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Background: Internal haemorrhagic pachymeningiosis (IHP) is a rare disease characterized by a fibrous thickening and inflammatory infiltration in dural space mimicking chronic subdural hematoma. The pathogenesis of IHP is not entirely clear yet and treatment is still controversial., Objective: We want to emphasize the importance of differentiating pachymeningiosis from chronic subdural hematoma as distinct pathological entities., Patients and Methods: The records of five selected cases of IHP histologically confirmed were reviewed, focusing onset, neuroimaging, surgery and outcomes., Conclusions: IHP is most likely underestimated. Only through multidisciplinary approach it is possible to plane the proper therapeutic strategy. The diagnosis of IHP is confirmed by definitive histology but in some cases is possible with intraoperative frozen section.

Habituation is an important tool in the investigation of learning/memory throughout life. Despite that, few studies describe habituation from an ontogenetic perspective. Considering that, as soon as they are born, rodents can twist their bodies when lifted by their tails in an attempt to escape, this behavior should be well suited to study habituation behavior from birth to adulthood. Here, we implement a tail suspension test to study the ontogenetic development of habituation in Swiss mice. Our data indicate that a continuous within-session decrease in trunk movements can be observed from postnatal day (P) 10 onwards and that between-sessions habituation (from one day to another) can be observed from P16 onwards. Furthermore, we show that the adult pattern of within- and between-sessions reductions in activity is already present by the beginning of adolescence, at P28. Our results indicate that between-sessions habituation involves a more complex mechanism of memory and learning than within-session habituation, requiring a longer period of brain maturation before it can be displayed., (© 2013 Wiley Periodicals, Inc.)

Opportunistic yeasts and yeast-like fungi have been recognized as important pathogens in high-risk patients. This study aimed to evaluate the presence of these microorganisms in the microbiota of captive rheas and to investigate the antifungal susceptibility of the isolated strains. Isolates representing Magnusiomyces capitatus (Geotrichum capitatum, n = 11), Trichosporon mucoides (n = 11), Trichosporon asteroides (n = 5), Rhodotorula mucilaginosa (n = 4), Trichosporon asahii (n = 3), Trichosporon cutaneum (n = 3), and Trichosporon ovoides (n = 3) were obtained from the oropharynx, cloaca, and feces of 58 animals. Most of the isolates were susceptible to antifungals in vitro; however, resistance against fluconazole (n = 1) and itraconazole (n = 2) was detected among T. mucoides. This study indicates that healthy rheas can be reservoirs of opportunistic pathogens. Primary resistance to azoles in T. mucoides obtained from these animals demonstrates the potential risk to humans.

