Zsolt Juranyi

Egis Gyógyszergyár Nyrt., Budapeŝto, Budapest, Hungary

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Publications (21)50.67 Total impact

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    ABSTRACT: The most dominant hypotheses for the pathogenesis of schizophrenia have focused primarily upon hyperfunctional dopaminergic and hypofunctional glutamatergic neurotransmission in the central nervous system. The therapeutic efficacy of all atypical antipsychotics is explained in part by antagonism of the dopaminergic neurotransmission, mainly by blockade of D(2) dopamine receptors. N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia can be reversed by glycine transporter type-1 (GlyT-1) inhibitors, which regulate glycine concentrations at the vicinity of NMDA receptors. Combined drug administration with D(2) dopamine receptor blockade and activation of hypofunctional NMDA receptors may be needed for a more effective treatment of positive and negative symptoms and the accompanied cognitive deficit in schizophrenia. To investigate this type of combined drug administration, rats were treated with the atypical antipsychotic risperidone together with the GlyT-1 inhibitor Org-24461. Brain microdialysis was applied in the striatum of conscious rats and determinations of extracellular dopamine, DOPAC, HVA, glycine, glutamate, and serine concentrations were carried out using HPLC/electrochemistry. Risperidone increased extracellular concentrations of dopamine but failed to influence those of glycine or glutamate measured in microdialysis samples. Org-24461 injection reduced extracellular dopamine concentrations and elevated extracellular glycine levels but the concentrations of serine and glutamate were not changed. When risperidone and Org-24461 were added in combination, a decrease in extracellular dopamine concentrations was accompanied with sustained elevation of extracellular glycine levels. Interestingly, the extracellular concentrations of glutamate were also enhanced. Our data indicate that coadministration of an antipsychotic with a GlyT-1 inhibitor may normalize hypofunctional NMDA receptor-mediated glutamatergic neurotransmission with reduced dopaminergic side effects characteristic for antipsychotic medication.
    Neurochemical Research 12/2010; 35(12):2096-106. · 2.13 Impact Factor
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    ABSTRACT: Single neuron firing rate was recorded from dorsal raphe nucleus of anesthetized rats. The firing rate of raphe neurons varied from 4 to 8 discharge per second before drug administration and this neuronal activity was decreased by L-701,324 (2 mg/kg i.v. injection), a competitive antagonist of glycineB binding site of N-methyl-D-aspartate (NMDA) receptors. The glycine transporter type-1 (GlyT1) antagonists Org-24461 (10 mg/kg i.v.) and NFPS (3 mg/kg i.v.) reversed the inhibitory effect of L-701,324 on single neuron activity recorded from dorsal raphe nucleus of the rat. Org-24461 and NFPS both tended to increase the raphe neuronal firing rate also when given alone but their effect was not significant. This finding serves further evidence that glutamate released from axon terminals of the cortico-striatal projection neurons stimulates serotonergic neurons in the raphe nuclei and this effect is mediated at least in part by postsynaptic NMDA receptors. Thus, GlyT1 inhibitors are able to reverse the hypofunctional state of NMDA receptors, suggesting that these drugs may have beneficial therapeutic effects in neurological and psychiatric disorders characterized with impaired NMDA receptor-mediated transmission.
