On the growth impact of different eco-innovation business strategies.

The paper investigates whether standard innovation and different types of eco-innovation activities have different effects on firm employment growth. Heterogeneity in terms of growth effects is analyzed by considering how the influence of different innovation strategies varies across firms grouped by their pace of growth. Relying on a sample of 3000 Italian manufacturing firms observed between 2012 and 2016, we find that innovative companies tend to grow faster than their non-innovative counterparts. However, when distinct paces of growth are taken into account, the employment growth impact of innovation will depend on the specific types of innovation strategies pursued by companies. In particular, more complex eco-innovation activities have no impact on employment growth for high-growth firms. This finding suggests that, on average, high-growth firms tend to be too small and too young to be able to expand through more complex EI strategies which, to be handled, require a wide range of cognitive, technological, and financial capabilities. Supplementary Information: The online version contains supplementary material available at 10.1007/s40888-022-00263-x.

European Technological Sovereignty: An Emerging Framework for Policy Strategy.

The COVID-19 crisis has revealed the deep technological and production dependencies of the EU on third countries in sectors deemed as particularly strategic and has thus fuelled the debate on (the lack of) European technological sovereignty in critical fields. This article argues that in the light of a renewed interest in relaunching a European industrial policy, technological sovereignty considerations must be fully incorporated into policy objectives and instruments.

Central [CNS] and Peripheral [Gastric Tissue] Selective Monitoring of Somatostatin (SRIF) with Micro-Sensor and Voltammetry in Rats: Influence of Growth Factors (GH, EGF).

Somatostatin (SRIF) is widely distributed throughout the body, and regulates the endocrine system via interactions with various hormones, including the pituitary growth hormone, the thyroid stimulating hormone and the majority of the hormones of the gastrointestinal tract. SRIF is present in the central nervous system (CNS), where it affects rates of neurotransmission, and is also reported to be active in the intestinal tract, with evidence that stressed rats present a significant decrease in antral somatostatin-like immunoreactivity (SLI). Analysis of SRIF has mainly been carried out by means of radioimmunoassay methods. Here, we propose the use of an electrochemical method, such as voltammetry, applied with carbon-based sensors and, in particular, the combination of differential pulse voltammetry with treated carbon fiber micro electrodes (DPV-µCFE) to facilitate the analysis of such peptidergic electro active hormones in the rat striatum and gastric tissue; the effect of growth hormone (GH) and epidermal growth factor (EGF), in particular, upon the SRIF signal has been studied in such tissues.

In vivo real time non invasive monitoring of brain penetration of chemicals with near-infrared spectroscopy: Concomitant PK/PD analysis.

BACKGROUND: Near-infrared spectroscopy (NIRS) is a non-invasive technique that monitors changes in oxygenation of haemoglobin. The absorption spectra of near-infrared light differ for the oxygenation-deoxygenation states of haemoglobin (oxygenate (HbO2) and deoxygenate (Hb), respectively) so that these two states can be directly monitored. COMPARISON WITH EXISTING METHOD(S): Different methodologies report different basal values of HbO2 and Hb absolute concentrations in brain. Here, we attempt to calculate basal HbO2 levels in rat CNS via evaluation of the influence of exogenous oxygen or exogenous carbon dioxide on the NIRS parameters measured in vivo. NEW METHOD: Furthermore the possibility that changes of haemoglobin oxygenation in rat brain as measured by NIRS might be a useful index of brain penetration of chemical entities has been investigated. Different compounds from different chemical classes were selected on the basis of parallel ex vivo and in vivo pharmacokinetic (PK/PD) studies of brain penetration and overall pharmacokinetic profile. RESULTS: It appeared that NIRS might contribute to assess brain penetration of chemical entities, i.e. significant changes in NIRS signals could be related to brain exposure, conversely the lack of significant changes in relevant NIRS parameters could be indicative of low brain exposure. CONCLUSIONS: This work is proposing a further innovation on NIRS preclinical applications i.e. a "chemical" NIRS [chNIRS] approach for determining penetration of drugs in animal brain. Therefore, chNIRS could became a non invasive methodology for studies on neurobiological processes and psychiatric diseases in preclinical but also a translational strategy from preclinical to clinical investigations.