Objective: The aim of this work was to evaluate the role of ubiquitin-proteasome system (UPS) on mitochondrial-driven alpha-synuclein (aSN) clearance in in vitro, ex vivo and in vivo Parkinson's disease (PD) cellular models., Method: We used SH-SY5Y ndufa2 knock-down (KD) cells, PD cybrids and peripheral blood mononuclear cells (PBMC) from patients meeting the diagnostic criteria for PD. We quantified aSN aggregation, proteasome activity and protein ubiquitination levels. In PBMC of PD patient population we evaluated the aSN levels in the plasma and the influence of several demographic characteristics in the above mentioned determinations., Results: We found that ubiquitin-independent proteasome activity was up-regulated in SH-SY5Y ndufa2 KD cells while a downregulation was observed in PD cybrids and PBMC. Moreover, we observed an increase in protein ubiquitination that correlates with a decrease in ubiquitin-dependent proteasome activity. Accordingly, proteasome inhibition prevented ubiquitin-dependent aSN clearance. Ubiquitin-independent proteasome activity was positively correlated with ubiquitination in PBMC. We also report a negative correlation of chymotrypsin-like activity with age in control and late-onset PD groups. Total ubiquitin content is positively correlated with aSN oligomer levels, which leads to an age-dependent increase of aSN ubiquitination in LOPD. Moreover, aSN levels are increased in the plasma of PD patients., Interpretation: aSN oligomers are ubiquitinated and we identified a ubiquitin-dependent clearance insufficiency with the accumulation of both aSN and ubiquitin. However, SH-SY5Y ndufa2 KD cells showed a significant up-regulation of ubiquitin-independent proteasomal enzymatic activity that could mean a cell rescue attempt. Moreover, we identified that UPS function is age-dependent in PBMC., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Several researchers investigated the induction of metallothioneins (MTs) in the presence of metals, namely Cadmium (Cd). Fewer studies observed the induction of MTs due to oxidizing agents, and literature comparing the sensitivity of MTs to different stressors is even more scarce or even nonexistent. The role of MTs in metal and oxidative stress and thus their use as a stress biomarker, remains to be clearly elucidated. To better understand the role of MTs as a biomarker in Cerastoderma edule, a bivalve widely used as bioindicator, a laboratory assay was conducted aiming to assess the sensitivity of MTs to metal and oxidative stressors. For this purpose, Cd was used to induce metal stress, whereas hydrogen peroxide (H2O2), being an oxidizing compound, was used to impose oxidative stress. Results showed that induction of MTs occurred at very different levels in metal and oxidative stress. In the presence of the oxidizing agent (H2O2), MTs only increased significantly when the degree of oxidative stress was very high, and mortality rates were higher than 50 percent. On the contrary, C. edule survived to all Cd concentrations used and significant MTs increases, compared to the control, were observed in all Cd exposures. The present work also revealed that the number of ions and the metal bound to MTs varied with the exposure conditions. In the absence of disturbance, MTs bound most (60-70 percent) of the essential metals (Zn and Cu) in solution. In stressful situations, such as the exposure to Cd and H2O2, MTs did not bind to Cu and bound less to Zn. When organisms were exposed to Cd, the total number of ions bound per MT molecule did not change, compared to control. However the sort of ions bound per MT molecule differed; part of the Zn and all Cu ions where displaced by Cd ions. For organisms exposed to H2O2, each MT molecule bound less than half of the ions compared to control and Cd conditions, which indicates a partial oxidation of thiol groups in the cysteine residues through ROS scavenging. The present results suggest that MTs are excellent markers of metal stress, but not of oxidative stress., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Evidence exists indicating that cerebral lateralization is a fundamental feature of all vertebrates. In humans, a series of studies demonstrated that the left hemisphere plays a major role in controlling movement. No such asymmetries have been identified in rodents, in spite of the fact that these animals have been frequently used in studies assessing motor behavior. In this regard, here, we used unilateral hemispherectomy to study the relative importance of each hemisphere in controlling movement. Adult Swiss mice were submitted to right unilateral hemispherectomy (RH), left unilateral hemispherectomy (LH) or sham surgery. Fifteen days after surgery, motor performance was assessed in the accelerating rotarod test and in the foot-fault test (in which performance depends on skilled limb use) and in the elevated body swing test (in which performance depends on trunk movements). The surgical removal of the right hemisphere caused a more pronounced impairment in performance than the removal of the left hemisphere both in the rotarod and in the foot-fault tests. In the rotarod, the RH group presented smaller latencies to fall than both LH and sham groups. In the foot-fault test, while both the sham and the LH groups showed no differences between left and right hind limbs, the RH group showed significantly worse performance with the left hind limb than with the right one. The elevated body swing test revealed a similar impairment in the two hemispherectomized groups. Our data suggest a major role of the right hemisphere in controlling skilled limb movements in mice.