    Neurochemistry International 02/2008; 52(1-2):130-4. · 2.66 Impact Factor
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    ABSTRACT: Glycine is a critical factor in ischemia as reduced astrocytic and increased extracellular glycine levels aggravate the neurotoxic effect of glutamate and consequently, increase the extent of brain damage. Extracellular levels of glycine are primarily regulated by the plasma membrane glycine transporter 1. In the present study, we examined the effects of transient ischemia (1 h occlusion of the middle cerebral artery; followed by 0 h, 0.5 h, 1 h, 2 h, 4 h, 24 h or 48 h reperfusion) on immunoreactivity and mRNA expression of glycine transporter 1 in the rat forebrain. In control animals, glycine transporter 1-immunoreactivity was strong in diencephalic and certain telencephalic structures, moderate in the globus pallidus, and rather low in the cortex and striatum. In situ hybridization studies revealed a similar distribution pattern of glycine transporter 1 mRNA expression. One hour occlusion of the middle cerebral artery resulted in a significant decrease in ipsilateral glycine transporter 1-immunoreactivity and mRNA expression in a circumscribed region of the preoptic/hypothalamic area; both the immunoreactivity and mRNA exhibited further reductions with increasing reperfusion time. In contrast, the cerebral cortex and the globus pallidus showed an increase of glycine transporter 1-immunoreactivity after 0.5 h reperfusion; the elevation proved to be transient in the somatosensory cortex and remained sustained in the globus pallidus after longer reperfusion times. Western blot analysis of globus pallidus samples from the ipsilateral side confirmed higher glycine transporter 1 protein levels. These results suggest an elevated expression of the transporter protein facilitating the glial uptake of glycine from the extracellular space. However, glycine transporter 1 mRNA expression was not significantly different in the penumbra regions from the corresponding contralateral sites of the injury. Together, these findings indicate that post-translational mechanisms are of primary importance in elevating glycine transporter 1 protein levels following transient ischemia.
    Neurochemistry International 01/2008; 52(4-5):799-808. · 2.66 Impact Factor
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    ABSTRACT: Although levodopa is the current "gold standard" for treatment of Parkinson's disease, there has been disputation on whether AMPA receptor antagonists can be used as adjuvant therapy to improve the effects of levodopa. Systemic administration of levodopa, the precursor of dopamine, increases brain dopamine turnover rate and this elevated turnover is believed to be essential for successful treatment of Parkinson's disease. However, long-term treatment of patients with levodopa often leads to development of dyskinesia. Therefore, drugs that feature potentiation of dopamine turnover rate and are able to reduce daily levodopa dosages might be used as adjuvant in the treatment of patients suffering from Parkinson's disease. To investigate such combined treatment, we have examined the effects of two non-competitive AMPA receptor antagonists, GYKI-52466 and GYKI-53405, alone or in combination with levodopa on dopamine turnover rate in 6-hydroxydopamine-lesioned striatum of the rat. We found here that repeated administration of levodopa, added with the peripheral DOPA decarboxylase inhibitor carbidopa, increased dopamine turnover rate after lesioning the striatum with 6-hydroxydopamine. Moreover, combination of levodopa with GYKI-52466 or GYKI-53405 further increased dopamine turnover enhanced by levodopa administration while the AMPA receptor antagonists by themselves failed to influence striatal dopamine turnover. We concluded from the present data that potentiation observed between levodopa and AMPA receptor antagonists may reflect levodopa-sparing effects in clinical treatment indicating the therapeutic potential of such combination in the management of Parkinson's disease.
    Brain Research Bulletin 04/2007; 71(5):501-7. · 2.94 Impact Factor
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    ABSTRACT: 2,3,5-Triphenyltetrazolium chloride (TTC) staining measures tissue viability used to evaluate infarct size. The goal of this study was to compare viability of neuronal tissue during the early phases of ischemia-reperfusion assessed either by perfusion of the brain with TTC solution transcardially, in vivo, or by staining brain slices, in vitro. The middle cerebral artery was occluded for 1 h in male SPRD rats and then reperfused for 0, 1, 4, 8, 16 and 24 h. Ischemic damage was evaluated by TTC staining, in vivo and in vitro, and by histology (Luxol Fast Blue and Fluoro-Jade staining, electron microscopy). Core volume of tissue injury measured in vivo was large at 0 h and steadily decreased by 50% (p<0.001) up to 16 h, but substantially increased from 16 to 24 h of reperfusion. In contrast, a significant core volume appeared at 4 h only, in vitro, and gradually increased up to 24 h. Core volume was larger in vivo than in vitro at all times except at 16 h when the opposite was observed. Evans blue administered intracardially stained TTC-negative areas at 1 and 24 h. Histology covered the evolution of serious tissue injury but also demonstrated some morphologically preserved neurons in the infracted area at 24 h. Formation of formazan from TTC can depend on both the staining method and the metabolic burden of the brain tissue causing uncertainties in the volume of ischemia-induced brain injury measured by TTC staining.