In vivo oxymetric analysis of mild hypercapnia upon cerebral oxygen, temperature and blood flow: markers of mood as proposed by concomitant bupropion challenge and electrochemical analysis?

Scientific interest has increased the influence of temperature in neurodegenerative and psychiatric disorders, and according to the monoamine hypothesis, depression is a neurochemical disorder arising from hypofunctioning of brain monoamine systems. Here, in vivo flow-oxymetry is applied to verify relationships between cerebral oxygen tension (pO2), blood flow (CBF), that are markers of brain metabolism, and temperature (T), while in vivo voltammetry is concomitantly applied in the medial prefrontal cortex of anaesthetized rats to monitor monoamine levels such as dopamine (DA) and serotonin. An induced mild hypercapnia via increasing exogenous carbon dioxide (CO2) concentration resulted in increased pO2, CBF and T in discrete brain areas. Concomitant in situ voltammetric analysis of extracellular levels of serotonin and DA has revealed significant changes in the latter, only. Parallel treatment with antidepressant bupropion has confirmed its described central thermogenic properties and its positive influence on dopaminergic activity. CBF was also enhanced by such antidepressant. Altogether these data support direct relationships between markers of brain metabolism such as pO2, CBF, T and brain monoamine[s], indicating the coupled in vivo methodology: oxymetry-voltammetry as a rapid in vivo tool for analyses of such indicators in psychiatric disorders.

Influence of melatonin or its antagonism on alcohol consumption in ethanol drinking rats: a behavioral and in vivo voltammetric study.

Melatonin, an indoleamine hormone synthesized in the pinealocytes, has been implicated as influencing the intake of alcohol in rats. It has been shown that this hormone is voltammetrically electroactive at the surface of pretreated carbon fiber microelectrodes in vitro and in vivo, in rat cerebral melatonergic regions such the pineal gland. The aim of this work consisted in the study of the influence of melatonin on spontaneously ethanol drinking or ethanol avoiding rats selected throughout a free choice two bottle test. It appeared that only the water preferring rats were affected by treatment with the hormone and that in vivo voltammetric related levels of melatonin were higher in the pineal gland of ethanol drinking rats versus water preferring rats. In addition, when treated with the melatonin antagonist GR128107 ethanol drinking rats significantly reduced the spontaneous consumption of alcohol.

Influence of Neuropeptide Y and antidepressants upon cerebral monoamines involved in depression: an in vivo electrochemical study.

Neuropeptide Y (NPY) and its receptors are present in the peripheral as well as the central nervous system (CNS). In vitro data have indicated NPY as an important mediator in the regulation of different diseases e.g. related to obesity, anxiety, depression, pain, memory loss and sleep disorders. In particular, studies of NPY levels in the cerebral spinal fluid (CSF) of depressed patients have shown a significant reduction of NPY levels when compared to control subjects. In addition, decreased concentrations of NPY were measured in the brain of suicide victims. These studies suggest that a reduction in cerebral NPY function may be associated with depressive symptoms. In the present work, a putative interaction between NPY, the catecholaminergic and serotonergic systems has been analysed by means of in vivo Differential Pulse Voltammetry (DPV) with treated carbon fibre micro electrodes (mCFE). It appeared that DPV with mCFE is an efficacious tool to monitor in vivo basal levels of catechols (Peak 2) and indoles (Peak 3) in discrete brain regions of rodents. Furthermore, it is shown that the peptidergic signal (Peak 5) simultaneously recorded with Peaks 2 and 3 in the amygdala could correspond to the oxidation of basal endogenous NPY. In addition, pharmacological treatments performed in vivo with exogenous NPY and with Y1 receptor antagonist BIBP3226 have indicated that these compounds interact positively with endogenous catecholaminergic and serotoninergic systems, in a way similar to that of the antidepressants imipramine and fluoxetine. In addition, the observed decrease of endogenous Peak 5 after treatment with imipramine or fluoxetine could be related to the concomitant stimulation of the catecholaminergic system with consequent reduced need for endogenous NPY. This would imply that NPY could be one of the endogenous chemicals acting on the maintenance of the mood. Thus, an antidepressant therapeutic potential of NPY and related compounds (e.g. BIBP3226) could be proposed.