Histoplasmosis is a systemic infection caused by the fungus Histoplasma capsulatum. Environmental sources of infection for humans and animals in certain regions and the prevalence of infection in animals are frequently unknown. Because of the clinical and epidemiological similarities between histoplasmosis and leishmaniasis in northeastern Brazil, we decided to investigate the serologic evidence of H. capsulatum in dogs, considering that these animals can act as sentinels for histoplasmosis. A total of 224 serum samples from dogs were tested for antibodies against H. capsulatum through immunodiffusion. A total of 128 (57.14%) samples were positive for leishmaniasis by indirect immunofluorescence assay and four (1.78%) samples were positive for antibodies against H. capsulatum. Immunological evidence of the co-existence of histoplasmosis and leishmaniasis in dogs living in urban areas was observed. Diagnosis and clinical management of these diseases in endemic areas should be improved by veterinarians., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Commercial and recreational harvesting of shellfish within the coastal systems is usually very extensive. Since these ecosystems are frequently subjected to contamination, namely from agricultural, urban and industrial activities, and shellfish generally display a high capacity to bioaccumulate metals, populations may be at risk in terms of toxic metal exposure as a consequence of the harvesting and ingestion of near shore coastal marine organisms. Shellfish is regularly tested for concentrations of metals and other contaminants by legal authorities for commercial purposes, but although health officials use total metal as standards of food safety, only a part of the metal accumulated in shellfish is available to be assimilated and to cause toxic effect. In order to elucidate these issues an investigation on cockles inhabiting the Aveiro estuary was conducted. Element levels in sediments and wild Cerastoderma edule from sampling areas with different levels of contamination were measured; total element burden of cockles was related to accessible fraction for assimilation (TAM); element concentrations in wild C. edule were compared to EFSA (European Food Safe Authorities), USFDA (United States Food and Drug Administration) and FSANZ (Food Standards Australia and New Zealand) maximum levels (MLs); and the amount of cockle flesh needed to be consumed to exceed provisional tolerable weekly intake (PTWI) was determined. The present work showed that although sediment metal and metalloid contamination in Aveiro estuary is low the concentration of elements in C. edule does not reflect the contamination of the sediment. Aluminium (Al) and mercury (Hg) were the less and nickel (Ni), lead (Pb), zinc (Zn) and cadmium (Cd) were the most bioaccumulated metals by cockles. Comparison of MLs from international organisations with the concentration of elements in C. edule showed that arsenic (As) and Pb exceeded standard levels. The ingestion of less than 1 kg for As and 1.5 kg for Pb of cockles would result in exceeding the PTWI threshold (0.015 and 0.025 mg kg⁻¹ week⁻¹ respectively) in any of the areas considered in the study. Cd and Al also appear to be limiting elements for human consumption. Indeed, consumption of more than 3.1 kg and 2.1 kg of whole cockle soft part from one of the study areas during a single week would lead to exceedance of the recommended PTWI value for Cd (0.007 mg kg⁻¹ week⁻¹) and Al (7 mg kg⁻¹ week⁻¹) respectively. The health concerns to humans from cockle consumption from Aveiro estuary are discussed., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Cellular homeostasis relies on quality control systems so that damaged biologic structures are either repaired or degraded and entirely replaced by newly formed proteins or even organelles. The clearance of dysfunctional cellular structures in long-lived postmitotic cells, like neurons, is essential to eliminate, per example, defective mitochondria, lipofuscin-loaded lysosomes and oxidized proteins. Short-lived proteins are degraded mainly by proteases and proteasomes whether most long-lived proteins and all organelles are digested by autophagy in the lysosomes. Recently, it an interplay was established between the ubiquitin-proteasome system and macroautophagy, so that both degradative mechanisms compensate for each other. In this article we describe each of these clearance systems and their contribution to neuronal quality control. We will highlight some of the findings that provide evidence for the dysfunction of these systems in Alzheimer's and Parkinson's diseases. Ultimately, we provide an outline on potential therapeutic interventions based on the modulation of cellular degradative systems.

