RESUMEN
BACKGROUND: Atrial fibrillation (AF) is a major cause of stroke in older people. Exacerbated by age and co-morbidities, residents of care homes are more likely to develop AF and less likely to receive oral anticoagulants. AIM: To determine the prevalence of AF using the design and methodology of the Pharmacists Detecting Atrial Fibrillation (PDAF) study in a care home setting. METHOD: A cross-sectional AF screening pilot study within four UK care homes, three residential and one residential/nursing. Screening followed the original PDAF protocol: a manual pulse check, followed by a single-Lead ECG (SLECG, AliveCor Kardia Mobile (KMD)) delivered by a pharmacist. All recorded SLECG were reviewed by a cardiologist and any residents requiring follow-up investigations were referred to their general practitioner. RESULTS: Fifty-three of 112 care home residents participated. From 52 SLECGs recorded, the cardiologist interpreted 13.5% (7/52) as having possible AF of which 9.6% (5/52) were previously unknown. One resident with previously unknown AF received anticoagulation. CONCLUSION: This study has shown a need for AF screening in care homes and that elements of the PDAF screening protocol are transferable in this setting. Early diagnosis and treatment of AF are essential to reduce the risk of stroke in this population.
Asunto(s)
Fibrilación Atrial , Accidente Cerebrovascular , Humanos , Anciano , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/epidemiología , Proyectos Piloto , Estudios Transversales , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/prevención & control , Electrocardiografía , Palpación , Tamizaje Masivo/métodosRESUMEN
TRAAK (KCNK4, K2P4.1) is a mechanosensitive two-pore domain potassium (K2P) channel. Due to its expression within sensory neurons and genetic link to neuropathic pain it represents a promising potential target for novel analgesics. In common with many other channels in the wider K2P sub-family, there remains a paucity of small molecule pharmacological tools. Specifically, there is a lack of molecules selective for TRAAK over the other members of the TREK subfamily of K2P channels. We developed a thallium flux assay to allow high throughput screening of compounds and facilitate the identification of novel TRAAK activators. Using a library of â¼1200 drug like molecules we identified Aprepitant as a small molecule activator of TRAAK. Aprepitant is an NK-1 antagonist used to treat nausea and vomiting. Close structural analogues of Aprepitant and a range of NK-1 antagonists were also selected or designed for purchase or brief chemical synthesis and screened for their ability to activate TRAAK. Electrophysiology experiments confirmed that Aprepitant activates both the 'long' and 'short' transcript variants of TRAAK. We also demonstrated that Aprepitant is selective and does not activate other members of the K2P superfamily. This work describes the development of a high throughput assay to identify potential TRAAK activators and subsequent identification and confirmation of the novel TRAAK activator Aprepitant. This discovery identifies a useful tool compound which can be used to further probe the function of TRAAK K2P channels.
Asunto(s)
Aprepitant/farmacología , Canales de Potasio/metabolismo , Línea Celular , Humanos , Activación del Canal Iónico/efectos de los fármacos , Antagonistas del Receptor de Neuroquinina-1/farmacología , Técnicas de Placa-Clamp , Receptores de Neuroquinina-1/metabolismo , Relación Estructura-Actividad , Talio/metabolismoRESUMEN
BACKGROUND AND PURPOSE: The TASK subfamily of two pore domain potassium channels (K2P) encodes for leak K currents, contributing to the resting membrane potential of many neurons and regulating their excitability. TASK1 and TASK3 channels are regulated by a number of pharmacological and physiological mediators including cannabinoids such as methanandamide. In this study, we investigate how methanandamide blocks these channels. EXPERIMENTAL APPROACH: Currents through wild type and mutated TASK1 and TASK3 channels expressed in modified HEK-293 cells were measured using whole-cell electrophysiological recordings in the presence and absence of methanandamide. KEY RESULTS: Methanandamide (3 microM) produced substantial block of hTASK1, hTASK3 and mTASK3 channels but was most potent at blocking hTASK3 channels. Block of these channels was irreversible unless cells were washed with buffer containing bovine serum albumin. Mutation of the distal six amino acids of TASK1 did not alter methanandamide inhibition, whilst C terminal truncation of TASK3 channels caused a small but significant reduction of inhibition. However, deletion of six amino acids (VLRFLT) at the interface between the final transmembrane domain and cytoplasmic C terminus of TASK3 channels gave functional currents that were no longer inhibited by methanandamide or by activation of GPCRs. CONCLUSIONS AND IMPLICATIONS: Methanandamide potently blocked TASK3 and TASK1 channels and both methanandamide and G protein-mediated inhibition converged on the same intracellular gating pathway. Physiologically, methanandamide block of TASK1 and TASK3 channels may underpin a number of CNS effects of cannabinoids that are not mediated through activation of CB1 or CB2 receptors.