Further Electrochemical and Behavioural Evidence of a Direct Relationship Between Central 5-HT and Cytoskeleton in the Control of Mood.

Reduced activity of CNS serotonin is reported in unipolar depression and serotonin is the major target of recent antidepressant drugs. However, an acute depletion of serotonin in healthy individuals does not induce depressive symptoms suggesting that depression does not correlate with the serotonin system only. Neuronal plasticity (structural adaptation of neurons to functional requirements) includes synthesis of microtubular proteins such as tyrosinated isoform of alpha-tubulin and presence of serotonin as regulator of synaptogenesis. In depression neuronal plasticity is modified.HERE, IN RATS SUBMITTED TO A BEHAVIOURAL TEST WIDELY USED TO PREDICT THE EFFICACY OF ANTIDEPRESSANT DRUGS (FORCED SWIMMING TEST: FST) a significant decrease of both cerebral tyrosinated alpha-tubulin expression and serotonin levels is monitored. Moreover, treatment with para-chlorophenylalanine (PCPA, compound that specifically depletes brain serotonin) but not alpha-methyl para tyrosine (alpha-MPT, compound that blocks synthesis of catechols: chemicals also implicated in depression) significantly reduced tyrosinated alpha-tubulin. Thus, a direct relationship between serotonin and tyrosinated alpha-tubulin appears to be present both in "physiological" and in "pathological" states. In addition, data obtained in animals submitted to FST and/or treated with the selective serotonin reuptake inhibitor (SSRI) fluoxetine further support the interrelationship between central serotonin and cytoskeleton. These data propose that direct relationship between serotonin and tyrosinated alpha-tubulin could be considered within the mechanism(s) involved in the pathogenesis of depression.

Wireless in vivo voltammetric measurements of neurotransmitters in freely behaving rats.

An improved telemetric system based on either differential pulse voltammetry (DPV) or direct current amperometry (DCA) "diffused" via a single-way infrared (IR) transmission channel is introduced. The structural design of this system is very small and weighting only few grams but above all and unlike similar pre-existing instruments based on IR transmission, the present system works on a single-way communication, thus avoiding problems related to cross-talking between two-way channels that ends in altered functionality of the measuring electrode system. In addition, it is immune from electromagnetic interferences that disturb radio-frequency transmission. The system appeared already sensitive to both dopamine (DA) and serotonin (5-HT) using DCA and DPV either in vitro as well as in vivo. In particular, parallel in vivo experiments within anaesthetised rats prepared for classical wire-connected DCA or for wireless DCA resulted in superimposing data when the 5-HT system in the frontal cortex of anaesthetised rats was challenged with fluoxetine. In the present study, we have further refined and then successfully extended the wireless methodology to conscious freely moving rats and further verified the chemical nature of the DA and 5-HT current related signals recorded with wireless DCA in prefrontal cortex using Nafion coated micro-biosensors via dedicated pharmacological treatments.

SK channel blocker apamin attenuates the effect of SSRI fluoxetine upon cell firing in dorsal raphe nucleus: a concomitant electrophysiological and electrochemical in vivo study reveals implications for modulating extracellular 5-HT.

