Control de la presión arterial mediante el uso de una aplicación para teléfono inteligente con estrategia de retroalimentación y competitividad. Proyecto Control HTApp / Control of blood pressure by using an intelligent telephone application with feedback and competitiveness strategy. HTApp Control project

Introducción y objetivo. La hipertensión arterial es un factor de riesgo cardiovascular de gran importancia y con bajos porcentajes de control. Las nuevas tecnologías pueden ayudar a obtener un mejor control de esta enfermedad, por lo que se pretende conocer si una aplicación móvil puede ayudar a conseguir este objetivo. Método. Se utiliza una aplicación para teléfonos móviles que permite dar información de retroalimentación a los médicos con intención de generar competitividad en la consecución de objetivos. La aplicación permitía conocer en todo momento la tasa de pacientes controlados (<140/90mmHg) por cada médico, y compararlos con la media de pacientes controlados por el grupo. También se analizan los posibles cambios en la actitud terapéutica de los médicos y se comparan diferencias en consecución de objetivos en función de determinadas características de los pacientes. Resultados. Se incluyeron 220 pacientes, de 18 a 80 años, con cifras de presión arterial>140/90mmHg a pesar de tratamiento médico, seguidos durante 4 visitas. Al final del seguimiento, el 69,03% logró un buen control, en comparación con el 12,8% en el estudio basal (p<0,001), sin que se observaran diferencias entre ambos sexos (control del 68,6 y 69,29% en mujeres y hombres, respectivamente) ni entre los distintos niveles de riesgo cardiovascular. Conclusiones. El uso de herramientas interactivas que permitan el proceso dinámico de retroalimentación sobre los propios resultados favorece la motivación y mejora la inercia terapéutica en el control de la presión arterial (AU)

Introduction and objective. Arterial hypertension is a highly important cardiovascular risk factor, with low control percentages. New technologies can help to obtain a better control of this disease. The intention is to know if a mobile application can help achieve this goal. Method. A mobile phone application is used to give feedback to physicians with the aim of generate competitiveness in achieving objectives. The application could, at any time, determine the rate of controlled patients (<140/90mmHg) by each physician, and compare them with the mean number of the patients controlled by the group. The possible changes in the therapeutic attitude of physicians are also analysed and the differences in achieving objectives are compared based on specific characteristics of patients. Results. The study included 220 patients aged 18-80 years, with mean blood pressure>140/90mmHg, despite medical treatment, tracked for 4 visits. At the end of the follow-up, 69.03% achieved good control, compared to 12.8% in the baseline study (P<.001), with no differences between gender (control of 68.6 and 69.29% of women and men, respectively), nor among the different levels of cardiovascular risk. Conclusions. The use of interactive tools that allow the dynamic process of feedback on the results fosters the motivation and improves the therapeutic inertia in the control of blood pressure (AU)

[Control of blood pressure by using an intelligent telephone application with feedback and competitiveness strategy. HTApp Control project]. / Control de la presión arterial mediante el uso de una aplicación para teléfono inteligente con estrategia de retroalimentación y competitividad. Proyecto Control HTApp.

INTRODUCTION AND OBJECTIVE: Arterial hypertension is a highly important cardiovascular risk factor, with low control percentages. New technologies can help to obtain a better control of this disease. The intention is to know if a mobile application can help achieve this goal. METHOD: A mobile phone application is used to give feedback to physicians with the aim of generate competitiveness in achieving objectives. The application could, at any time, determine the rate of controlled patients (<140/90mmHg) by each physician, and compare them with the mean number of the patients controlled by the group. The possible changes in the therapeutic attitude of physicians are also analysed and the differences in achieving objectives are compared based on specific characteristics of patients. RESULTS: The study included 220 patients aged 18-80 years, with mean blood pressure>140/90mmHg, despite medical treatment, tracked for 4 visits. At the end of the follow-up, 69.03% achieved good control, compared to 12.8% in the baseline study (P<.001), with no differences between gender (control of 68.6 and 69.29% of women and men, respectively), nor among the different levels of cardiovascular risk. CONCLUSIONS: The use of interactive tools that allow the dynamic process of feedback on the results fosters the motivation and improves the therapeutic inertia in the control of blood pressure.

Daidzein has neuroprotective effects through ligand-binding-independent PPARγ activation.