Asunto(s)
Ácidos Araquidónicos/farmacología , Canales de Potasio de Dominio Poro en Tándem/antagonistas & inhibidores , Canales de Potasio de Dominio Poro en Tándem/fisiología , Aminoácidos/genética , Animales , Sitios de Unión/genética , Bovinos , Línea Celular , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Concentración de Iones de Hidrógeno , Potenciales de la Membrana/efectos de los fármacos , Ratones , Mutagénesis Sitio-Dirigida/métodos , Mutación , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/fisiología , Técnicas de Placa-Clamp , Fosforilación/efectos de los fármacos , Canales de Potasio de Dominio Poro en Tándem/genética , Proteína Quinasa C/metabolismo , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/fisiología , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/fisiología , Albúmina Sérica Bovina/farmacología , Zinc/farmacologíaRESUMEN
The pharmacological action of vitamin E on the mechanical activity of isolated guinea pig colonic smooth muscle was examined in normoxic and hypoxic conditions. In hypoxia, but not normoxia, alpha-tocopherol (1-160 microM) evoked rapid concentration-dependent contractions from the colon. This was also seen with other members of the vitamin E family, and potency measurements gave EC(50) values (microM) of 10.6 +/- 0.9 for D-alpha-tocopherol, 6.0 +/- 1.2 for D-beta-tocopherol, 7.5 +/- 0.7 for D-gamma-tocopherol, and 6.1 +/- 1.5 for D-delta-tocopherol. This order of potency for the components of the vitamin differs from previously studied bioassay systems and from their antioxidant activity. A range of potent natural and synthetic antioxidants was not active in this system. Compounds with structural similarities to the side chain of vitamin E produced similar stimulatory responses and some, like phytol, were more potent than the vitamin (EC(50): 1.0 +/- 0.2 microM), whereas ring structures related to the vitamin, like Trolox C, antagonized the stimulant responses in a concentration-dependent manner. Therefore, this model system measures, directly, vitamin E-induced responses through a mechanism that does not appear to be related to the known antioxidant capacity of these agents.
Asunto(s)
Antioxidantes/farmacología , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , alfa-Tocoferol/farmacología , Animales , Antioxidantes/química , Ácido Ascórbico/farmacología , Cromanos/farmacología , Colon Transverso/efectos de los fármacos , Colon Transverso/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Cobayas , Hipoxia , Técnicas In Vitro , Contracción Isométrica/efectos de los fármacos , Masculino , Metacrilatos/farmacología , Músculo Liso/fisiología , Fitol/farmacología , Pirogalol/farmacología , Relación Estructura-Actividad Cuantitativa , Estereoisomerismo , Temperatura , Terpenos/química , Terpenos/farmacología , alfa-Tocoferol/químicaRESUMEN
Neuronal ion channels are gated pores whose opening and closing is usually regulated by factors such as voltage or ligands. They are often selectively permeable to ions such as sodium, potassium or calcium. Rapid signalling in neurons requires fast voltage sensitive mechanisms for closing and opening the pore. Anything that interferes with the membrane voltage can alter channel gating and comparatively small changes in the gating properties of a channel can have profound effects. Extremely low frequency electrical or magnetic fields are thought to produce, at most, microvolt changes in neuronal membrane potential. At first sight, such changes in membrane potential seem orders of magnitude too small to significantly influence neuronal signalling. However, in the central nervous system, a number of mechanisms exist which amplify signals. This may allow such small changes in membrane potential to induce significant physiological effects.