A dual probing methodology was implemented so that combined in vivo voltammetric (electrochemical) and in vivo electrophysiological analysis could be carried out concomitantly in two distinct brain regions of the same anaesthetized animal, i.e., cell body such as the dorsal raphe nucleus (DRN) and related terminal region such as the hippocampus, the frontal cortex, and the amygdala. In particular, this methodology allowed: In addition, the dual probing methodology has been applied to verify the original proposal that a combined treatment with a potassium (SK) channel blocker such as apamin and an SSRI (i.e., fluoxetine) could overcome the slow onset of the SSRI upon central 5-HT activity that could be related to the slow onset of its therapeutic action. Briefly, the effect of apamin either alone or followed by fluoxetine upon cell firing in the DRN (in vivo electrophysiology) and concomitantly upon 5-HT levels (in vivo voltammetry) in the amygdala (forebrain structure involved in mood regulation and innervated by ascending 5-HT projections from the DRN) was studied.

The selective serotonin reuptake inhibitor fluoxetine reduces striatal in vivo levels of voltammetric nitric oxide (NO): a feature of its antidepressant activity?

Voltammetric (electrochemical) methodologies such as differential pulse voltammetry and amperometry used together with electrically and chemically treated carbon fibre micro-electrodes (mCFE) allow selective monitoring of nitric oxide (NO). Preliminary in vitro studies have shown that the selective serotonin reuptake inhibitor (SSRI) antidepressant paroxetine inhibits constitutive nitric oxide synthase (cNOS) activity in animals and humans and that another SSRI such as fluoxetine reduced NO release in the media of synovial cells. The aim of this work was to verify by means of amperometry and specifically treated mCFE the capability of fluoxetine to alter the in vivo release of central NO, in the attempt to further clarify such putative antidepressant mechanism of action of this SSRI compound. The in vivo results support the chemical NO related nature of the endogenous amperometric signal evoked by NMDA injection in the striatum of anaesthetised rats, as pre-treatment with NOS inhibitor l-NAME prevented its appearance. Subsequently fluoxetine treatment resulted in decreased striatal NO, further supporting in vitro studies proposing a link between the serotonergic system and the NO system.

Anxiolytics antagonize yohimbine-induced central noradrenergic activity: a concomitant in vivo voltammetry-electrophysiology model of anxiety.

It has been shown that increased cerebral noradrenergic activity is closely related to anxiety-related behaviours. Furthermore, the noradrenergic alpha-2 receptor antagonist yohimbine (YOH) increases noradrenaline- (NA) cell firing and release in discrete brain areas involved in the modulation of anxiety such as the locus coeruleus (LC) and amygdala (AMY). In addition, YOH is highly anxiogenic in both humans and laboratory animals. Here we used an in vivo dual methodology to measure concomitantly the extracellular levels of catecholamines in AMY with voltammetry and the cell firing rate in LC with field electrophysiology in anaesthetized rats to characterize the pharmacological effects of YOH. We found that systemic administration of YOH increases both noradrenergic cell firing in the LC and catecholamines release in the AMY. Prior administration of the alpha-2 agonist clonidine prevents these effects on both the electrophysiological and the voltammetric signals, suggesting that YOH effects are mainly mediated by the alpha-2 adrenoceptors. In addition, we found that pre-treatment with the behaviourally active doses of the benzodiazepine (BDZ) anxiolytic chlordiazepoxide (CDE, Librium: BDZ very similar to diazepam) and of the non-BDZ buspirone counteract the effects of YOH on catecholamines release and cell firing. This suggests that the neurochemical and physiological effects of YOH measured in this study might be related to the anxiogenic effects of the drug. Thus, the presented electrophysiological-voltammetric-YOH study may be proposed as in vivo real time model of anxiety and this approach might be suitable for the evaluation of the neurochemical and physiological effects of new anxiolytic compounds.

Selective D3 Receptor Antagonist SB-277011-A Potentiates the Effect of Cocaine on Extracellular Dopamine in the Nucleus Accumbens: a Dual Core-Shell Voltammetry Study in Anesthetized Rats.

