (30–50Hz) frequencies for a 50ms time window centred around the peak of the target P3. Delta power around the P3 peak was significantly reduced when participants were given dexamphetamine. Delta phase-locking was also reduced but only when analysis was targeted at the location of the peak P3 amplitude. In contrast, theta power and phase-locking were not affected by dexamphetamine. These findings suggest that increased catecholamine activity may be responsible for the power and phase-locking reductions of the auditory P3 delta component in patients with schizophrenia. Interestingly, dexamphetamine significantly increased gamma power around the P3 peak. We attempt to link this finding with the gamma alterations that have been found in patients with schizophrenia.

褐色細胞腫に対する腹腔鏡下手術の臨床的検討―手術時間と術中高血圧に影響する術前の臨床パラメーターの解析―

We retrospectively analyzed the preoperative clinical parameters which influence operative time and intraoperative maximum systolic blood pressure in patients undergoing laparoscopic adrenalectomy for pheochromocytoma. Between January 1992 and September 2010, we performed 28 laparoscopic adrenalectomies for pheochromocytoma at Hamamatsu University School of Medicine. These 28 cases were characterized based on the following parameters: body mass index (BMI), tumor size, history of hypertension, preoperative blood pressure, serum concentration of catecholamine, and 24-h urinary excretion of catecholamine metabolite. We retrospectively analyzed whether or not these parameters influenced operative time or intraoperative maximum systolic blood pressure. All 28 cases of laparoscopic adrenalectomy were performed safely and without intraoperative complications and needed neither blood transfusion nor conversion to laparotomy. The median operative time was 203 minutes, and intraoperative hypertension (systolic blood pressure > 200 mmHg) occurred in 46% (13/28) of cases. Median day of discharge in all patients was post-operative day 5. Significant positive correlation was shown between tumor size and operative time and between intraoperative maximum systolic blood pressure and serum concentration of catecholamine or 24-h urinary excretion of catecholamine metabolite (p < 0.05). The lengthened operative time for large tumors and elevated intraoperative blood pressure for tumors with high preoperative catecholamine activity necessitate careful perioperative management in patients receiving laparoscopic adrenalectomy for pheochromocytoma.

Prefrontal/accumbal catecholamine system processes emotionally driven attribution of motivational salience

Motivational salience regulates the strength of goal seeking, the amount of risk taken, and the energy invested, from mild to extreme. Emotional experiences promote highly persistent memories. Although this phenomenon is adaptive in normal conditions, experiences with extremely high levels of motivational salience can promote the development of memories, resulting in maladaptive outcomes such as compulsive seeking or avoidance. We have offered evidence that prefrontal cortical norepinephrine transmission is a necessary condition for motivational salience attribution to highly salient stimuli through modulation of dopamine in the nucleus accumbens, a brain area involved in motivated behaviors. Moreover, the prefrontal-accumbal catecholamine system determines approach or avoidance responses to both reward- and aversion-related stimuli only when the salience of the unconditioned stimulus is high enough to induce sustained catecholamine activation, thus affirming that this system processes motivational salience attribution selectively to highly salient events. This system, when activated by highly salient stimuli, is likely to lead to motivational and neural processes that trigger mechanisms causing aberrant motivational salience attribution and to engage other frontal-subcortical systems, resulting in compulsion-driven behavioral disorders.