Phytoestrogens are a group of plant-derived compounds that include mainly isoflavones like daidzein. Phytoestrogens prevent neuronal damage and improve outcome in experimental stroke; however, the mechanisms of this neuroprotective action have not been fully elucidated. In this context, it has been postulated that phytoestrogens might activate the peroxisome proliferator-activated receptor-γ (PPARγ), which exerts neuroprotective effects in several settings. The aim of this study was to determine whether the phytoestrogen daidzein elicits beneficial actions in neuronal cells by mechanisms involving activation of PPARγ. Our results show that daidzein (0.05-5 µM) decreases cell death induced by exposure to oxygen-glucose deprivation (OGD) from rat cortical neurons and that improves synaptic function, in terms of increased synaptic vesicle recycling at nerve terminals, being both effects inhibited by the PPARγ antagonist T0070907 (1 µM). In addition, this phytoestrogen activated PPARγ in neuronal cultures, as shown by an increase in PPARγ transcriptional activity. Interestingly, these effects were not due to binding to the receptor ligand site, as shown by a TR-FRET PPARγ competitive binding assay. Conversely, daidzein increased PPARγ nuclear protein levels and decreased cytosolic ones, suggesting nuclear translocation. We have used the receptor antagonist (RE) fulvestrant to study the neuroprotective participation of daidzein via estrogen receptor and at least in our model, we have discarded this pathway. These results demonstrate that the phytoestrogen daidzein has cytoprotective properties in neurons, which are due to an increase in PPARγ activity not mediated by direct binding to the receptor ligand-binding domain but likely due to post-translational modifications affecting its subcellular location and not depending to the RE and it is not additive with the agonist rosiglitazone.

"Full moon" endoscopic sign in intraventricular neurocysticercosis.

INTRODUCTION: Despite improvements in sanitation, diagnosis and treatment, neurocysticercosis is still a public health problem in many countries. In symptomatic patients, there is a broad spectrum of clinical manifestations. When cysticerci are lodged in the ventricles or the subarachnoid space, the flow of cerebrospinal fluid can be obstructed and lead to hydrocephalus and intracranial hypertension. The endoscopic view may be useful as a diagnostic tool. PATIENTS: This report clearly shows a common endoscopic pattern in 4 selected patients with ventricular cysticercosis (2 third ventricle/2 lateral ventricle). The endoscopic view of the cysts in the ventricles resembles a "full moon". This analogy helped to identify the features of cysticerci with intact walls and the vesicular stage, malleable due to its cystic content and having an irregular surface, as evidence of the microscopic structure of the cyst wall in a cysticercus. CONCLUSIONS: This finding is not seen in other intraventricular cysts or tumors that can actually be considered as an additional diagnostic criterion among the definitive findings to establish the diagnosis of cysticercosis, since it involves direct endoscopic visualization of a cysticercus under histopathological demonstration. Additionally, the endoscopic approach can be used as primary treatment for these cases, following the minimally invasive approach principle.

Longitudinal studies of ischemic penumbra by using 18F-FDG PET and MRI techniques in permanent and transient focal cerebral ischemia in rats.

At present, the goal of stroke research is the identification of a potential recoverable tissue surrounding the ischemic core, suggested as ischemic penumbra, with the aim of applying a treatment that attenuates the growth of this area. Our purpose was to determine whether a combination of imaging techniques, including (18)F-FDG PET and MRI could identify the penumbra area. Longitudinal studies of (18)F-FDG PET and MRI were performed in rats 3 h, 24 h and 48 h after the onset of ischemia. A transient and a permanent model of focal cerebral ischemia were performed. Regions of interest were located, covering the ischemic core, the border that progresses to infarction (recruited tissue), and the border that recovers (recoverable tissue) with early reperfusion. Analyses show that permanent ischemia produces severe damage, whereas the transient ischemia model does not produce clear damage in ADC maps at the earliest time studied. The only significant differences between values for recoverable tissue, (18)F-FDG (84±2%), ADC (108±5%) and PWI (70±8%), and recruited tissue, (18)F-FDG (77±3%), ADC (109±4%) and PWI (77±4%), are shown in (18)F-FDG ratios. We also show that recoverable tissue values are different from those in non-infarcted tissue. The combination of (18)F-FDG PET, ADC and PWI MRI is useful for identification of ischemic penumbra, with (18)F-FDG PET being the most sensitive approach to its study at early times after stroke, when a clear DWI deficit is not observed.

Suppression of guanylyl cyclase (beta1 subunit) expression impairs neurite outgrowth and synapse maturation in cultured cerebellar granule cells.