    Brain Research 10/2006; 1116(1):159-65. · 2.88 Impact Factor
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    ABSTRACT: Cholinesterase inhibitors including donepezil, rivastigmine, and galantamine and the N-methyl-D-aspartate (NMDA) antagonist, memantine are the medications currently approved for the treatment of Alzheimer's disease (AD). In addition to their beneficial effects on cognitive and functional domains typically disrupted in AD, these agents have also been shown to slow down the emergence of behavioral and psychotic symptoms associated with this disease. However, the underlying mechanisms for these therapeutic effects remain poorly understood and could involve effects of these medications on non-cholinergic or non-glutamatergic neurotransmitter systems respectively. These considerations prompted us to initiate a series of investigations to examine the acute and chronic effects of donepezil (Aricept (+/-)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-1 hydrochloride and memantine (1-amino-3,5-dimethyladamantane hydrochloride C12H21N.HCl)). The present study focuses on the acute effects of donepezil and memantine on brain extracellular levels of acetylcholine, dopamine, serotonin, norepinephrine and their metabolites. We assayed changes in the ventral and dorsal hippocampus and the prefrontal and medial temporal cortex by microdialysis. Memantine resulted in significant increases in extracellular dopamine (DA), norepinephrine (NE), and their metabolites, in the cortical regions, and in a reduction of DA in the hippocampus. Donepezil produced an increase in extracellular DA in the cortex and in the dorsal hippocampus. Norepinephrine increased in the cortex; with donepezil it increased in the dorsal hippocampus and the medial temporal cortex, and decreased in the ventral hippocampus. Interestingly both compounds decreased extracellular serotonin (5HT) levels. The metabolites of the neurotransmitters were increased in most areas. We also found an increase in extracellular acetylcholine (ACh) by memantine in the nucleus accumbens and the ventral tegmental area. Our results suggest both region and drug specific neurotransmitter effects of these agents as well as some similarities. We conclude that drugs influencing cognitive mechanisms induce changes in a number of neurotransmitters with the changes being both region and drug specific. Release and metabolism are altered and extracellular neurotransmitter levels can be increased or decreased by the drugs. Other studies are in progress to determine the pharmacological effects associated with chronic treatment with these compounds, which may be more pertinent to the clinical situation in which patients take these medications for months or years.
    Brain Research Bulletin 04/2006; 69(2):204-13. · 2.94 Impact Factor
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    ABSTRACT: The ionotropic glutamate receptor NMDA is allosterically modulated by glycine, a coagonist, its presence is an absolute requirement for receptor activation. The transport of glycine in glutamatergic synapse is carried out by glycine transporter-1 (GlyT1), a Na+/Cl(-)-dependent carrier molecule. The primary role of GlyT1 is to maintain glycine concentrations below saturation level at postsynaptic NMDA receptors. Several isoforms of GlyT1 (a-e) have been identified, which are expressed both in glial and neuronal cell membranes. GlyT1 operates bidirectionally: it decreases synaptic glycine concentration when operates in normal mode and releases glycine from glial cells as operates in a reverse mode. It is expected that non-transportable, non-competitive inhibitors of GlyT1 may have therapeutic value in CNS disorders characterized by hypofunctional NMDA receptor-mediated glutamatergic neurotransmission. Accordingly, GlyT1 inhibitors exhibited antipsychotic profile in a number of animal tests. The first promising in vitro and in vivo experiments with glycine itself, and its N-methyl analogue, sarcosine, had initiated the syntheses of potential GlyT1 inhibitors with more complex structures, in which, however, the glycine or sarcosine moiety had always been incorporated. Those attempts led to the development of two compounds, ALX-5407 and Org-24461 with high inhibitory potency; however, none of which is now considered as a drug candidate due, most probably, to safety and/or pharmacokinetic issues. More recently, several structurally new series of highly potent inhibitors with no aminomethylcarboxy group have also been discovered. Some of them might be expected to fulfill all requirements for clinical development. The new generation of GlyT1 inhibitors may represent a novel treatment of patients suffering from schizophrenia and/or other neuropathological conditions.