Asunto(s)
Campos Electromagnéticos , Activación del Canal Iónico/fisiología , Activación del Canal Iónico/efectos de la radiación , Canales Iónicos/fisiología , Canales Iónicos/efectos de la radiación , Neuronas/fisiología , Neuronas/efectos de la radiación , Canales Iónicos/química , Potenciales de la Membrana/fisiología , Potenciales de la Membrana/efectos de la radiación , Red Nerviosa/fisiología , Red Nerviosa/efectos de la radiación , Neuronas/química , Canales de Potasio/química , Canales de Potasio/fisiología , Canales de Potasio/efectos de la radiación , Dosis de Radiación , Relación Estructura-ActividadRESUMEN
IK(SO) is a standing-outward potassium current found in cerebellar granule neurons which is inhibited by the activation of muscarinic M(3) receptors. However the pathway between muscarinic receptor activation and current inhibition is unknown. Using two structurally distinct inhibitors of the activation of MEK1 (mitogen activated protein (MAP) kinase kinase 1), PD 98059 and U 0126, we have shown that the MAP kinase signalling cascade does not appear to underlie muscarinic inhibition of IK(SO), recorded using whole-cell patch-clamp methods. Nevertheless, both PD 98059 and U 0126 caused an inhibition of IK(SO) when applied acutely with 30 microM of each compound producing around 50% inhibition of the current. In addition, U 0125, which is structurally related to U 0126 but has a much lower potency for inhibiting MEK1 activation, was also able to inhibit IK(SO) to a similar degree. Neither the inhibition by PD 98059 nor that by U 0126 was found to be voltage dependent. This was true whether the IK(SO) current was outward or inward. Block of IK(SO) by these two compounds may compromise interpretation of studies in intact neuronal preparations when they are used as MEK1 inhibitors.
Asunto(s)
Butadienos/farmacología , Cerebelo/fisiología , Inhibidores Enzimáticos/farmacología , Flavonoides/farmacología , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Nitrilos/farmacología , Bloqueadores de los Canales de Potasio , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Cerebelo/citología , Cerebelo/efectos de los fármacos , Electrofisiología , Activación Enzimática/efectos de los fármacos , Femenino , MAP Quinasa Quinasa 1 , Masculino , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Antagonistas Muscarínicos/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: To evaluate the association between vertebral "end plate sclerosis" and neck pain. DESIGN: A retrospective study was carried out of lateral cervical spine radiographs with a Picture Archive and Communication System (PACS). PATIENTS: Two hundred patients' files were randomly assessed, comprising four equal groups, A to D. The mean ages of the patients were 62+/-7.4 years, 61+/-7.5 years, 40+/-5.6 years and 23+/-5.6 years respectively. In group A, all patients had symptoms of neck pain and a radiographic diagnosis of "end plate sclerosis" of the cervical spine. In groups B to D, asymptomatic patients were recruited and their age groups were 50-69, 30-49 and 10-29 years respectively. Using the PACS, the radiographic density and the sagittal diameter, thickness and area of the end plates at the C5 level were measured. RESULTS AND CONCLUSIONS: No significant differences were found in the radiographic density of the end plates either between the symptomatic and asymptomatic groups (groups A and B), or between different age groups (groups B, C and D). A significant increase in end plate area and thickness was found, however, in both group B (P<0.005) and group C (P<0.01) in comparison with group D. This indicates that the extent of end plate sclerosis increases with age. Our results suggest that the radiographic density of cervical vertebral end plates correlates neither with neck pain nor with increasing age. The radiological sign of "end plate sclerosis" may be over-reported, further limiting its value in the assessment of patients with cervical spondylosis.
