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1.
Mol Psychiatry ; 23(4): 824-832, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-28397841

RESUMEN

The mechanisms of action of the rapid antidepressant effects of ketamine, an N-methyl-D-aspartate glutamate receptor antagonist, have not been fully elucidated. This study examined the effects of ketamine on ligand binding to a metabotropic glutamatergic receptor (mGluR5) in individuals with major depressive disorder (MDD) and healthy controls. Thirteen healthy and 13 MDD nonsmokers participated in two [11C]ABP688 positron emission tomography (PET) scans on the same day-before and during intravenous ketamine administration-and a third scan 1 day later. At baseline, significantly lower [11C]ABP688 binding was detected in the MDD as compared with the control group. We observed a significant ketamine-induced reduction in mGluR5 availability (that is, [11C]ABP688 binding) in both MDD and control subjects (average of 14±9% and 19±22%, respectively; P<0.01 for both), which persisted 24 h later. There were no differences in ketamine-induced changes between MDD and control groups at either time point (P=0.8). A significant reduction in depressive symptoms was observed following ketamine administration in the MDD group (P<0.001), which was associated with the change in binding (P<0.04) immediately after ketamine. We hypothesize that glutamate released after ketamine administration moderates mGluR5 availability; this change appears to be related to antidepressant efficacy. The sustained decrease in binding may reflect prolonged mGluR5 internalization in response to the glutamate surge.


Asunto(s)
Depresión/diagnóstico por imagen , Ketamina/metabolismo , Receptor del Glutamato Metabotropico 5/efectos de los fármacos , Adulto , Antidepresivos/farmacología , Encéfalo/metabolismo , Radioisótopos de Carbono , Estudios de Casos y Controles , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/metabolismo , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Ácido Glutámico/metabolismo , Humanos , Ketamina/farmacología , Masculino , Tomografía de Emisión de Positrones/métodos , Receptor del Glutamato Metabotropico 5/metabolismo
2.
Transl Psychiatry ; 5: e693, 2015 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-26645628

RESUMEN

The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in the pathophysiology of mood and anxiety disorders and is a potential treatment target in major depressive disorder (MDD). This study compared brain mGluR5 binding in elderly patients suffering from MDD with that in elderly healthy volunteers using positron emission tomography (PET) and [(11)C]ABP688. Twenty elderly (mean age: 63.0 ± 6.3) subjects with MDD and twenty-two healthy volunteers in the same age range (mean age: 66.4 ± 7.3) were examined with PET after a single bolus injection of [(11)C]ABP688, with many receiving arterial sampling. PET images were analyzed on a region of interest and a voxel level to compare mGluR5 binding in the brain between the two groups. Differences in [(11)C]ABP688 binding between patients with early- and late-onset depression were also assessed. In contrast to a previously published report in a younger cohort, no significant difference in [(11)C]ABP688 binding was observed between elderly subjects with MDD and healthy volunteers. [(11)C]ABP688 binding was also similar between subgroups with early- or late-onset depression. We believe this is the first study to examine mGluR5 expression in depression in the elderly. Although future work is required, results suggest potential differences in the pathophysiology of elderly depression versus depression earlier in life.


Asunto(s)
Encéfalo/metabolismo , Radioisótopos de Carbono , Trastorno Depresivo Mayor/metabolismo , Oximas , Tomografía de Emisión de Positrones , Piridinas , Receptor del Glutamato Metabotropico 5/metabolismo , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto
3.
Int J Toxicol ; 30(6): 611-8, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21994241

RESUMEN

Sprague Dawley rats (10/sex/group) were given a single intravenous (iv) dose of CUMI-101 to determine acute toxicity of CUMI-101 and radiation dosimetry estimations were conducted in baboons with [(11)C]CUMI-101. Intravenous administration of CUMI-101 did not produce overt biologically or toxicologically significant adverse effects except transient hypoactivity immediately after dose in the mid- and high-dose groups, which is not considered to be a dose-limiting toxic effect. No adverse effects were observed in the low-dose group. The no observed adverse effect level (NOAEL) is considered to be 44.05 µg/kg for a single iv dose administration in rats. The maximum tolerated dose (MTD) was estimated to be 881 µg/kg for a single iv dose administration. The Medical Internal Radiation Dose (MIRDOSE) estimates indicate the maximum permissible single-study dosage of [(11)C]CUMI-101 in humans is 52 mCi with testes and urinary bladder as the critical organ for males and females, respectively.