The increased expression of different soluble guanylyl cyclase (sGC) subunits during development is consistent with these proteins participating in the formation and establishment of interneuronal contacts. Functional sGC is generated by the dimerization of an alpha-subunit (sGCalpha1/2) with the beta1-subunit (sGCbeta1), and both depletion of the sGCbeta1 subunit and inhibiting sGC activity impair neurite outgrowth. Similarly, impairing sGC activity diminishes the amount of growth-associated protein (GAP-43) and synapsin I, two proteins that participate in axon elongation and synaptogenesis, suggesting a role for sGC in these processes. Indeed, fewer synapses form when sGC is inhibited, as witnessed by FM1-43 imaging and synapsin I immunostaining, and the majority of synapses that do form remain functionally immature. These findings highlight the importance of sGC in the regulation of neurite outgrowth and synapse formation, and in the functional maturation of cerebellar granule cells in vitro.

Inhibition of N- and P/Q-type Ca2+ channels by cannabinoid receptors in single cerebrocortical nerve terminals.

Since cannabinoid receptors inhibit excitatory synaptic transmission by reducing glutamate release, we have examined whether this might occur through the direct inhibition of presynaptic Ca2+ channels. In cerebrocortical nerve terminals, activation of cannabinoid receptors with WIN55,212-2 reduces the KCl-evoked release of glutamate. However, this inhibition is attenuated when N- and P/Q-type Ca2+ channels are blocked. Through Ca2+ imaging in single nerve terminals, we found that WIN55,212-2 reduced the influx of Ca2+ both in nerve terminals that contain N-type Ca2+ channels and those that contain P/Q-type Ca2+ channels. Thus, cannabinoid receptors modulate the two major Ca2+ channels coupled to glutamate release in the cerebral cortex.

Dual signaling by mGluR5a results in bi-directional modulation of N-type Ca2+ channels.

We have studied how N-type Ca2+ channels are modulated by the metabotropic glutamate receptor 5a (mGluR5a) in Xenopus oocytes. Stimulation of the receptor with glutamate initiated two parallel responses, a rapid inhibition followed by an upregulation of the Ca2+ current. Although a subsequent stimulation did not upregulate the Ca2+ current, it did still produce a reduction in the amplitude of the current. The upregulation of Ca2+ channels was prevented by the protein kinases inhibitor staurosporine and it was mimicked by the activation of PKC with phorbol esters. In contrast, the inhibition of the Ca2+ current was insensitive to staurosporine. These results show that mGluR5a exerts a bi-directional influence on Ca2+ channels, which may explain how group I mGluRs facilitate and inhibit glutamate release at central synapses.

An activity-dependent switch from facilitation to inhibition in the control of excitotoxicity by group I metabotropic glutamate receptors.

Activation of group I metabotropic glutamate receptors (mGlu1 or -5 receptors) is known to either enhance or attenuate excitotoxic neuronal death depending on the experimental conditions. We have examined the possibility that these receptors may switch between two different functional modes in regulating excitotoxicity. In mixed cultures of cortical cells, the selective mGlu1/5 agonist, 3,5-dihydroxyphenylglycine (DHPG), amplified neurodegeneration induced by a toxic pulse of NMDA. This effect was observed when DHPG was either combined with NMDA or transiently applied to the cultures prior to the NMDA pulse. However, two consecutive applications of DHPG consistently produced neuroprotection. Similar effects were observed with DHPG or quisqualate (a potent agonist of mGlu1/5 receptors) in pure cultures of cortical neurons virtually devoid of astrocytes. In cultures of hippocampal pyramidal neurons, however, only protective effects of DHPG were seen suggesting that, in these particular cultures, group I mGlu receptors were endogenously switched into a "neuroprotective mode". The characteristics of the activity-dependent switch from facilitation to inhibition were examined in mixed cultures of cortical cells. The switch in the response to DHPG was observed when the two applications of the drug were separated by an interval ranging from 1-45 min, but was lost when the interval was extended to 90 min. In addition, this phenomenon required the initial activation of mGlu5 receptors (as indicated by the use of subtype-selective antagonists) and was mediated by the activation of protein kinase C. We conclude that group I mGlu receptors are subjected to an activity-dependent switch in regulating excitotoxic neuronal death and, therefore, the recent "history" of these receptors is critical for the response to agonists or antagonists.

Protein phosphatase 1 and 2A inhibitors prolong the switch in the control of glutamate release by group I metabotropic glutamate receptors: characterization of the inhibitory pathway.