Human activities have been increasing the cadmium levels in soils and waters, disturbing many organisms in the primary trophic levels such as microalgae. Toxic metal pollution is a focus point of serious concern and the examination and monitoring water quality are becoming essential procedures. Diatoms are important bioindicators to monitor the metal concentrations in diverse habitats. The present study was planned to determine the biochemical mechanisms used by freshwater diatoms to cope with cadmium stress and to identify biomarkers of metal stress. For this, Nitzschia palea (Kützing) W. Smith was grown under different concentrations of Cd (0.01-0.1 mg l(-1)) and the IC(50) determined. Three concentrations (0.1, 0.2 and 0.3 mg Cd l(-1)) and a control (no cadmium) were used to undergo the experimental assays which allowed the determination of cadmium accumulation and several biochemical markers currently used to assess metal stress. N. palea was sensitive to cadmium, as the IC(50) calculated was 0.0276 mg Cd l(-1). Cadmium accumulation increased sharply and was mainly associated to the frustule. Total protein content increased with cadmium exposure, inducing increases and decreases in polypeptide expression, indicating an attempt of N. palea cells to adjust to the new prevailing conditions induced by metal stress. In order to cope with cadmium stress, cells induced the synthesis of chelating molecules such as phytochelatins (PCs). The enzymatic (SOD and CAT) and non-enzymatic (glutathione and proline) ROS scavenging mechanisms were also induced. Our results indicate the existence of diverse metal stress-mediated mechanisms in order to lessen metal damages to the cell. PCs showed to be a suitable biomarker of metal stress; besides being metal specific and concentration respondent it also allows to infer about the level of stress imposed to cells, constituting a useful tool to complement the evaluation of diatom communities when accessing aquatic metal toxicity., ((c) 2010 Elsevier B.V. All rights reserved.)

The genetic basis of myotonic dystrophy type I (DM1) is the expansion of a CTG tract located in the 3' untranslated region of DMPK. Expression of mutant RNAs encoding expanded CUG repeats plays a central role in the development of cardiac disease in DM1. Expanded CUG tracts form both nuclear and cytoplasmic aggregates, yet the relative significance of such aggregates in eliciting DM1 pathology is unclear. To test the pathophysiology of CUG repeat encoding RNAs, we developed and analyzed mice with cardiac-specific expression of a beta-galactosidase cassette in which a (CTG)(400) repeat tract was positioned 3' of the termination codon and 5' of the bovine growth hormone polyadenylation signal. In these animals CUG aggregates form exclusively in the cytoplasm of cardiac cells. A key pathological consequence of expanded CUG repeat RNA expression in DM1 is aberrant RNA splicing. Abnormal splicing results from the functional inactivation of MBNL1, which is hypothesized to occur due to MBNL1 sequestration in CUG foci or from elevated levels of CUG-BP1. We therefore tested the ability of cytoplasmic CUG foci to elicit these changes. Aggregation of CUG RNAs within the cytoplasm results both in Mbnl1 sequestration and in approximately a two fold increase in both nuclear and cytoplasmic Cug-bp1 levels. Significantly, despite these changes RNA splice defects were not observed and functional analysis revealed only subtle cardiac dysfunction, characterized by conduction defects that primarily manifest under anesthesia. Using a human myoblast culture system we show that this transgene, when expressed at similar levels to a second transgene, which encodes expanded CTG tracts and facilitates both nuclear focus formation and aberrant splicing, does not elicit aberrant splicing. Thus the lack of toxicity of cytoplasmic CUG foci does not appear to be a consequence of low expression levels. Our results therefore demonstrate that the cellular location of CUG RNA aggregates is an important variable that influences toxicity and support the hypothesis that small molecules that increase the rate of transport of the mutant DMPK RNA from the nucleus into the cytoplasm may significantly improve DM1 pathology.

Using direct cortical stimulation to map language function during awake craniotomy is a well-described and useful technique. However, the optimum neuropsychological tasks to use have not been detailed. We used both functional MRI (fMRI) and direct cortical stimulation to compare the sensitivity of two behavioral paradigms, number counting and object naming, in the demonstration of eloquent cortical language areas. Fifteen patients with left hemisphere lesions and seven healthy control subjects participated. Patients had both preoperative fMRI at 3 T and direct cortical stimulation. Patients and controls performed object naming and number counting during fMRI at 3 T. Laterality indices were calculated from the fMRI maps for the Number-counting>Object-naming and Object-naming>Number-counting contrasts. The same number-counting and object-naming paradigms were tested during awake craniotomy and assessed for sensitivity to speech disruption. In all patients during intraoperative cortical stimulation, speech disruption occurred at more sites during object naming than during number counting. Subtle speech errors were only elicited with the object-naming paradigm, whereas only speech arrest and/or hypophonia were measured using the number counting paradigm. In both patients and controls, fMRI activation maps demonstrated greater left lateralization for object naming as compared to number counting in both frontal and temporal language areas. Number counting resulted in a more bihemispheric distribution of activations than object naming. Both cortical stimulation testing and fMRI suggest that automated speech tasks such as number counting may not fully engage putative language networks and therefore are not optimal for language localization for surgical planning.