Prefrontal/accumbal catecholamine system processes high motivational salience

Motivational salience regulates the strength of goal seeking, the amount of risk taken, and the energy invested from mild to extreme. Highly motivational experiences promote highly persistent memories. Although this phenomenon is adaptive in normal conditions, experiences with extremely high levels of motivational salience can promote development of memories that can be re-experienced intrusively for long time resulting in maladaptive outcomes. Neural mechanisms mediating motivational salience attribution are, therefore, very important for individual and species survival and for well-being. However, these neural mechanisms could be implicated in attribution of abnormal motivational salience to different stimuli leading to maladaptive compulsive seeking or avoidance. We have offered the first evidence that prefrontal cortical norepinephrine (NE) transmission is a necessary condition for motivational salience attribution to highly salient stimuli, through modulation of dopamine (DA) in the nucleus accumbens (NAc), a brain area involved in all motivated behaviors. Moreover, we have shown that prefrontal-accumbal catecholamine (CA) system determines approach or avoidance responses to both reward- and aversion-related stimuli only when the salience of the unconditioned stimulus (UCS) is high enough to induce sustained CA activation, thus affirming that this system processes motivational salience attribution selectively to highly salient events.

Role of β3-adrenoceptors in regulation of retinal vascular tone in rats

The aim of this study was to determine the role of β(3)-adrenoceptors in the action of endogenous catecholamines (adrenaline and noradrenaline) on rat retinal arterioles in vivo. Using an original high-resolution digital fundus camera, the rat ocular fundus images were captured. The diameter of retinal arterioles contained in the images was measured. Both systemic blood pressure and heart rate were recorded continuously. Adrenaline (0.3-5.0μg/kg/min, i.v.) increased the diameter of retinal arterioles, mean blood pressure and heart rate in a dose-dependent manner. Under blockade of β(1)/β(2)-adrenoceptors with propranolol (2mg/kg, i.v. bolus followed by 100μg/kg/min infusion), adrenaline decreased the diameter of retinal arterioles. Similar observation was made under treatment with the β(3)-adrenoceptor antagonist L-748337 (50μg/kg, i.v.). The pressor response to adrenaline was enhanced by propranolol, but not by L-748337. The positive chronotropic action of adrenaline was markedly prevented by propranolol, whereas it was unaffected by L-748337. Noradrenaline (0.03-1.0μg/kg/min, i.v.) decreased the diameter of retinal arterioles but increased the mean blood pressure and heart rate. The effects of noradrenaline on retinal arteriolar diameter and blood pressure were unaffected by propranolol or L-748337. The positive chronotropic action of noradrenaline was almost completely abolished by propranolol. These results suggest that β(3)-adrenoceptors play crucial roles in vasodilator responses to adrenaline of retinal arterioles but have minor or no effect on noradrenaline-induced responses. The results also indicate that the functional role of β(3)-adrenoceptors may be more important than that in peripheral resistance vessels.

Individual differences in the motivation to communicate relate to levels of midbrain and striatal catecholamine markers in male European starlings

Individuals display dramatic differences in social communication even within similar social contexts. Across vertebrates dopaminergic projections from the ventral tegmental area (VTA) and midbrain central gray (GCt) strongly influence motivated, reward-directed behaviors. Norepinephrine is also rich in these areas and may alter dopamine neuronal activity. The present study was designed to provide insight into the roles of dopamine and norepinephrine in VTA and GCt and their efferent striatal target, song control region area X, in the regulation of individual differences in the motivation to sing. We used high pressure liquid chromatography with electrochemical detection to measure dopamine, norepinephrine and their metabolites in micropunched samples from VTA, GCt, and area X in male European starlings (Sturnus vulgaris). We categorized males as sexually motivated or non-sexually motivated based on individual differences in song produced in response to a female. Dopamine markers and norepinephrine in VTA and dopamine in area X correlated positively with sexually-motivated song. Norepinephrine in area X correlated negatively with non-sexually-motivated song. Dopamine in GCt correlated negatively with sexually-motivated song, and the metabolite DOPAC correlated positively with non-sexually-motivated song. Results highlight a role for evolutionarily conserved dopaminergic projections from VTA to striatum in the motivation to communicate and highlight novel patterns of catecholamine activity in area X, VTA, and GCt associated with individual differences in sexually-motivated and non-sexually-motivated communication. Correlations between dopamine and norepinephrine markers also suggest that norepinephrine may contribute to individual differences in communication by modifying dopamine neuronal activity in VTA and GCt.