Dopamine (DA) D3 receptors have been associated with drug intake and abuse and selectively distribute in the brain circuits responding to drug administration. Here we examined the effects of an acute systemic administration of cocaine (15 mg/kg) alone or preceded by treatment with the selective D3 receptor antagonist SB-277011-A (10 mg/kg) on DA levels concurrently in the rat nucleus accumbens shell and core sub-regions (NAcshell and NAccore, respectively). It is shown that cocaine increases extracellular DA in both compartments and that blocking D3 receptors with SB-277011-A, although the latter is devoid of dopaminergic effects per se, potentiates these effects. No differences in the amplitude of the response were observed between NAcshell and NAccore compartments, though the dopaminergic response in the NAcshell was transient whereas that in the NAccore rose slowly to reach a plateau. These results demonstrate the feasibility to use multiprobe voltammetry to measure discrete monoaminergic responses in discrete areas of the brain and confirm the effect of D3 receptors antagonist at modifying the neurochemical effects of cocaine.

Near-infrared spectroscopy (NIRS): a non-invasive in vivo methodology for analysis of brain vascular and metabolic activities in real time in rodents.

Near infrared spectroscopy (NIRS) was first used as a tool for the in vivo monitoring of tissue oxygenation in the late seventies. Today, NIRS instruments are more and more used in clinical environments since they are now easy to use, sensitive, robust, provide rapid analysis and could be complementary to other non invasive methodologies such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). The feasibility of non-invasive analysis of brain activities is studied in the attempt to overcome the major limitation of invasive in vivo methodologies. In the present work, optic fibre probes were used as optical head of a novel, highly sensitive near infrared continuous wave spectroscopy (CW-NIR) instrument adapted for in vivo NIRS measurements in the brain of rodents. This prototype was designed for non-invasive analysis of the 2 main forms of haemoglobin: oxy-haemoglobin (HbO(2)) and deoxy-haemoglobin (Hb), chromophores present in biological tissues as these are markers of the degree of tissue oxygenation, thus providing an index of blood level and therefore of tissue metabolism. It was first tested in peripheral tissue (human gastrocnemius muscle) and then reset to perform measurement on rat brain. In animal studies, the optical head was firmly placed using stereotaxic apparatus upon the sagittal line of anaesthetised adult rat's head, without any surgery. 'Physiologic' (i.e. with exogenous oxygen (O(2)) or carbon dioxide (CO(2)) supplied orally) or pharmacologic (i.e. with drugs of abuse such as cocaine) experiments have been performed to support the effectiveness of the methodology in preclinical studies. In addition, the possibility that changes in brain metabolism as measured by NIRS might be a useful index of brain penetration of new chemical entities has been investigated using different compounds from different chemical classes that were selected on the basis of their known brain penetration and overall pharmacokinetic profile. Finally, the feasibility of coupling NIRS with another although invasive in vivo method such as electrophysiology for concomitant analysis of cerebral cell firing in discrete brain areas was tested in the attempt to study in real time the putative correlation between blood levels, brain metabolism and neuronal activities in rat CNS, i.e. apply NIRS to pharmacodynamic investigations. The data gathered in rat treated with exogenous O(2), indicate an original relationship between NIRS analysis of brain metabolism and electrical changes in this major nucleus of CNS involved in neurophysiologic and pathologic activities.

Non-invasive in vivo infrared laser spectroscopy to analyse endogenous oxy-haemoglobin, deoxy-haemoglobin, and blood volume in the rat CNS.

Oxy-haemoglobin (HbO2) and deoxy-haemoglobin (Hb) are chromophores present in biological tissues. Near infrared spectroscopy (NIRS) is a non-invasive methodology based on the low extinction coefficient of tissue in the near infrared region. NIRS can be used to measure changes in the concentration of these chromophores, i.e., haemoglobin, in muscular tissue. In the present work, NIRS has been used for the non-invasive monitoring of HbO2, Hb, and blood volume (V: representing total haemoglobin, i.e., HbO2+Hb) in vivo in the whole rat brain. This has been performed by means of prototype instrumentation based on optic fibre probes placed in contact with the head of anaesthetised rats held in a stereotaxic frame. A preliminary test of the instrument has been performed on human muscle, i.e., lateral gastrocnemius, in order to evaluate the ability of the instrument to detect oxygenation changes. Afterwards, the effects of pharmacological treatments, such as systemic amphetamine and nicotine treatments on the CNS have been detected.