Asunto(s)
Disco Intervertebral/patología , Enfermedades de la Columna Vertebral/patología , Adolescente , Adulto , Anciano , Vértebras Cervicales/diagnóstico por imagen , Niño , Femenino , Humanos , Disco Intervertebral/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Dolor de Cuello/diagnóstico por imagen , Dolor de Cuello/etiología , Radiografía , Sistemas de Información Radiológica , Estudios Retrospectivos , Esclerosis/patología , Enfermedades de la Columna Vertebral/diagnóstico por imagenRESUMEN
Cerebellar granule neurons (CGNs) possess a standing outward potassium current (IK(SO)) which shares many similarities with current through the two-pore domain potassium channel TASK-1 and which is inhibited following activation of muscarinic acetylcholine receptors. The action of muscarine on IK(SO) was unaffected by the M2 receptor antagonist methoctramine (100 nM) but was blocked by the M3 antagonist zamifenacin, which, at a concentration of 100 nM, shifted the muscarine concentration-response curve to the right by around 50-fold. Surprisingly, M3 receptor activation rarely produced a detectable increase in [Ca2+]i unless preceded by depolarization of the cells with 25 mM K+. Experiments with thapsigargin and ionomycin suggested that the endoplasmic reticulum Ca2+ stores in CGNs were depleted at rest. In contrast, cerebellar glial cells in the same fields of cells possessed substantial endoplasmic reticulum Ca2+ stores at rest. Pretreatment of the cells with BAPTA AM, thapsigargin or the phospholipase C (PLC) inhibitor U-73122 all blocked the muscarine-induced Ca2+ signal but had little or no effect on muscarinic inhibition of IK(SO). Raising [Ca2+]i directly with ionomycin caused a small but significant inhibition of IK(SO). It is concluded that muscarine acts on M3 muscarinic acetylcholine receptors both to inhibit IK(SO) and to mobilize Ca2+ from intracellular stores in CGNs. While the mobilization of Ca2+ occurs through activation of PLC, this does not seem to be the primary mechanism underlying muscarinic inhibition of IK(SO).
Asunto(s)
Calcio/fisiología , Cerebelo/fisiología , Ácido Egtácico/análogos & derivados , Conductividad Eléctrica , Canales de Potasio/metabolismo , Receptores Muscarínicos/fisiología , Animales , Animales Recién Nacidos , Señalización del Calcio/efectos de los fármacos , Células Cultivadas , Cerebelo/citología , Cerebelo/efectos de los fármacos , Quelantes/farmacología , Dioxoles/farmacología , Ácido Egtácico/farmacología , Estrenos/farmacología , Femenino , Masculino , Potenciales de la Membrana , Antagonistas Muscarínicos/farmacología , Piperidinas/farmacología , Potasio/metabolismo , Isoformas de Proteínas/fisiología , Pirrolidinonas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor Muscarínico M3 , Tapsigargina/farmacologíaRESUMEN
The nature of metabotropic purinergic and muscarinic receptor-mediated increases in intracellular calcium in primary rat neocortical neurons and glial cells has been investigated using fluorescence imaging techniques. Bath-application of ATP and muscarine (10 microM) elicited a characteristic increase in intracellular calcium in both neurons and glial cells. The profile of this response consisted of an initial transient increase followed by a sustained elevation (the plateau phase) which was dependent on extracellular calcium. Examination of the pharmacological basis of the purinergic receptor-mediated calcium response using 10 microM 2-methyl-thio ATP (MeS-ATP) and UTP revealed that P(2Y) receptor activation underlies this response. The calcium influx pathway responsible for the sustained calcium response was inhibited by metal ions. In both cell types La(3+) and Zn(2+) (100 microM) effectively inhibited the plateau phase of the response, whilst 100 microM Ni(2+) had little or no effect. In conclusion, P(2Y) purinergic and muscarinic receptor activation evoke a sustained increase in intracellular calcium in neocortical neurons and glial cells. This response has similar characteristics to that we have previously described following mGlu(5) activation. We propose that in these cell types stimulation of metabotropic receptors coupled to phosphoinositide turnover activates a common calcium entry pathway that is distinct from voltage-gated calcium channels and resembles store-operated calcium entry.