    Current Medicinal Chemistry 02/2006; 13(9):1017-44. · 3.72 Impact Factor
  • Current Medicinal Chemistry - CURR MEDICINAL CHEM. 01/2006; 13(9):1017-1044.
  • European Neuropsychopharmacology - EUR NEUROPSYCHOPHARMACOL. 01/2006; 16.
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    ABSTRACT: Midbrain slices containing the dorsal and medial raphe nuclei were prepared from rat brain, loaded with [3H]serotonin ([3H]5-HT), superfused, and the electrically induced efflux of radioactivity was determined. The nonselective 5-HT receptor agonist 5-carboxamido-tryptamine (5-CT; 0.001 to 1 microM) inhibited the electrically stimulated [3H]5-HT overflow from raphe nuclei slices (IC50 of 3.34 +/- 0.37 nM). This effect of 5-CT on [3H]5-HT overflow was antagonized by the 5-HT7 receptor antagonist SB-258719 (10 microM) and the 5-HT(1B/1D) antagonist SB-216641 (1 microM), the IC50 values for 5-CT in the presence of SB-258719 and SB-216641 were 94.23 +/- 4.84 and 47.81 +/- 4.66 nM. The apparent pA2 values for SB-258719 and SB-216641 against 5-CT were 6.43 and 7.12, respectively. The inhibitory effect of 5-CT on [3H]5-HT overflow was weakly antagonized by 10 microM of WAY-100635, a 5-HT1A receptor antagonist (IC50 6.65 +/- 0.56 nM, apparent pA2 4.99). The antagonist effect of SB-258719 (10 microM) on 5-CT-evoked [3H]5-HT overflow inhibition was also determined in the presence of 1 microM SB-216641 or 1 microM SB-216641 and 10 microM WAY-100635, and additive interactions were found between the antagonists of 5-HT7 and 5-HT1 receptor subtypes. Addition of the Na+ channel blocker tetrodotoxin (1 microM) in the presence of SB-216641 (1 microM) and WAY-100635 (10 microM) attenuated the inhibitory effect of 5-CT on KCl-induced [3H]5-HT overflow. These findings indicate that 5-CT inhibits [3H]5-HT overflow from raphe nuclei slices of the rat by stimulation of 5-HT7 and 5-HT(1B/1D receptors, whereas the role of 5-HT1A receptors in this inhibition is less pronounced. They also suggest that 5-HT7 receptors are probably not located on serotonergic neurons and thus may serve as heteroreceptors in regulation of 5-HT release in the raphe nuclei. 5-CT (0.1 microM) also inhibited [3H]glutamate release, and SB-258719 (10 microLM) suspended this effect. We therefore speculated that the axon terminals of the glutamatergic cortico-raphe neurons may possess 5-HT7 receptors that inhibit glutamate release, which consequently leads to decreased activity of serotonergic neurons. The postulated glutamatergic-serotonergic interaction in the raphe nuclei was further evidenced by the finding that N-methyl-D-aspartate and AMPA enhanced [3H]5-HT release.