Mechanisms involved in α1B‐adrenoceptor desensitization

α(1B)-Adrenergic receptors mediate many of the actions of the natural catecholamines, adrenaline and noradrenaline. They belong to the seven transmembrane domains G protein-coupled receptor superfamily and exert their actions mainly through activation of Gq proteins and phosphoinositide turnover/calcium signaling. Many hormones and neurotransmitters are capable of inducing α(1B)-adrenergic receptor phosphorylation and desensitization; among them: adrenaline and noradrenaline, phorbol esters, endothelin-I, bradykinin, lysophosphatidic acid, insulin, EGF, PDGF, IGF-I, TGF-β, and estrogens. Key protein kinases for these effects are G protein coupled receptor kinases and protein kinase C. The lipid/protein kinase, phosphoinositide-3 kinase also appears to play a key role, acting upstream of protein kinase C. In addition to the agents employed for cells stimulation, we observed that paracrine/autocrine mediators also participate; these processes include EGF transactivation and sphingosine-1-phosphate production and action. The complex regulation of these receptors unlocks opportunities for therapeutic intervention.

Personality traits of aggression-submissiveness and perfectionism associate with ABO blood groups through catecholamine activities

Personality trait research has shown associations with many genes, prominently those of the catecholamine metabolism such as dopamine beta hydroxylase (DBH), catechol-O-methyltransferase (COMT), and monoamine oxidase A (MAOA). Because DBH gene is in linkage disequilibrium with ABO gene, there is reason to think that other catecholamine genes using the same substrate as DBH may also have associations with ABO blood groups, and this paper demonstrates how this may be so. Reasons include similarities in hapmap population frequency distributions, similarities in illness risks between ABO blood groups and DBH activities as well as between ABO blood groups and COMT activities and between ABO blood groups and MAOA activities. If ABO blood groups can be demonstrated to associate with all these catecholamine genes, then the catecholamine personality trait research can be applied to ABO blood groups and tested for confirmation. ABO blood typing is widely available and affords ability to test this hypothesis and thus confirm the possible joint association of personality traits of aggression-submissiveness and perfectionism to catecholamine genes and to ABO blood groups. Clinical applications and implications are discussed.

EFFECT OF PRONETHALOL ON SOME INHIBITORY ACTIONS OF CATECHOLAMINES.

Abstract On the blood pressure of the pithed rat isoprenaline produced a vasodepressor, noradrenaline a pressor, and adrenaline a biphasic response consisting of a rise followed by a fall in the pressure. The magnitude of the responses to increasing doses of adrenaline was not proportional to the doses. An intravenous injection of pronethalol (nethalide) hydrochloride (1 mg./kg.) changed the responses to adrenaline into purely pressor, well-graded responses; they were also increased. The responses to isoprenaline after pronethalol were reduced, but those to noradrenaline remained usually unaltered. Similar results were obtained in anaesthetised rats, rabbits and guinea-pigs, but the augmentation of the pressor effect of adrenaline was not so marked as in pithed rats. The vasodepressor action of dopamine in rabbits and guinea-pigs was not blocked by pronethalol (2·5 to 10 mg./kg.). The inhibitory actions of adrenaline, noradrenaline and isoprenaline on the isolated rat uterus and rabbit colon were not consistently antagonised by concentrations of pronethalol up to 1·0 μg./ml. In experiments on the rabbit duodenum and ileum, pronethalol, 0·2 to 1·0 μg./ml., reduced the relaxations produced by all three catecholamines. These results are discussed in relation to Ahlquist's theory of a dual adrenergic receptor mechanism.