We have addressed the role of protein phosphatases (PPs) in the modulation of the switch in glutamate release observed after repetitive stimulation of group I metabotropic glutamate receptors (mGluRs). In cerebrocortical nerve terminals the agonist (S:)-3, 5-dihydroxyphenylglycine facilitated evoked glutamate release. However, a second stimulation, 5 min later, reduced rather than facilitated this release. This switch in the control of glutamate release was reversed when a 30-min interval was left between stimulations. Inhibition of the endogenous PPs, PP1 and PP2A, with calyculin A and okadaic acid prevented the recovery of the facilitatory response and maintained the receptor permanently coupled to the inhibitory pathway. The inhibitors of PP2B, cyclosporin A and cypermethrine, had no effect. The inhibition of glutamate release was insensitive to pertussis toxin and was the result of the loss of the release component coupled to N-type Ca(2+) channels. This inhibitory action was suppressed by addition of the protein kinase C activator 4beta-phorbol 12,13-dibutyrate. We conclude that the balance between protein kinase and phosphatase activity at the nerve terminal plays a key role in accommodating the modulation of glutamate release by group I mGluRs.

Protein phosphatase 2B inhibitors mimic the action of arachidonic acid and prolong the facilitation of glutamate release by group I mGlu receptors.

We have addressed the role of arachidonic acid in the facilitation of glutamate release by group I metabotropic glutamate (mGlu) receptors. The activation of these receptors with the specific agonist 3,5-dihydroxyphenylglycine (DHPG) failed to enhance the cumulative Ca(2+)-dependent release of glutamate evoked by a 5 min depolarization with 4-aminopyridine, in the absence but not in the presence of arachidonic acid. However, DHPG, in the absence of arachidonic acid, transiently enhanced diacylglycerol levels, transiently potentiated 4AP-evoked depolarization, and significantly enhanced the fast but not the slow component of glutamate release observed after prolonged stimulations of nerve terminals. Further evidence that DHPG was able to initiate release facilitation in the absence of arachidonic acid was obtained in experiments where the protein phosphatase 2B (cyclosporine A and cypermethrine) but not protein phosphatase 1 or 2A inhibitors (okadaic acid and calyculin A) facilited glutamate release to a maximal extent comparable to that induced by arachidonic acid. We conclude that an active protein phosphatase 2B (calcineurin) dephosphorylates the presynaptic target/s responsible for facilitation of glutamate release.

Presynaptic group 1 metabotropic glutamate receptors may contribute to the expression of long-term potentiation in the hippocampal CA1 region.

In this study, we investigated the possible contribution of presynaptic group 1 metabotropic glutamate receptor activation to changes in synaptic efficacy by means of analysis of glutamate release in hippocampal synaptosomes. Data were interpreted in the context of group 1 metabotropic glutamate receptor involvement in synaptic plasticity in the CA1 region of freely moving rats. In synaptosomes, 3,5-dihydroxyphenylglycine enhanced diacylglycerol formation and facilitated vesicular Ca(2+)-dependent glutamate release, whereas trans-azetidine-2,4-dicarboxylic acid had no effect on these processes. Trans-azetidine-2,4-dicarboxylic acid enhanced glutamate release, but in a Ca(2+)-independent manner. This effect was mimicked by the L-glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid. (R,S)-alpha-Methyl-4-carboxyphenylglycine blocked the effects of 3,5-dihydroxyphenylglycine, but not trans-azetidine-2,4-dicarboxylic acid in synaptosomes. Short-term potentiation (100 Hz, three bursts of 10 stimuli, 0.1 ms stimulus duration, 10 s interburst interval) was induced in the CA1 region in vivo. The metabotropic glutamate receptor agonist 1S,3R-aminocyclopentane-2,3-dicarboxylic acid, or the group 1 metabotropic glutamate receptor agonists, 3,5-dihydroxyphenylglycine and trans-azetidine-2,4-dicarboxylic acid, dose-dependently facilitated short-term potentiation into long-term potentiation, which lasted > 24 h. The facilitation was inhibited by the metabotropic glutamate receptor antagonist, (R,S)-alpha-methyl-4-carboxyphenylglycine, and the group 1 metabotropic glutamate receptor antagonist, (S)-4-carboxy-phenylglycine, but not by the group 2 metabotropic glutamate receptor antagonist, (R,S)-alpha-methylserine-O-phosphate monophenyl ester. L-Trans-pyrrolidine-2,4-dicarboxylic acid dose-dependently facilitated short-term potentiation into long-term potentiation, which lasted < 4 h. These data suggest that activation of group 1 metabotropic glutamate receptors results in presynaptic modulation of glutamate release. This effect may contribute to group 1 metabotropic glutamate modulation of the expression of long-term potentiation in vivo.