    Neurochemical Research 09/2004; 29(8):1487-97. · 2.13 Impact Factor
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    ABSTRACT: Stroke or cerebrovascular accident reduces blood flow and decreases oxygen supply (ischemia) in brain tissue. This may be resulted from vascular obstruction when a blood vessel is blocked or by hemorrhage when bleeding occurs into the brain tissue. Decrease in oxygen supply shifts pH to acidosis and increases extracellular K+ concentration, which depolarizes neural cell membrane. Anoxic depolarization leads to excessive release of glutamate, which then activates various glutamate receptors in the synapse or the extrasynaptic space. Opening of ionotropic glutamate receptors (NMDA, AMPA and kainate receptors) causes influx of Na+ through the activated glutamate-gated ion channels. In response to anoxia, Ca2+ also enters the cells in excessive amounts via activated NMDA receptors and Ca2+-permeable AMPA receptors. This will lead to activation of several Ca2+-dependent intracellular signal transduction pathways (proteases, kinases, endonucleases, lipoxygeneses and nitric oxide synthase), which ultimately leads to neural death (Vizi et al., 1996; Parsons et al., 1998).
    Advances in experimental medicine and biology 02/2004; 541:21-37. · 1.83 Impact Factor
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    ABSTRACT: The release of [3H]dopamine was measured in rat corticostriatal slice preparations that contained the striatum and the adjacent prefrontal cortex to maintained glutamatergic corticostriatal afferentation. These slices were prepared from either nontreated or 6-hydroxydopamine-pretreated rats. The slices were loaded with [3H]dopamine, submerged in a two-compartment bath so that the cortical region was contained in one compartment, the corpus callosum was passed through a silicone greased slot, and the striatal region was contained in the other compartment. The cortical and the striatal parts were superfused with Krebs-bicarbonate buffer independently. The release of [3H]dopamine was determined from the striatal part at rest and in response to electrical stimulation of the cortical area. Electrical stimulation of the cortical part increased the release of [3H]dopamine from the striatal part of the slices, and this release was found to be higher after lesion of the nigrostriatal dopaminergic pathway with 6-hydroxydopamine. Cortically evoked [3H]dopamine release was even higher in the presence of the dopamine precursor L-DOPA after 6-hydroxdopamine lesion. Perfusion of GYKI-53405, a noncompetitive AMPA receptor antagonist, in combination with L-DOPA further increased both basal and stimulation-evoked [3H]dopamine release, whereas GYKI-53405 by itself did not influence basal [3H]dopamine outflow from striatum. These findings indicate that, in parkinsonian striatum, the stimulatory effect of L-DOPA on dopamine release is potentiated by AMPA receptor blockade, and the antiparkinsonian effect of GYKI-53405 may be due to its L-DOPA sparing effect.
    Critical Reviews in Neurobiology 02/2004; 16(1-2):129-39.
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    ABSTRACT: A new method has been developed to investigate corticostriatal glutamatergic influence on [3H]dopamine release in striatum in complex corticostriatal slice preparation in vitro. Horizontal slices containing the striatum and the adjacent prefrontal cortex of rat brain were cut in a plane that maintains corticostriatal connections. After incubation with [3H]dopamine, slices were submerged in a two-compartment bath so that the cortical region was contained entirely in one compartment, corpus callosum passed through a silicone greased slot, and the striatal region was contained in the other compartment. A cannula was placed just above the striatal part of the slice and effluent was collected with a peristaltic pump, released tritiated materials were counted with a liquid scintillation counter. Electric field stimulation of cortex increased the release of [3H]dopamine in the striatum. Bicuculline (1 mM) increased the basal and stimulated release of [3H]dopamine in the striatum in response to cortical stimulation of cortex indicating the GABAergic control on dopamine release. This method allows investigation of the effect of cortical stimulation on glutamate-dopamine-GABA interactions in the striatum in vitro that might help to understand better the neurochemical background of schizophrenia or Parkinson's disease.