Dihydropyridines, nitric oxide and vascular protection.

For more than decades calcium antagonists (CEBs) have been widely used for the treatment of myocardial ischaemia (angina pectoris). Among the classes of CEBs, the 1,4-dihidropyridine (DHPs) have been used for this indication because of their haemodynamic and electrophysiological properties. In particular, DHPs are compounds capable of vascular protection on both smooth muscle and endothelium. The main protective activity is related to their calcium antagonist activity. In addition, they present vascular dilatation function, which has been related to an anti-endothelin efficacy. The newer DHPs are endowed with slow onset and long duration of vasodilator activity and reduce coronary resistance with little or no effect on heart rate. The more lipophilic DHP, lacidipine, is also able to reduce the formation of atheroma plaque in animal models at therapeutic doses. It has potent and long-lasting antihypertensive properties and appears to protect the arterial wall against the development of atherosclerotic lesions in animal models or human subjects with severe and multiple risk factors. Additionally, it has been observed that: i) NO/cyclic GMP pathway facilitates the inhibitory effect of Ca(++) antagonists on KCl-evoked contraction in rat aorta; ii) Vasodilator effect of lacidipine was significantly attenuated in the presence of NO-synthase inhibitors; iii) DHPs stimulate an electrochemical activity related to the nitric oxide (NO) system within the aortic vessel tissue, in rats and mice. In particular, they implement endothelial NO at "useful" and not toxic nanomolar levels. These activities join the already described positive effects of these compounds upon vascular functions.

In vivo autofluorescence spectrofluorometry of central serotonin.

The autofluorescence properties of serotonin (5-HT) were investigated by light spectrofluorometry in in vitro, ex vivo and in vivo experiments. Ex vivo samples were prepared from rat brain regions containing serotonin (5-HT) i.e. cortex, striatum, hippocampus. Rats were untreated (controls) or previously submitted to chronic behavioural or pharmacological treatments known to affect endogenous 5-HT levels. Autofluorescence analysis (excitation: 366 nm) on hippocampus homogenates supplied with exogenous 5-HT revealed spectral alterations attributable to changes of endogenous 5-HT levels. In vivo, real time fluorescence studies were performed via a 50 microm diameter optic fiber probe stereotaxically implanted into selected brain areas of anaesthetised rats treated with fluoxetine or 5-OH-tryptophan. All autofluorescence data were consistent with those obtained in parallel experiments performed with ex vivo or in vivo voltammetry, confirming that auto-fluorescence spectroscopy is a suitable technique for the direct assessment of fluorescent neurotransmitters. This is a reliable evidence of the in vivo application of spectroscopy together with optic fiber probe for in vivo, in situ and real time measurement of 5-HT in discrete brain areas.

In vivo voltammetry: from wire to wireless measurements.

A novel telemetric system based on either differential pulse voltammetry (DPV) or direct current amperometry (DCA) by using a diffused infrared transmission channel is presented. Unlike similar pre-existing instruments based on infrared transmission, the present system works on a single-way communication, thus avoiding problems related to cross-talking between two-way channels. The infrared channel is also immune from electromagnetic interferences from the surrounding environment. Further advancement is the development of an original miniaturised system (dimension 1cm x 1.2 cm x 0.5 cm) with reduced weight (5-6 g), suitable for affixing to the rat head and allowing real time telemetric monitoring using DCA sampling of neurotransmitters such as dopamine or serotonin every 100 ms. The set-up is based on a transmitter (TX) circuit mounted on the animal's head and connected to the electrodes inserted into its brain. The TX circuit generates the proper electrical signals for DPV or DCA, collects the electrical response of the brain and transmits it, via an infrared channel, to a receiving station (RX) interfaced with a personal computer. The PC performs the sampling and elaboration of polarographic traces in a flexible and programmable way.

Inhibition of nitric oxide release in vivo by ethanol.