Asunto(s)
Piperazinas/farmacocinética , Agonistas del Receptor de Serotonina 5-HT1/farmacocinética , Triazinas/farmacocinética , Animales , Radioisótopos de Carbono , Femenino , Ligandos , Masculino , Papio , Piperazinas/toxicidad , Tomografía de Emisión de Positrones , Radiometría , Ratas , Ratas Sprague-Dawley , Agonistas del Receptor de Serotonina 5-HT1/toxicidad , Distribución Tisular , Triazinas/toxicidad
4.
Biol Psychiatry ; 50(5): 313-22, 2001 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-11543733

RESUMEN

BACKGROUND: Reduced dopaminergic transmission has been implicated in the pathophysiology of major depression. The aim of the present study was to measure striatal D(2) receptor availability and amphetamine-induced dopamine release in nonpsychotic, unmedicated, unipolar patients during an episode of major depression. METHODS: The striatal equilibrium specific to nonspecific partition coefficient (V(3)") of the D(2) receptor antagonist [(123)I]IBZM was measured with single photon emission computerized tomography before and after amphetamine administration in 9 depressed subjects and 10 matched healthy control subjects. RESULTS: No significant differences were observed in preamphetamine D(2) receptor availability between depressed patients (0.73 +/- 0.08) and control subjects (0.78 +/- 0.10, p =.23). Amphetamine-induced reduction in [(123)I]IBZM V(3)" (DeltaV(3)") was similar in depressed patients (-9.8 +/- 5.5%) and control subjects (-7.8 +/- 2.5%, p =.32). Amphetamine induced a transient improvement in symptomatology in depressed patients, but this improvement did not correlate with [(123)I]IBZM DeltaV(3)". CONCLUSIONS: This study did not replicate previously reported alterations in striatal D(2) receptor density in depressed patients and suggests that stimulant-induced dopamine release is not altered in major depression.


Asunto(s)
Anfetamina/farmacología , Cuerpo Estriado/fisiopatología , Trastorno Depresivo Mayor/fisiopatología , Dopamina/metabolismo , Receptores de Dopamina D2/fisiología , Tomografía Computarizada de Emisión de Fotón Único , Adolescente , Adulto , Anfetamina/farmacocinética , Benzamidas , Cuerpo Estriado/diagnóstico por imagen , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/psicología , Femenino , Humanos , Radioisótopos de Yodo , Masculino , Persona de Mediana Edad , Pirrolidinas , Receptores de Dopamina D2/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología
5.
Neuropsychopharmacology ; 24(3): 209-29, 2001 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11166513

RESUMEN

Augmentation of selective serotonin reuptake inhibitors (SSRIs) therapy by the 5-HT(1A) receptor agent pindolol may reduce the delay between initiation of antidepressant treatment and clinical response. This hypothesis is based on the ability of pindolol to block 5-HT(1A) autoreceptors in the dorsal raphe nuclei (DRN) and to potentiate the increase in 5-HT transmission induced by SSRIs. However, placebo-controlled clinical studies of pindolol augmentation of antidepressant therapy have reported inconsistent results. Here, we evaluated the occupancy of 5-HT(1A) receptors during treatment with pindolol controlled release (CR) in nine healthy volunteers with Positron Emission Tomography and [11C]WAY 100635. Subjects were studied four times: at baseline, following one week of pindolol CR 7.5 mg/day (4 and 10 hrs post dose), and following one dose of pindolol CR 30 mg(4 hrs post dose). Occupancy of the DRN was 40 +/- 29% on scan 2, 38 +/- 26% on scan 3, and 64 +/- 15% on scan 4. The average occupancy in all other regions was significantly lower at each doses (18 +/- 5% on scan 2, 12 +/- 3% on scan 3, and 42 +/- 4% on scan 4). These results suggest that the blockade in the DRN reached in clinical studies (7.5 mg/day) might be too low and variable to consistently augment the therapeutic effect of SSRIs. However, these data indicate that pindolol exhibits in vivo selectivity for the DRN 5-HT(1A) autoreceptors. As DRN selectivity is desirable for potentiation of 5-HT function, this observation represents an important proof of concept for the development of 5-HT(1A) agents in this application.