    Journal of Neuroscience Methods 07/2003; 126(1):57-67. · 2.11 Impact Factor
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    ABSTRACT: The objective of this study was to study how the outflow of []purines is altered during a brief period of ischemic-like conditions in superfused hippocampal slices and to show whether it is regulated by P2 purinoceptors and the nitric oxide (NO) pathway. The outflow of []purines increased in response to 5 min of combined hypoxia/hypoglycemia. High performance liquid chromatography analysis verified the efflux of []adenosine-triphosphate, []adenosine-diphosphate, []adenosine-monophosphate, []adenosine, []inosine, and []hypoxanthine in response to ischemic-like conditions. The P2 receptor antagonists suramin and pyridoxal-phosphate-6-azophenyl-2′-4′-disulphonic-acid-tetrasodium (PPADS) reduced significantly the []purine efflux evoked by ischemic-like conditions, showing that P2 purinoceptors are involved in the initiation of purine outflow. The NO synthase inhibitor N-nitro-l-arginine-methyl-ester (l-NAME) attenuated significantly the []purine outflow, evoked by ischemic-like conditions, while 7-nitroindazole (7-NI) caused only a mild decrease in the outflow. The NO donor sodium nitroprusside increased significantly the basal efflux of []purines. In summary, a brief period of combined hypoxia/hypoglycemia induced the efflux of ATP in addition to the outflow of other purines. Since P2 receptor antagonists decreased the []purine outflow evoked by ischemic-like conditions we propose that ATP, acting on P2 purinoceptors, is responsible for further efflux of purines after ischemic-like period. It seems likely that NO is also involved in the regulation of purine outflow, since inhibition of NO production attenuated the []purine outflow, evoked by ischemic-like conditions, while exogenous NO facilitated the basal outflow.
    Brain Research 04/1999; · 2.88 Impact Factor
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    ABSTRACT: It is now widely accepted that ATP functions as a signalling substance in the nervous system. The presence of P2 receptors mediating the action of extracellular ATP in brain regions involved in hormonal regulation raises the possibility that a similar role for ATP might also exist in the neuroendocrine system. In this study, the release from the rat isolated neurohypophysis preparation of endogenous ATP, oxytocin and vasopressin (AVP) were measured simultaneously using luciferin-luciferase and RIA techniques. After 70 min preperfusion, electrical field stimulation caused a rapid increase in the amount of ATP in the effluent and the release of AVP and oxytocin also increased stimulation-dependently. Inhibition of voltage-dependent Na+ channels by tetrodotoxin (1 microM) reduced the stimulation-evoked release of AVP and oxytocin; however, the evoked release of ATP remained unaffected. The effect of endogenous ATP on the hormone secretion was tested by suramin (300 microM), the P2 receptor antagonist. Suramin significantly increased the release of AVP, and the release of oxytocin was also enhanced. ATP, when applied to the superfusing medium, decreased the release of AVP, but not that of oxytocin, and its effect was prevented by suramin. ATP (60 nmol), added to the tissues, was readily decomposed to ADP, AMP and adenosine measured by HPLC combined with ultraviolet light detection, and the kinetic parameters of the enzymes responsible for inactivation of ATP (ectoATPase and ecto5'-nucleotidase) were also determined (Km=264+/-2.7 and 334+/-165 microM and vmax=6.7+/-1.1 and 2.54+/-0.24 nmol/min per preparation (n=3) for ectoATPase and ecto5'-nucleotidase respectively). Taken together, our data demonstrate the stimulation-dependent release, P2 receptor-mediated action and extracellular metabolism of endogenous ATP in the posterior lobe of the hypophysis and indicate its role, as a paracrine regulator, in the local control of hormone secretion.