Objectives: We sought to characterize an animal model of the Wolff-Parkinson-White (WPW) syndrome to help elucidate the mechanisms of accessory pathway formation., Background: Patients with mutations in PRKAG2 manifest cardiac hypertrophy and ventricular pre-excitation; however, the mechanisms underlying the development and conduction of accessory pathways remain unknown., Methods: We created transgenic mice overexpressing either the Asn488Ile mutant (TG(N488I)) or wild-type (TG(WT)) human PRKAG2 complementary deoxyribonucleic acid under a cardiac-specific promoter. Both groups of transgenic mice underwent intracardiac electrophysiologic, electrocardiographic (ECG), and histologic analyses., Results: On the ECG, approximately 50% of TG(N488I) mice displayed sinus bradycardia and features suggestive of pre-excitation, not seen in TG(WT) mice. The electrophysiologic studies revealed a distinct atrioventricular (AV) connection apart from the AV node, using programmed stimulation. In TG(N488I) mice with pre-excitation, procainamide blocked bypass tract conduction, whereas adenosine infusion caused AV block in TG(WT) mice but not TG(N488I) mice with pre-excitation. Serial ECGs in 16 mice pups revealed no differences at birth. After one week, two of eight TG(N488I) pups had ECG features of pre-excitation, increasing to seven of eight pups by week 4. By nine weeks, one TG(N488I) mouse with WPW syndrome lost this phenotype, whereas TG(WT) pups never developed pre-excitation. Histologic investigation revealed postnatal development of myocardial connections through the annulus fibrosum of the AV valves in young TG(N488I) but not TG(WT) mice., Conclusions: Transgenic mice overexpressing the Asn488Ile PRKAG2 mutation recapitulate an electrophysiologic phenotype similar to humans with this mutation. This includes procainamide-sensitive, adenosine-resistant accessory pathways induced in postnatal life that may rarely disappear later in life.

1. Nebivolol (a new beta 1-adrenoceptor blocking drug) has particular effects on the cardiovascular system, i.e. it induces hypotension without affecting cardiac function or increasing peripheral vascular resistances. In this study, we aimed to evaluate the effects of nebivolol and its stereoisomers on the actions of adrenaline (AD) at the cardiovascular level as well as at the prejunctional level (as ascertained by modification of noradrenaline (NA) and dihydroxyphenylglycol (DOPEG) plasma levels in the anaesthetized dog. 2. AD infusion (0.1 micrograms kg-1 min-1) did not induce statistically significant changes in mean blood pressure and heart rate; it caused a pronounced and sustained rise of AD levels, no significant alterations in NA levels and a marked, progressive and sustained increase in DOPEG levels. 3. Mean blood pressure was not affected by any of the nebivolol isomers. d- and dl-nebivolol in the two doses used (0.3 and 0.03 mg kg-1 in 15 min) caused a significant and dose-dependent decrease in heart rate. Plasma levels of AD and NA were not changed by any of the nebivolol isomers tested. However, all of them significantly reduced the increase in plasma levels of DOPEG induced by adrenaline infusion. 4. We conclude (1) that AD infusion in the dog facilitates NA release and that DOPEG is a good index of this effect; and (2) nebivolol appears to act at the prejunctional level, reducing the increase in NA release induced by adrenaline, as shown by the effect on DOPEG plasma levels.