Asunto(s)
Trastornos del Humor/tratamiento farmacológico , Pindolol/farmacología , Piperazinas/uso terapéutico , Piridinas/uso terapéutico , Núcleos del Rafe/metabolismo , Receptores de Serotonina/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Adulto , Antidepresivos/uso terapéutico , Encéfalo/efectos de los fármacos , Humanos , Cinética , Imagen por Resonancia Magnética , Masculino , Pindolol/administración & dosificación , Pindolol/sangre , Pindolol/uso terapéutico , Piperazinas/sangre , Piperazinas/farmacocinética , Piridinas/sangre , Piridinas/farmacocinética , Receptores de Neurotransmisores/fisiología , Receptores de Serotonina 5-HT1 , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Transmisión Sináptica/fisiología , Tomografía Computarizada de Emisión
6.
J Nucl Med ; 41(9): 1465-77, 2000 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-10994724

RESUMEN

UNLABELLED: Abnormal brain regional densities of serotonin (5-hydroxytryptamine [5-HT]) transporters have been reported in postmortem studies in several neuropsychiatric conditions, such as major depression and schizophrenia. trans-1,2,3,5,6,10-beta-Hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]-isoquinoline ([11C]McN 5652) is the first PET radioligand successfully developed to label 5-HT transporters in the living human brain. The purpose of this study was to develop an imaging protocol and analytic method to measure regional 5-HT transporter binding potential (BP) with [11C]McN 5652 in humans. METHODS: The arterial input function and brain uptake of (+)-[11C]McN 5652 and (-)-[11C]McN 5652, the active and inactive enantiomers, respectively, were measured in 6 healthy volunteers. RESULTS: (+)-[11C]McN 5652 concentrated in brain regions rich in 5-HT transporters (midbrain, thalamus, basal ganglia, and medial temporal lobe structures), whereas the uptake of (-)-[11C]McN 5652 was more uniformly distributed. Total distribution volumes (V(T)) were derived using kinetic 2-compartment analysis and graphic analysis. V(T) derived by both methods were highly correlated. (+)-[11C]McN 5652 regional V(T) ranged from 18 +/- 2 mL/g in the cerebellum to 46 +/- 13 mL/g in the midbrain. (-)-[11C]McN 5652 regional VT ranged from 10 +/- 2 mL/g in the cerebellum to 14 +/- 3 mL/g in the thalamus. (+)-[11C]McN 5652 V(T) were higher than (-)-[11C]McN 5652 V(T) in all regions, including the cerebellum, a region devoid of 5-HT transporters. Blocking experiments were also performed in baboons with saturating doses of citalopram and in humans with nonsaturating doses of paroxetine. Cerebellar and neocortical (+)-[11C]McN 5652 V(T) were unaffected by pretreatment with 5-HT transporter blockers. In areas of high receptor concentration (midbrain, caudate, and thalamus) 5-HT transporter blockers decreased (+)-[11C]McN 5652 V(T) to the level of cerebellum (+)-[11C]McN 5652 V(T). CONCLUSION: These experiments indicate that the use of the difference between (+)- and (-)-[11C]McN 5652 V(T) to define specific binding to 5-HT transporters leads to an overestimation of specific binding. 5-HT transporter BP was derived as the difference between the regional and cerebellar (+)-[11C]McN 5652 V(T). BP values were in good agreement with the distribution of 5-HT transporters in the human brain, except for regions of relatively low 5-HT transporter concentration, such as the prefrontal cortex, where no specific binding was detected using (+)-[11C]McN 5652. (+)-[11C]McN 5652 is an appropriate radiotracer to quantify 5-HT transporters in regions with relatively high concentration of 5-HT transporters, such as the midbrain, thalamus, and basal ganglia, and should prove useful in elucidating abnormalities of 5-HT transmission in neuropsychiatric conditions.


Asunto(s)
Encéfalo/metabolismo , Proteínas Portadoras/metabolismo , Radioisótopos de Yodo/farmacocinética , Isoquinolinas/farmacocinética , Glicoproteínas de Membrana/metabolismo , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Antagonistas de la Serotonina/farmacocinética , Adulto , Encéfalo/diagnóstico por imagen , Proteínas Portadoras/análisis , Humanos , Cinética , Imagen por Resonancia Magnética , Masculino , Glicoproteínas de Membrana/análisis , Mesencéfalo/diagnóstico por imagen , Mesencéfalo/metabolismo , Valores de Referencia , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Distribución Tisular , Tomografía Computarizada de Emisión
7.
Nucl Med Biol ; 27(5): 487-92, 2000 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-10962256