Group-I metabotropic glutamate receptors: hypotheses to explain their dual role in neurotoxicity and neuroprotection.

The role of group-I metabotropic glutamate receptors (mGlu1 and 5) in neurodegeneration is still controversial. While antagonists of these receptors are consistently neuroprotective, agonists have been found to either amplify or attenuate excitotoxic neuronal death. At least three variables affect responses to agonists: (i) the presence of the NR2C subunit in the NMDA receptor complex; (ii) the existence of an activity-dependent functional switch of group-I mGlu receptors, similar to that described for the regulation of glutamate release; and (iii) the presence of astrocytes expressing mGlu5 receptors. Thus, a number of factors, including the heteromeric composition of NMDA receptors, the exposure time to drugs or to ambient glutamate, and the function of astrocytes clearing extracellular glutamate and producing neurotoxic or neuroprotective factors, must be taken into account when examining the role of group-I mGlu receptors in neurodegeneration/neuroprotection.

Functional switch from facilitation to inhibition in the control of glutamate release by metabotropic glutamate receptors.

We have investigated the role of metabotropic glutamate receptors linked to phosphoinositide hydrolysis in the control of glutamate release in cerebrocortical nerve terminals. The activation of these receptors with the agonist 3,5-dihydroxyphenylglycine enhanced intra-synaptosomal diacylglycerol and facilitated both the depolarization-induced increase in the cytosolic free Ca2+ concentration and the release of glutamate. However, 5 min after receptor activation, a second stimulation of the pathway with the agonist failed to produce diacylglycerol and to facilitate glutamate release. Interestingly, during the period in which the diacylglycerol response was desensitized, a strong agonist-induced inhibition of Ca2+ entry and glutamate release was observed. This change in the presynaptic effects of 3,5-dihydroxyphenylglycine is reversible since 30 min after the first stimulation, the agonist-induced inhibition of release disappeared, whereas both the production of diacylglycerol and the facilitation of glutamate release were recovered. The tonic elevation of the extracellular glutamate concentration from basal levels (0.8 microM) up to 5 microM also produced the switch from facilitation to inhibition in the receptor response. The existence of this activity-dependent switch in the presynaptic control of glutamate release suggests that release facilitation is limited to conditions under which an appropriate clearance of synaptic glutamate exists, probably to prevent the neurotoxic accumulation of glutamate in the synapse.

Switch from facilitation to inhibition of excitatory synaptic transmission by group I mGluR desensitization.

We have explored whether the desensitization of metabotropic glutamate receptors (mGluRs) coupled to phosphoinositide hydrolysis affects the role that they play in modulating glutamate release. In hippocampal nerve terminals, the agonist 3,5-dihydroxyphenylglycine (DHPG) facilitated evoked glutamate release, but a second stimulation 5 min later reduced rather than facilitated release. After a 30 min interval between stimulations, DHPG again facilitated glutamate release. In hippocampal slices, DHPG caused an inhibition of excitatory postsynaptic currents (EPSCs) recorded from CA1 neurons. However, when the effects of ambient glutamate were prevented, mGluR activation initially induced a facilitation of synaptic transmission, followed by an inhibition. We conclude that group I mGluRs have a dual action on glutamate release, switching from facilitatory to inhibitory upon receptor desensitization triggered by low concentrations of glutamate.

The metabotropic glutamate receptor 1 is not involved in the facilitation of glutamate release in cerebrocortical nerve terminals.

In this study we have addressed the identification of the metabotropic glutamate receptor (mGluR) involved in the facilitation of glutamate release in nerve terminals from the cerebral cortex. mGluR1 and 5 are coupled to phosphoinositide hydrolysis and the activation of these receptors with the specific agonist 3,5-dihydroxyphenylglycine (DHPG) enhances the release of glutamate. We have examined whether mGluR1 is responsible for this modulatory effect by preparing nerve terminals from mGluR 1 deficient mice. The Ca2+-dependent glutamate release evoked by a submaximal depolarization is enhanced by the agonist DHPG in nerve terminals from both wild and mutant mice. This result is consistent with the finding that the mGluR agonist also induces a similar increase in the levels of diacylglycerol (DAG) in the nerve terminals from wild and mutant mice. Moreover, the activity-dependent switch from facilitation to inhibition of release, observed when a second stimulation of the receptor is applied shortly after (5 min) the first pulse, was also observed in the mutant mice. These results indicate therefore, that the facilitation of glutamate release is unlikely to be due to the activation of mGluR1 but related to another phosphoinositide coupled mGluR.