OBJECTIVE: Previous studies indicate that the nitric oxide (NO(.)) pathway is involved in the acute or chronic effects of ethanol on the central nervous system. However, direct evidence for the effect of ethanol on NO(.) production in vivo is lacking, and it is not clear whether it is inhibition or stimulation of the NO(.) pathway that contributes to the behavioral effects of ethanol. Herein the release of NO(.) in the rat striatum in vivo in response to NMDA receptor activation--the dominant mechanism controlling NO(.) formation-has been investigated after systemic or local injections of ethanol. METHODS: NMDA-induced release of authentic NO(.) was measured directly in the striatum of urethane-anesthetized (1.2 g/kg intraperitoneally) male Sprague-Dawley rats by using a direct-current amperometric method coupled to an electrically modified carbon microelectrode. An injector cannula was implanted in the proximity of the electrode (250 microm apart) for focal drugs application. RESULTS: Local application of NMDA (1 microl, 100 microM) produced a sharp and transient NO(.) signal. Systemic ethanol, 1 or 2.5 g/kg intraperitoneally, caused a long-lasting, dose-dependent inhibition of NMDA-induced NO(.) release to 12.2 +/- 5.9 and 6.4 +/- 3.7% of control, respectively, 60 min after ethanol administration. Dizocilpine (0.5 mg/kg intraperitoneally) mimicked the ethanol effect, inhibiting NO release to 1.6 +/- 0.66% of control. Local application of ethanol (1 microl, 2.5% v/v) in the striatum reduced the NMDA-induced response to 28.6 +/- 3.8% of control. Focal application of the competitive NMDA receptor antagonist D-(-)-2-amino-5-phosphonopentanoic acid (100 microM) or the nonselective NO synthase inhibitor L-N(G)-nitro-arginine methyl esther (100 microM) also caused inhibition of NMDA-induced NO(.) release to 2.4 +/- 0.7 and 4.3 +/- 0.9% of control, respectively. CONCLUSIONS: Ethanol, at pharmacologically significant doses, strongly inhibits striatal NO(.) production and release apparently through inhibition of NMDA receptor function. Inhibition of NMDA receptor-mediated activation of the NO(.) pathway could be a primary neurobiological mechanism contributing to the effects of ethanol.

Involvement of the nitric oxide system in the anti-atherosclerotic potential of lacidipine in the ApoE-deficient mouse: a morphological, functional, and electrochemical study.

The present study investigated the anti-atherosclerotic activity of lacidipine, a calcium antagonist with antioxidant properties in apoE-deficient mice. These mice show widespread vascular lesions which closely resemble the inflammatory-fibrous plaques seen in humans in atherosclerosis. Mice were fed a Western-type diet (WTD), and treated for 8 weeks with either vehicle or lacidipine at 3 or 10 mg/kg/day. In parallel with histological studies of atherosclerotic lesions in the aorta, functional studies on vascular acetylcholine (ACh) reactivity and analysis of voltammetric levels of nitric oxide (NO) were performed. Recent work has suggested that dihydropyridines (DHPs) modulate vascular relaxation via an increase in the release of NO. Lacidipine treatment had no effect on the plasma lipid profile. However, a significant (p < 0.01) dose-related reduction of 36.4% and 43.3% of the aortic lesion area in respect to methocel-treated mice was observed. Moreover, the aortic ring from control apoE-deficient mice fed a WTD for 8 weeks showed a lower relaxation in response to ACh in comparison to wild-type C57BL/6J mice; on the contrary, lacidipine-treated apoE-deficient mice lacidipine-treated displayed a response similar to that of wildtype C57BL/6J mice. Voltammetric analyses demonstrated a significant decrease of NO release in apoE-deficient mice, while lacidipine-treated mice showed enhanced activity of the NO system. We conclude that lacidipine reduced the extent of atherosclerotic area in hypercholesterolemic apoE-deficient mice, and this reduction may be associated with the capacity of the drug to maintain endothelial NO levels at concentrations useful to protect against vascular damage.