RESUMEN

In several positron-emission tomography studies of human subjects, analyses of data from the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor radioligand, [(11)C]WAY-100635 ¿[carbonyl-(11)C]N-(2-(4-methoxy-phenyl)-1-piperazin-1-yl)ethyl)-N -(2 -pyridyl)cyclohexanecarboxamide¿ have shown a discrepancy between the outcome measure k(3)/k(4) (binding potential normalized to cerebellum) as estimated by the simplified reference region method and results obtained by conventional kinetic modeling with an arterial input function. The reference region method has yielded results that are lower than the conventional approach, with the relative underestimation appearing to be an increasing function of k(3)/k(4). We performed simulations on idealized data to identify the source of the discrepancy. Both the simplified reference tissue model (SRTM) and the original full reference tissue model (FRTM) were tested to determine (a) if the error in estimated k(3)/k(4) is dependent on the blood flow in the region of interest relative to the blood flow in the region of reference (R(1)) and on the receptor density in the region of interest (true k(3)/k(4)), and (b) which violation of the reference model assumptions were responsible for this effect. FRTM returned parameter estimates that were independent and accurate if the reference region was constructed precisely as a one-tissue compartment model. SRTM overestimated k(3)/k(4) when the reference region was constructed as a one-tissue compartment model and underestimated k(3)/k(4) when the reference region was constructed as a two-tissue compartment model (which is the case for [(11)C]WAY-100635). In both cases, the magnitude of the error in k(3)/k(4) returned by SRTM was dependent on true R(1) and true k(3)/k(4). In conclusion, the SRTM is associated with a bias in the derivation of k(3)/k(4) that is not a simple scaling factor. This magnitude of these errors should be carefully evaluated for each new radioligand.


Asunto(s)
Radioisótopos de Carbono , Piperazinas/farmacocinética , Piridinas/farmacocinética , Receptores de Serotonina/análisis , Antagonistas de la Serotonina/farmacocinética , Humanos , Modelos Biológicos , Racloprida/farmacocinética , Receptores de Serotonina 5-HT1
8.
Nucl Med Biol ; 27(5): 523-7, 2000 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-10962261

RESUMEN

Preclinical studies in rodents suggest that augmentation of serotonin reuptake inhibitors (SSRIs) therapy by the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor agent pindolol might reduce the delay between initiation of treatment and antidepressant response. This hypothesis is based on the ability of pindolol to potentiate the increase in serotonin (5-HT) transmission induced by SSRIs, an effect achieved by blockade of the 5-HT(1A) autoreceptors in the dorsal raphe nuclei (DRN). However, placebo-controlled clinical studies of pindolol augmentation of antidepressant therapy have reported inconsistent results. Here, we evaluated the occupancy of 5-HT(1A) receptors following treatment with controlled release pindolol in nine healthy volunteers with positron-emission tomography (PET). Each subject was studied four times: at baseline (scan 1), following 1 week of oral administration of pindolol CR (7.5 mg/day) at peak level, 4 h after the dose (scan 2), and at 10 h following the dose (scan 3), and following one dose of pindolol CR (30 mg) (at peak level, 4 h) (scan 4). Pindolol occupancy of 5-HT(1A) receptors was evaluated in the DRN and cortical regions as the decrease in binding potential (BP) of the radiolabelled selective 5-HT(1A) antagonist [carbonyl-(11)C]WAY-100635 or [carbonyl-(11)C] N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)cyclohexa necarboxamide abbreviated as [(11)C]WAY-100635. Pindolol dose-dependently decreased [(11)C]WAY-100635 BP. Combining all the regions, occupancy was 20 +/- 8% at scan 2, 14 +/- 8% at scan 3, and 44 +/- 8% at scan 4. The results of this study suggest that at doses used in clinical studies of augmentation of the SSRI effect by pindolol (2.5 mg t.i.d.), the occupancy of 5-HT(1A) receptors is moderate and highly variable between subjects. This factor might explain the variable results obtained in clinical studies. On the other hand, at each dose tested, pindolol occupancy of 5-HT(1A) receptors was higher in the DRN compared to cortical regions, demonstrating a significant in vivo selectivity for DRN 5-HT(1A) autoreceptors relative to cortico-limbic postsynaptic receptors. This selectivity is necessary for the potentiation of 5-HT transmission, and this finding represents an important proof of concept in the development of 5-HT(1A) agents for this application. Early evaluation of new drugs with PET imaging will enable rapid screening of compounds based on DRN selectivity and more appropriate determination of doses for clinical trials.