Inhibitory effects of catecholamines on cholinergically and non-cholinergically mediated contractions of guinea-pig isolated bronchial muscle

The actions of catecholamines on the responses evoked by electrical field stimulation or by acetylcholine and substance P in guinea-pig bronchial strip chain have been examined. Electrical field stimulation evoked a biphasic contraction, consisting of a cholinergically-mediated fast contraction followed by a non-cholinergically-mediated slow contraction. All catecholamines tested caused a concentration-dependent reduction in the height of the biphasic contraction, where non-cholinergic contractions were more potently inhibited. The inhibitory effect of isoprenaline was largely prevented by propranolol (2 microM) alone, whereas those of noradrenaline and adrenaline were prevented by treatment with both propranolol (2 microM) and yohimbine (2 microM). The inhibitory effect of dopamine was unaffected either by propranolol (2 microM), yohimbine (2 microM) or haloperidol (10 microM). Submaximal contractions of bronchial muscle evoked by exogenous acetylcholine (2 microM) or substance P (0.2 microM) were also inhibited by catecholamines, except dopamine, but the effects were antagonized by propranolol (2 microM) alone. The results suggest that in guinea-pig isolated bronchial muscle, catecholamines can inhibit both cholinergic and non-cholinergic excitatory neurotransmissions not only by postjunctional beta-adrenoceptors but also by prejunctional alpha 2-adrenoceptors.

Antibronchoconstrictor activity of two new phosphodiesterase inhibitors, a triazolopyrazine (ICI 58 301) and a triazolopyrimidine (ICI 63 197).

Abstract A triazolopyrazine (ICI 58 301) and a triazolopyrimidine (ICI 63 197), both potent inhibitors of 3′5′-cyclic adenosine monophosphate phosphodiesterase, protected conscious guinea-pigs against an otherwise lethal bronchospasm caused by inhalation of histamine. Both compounds were active when given by mouth and the activity was both rapid in onset and persistent. Bronchospasm caused by histamine or acetylcholine in guinea-pig isolated lungs was reduced when the lungs were perfused with dilute solutions of the compounds and the bronchodilator activity of catecholamines was potentiated. In anaesthetized animals the compounds were relatively more active against severe bronchospasm than against milder stimuli. The antibronchoconstrictor effects on conscious guinea-pigs were blocked by propranolol but not by practolol even in much larger doses. Propranolol did not, however, block the effect on the isolated lung. It appears possible that the antibronchoconstrictor activity is a manifestation of the inhibition of phosphodiesterase.

Sympathetic activation by the cold pressor test does not increase the muscle force generation capacity

A positive inotropic action by the sympathetic nervous system on skeletal muscles has been observed and investigated in animal and in vitro studies. This action provided a theoretical basis for the putative ergogenic action of catecholamines and adrenergic agonists, although there is no clear evidence of this effect in humans. The aim of this study was to investigate the occurrence of inotropic effects associated to physiological sympathetic activation in healthy subjects. The muscle force capacity was investigated in the tibialis anterior (n = 9 subjects) and in the soleus (n = 9) muscles electrically stimulated with single pulses and double pulses with variable interspike interval (4-1,000 ms) and short pulse trains (frequency: 5-14 Hz) before, during, and after sympathetic activation by the cold pressor test (CPT). CPT significantly decreased by 10.4 ± 7.2 and 10.6 ± 4.4% the force produced by single and double pulse stimulation, respectively, and produced smaller decreases in the force obtained by train stimulation in the tibialis anterior, while no significant changes were observed in either type of contraction in the soleus muscle. CPT failed to induce any increase in the force capacity of the investigated muscles. The prevalent decrease in force evidenced in this study supports the concept that the weakening sympathetic action on type I fiber, already shown to occur in humans, prevails over the putative potentiating action.