Longitudinal strips were prepared from human uterine arteries obtained at hysterectomy. The artery had a low content of noradrenaline and dopamine, contrasting with a high content of the deaminated catechols, dihydroxyphenylglycol (DOPEG) and dihydroxymandelic acid (DOMA), which together represented 98% of endogenous catechols. When incubated with 3H-noradrenaline (0.1 mumol/l), the uterine artery removed, accumulated and metabolized noradrenaline. Deaminated metabolites predominated, DOMA being the most abundant metabolite. Cocaine markedly reduced the accumulation of 3H-noradrenaline and abolished 3H-DOPEG formation, but did not change 3H-DOMA. Selective monoamine oxidase (MAO) inhibitors (clorgyline, selegiline and 2-amino ethyl carboxamide derivatives) caused a marked decrease in the amounts of 3H-DOPEG, 3H-DOMA and 3H-O-methylated and deaminated metabolites (OMDA) formed by the tissue and an increase in 3H-normetanephrine (NMN) formation. Inhibition of catechol-O-methyltransferase suppressed NMN formation and reduced that of OMDA; hydrocortisone slightly depressed the formation of DOMA and OMDA. Homogenates of the uterine artery deaminated 3H-5-HT, 14C-phenylethylamine and 3H-tyramine; inhibition curves of the deamination of 3H-tyramine by clorgyline and selegiline were compatible with the presence of both MOA A and MOA B. Exposure of the strips to 6-hydroxydopamine (1.5 mmol/l for 20 min; 3 exposure periods followed by washout periods of 15,15 and 30 min) resulted in complete and selective chemical denervation of the arterial tissue. This chemical denervation had effects which were similar to those of cocaine. The 2-amino ethyl carboxyamide derivatives markedly reduced the formation of deaminated metabolites by the denervated strips.(ABSTRACT TRUNCATED AT 250 WORDS)

Surgical denervation of the lateral saphenous vein of the dog causes marked extraneuronal changes, both of a morphological and functional type. In an attempt to investigate the factor(s) responsible for the trophic effects exerted by the sympathetic innervation on the dog saphenous vein we studied the effects of noradrenaline, adenosine, inosine and N-ethylcarboxamidoadenosine (NECA) on vascular tissue after sympathetic denervation. The saphenous vein was denervated using either surgical or chemical (6-hydroxydopamine, 6-OHDA) methods. Noradrenaline (0.1 microgram/kg per h), adenosine (10 micrograms/kg per h), inosine (10 micrograms/kg per h) or NECA (0.1 microgram/kg per h) were delivered continuously for 5 days through Alzet minipumps connected to the vein. 6-OHDA-induced denervation resulted in morphological changes similar to those described for surgical denervation. Smooth muscle cells and fibroblasts showed ultrastructural signs of increased synthetic activity and their size was significantly increased. In confirmation of earlier studies, constant i.v. infusions of noradrenaline did not prevent the morphological changes induced by denervation. Adenosine prevented the morphological changes induced by chemical or surgical denervation. Similarly to adenosine, infused NECA prevented the structural consequences of denervation. In contrast, inosine did not prevent the changes caused by surgical denervation. The results are compatible with an involvement of purines in the trophic effects of sympathetic innervation. Moreover, the effects of adenosine do not appear to be mediated by inosine.

Uptake and metabolism of tritiated noradrenaline by the mesenteric arteries of the dog and concomitant behaviour changes in endogenous noradrenaline are described. Posterior mesenteric artery strips were incubated for 30 min in Krebs solution containing (-)-7-3H-noradrenaline (1,084 muM); suitable pretreatments and/or preincubations were performed to study the influence of some drugs on these parameters. The atrial strips showed a high capacity to retain, accumulate and metabolize exogenous noradrenaline. At the concentration of noradrenaline studied, neuronal uptake and deamination represented the main inactivation mechanism, however, when neuronal uptake was blocked, extraneuronal deamination and o-methylation played a more important role, o-Methylation represented a vicarious enzymatic route when monoamine oxidase activity was inhibited. Iproniazid pretreatment increased markedly the endogenous noradrenaline content of the mesenteric arteries. During incubation with tritiated noradrenaline both an outflow of endogenous noradrenaline and an inflow of tritiated noradrenaline were observed.