Asunto(s)
Pindolol/metabolismo , Receptores de Serotonina/análisis , Antagonistas de la Serotonina/metabolismo , Tomografía Computarizada de Emisión , Adulto , Química Encefálica , Humanos , Masculino , Persona de Mediana Edad , Núcleos del Rafe/química , Receptores de Serotonina 5-HT1
9.
J Cereb Blood Flow Metab ; 20(7): 1111-33, 2000 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-10908045

RESUMEN

Serotonin 5-HT(1A) receptors are implicated in the pathophysiology of neuropsychiatric conditions. The goal of this study was to evaluate methods to derive 5-HT(1A) receptor parameters in the human brain with positron emission tomography (PET) and [carbonyl-(11)C]WAY 100635. Five healthy volunteer subjects were studied twice. Three methods of analysis were used to derive the binding potential (BP), and the specific to nonspecific equilibrium partition coefficient (k3/k4). Two methods, kinetic analysis based on a three compartment model and graphical analysis, used the arterial plasma time-activity curves as the input function to derive BP and k3/k4. A third method, the simplified reference tissue model (SRTM), derived the input function from uptake data of a region of reference, the cerebellum, and provided only k3/k4. All methods provided estimates of regional 5-HT(1A) receptor parameters that were highly correlated. Results were consistent with the known distribution of 5-HT(1A) receptors in the human brain. Compared with kinetic BP, graphical analysis slightly underestimated BP, and this phenomenon was mostly apparent in small size-high noise regions. Compared with kinetic k3/k4, the reference tissue method underestimated k3/k4 and the underestimation was apparent primarily in regions with high receptor density. Derivation of BP by both kinetic and graphical analysis was highly reliable, with an intraclass correlation coefficient (ICC) of 0.84 +/- 0.14 (mean +/- SD of 15 regions) and 0.84 +/- 0.19, respectively. In contrast, the reliability of k3/k4 was lower, with ICC of 0.53 +/- 0.28, 0.47 +/- 0.28, and 0.55 +/- 0.29 for kinetic, graphical, and reference tissue methods, respectively. In conclusion, derivation of BP by kinetic analysis using the arterial plasma input function appeared as the method of choice because of its higher test-retest reproducibility, lower vulnerability to experimental noise, and absence of bias.


Asunto(s)
Encéfalo/metabolismo , Receptores de Serotonina/metabolismo , Adulto , Encéfalo/diagnóstico por imagen , Cerebelo/metabolismo , Estudios de Evaluación como Asunto , Humanos , Cinética , Masculino , Modelos Biológicos , Piperazinas/farmacocinética , Piridinas/farmacocinética , Receptores de Serotonina/sangre , Receptores de Serotonina 5-HT1 , Reproducibilidad de los Resultados , Antagonistas de la Serotonina/farmacocinética , Tomografía Computarizada de Emisión
10.
Psychiatry Res ; 82(3): 181-5, 1998 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-9754442

RESUMEN

Hypointensities (focal areas of decreased signal intensity) have been reported on T2 weighted magnetic resonance images (MRI) in normal aging and in some neurological disease processes. Increased concentrations of iron have been suggested as one cause of these hypointensities. In Alzheimer's Disease, data suggests that there is both a disruption in iron metabolism as well as the presence of T2 hypointensities. We endeavored to determine if the decreased signal intensities could be quantitatively determined and, if so, in what regions, in an effort to establish a non-invasive biological marker and diagnostic aide. We performed a quantitative analysis of the T2 signal intensities in 13 MRIs from AD patients and 16 age- and sex-matched control subjects. We found that while there were statistically significant differences in the intensities of the putamen and red nucleus, these differences were small. We were unable to detect differences in intensities in a whole slice or the frontal lobe. To our knowledge this is the first quantitative comparison of MRI signal intensities in Alzheimer's Disease.


Asunto(s)
Enfermedad de Alzheimer/patología , Encéfalo/patología , Hierro/metabolismo , Anciano , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Femenino , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Putamen/metabolismo , Putamen/patología
11.
Artículo en Inglés | MEDLINE | ID: mdl-9460090

RESUMEN

1. Alzheimer's Disease (AD) is accompanied by a disruption in iron metabolism. There is no universally accepted method for detecting brain iron. 2. The authors have developed a novel "ratio" method which uses the red nucleus as an internal reference. We postulated that this method would improve our sensitivity in detecting differences in MRI signal intensities and that it would allow us to measure brain iron deposition. 3. The ratio method reasonably reproduced previous reports of the normal deposition of iron in brain that occurs with aging. It failed to distinguish any differences in three brain areas: putamen, left frontal lobe and whole slice in AD patients versus age and sex matched controls. 4. It also failed to detect differences with AD progression or severity. 5. The ratio method itself warrants further investigation.