Combined Effects of Manganese, Iron, Copper, and Dopamine on Oxidative DNA Damage

Manganese (Mn) damages the central nervous system and causes Parkinson's disease (PD)-like syndrome called manganism. Abnormal accumulation of Mn and iron (Fe) is observed in the basal nuclei of patients with PD. Dopamine induces oxidative DNA damage in the presence of Fe or copper (Cu) in vitro. Therefore, an Mn-induced neural disorder may involve combined actions of Mn, Fe/Cu, and catecholamines. Here we investigated the combined effects of Mn(II) on the DNA damage induced by dopamine and either Fe(III) or Cu(II). Mn(II) enhanced the formation of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG) induced by dopamine and Fe(III)/Cu(II), whereas Mn(II) did not induce 8-oxodG formation in the absence of Fe(III)/Cu(II). Mn(II) accelerated hydrogen peroxide (H2O2) production in the dopamine-Fe(III)/Cu(II) system. Furthermore, Mn(II) decreased superoxide anion radicals (O2•-) generated in the xanthine-xanthine oxidase system. These results indicate that Mn(II)-mediated enhancement of DNA damage is caused by facilitated conversion of O2•- to H2O2. In addition, Mn(II) accelerated the formation of aminochrome, an oxidized dopamine product, in the presence of Cu(II). This reaction may have involved Mn(III) accompanied by H2O2 production from O2•-, suggesting a mechanism for Mn-induced oxidative stress on dopaminergic neurons through the combined actions of Mn, Fe, Cu, and dopamine.

Stress-induced reduction in reward-related prefrontal cortex function

Acute psychological stress can trigger normal and abnormal motivated behaviors such as reward seeking, habitual behavior, and drug craving. Animal research suggests that such effects may result from actions of catecholamines and glucocorticoids that converge in brain regions that regulate motivated behaviors and incentive processing. At present, however, little is known about the acute effects of stress on these circuits in humans. During functional magnetic resonance imaging (fMRI), twenty-seven healthy young women performed a modified version of the monetary incentive delay (MID) task, which is known to robustly engage ventral striatal and medial prefrontal regions. To induce psychological stress, strongly aversive movie clips (versus neutral movie clips) were shown with the instruction to imagine being an eyewitness. Physiological (cortisol levels, heart rate frequency, and heart rate variability) and subjective measurements confirmed successful induction of moderate levels of acute psychological stress. Brain imaging data revealed that stress induction resulted in a significant decrease in reward-related responses in the medial prefrontal cortex (PFC) without affecting ventral striatal responses. Our results thus show that acute psychological stress induces regionally specific changes in functioning of incentive processing circuits. This regional specificity is in line with animal data showing inverted U-shaped relations between levels of stress-related neuromodulators and functioning of the PFC, a structure that is believed to be critical for coordinating behavior in accordance with higher order internal goals. Our findings thus suggest that stress-related increases in habitual and reward-seeking behaviors may be triggered primarily by an impairment of such PFC-dependent cognitive control mechanisms.

Role of organic cation transporter 3 (SLC22A3) and its missense variants in the pharmacologic action of metformin.

The goals of this study were to determine the role of organic cation transporter 3 (OCT3) in the pharmacological action of metformin and to identify and functionally characterize genetic variants of OCT3 with respect to the uptake of metformin and monoamines. For pharmacological studies, we evaluated metformin-induced activation of AMP-activated protein kinase, a molecular target of metformin. We used quantitative PCR and immunostaining to localize the transporter and isotopic uptake studies in cells transfected with OCT3 and its nonsynonymous genetic variants for functional analyses. Quantitative PCR and immunostaining showed that OCT3 was expressed high on the plasma membrane of skeletal muscle and liver, target tissues for metformin action. Both the OCT inhibitor, cimetidine, and OCT3-specific short hairpin RNA significantly reduced the activating effect of metformin on AMP-activated protein kinase. To identify genetic variants in OCT3, we used recent data from the 1000 Genomes and the Pharmacogenomics of Membrane Transporters projects. Six novel missense variants were identified. In functional assays, using various monoamines and metformin, three variants, T44M (c.131C>T), T400I (c.1199C>T) and V423F (c.1267G>T) showed altered substrate specificity. Notably, in cells expressing T400I and V423F, the uptakes of metformin and catecholamines were significantly reduced, but the uptakes of metformin, 1-methyl-4-phenylpyridinium and histamine by T44M were significantly increased more than 50%. Structural modeling suggested that these two variants may be located in the pore lining (T400) or proximal (V423) membrane-spanning helixes. Our study suggests that OCT3 plays a role in the therapeutic action of metformin and that genetic variants of OCT3 may modulate metformin and catecholamine action.