    Journal of Endocrinology 04/1999; 160(3):343-50. · 4.06 Impact Factor
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    ABSTRACT: Using histochemical and immunocytochemical methods, cholinergic nerve fibres were demonstrated in the rat adrenal cortex, primarily in the capsule and zona glomerulosa, and in the medulla. Some terminated among the glomerulosa cells or around blood vessels. Occasional fibres were also seen in the fasciculata, ending in islets of chromaffin tissue without ramifications on cortical cells. To clarify the role of cholinergic innervation, a microvolume perifusion system was used to study steroid production by the rat adrenal capsule-glomerulosa. Acetylcholine (ACh) itself had no reproducible effects; however, since variable amounts of endogenous ACh were present, the actions of antagonists were also studied. The M1 muscarinic receptor antagonist pirenzepine (10 and 100 microM) stimulated aldosterone secretion. This stimulation was abolished by co-incubation with carbachol, the M1 agonist McN A-343 and by atropine. We found that the action of pirenzepine was blocked by nifedipine (Ca2+ channel blocker), suggesting that pirenzepine (through release of endogenous ACh) provides an acute stimulus by enhancing Ca2+ inflow. Hemicholine, a choline uptake blocker, reduced the stimulatory effect of pirenzepine on steroid secretion, confirming that stimulation was of neural origin. Neither the non-selective muscarinic receptor antagonist atropine, the selective M1-M3 muscarinic receptor antagonist 4-DAMP, nor the selective M2 muscarinic receptor antagonist methoctramine influenced aldosterone output. Receptor-binding studies revealed the existence of M3 receptors in capsule-glomerulosa homogenates. We conclude that pirenzepine acts on presynaptic M1 autoreceptors to increase spontaneous ACh release from varicose axon terminals that lie in close proximity to the glomerulosa cells. In turn ACh may thus stimulate steroidogenesis acutely through M3 receptors. These results support the concept of a direct cholinergic influence on zona glomerulosa function in the rat.
    Journal of Endocrinology 06/1998; 157(2):305-15. · 4.06 Impact Factor
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    ABSTRACT: In addition to hypophyseal control, steroid synthesis and secretion in the adrenal cortex is also under direct local neural modulation. We obtained morphological and neurochemical evidence that a substantial proportion of the noradrenergic nerve endings lie in close proximity to zona glomerulosa cells without making synaptic contact, thus providing evidence for a direct local modulatory role of catecholamines in steroid secretion. These noradrenergic neurones, like other noradrenergic neurones in the central nervous system, are able to take up dopamine (DA), convert it partly into noradrenaline (NA) and to release both NA and DA together with the co-transmitter ATP when neuronal activity drives them to do so. These catecholamines and ATP may reach zona glomerulosa cells via diffusion in a paracrine way and modulate the synthesis of aldosterone. The presence of ecto-Ca-ATPases, enzymes that may terminate the effect of ATP, was demonstrated around the nerve profiles indicating that not only ATP but its metabolites (ADP, AMP, adenosine) can also influence the production of aldosterone. These data strongly support the possibility of a paracrine, non-synaptic modulatory role of catecholamines and ATP in the regulation of adrenocortical steroid secretion.
    Hormone and Metabolic Research 01/1998; 30(6-7):323-8. · 2.15 Impact Factor
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    ABSTRACT: The release of endogenous ATP, measured by the luciferin-luciferase assay, and the release of [3H]acetylcholine from the isolated superior cervical ganglion of the rat loaded with [3H]choline were studied simultaneously. Electrical field stimulation enhanced the release of endogenous ATP and acetylcholine in a [Ca2+]o-dependent manner. The Na+ channel blocker, tetrodotoxin (1 microM) inhibited the stimulation-evoked release of endogenous ATP and of [3H]acetylcholine, but did not change the resting release. The release of ATP was dependent on the frequency of stimulation between 2 and 10 Hz. when the number of shocks was kept constant (360 shocks), while acetylcholine was not released in a frequency-dependent fashion. Ten days after cutting of the preganglionic nerve of the superior cervical ganglion the stimulation-evoked release of acetylcholine and ATP was abolished and the uptake of [3H]choline was significantly reduced but not inhibited. Hexamethonium, (100 microM) a nicotinic acetylcholine receptor antagonist, significantly reduced the release of both acetylcholine and ATP, indicating a positive feedback modulation of ACh and ATP release. 