Asunto(s)
Envejecimiento/patología , Enfermedad de Alzheimer/patología , Imagen por Resonancia Magnética/métodos , Anciano , Anciano de 80 o más Años , Envejecimiento/metabolismo , Enfermedad de Alzheimer/metabolismo , Química Encefálica , Humanos , Procesamiento de Imagen Asistido por Computador , Hierro/metabolismo , Persona de Mediana Edad , Putamen/metabolismo , Putamen/patología
12.
J Gen Physiol ; 102(3): 503-23, 1993 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-8245821

RESUMEN

We have studied the effect of ascorbic acid on voltage-dependent calcium channels in pancreatic beta cells. Using the whole-cell and perforated-patch variants of the patch clamp technique to record calcium tail currents, we have shown that the slowly deactivating (SD) calcium channel, which is similar to the T-type channel in other cells, is inhibited in a voltage-dependent manner by ascorbic acid (AA). The other channels that carry inward current in beta cells, FD calcium channels and sodium channels, are unaffected by AA. Ascorbic acid causes a voltage-dependent decrease in the magnitude of the SD channel conductance which can be explained by the hypothesis that approximately 50-60% of the channels have their voltage dependence shifted by approximately 62 mV in the depolarizing direction. Thus, ascorbate appears to modify only a fraction of the SD channels. The activation kinetics of the ascorbate-modified channels are slower than control channels in a manner that is consistent with this hypothesis. Deactivation and inactivation kinetics are unaffected by ascorbate. These effects of ascorbate require metal ions, and it appears that some of the activity of ascorbate is due to a product of its metal catalyzed oxidation, perhaps dehydroascorbate.


Asunto(s)
Ácido Ascórbico/farmacología , Canales de Calcio/metabolismo , Islotes Pancreáticos/metabolismo , Animales , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/efectos de los fármacos , Células Cultivadas , Electrodos , Electrofisiología , Insulina/metabolismo , Islotes Pancreáticos/efectos de los fármacos , Cinética , Masculino , Metales/farmacología , Ratas , Ratas Sprague-Dawley
13.
J Membr Biol ; 122(2): 177-87, 1991 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-1654433

RESUMEN

We have used the nystatin perforated patch technique to study ionic currents in rat pancreatic beta-cells. The access resistance (Ra) between the pipette and the cell cytoplasm, measured by analyzing capacitive currents, decreased with a slow exponential time course (tau = 5.4 +/- 2.7 min) after seal formation. As Ra decreased, the magnitude of voltage-dependent K and Ca currents increased with a similar time course, and their activation kinetics became faster. After Ra stabilized, the macroscopic currents remained stable for up to an hour or more. When the final Ra was sufficiently low, Ca tail currents could be resolved which had properties similar to those recorded with the classical whole-cell technique. Two types of K channels could be characterized with perforated patch recordings of macroscopic K currents: (i) ATP-blockable K (KATP) channels which generate a time and voltage independent current that is blocked by glyburide and enhanced by pinacidil and (ii) voltage-dependent K (Kv) channels. Whole-cell recordings of KATP currents in the absence of ATP in the pipette showed that the maximum KATP conductance of the beta-cell was 83.8 +/- 40 nS. Perforated patch recordings show that the resting KATP conductance is 3.57 +/- 2.09 nS, which corresponds to about 4% of the channels being open in the intact beta-cell. In classical whole-cell recordings. Kv activation kinetics become faster during the first 10-15 min of recording, probably due to a dissipating Donnan potential. In perforated patch recordings where the Donnan potential is very small, Kv activation kinetics were nearly identical to the steady-state whole cell measurements.


Asunto(s)
Iones , Islotes Pancreáticos/citología , Adenosina Trifosfato/farmacología , Animales , Antihipertensivos/farmacología , Transporte Biológico/efectos de los fármacos , Transporte Biológico/fisiología , Calcio/metabolismo , Canales de Calcio/efectos de los fármacos , Canales de Calcio/fisiología , Células Cultivadas , Conductividad Eléctrica/efectos de los fármacos , Conductividad Eléctrica/fisiología , Gliburida/farmacología , Guanidinas/farmacología , Islotes Pancreáticos/fisiología , Islotes Pancreáticos/ultraestructura , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Nistatina/farmacología , Pinacidilo , Potasio/metabolismo , Canales de Potasio/efectos de los fármacos , Canales de Potasio/fisiología , Ratas , Ratas Endogámicas , Factores de Tiempo
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