Effects of β-adrenoceptor antagonists on anaphylactic hypotension in conscious rats

Anaphylactic shock is sometimes fatal or resistant to therapy in patients treated with propranolol, a nonselective β-adrenoceptor antagonist, against cardiovascular diseases. However, it remains unknown which subtype of β-adrenoceptors, β 1- or β 2-adrenoceptor, is primarily responsible for the detrimental effects of propranolol on anaphylactic hypotension. Effects of β 1- and β 2-adrenoceptor antagonists were therefore determined on the survival rate and systemic hypotension in conscious Sprague–Dawley rats that suffered from anaphylactic shock. Mean arterial pressure and portal venous pressure were simultaneously measured. The control rats showed a decrease in mean arterial pressure and an increase in portal venous pressure, but did not die within 48 h after an injection of ovalbumin antigen. The survival rate of the rats pretreated with propranolol (1 mg/kg; n = 7), the selective β 2-adrenoceptor antagonist ICI 118,551 (0.5 mg/kg; n = 7), or adrenalectomy ( n = 7) was significantly smaller than that with the selective β 1-adrenoceptor antagonist atenolol (2 mg/kg; n = 7). However, the changes in mean arterial pressure and portal venous pressure were similar for 10 min after antigen among any groups, although propranolol and atenolol attenuated the antigen-induced increase in heart rate. Furthermore, bolus injections of epinephrine (3 μg/kg) at 3 and 5 min after antigen prevented the death of the atenolol-pretreated rats, but only marginally prolonged the survival rates for the ICI 118,551- or propranolol-pretreated and adrenalectomized rats. In conclusion, in rat anaphylactic shock, inhibition of β 2-adrenoceptor causes more detrimental effects than that of the β 1-adrenoceptor. These β-adrenoceptor antagonists may exert detrimental effects on rat systemic anaphylaxis via inhibiting beneficial actions of catecholamines endogenously released from the adrenal gland.

Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside

To delineate some of the characteristics of septic vascular hypotension, to assess the most commonly cited and reported underlying mechanisms of vascular hyporesponsiveness to vasoconstrictors in sepsis, and to briefly outline current therapeutic strategies and possible future approaches. Source data were obtained from a PubMed search of the medical literature with the following MeSH terms: Muscle, smooth, vascular/physiopathology; hypotension/etiology; shock/physiopathology; vasodilation/physiology; shock/therapy; vasoconstrictor agents. Nitric oxide (NO) and peroxynitrite are crucial components implicated in vasoplegia and vascular hyporeactivity. Vascular ATP-sensitive and calcium-activated potassium channels are activated during shock and participate in hypotension. In addition, shock state is characterized by inappropriately low plasma glucocorticoid and vasopressin concentrations, a dysfunction and desensitization of alpha-receptors, and an inactivation of catecholamines by oxidation. Numerous other mechanisms have been individualized in animal models, the great majority of which involve NO: MEK1/2-ERK1/2 pathway, H(2)S, hyperglycemia, and cytoskeleton dysregulation associated with decreased actin expression. Many therapeutic approaches have proven their efficiency in animal models, especially therapies directed against one particular compound, but have otherwise failed when used in human shock. Nevertheless, high doses of catecholamines, vasopressin and terlipressin, hydrocortisone, activated protein C, and non-specific shock treatment have demonstrated a partial efficiency in reversing sepsis-induced hypotension.