Tissue noradrenaline content as well as uptake and metabolism of tritiated exogenous noradrenaline were studied comparatively, in vitro in mesenteric arteries, and in saphenous veins of normotensive and perinephritic hypertensive dogs. The influence of cocaine, iproniazid and 3'-4'-dihydroxy-2-methyl-propiophenone (U-0521) on these variables was also investigated. The concentration of (-)-7-3H-noradrenaline used was 1.08 microM. No changes were observed in noradrenaline content, uptake and metabolism in saphenous vein strips obtained from normotensive or hypertensive animals. However, in mesenteric artery strips obtained from hypertensive dogs, a marked reduction in endogenous noradrenaline content was observed as well as a reduction in noradrenaline accumulation (20 weeks after surgery). The deamination pattern was also modified in these strips: the formation of DOPEG was markedly diminished and the formation of DOMA was increased. These results agree well with the degeneration of the sympathetic innervation of the mesenteric arteries of hypertensive dogs described by Azevedo et al. (1981).

Intravenous adrenaline infusions (100 ng . kg-1 min-1) during 30 min resulted in an increase in dog plasma adrenaline and caused a very marked increase in noradrenaline, beginning at 15 min of the infusion and reaching a maximum (10-fold increase) at the end of the infusion. The heart, but not the vascular tissue, showed an increase in adrenaline content. Propranolol (0.5 + 0.5 mg . kg-1) or cocaine (0.5 + 0.5 mg . kg-1) prevented the increase in plasma noradrenaline caused by adrenaline. Isoprenaline (10 ng . kg-1 . min-1) infused during 30 min caused a smaller (2.7-fold) increase in noradrenaline levels, and those effects were also prevented by propranolol or cocaine. From these results, it is concluded that in vivo the increase in noradrenaline plasma levels is due to an activation of beta-adrenoceptors and that this plasma noradrenaline appears to be of neuronal origin. The results also suggest that adrenaline or isoprenaline, after being taken up into nerve terminals, when released activate presynaptic beta-receptors and facilitate the release of neuronal noradrenaline.

1. The effects of continuous intravenous infusion of noradrenaline (0.01 and 0.1 microgram kg-1 h-1) were studied in both the infused lateral saphenous vein and the contralateral saphenous vein of normal dogs. Noradrenaline, saline, noradrenaline + desipramine or noradrenaline + superoxide dismutase were infused using Alzet osmotic minipumps. 2. After a 5 day infusion period, the noradrenaline content in plasma and in both saphenous veins was determined, and the venous tissues submitted to light microscope morphometry and ultrastructural study and used for the determination of their O-methylation capacity (with [3H]-isoprenaline as a substrate). 3. Noradrenaline caused dose-dependent damage to the sympathetic nerve endings of the lateral saphenous veins. Concomitant changes in extraneuronal structure and function were observed (hypertrophy of smooth muscle cells, nuclear dysmorphy, thickening of the vessel wall, impairment in O-methylation capacity). 4. Desipramine and superoxide dismutase prevented or reduced the effects of noradrenaline on both the morphological and the biochemical parameters; the protection afforded by superoxide dismutase was more marked than that by desipramine. 5. It is concluded that moderately high doses of noradrenaline exert a 6-hydroxydopamine-like effect and that this chemical sympathectomy is partially or totally prevented by desipramine or superoxide dismutase. The data suggest that a substance derived from noradrenaline, in the formation of which free oxygen radicals are involved and which is subject to neuronal uptake, is the chemical entity responsible for the neurotoxic effect observed.

In order to study the fate of isoprenaline in the presence of drugs which inhibit its extraneuronal uptake and O-methylation, strips of canine lateral saphenous veins strips were incubated for 60 min with 3H-isoprenaline (2 microM) in the presence of cortexone 60 microM and U-0521 100 microM. Cortexone reduced to about 50% the amount of 3H-isoprenaline accumulated in the presence of U-0521 and the addition of cocaine further reduced it by about 30%. Field stimulation of strips treated with cortexone and U-0521 resulted in the release of significant, although small, amounts of 3H-isoprenaline; this release was prevented by cocaine or by pretreatment with reserpine. Thus, when extraneuronal uptake and O-methylation are inhibited, isoprenaline behaves like a false transmitter. Even in the presence of cortexone, U-0521 and cocaine, a considerable amount of isoprenaline accumulates in the strips, presumably in non-muscular structures of the tunica media.