Modulation of glutamate release by a nitric oxide/cyclic GMP-dependent pathway.

The mechanism by which changes in cyclic GMP (cGMP) regulate glutamate release was investigated in rat cerebrocortical nerve terminals. The elevation of cGMP levels by inhibition of cGMP-phosphodiesterase with 2-o-propoxy-phenyl-8-azapurin-6-one (zaprinast) reduced the Ca(2+)-dependent glutamate release evoked by depolarization with 30 mM KCl or 1 mM 4-aminopyridine. The nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine also enhanced cGMP and reduced glutamate release. In addition, the membrane-permeable analogs 8-bromoguanosine 3':5'-cyclic monophosphate (8-Br-cGMP) and N,2'-o-dibutyrylguanosine (dbcGMP) at 10 microM also mimic glutamate release inhibition. The reduction in glutamate release was observed with no modifications in the ATP/ADP ratio, and was reversed in the presence of the protein kinases inhibitor [N-[2-(methylamino)ethyl]-5-isoquinoline sulfonamide, HCl] (H-8). Interestingly, higher concentrations of dbcGMP (1 mM) abolished the inhibition observed with low concentrations although no facilitation was observed. This finding seems to indicate the existence of a dual role for cGMP in the control of glutamate exocytosis.

Presynaptic modulation of glutamate release targets different calcium channels in rat cerebrocortical nerve terminals.

We have studied which type/s of Ca2+-channel/s support glutamate exocytosis and its modulation by presynaptic receptors in cerebrocortical nerve terminals. Depolarization of nerve terminals with 30 mM KCl induced a Ca2+-dependent release of 3.64 +/- 0.25 nmol/mg of protein. The addition of either 2 microM omega-conotoxin-GVIA or 200 nM omega-agatoxin-IVA reduced the KCl-evoked release by 47.7 +/- 3.5% and 70.4 +/- 8.9% respectively, and by 85.7 +/- 4.1% when both toxins were co-applied. The activation of adenosine A1 receptors with N6-cyclohexyladenosine or the activation of metabotropic glutamate receptors with L(+)-2-amino-4-phosphonobutyrate inhibited the KCl-evoked release by 41.0 +/- 5.9 and 54.3 +/- 10% respectively. The extent of these inhibitions was not altered by the prior addition of 2 microM omega-conotoxin-GVIA but they were significantly enhanced when omega-agatoxin-IVA was added together with the adenosine A1 receptor agonist or the metabotropic glutamate receptor agonist, suggesting that omega-conotoxin-GVIA-sensitive and not omega-agatoxin-IVA-sensitive Ca2+-channels are involved in the action of these inhibitory receptors. By contrast, the facilitation of glutamate release that follows the activation of the protein kinase C, either with phorbol esters or with the stimulation of phospholipase C-linked metabotropic receptors, was expressed by both omega-conotoxin-GVIA-sensitive and omega-agatoxin-sensitive Ca2+-channels. It is concluded that different Ca2+-channels support the modulation of glutamate release by presynaptic receptors.

Two components of glutamate exocytosis differentially affected by presynaptic modulation.

The total Ca(2+)-dependent release of glutamate induced by depolarization of cerebrocortical nerve terminals with KCl was analyzed into a fast and a slow component. The fast component exhibited a decay time of < 1 s and accounted for 0.95 +/- 0.10 nmol of glutamate, whereas the slow component, which exhibited a decay time of 52 +/- 7 s, accounted for the release of 2.48 +/- 0.19 nmol of glutamate. These two components were differentially affected by the Ca2+ chelator BAPTA, the divalent cation Sr2+, or the botulinum neurotoxin A. The adenosine A1 receptor agonist N6-cyclohexyladenosine strongly reduced the fast component without altering the slow component. In contrast, the inhibitory effect of arachidonic acid and the facilitatory action of the metabotropic glutamate receptor agonist (1S, 3R)-1-aminocyclopentane-1, 3-dicarboxylic acid were observed as a decrease and an increase, respectively, in the two components. It is concluded, first, that the fast and slow components correspond to the release of docked and mobilized vesicles, respectively, and second, that presynaptic modulation more significantly alters the fast component of release.