PATHOPHYSIOLOGICAL ROLES OF PEROXYNITRITE IN CIRCULATORY SHOCK

Peroxynitrite is a reactive oxidant produced from nitric oxide and superoxide, which reacts with proteins, lipids, and DNA, and promotes cytotoxic and proinflammatory responses. Here, we overview the role of peroxynitrite in various forms of circulatory shock. Immunohistochemical and biochemical evidences demonstrate the production of peroxynitrite in various experimental models of endotoxic and hemorrhagic shock both in rodents and in large animals. In addition, biological markers of peroxynitrite have been identified in human tissues after circulatory shock. Peroxynitrite can initiate toxic oxidative reactions in vitro and in vivo. Initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane Na+/K+ ATPase activity, inactivation of membrane sodium channels, and other oxidative protein modifications contribute to the cytotoxic effect of peroxynitrite. In addition, peroxynitrite is a potent trigger of DNA strand breakage, with subsequent activation of the nuclear enzyme poly(ADP-ribose) polymerase, which promotes cellular energetic collapse and cellular necrosis. Additional actions of peroxynitrite that contribute to the pathogenesis of shock include inactivation of catecholamines and catecholamine receptors (leading to vascular failure) and endothelial and epithelial injury (leading to endothelial and epithelial hyperpermeability and barrier dysfunction), as well as myocyte injury (contributing to loss of cardiac contractile function). Neutralization of peroxynitrite with potent peroxynitrite decomposition catalysts provides cytoprotective and beneficial effects in rodent and large-animal models of circulatory shock.

P.4.b.009 Posttraumatic stress disorder and inflammation

Atenolol is a "cardioselective" beta-adrenoceptor antagonist. It inhibits selectively beta-1 receptors with a lower affinity for beta-2 receptor subtype. Atenolol does not have membrane-stabilizing or intrinsic sympathomimetic activities. It has relatively low lipid solubility. As with other beta blockers, atenolol exerts its effects primarily by blocking the action of the endogenous catecholamines, epinephrine and norepinephrine, at beta-adrenoceptors. The magnitude of the effect of atenolol is dependent on the degree of sympathetic tone. Atenolol also blocks the effects of drugs with beta-adrenoceptor agonist activity. Atenolol and other beta-adrenoceptor antagonists are used widely to treat many cardiovascular disorders, including hypertension, angina, arrhythmias, myocardial infarction, and congestive heart failure …

Chronic social isolation suppresses proplastic response and promotes proapoptotic signalling in prefrontal cortex of Wistar rats

Successful adaptation to stress involves synergized actions of glucocorticoids and catecholamines at several levels of the CNS, including the prefrontal cortex (PFC). Inside the PFC, hormonal signals trigger concerted actions of transcriptional factors, such as glucocorticoid receptor (GR) and nuclear factor kappa B (NFkappaB), culminating in a balanced, proadaptive expression of their common genes, such as proplastic NCAM and/or apoptotic Bax and Bcl-2. In the present study, we hypothesized that chronic stress may compromise the balance between GR and NFkappaB signals and lead to an altered/maladaptive expression of their cognate genes in the PFC. Our results obtained with Wistar rats exposed to chronic social isolation indicated alterations of the GR relative to the NFkappaB, in favor of the GR, in both the cytoplasmic and the nuclear compartments of the PFC. Although these alterations did not affect the induction of proplastic NCAM gene, they decreased the NCAM sialylation necessary for plastic response and caused marked relocation of the mitochondrial membrane antiapoptotic Bcl-2 protein to its cytoplasmic form. Moreover, the compromised PSA-NCAM plastic response found under chronic stress was sustained after exposure of animals to the subsequent acute stress, whereas the proapoptotic signals were further emphasized. It is concluded that chronic social isolation of Wistar animals leads to a maladaptive response of the PFC, considering the diminishment of its plastic potential and potentiating of apoptosis. Such conditions in the PFC are likely to compromise its ability to interact with other CNS structures, such as the hippocampus, which is necessary for successful adaptation to stress.