Asunto(s)
Calcio/metabolismo , Neocórtex/metabolismo , Neuroglía/metabolismo , Neuronas/metabolismo , Receptores Muscarínicos/metabolismo , Receptores Purinérgicos/metabolismo , Adenosina Trifosfato/farmacología , Animales , Animales Recién Nacidos , Células Cultivadas , Lantano/farmacología , Neocórtex/citología , Neocórtex/efectos de los fármacos , Neuroglía/citología , Neuroglía/efectos de los fármacos , Neuronas/citología , Neuronas/efectos de los fármacos , Níquel/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Purinérgicos P2 , Factores de Tiempo , Zinc/farmacologíaRESUMEN
Activation of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors in cerebellar granule cells during perforated-patch whole-cell recordings activated an inward current at negative voltages which was followed, after a delay, by the inhibition of an outward potassium current at voltages positive to -20 mV. The activated inward current was inwardly rectifying suggesting that the AMPA receptors were Ca2+-permeable. This was confirmed by direct measurements of intracellular calcium where Ca2+ rises were seen following AMPA receptor activation in Na+-free external solution. Ca2+ rises were equally large in the presence of 100 microM Cd2+ to block voltage-gated Ca2+ channels. Specific voltage-protocols, allowing selective activation of the delayed rectifier potassium current (KV) and the transient A current (KA), showed that kainate inhibited KV, but not to any great extent KA. The inhibition of KV was blocked by the AMPA receptor antagonist CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) and was no longer observed when the KV current was abolished with high concentrations of Ba2+. The responses to kainate were not altered by pre-treating the cells with pertussis toxin, suggesting that the AMPA receptor stimulation of the G-protein Gi cannot account for the effects observed. Replacing extracellular Na+ with choline did not alter the inhibition of KV by kainate, however, removing extracellular Ca2+ reduced the kainate response. The inhibition of KV by kainate was unaffected by the presence of 100 microM Cd2+. The guanylyl cyclase inhibitor, ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), did not alter kainate inhibition of KV. It is concluded that ion influx (particularly Ca2+ ions) through AMPA receptor channels following receptor activation leads to an inhibition of KV currents in cerebellar granule neurons.
Asunto(s)
Calcio/fisiología , Cerebelo/metabolismo , Agonistas de Aminoácidos Excitadores/farmacología , Ácido Kaínico/farmacología , Neuronas/metabolismo , Bloqueadores de los Canales de Potasio , Canales de Potasio con Entrada de Voltaje , Canales de Potasio , Receptores AMPA/agonistas , Animales , Calcio/metabolismo , Células Cultivadas , Cerebelo/citología , Cerebelo/efectos de los fármacos , Gránulos Citoplasmáticos/ultraestructura , Canales de Potasio de Tipo Rectificador Tardío , Electrofisiología , Femenino , Colorantes Fluorescentes , Fura-2 , Masculino , Potenciales de la Membrana/fisiología , Neuronas/efectos de los fármacos , Neuronas/ultraestructura , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Sodio/fisiologíaRESUMEN
Cerebellar granule neurons (CGNs) are one of the most populous cells in the mammalian brain. They express an outwardly rectifying potassium current, termed a "standing-outward" K(+) current, or IK(SO), which does not inactivate. It is active at the resting potential of CGNs, and blocking IK(SO) leads to cell depolarization. IK(SO) is blocked by Ba(2+) ions and is regulated by activation of muscarinic M(3) receptors, but it is insensitive to the classical broad-spectrum potassium channel blocking drugs 4-aminopyridine and tetraethylammonium ions. The molecular nature of this important current has yet to be established, but in this study, we provide strong evidence to suggest that IK(SO) is the functional correlate of the recently identified two-pore domain potassium channel TASK-1. We show that IK(SO) has no threshold for activation by voltage and that it is blocked by small extracellular acidifications. Both of these are properties that are diagnostic of TASK-1 channels. In addition, we show that TASK-1 currents expressed in Xenopus oocytes are inhibited after activation of endogenous M(3) muscarinic receptors. Finally, we demonstrate that mRNA for TASK-1 is found in CGNs and that TASK-1 protein is expressed in CGN membranes. This description of a functional two-pore domain potassium channel in the mammalian central nervous system indicates its physiological importance in controlling cell excitability and how agents that modify its activity, such as agonists at G protein-coupled receptors and hydrogen ions, can profoundly alter both the neuron's resting potential and its excitability.