8-Cyclopentyl-1,3-dipropylxanthine (10 nM), the selective A1-adenosine receptor antagonist exhibited similar effect on the release of ATP and acetylcholine: both of them were augmented, showing that the stimulation-evoked release of ATP and acetylcholine are under the inhibitory control of A1-adenosine receptors. When the temperature was reduced to 7 degrees C to inhibit carrier-mediated processes, the resting and stimulated release of acetylcholine was not changed. Conversely, the release of ATP in response to stimulation was reduced by 79.9 +/- 5.6%, and the basal release was also almost completely blocked. Carbamylcholine by itself was able to release ATP, but not acetylcholine, in a hexamethonium-inhibitable manner, even from ganglia whose preganglionic nerve had been cut 10 days prior to experiments, suggesting that ATP release can occur in response to nicotinic receptor stimulation of postsynaptic cells. The breakdown of ATP or AMP by superior cervical ganglion was measured by high performance liquid chromatography combined with UV detection. ATP and AMP, added to the tissues, were readily decomposed: the Km (apparent Michaelis constant) and Vmax (apparent maximal velocity) were 475 +/- 24 microM and 3.50 +/- 0.18 nmol/min per mg for ectoATPase and 1550 +/- 120 microM and 14.5 +/- 0.9 nmol/min per mg tissue for 5'-nucleotidase. In addition, by using electron microscopic enzyme histochemistry, the presence of ectoATPase was also shown in the superior cervical ganglion. It is concluded that endogenous ATP and acetylcholine are released simultaneously in response to stimulation of preganglionic nerve terminals in the superior cervical ganglion in a [Ca2+]o-dependent, tetrodotoxin-sensitive manner and is metabolized by ectoenzymes present in the tissue. The dissociation of the release of ATP and acetylcholine at different stimulation frequencies and temperatures shows that the release-ratio of acetylcholine and ATP can vary upon the condition of stimulation: this can reflect either the different composition of synaptic vesicles in the preganglionic nerve terminals or a significant contribution of non-exocytotic, carrier-mediated type of release of ATP to the bulk release.
    Neuroscience 09/1997; 79(3):893-903. · 3.12 Impact Factor
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    ABSTRACT: Both [3H]noradrenaline ([3H]NA) and ATP were released in response to supramaximal electric field stimulation in superfused rat adrenal capsule-glomerulosa preparations. The voltage-dependent potassium channel blocker 4-aminopyridine enhanced, while the ATP-sensitive potassium channel blocker glibenclamide failed to affect the stimulation-evoked release of [3H]NA. The selective alpha 2-adrenoceptor antagonist CH-38083 enhanced the evoked release of [3H]NA while the P2 receptor agonist ATP and alpha, beta-methylene-ATP failed to affect it. Neither the adenosine A1 receptor agonist N6-cyclopentyl-adenosine (CPA) nor the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) influenced the stimulation-evoked [3H]NA release. The data showed that ATP was released from capsule-glomerulosa preparations in response to field stimulation together with but independently from [3H]NA, and that the local noradrenergic varicose axon terminals are not equipped with purinoceptors sensitive to ATP and/or adenosine. High concentrations of ATP also stimulated steroid hormone secretion in vitro, and thus may have a physiological role in this tissue. The presence of ecto-Ca(2+)-ATPases, enzymes able to terminate the effect of ATP, was demonstrated around the nerve profiles at the border of the capsule and zona glomerulosa tissue.
    Journal of Endocrinology 05/1997; 153(1):105-14. · 4.06 Impact Factor
  • Annals of the New York Academy of Sciences 06/1995; 757:84-99. · 4.38 Impact Factor

Publication Stats

426 Citations
50.67 Total Impact Points

Institutions

  • 2004–2010
    • Egis Gyógyszergyár Nyrt.
      Budapeŝto, Budapest, Hungary
    • Acheuron Hungary Ltd.
      Algyő, Csongrád, Hungary
  • 2008
    • University of Szeged
      • Department of Public Health
      Szeged, Csongrad megye, Hungary
  • 1997
    • Hungarian Academy of Sciences
      • Department of Pharmacology
      Budapest, Budapest fovaros, Hungary