Asunto(s)
Cerebelo/fisiología , Gránulos Citoplasmáticos/fisiología , Neuronas/fisiología , Canales de Potasio de Dominio Poro en Tándem , Canales de Potasio/fisiología , Animales , Secuencia de Bases , Células Cultivadas , Cerebelo/citología , Cerebelo/metabolismo , Gránulos Citoplasmáticos/metabolismo , Cartilla de ADN , Potenciales de la Membrana/fisiología , Proteínas del Tejido Nervioso , Neuronas/metabolismo , Canales de Potasio/genética , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
1. The effect of the antidepressant drug, fluoxetine on neuronal delayed rectifier (KV) potassium (K) currents was investigated using perforated-patch whole-cell electrophysiological recording methods. 2. Fluoxetine was an effective inhibitor of KV currents in cerebellar granule neurons (CGNs) and also inhibited recombinant KV1.1 channels expressed in Chinese hamster ovary (CHO) cells. 3. Fluoxetine had an IC50 of 11 microM in CGNs but was slightly less potent on KV1.1 channels (IC50=55 microM). Interestingly, fluoxetine was a much more potent inhibitor of KV1.1 expressed in mammalian cells than has been found previously for the same homomeric channel expressed in Xenopus oocytes. 4. At concentrations that produced around 50% block, the shape of the KV currents in the presence of fluoxetine was simply scaled down when compared to control currents. 5. The effect of fluoxetine on KV currents in CGNs was neither voltage-dependent nor dependent on the channels being in their open state. Both of these observations suggest that fluoxetine does not act as a simple open channel blocking agent. 6. It is concluded that block of KV currents in mammalian neurons can occur at therapeutic levels of fluoxetine. This could lead to an increase in neuronal excitability and this effect may contribute to the therapeutic antidepressant action of fluoxetine.
Asunto(s)
Antidepresivos de Segunda Generación/farmacología , Fluoxetina/farmacología , Neuronas/efectos de los fármacos , Bloqueadores de los Canales de Potasio , Canales de Potasio con Entrada de Voltaje , Animales , Células CHO , Cerebelo/citología , Cerebelo/efectos de los fármacos , Cerebelo/fisiología , Cricetinae , Canales de Potasio de Tipo Rectificador Tardío , Femenino , Cinética , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Inhibición Neural , Neuronas/fisiología , Técnicas de Placa-Clamp , Canales de Potasio/biosíntesis , Canales de Potasio/genética , Canales de Potasio/fisiología , Ratas , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/genética , TransfecciónRESUMEN
OBJECTIVE: To assess the safety of performing iliac arterial stenting as an outpatient procedure. METHODS: Retrospective analysis of safety including all patients referred for elective iliac arterial stenting over a 1-year period. Sources of data for the analysis included pre- and post-stenting vascular surgical consultation records, hospital case notes, diagnostic and interventional angiography reports, computerized laboratory data, nursing records from our angiography holding area, and the results of routine post-stenting telephone follow-up. RESULTS: There were 29 outpatient iliac stenting procedures in 28 patients (19 men and 9 women, age range 41.0 to 79.8 years, mean age 66.1 years). Of these 29 procedures, 17 involved unilateral iliac stenting, and 12 involved bilateral iliac stenting. Adjunctive renal artery angioplasty was performed in 1 patient and internal iliac angioplasty and stenting were performed in 2 patients. A total of 51 stents were deployed through 42 femoral punctures via introducer sheaths ranging in size from 6 to 8 French. Percutaneous hemostatic closing devices were used in 6 punctures. Two patients required overnight inpatient observation for moderate-size hematomas; these had no clinical sequelae. All others were discharged safely 5 to 6 hours after sheath removal. No clinically significant sequelae were identified in any patient. CONCLUSION: Arterial stenting can be performed safely on an outpatient basis.
Asunto(s)
Atención Ambulatoria , Angioplastia , Arteriosclerosis/terapia , Stents , Adulto , Anciano , Arteriosclerosis/diagnóstico por imagen , Femenino , Humanos , Arteria Ilíaca/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Radiografía , Radiología Intervencionista , Estudios Retrospectivos , Resultado del TratamientoAsunto(s)
Arteriopatías Oclusivas/cirugía , Embolia/cirugía , Trombectomía/instrumentación , Enfermedad Aguda , Anciano , Arteriopatías Oclusivas/diagnóstico por imagen , Embolia/diagnóstico por imagen , Femenino , Humanos , Pierna/irrigación sanguínea , Masculino , Persona de Mediana Edad , RadiografíaRESUMEN
Activation of metabotropic glutamate receptors is known to elicit a rise in intracellular Ca2+ and the present study was undertaken to see whether they also modulate the intracellular pH (pHi) of neurons and glia. Measurements of the pHi of neurons and astrocytes were made with the ratiometric fluorescent dye 2',7'-biscarboxyethyl-5,6-carboxyfluorescein. In the absence of bicarbonate, stimulation with the specific metabotropic glutamate receptor agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid caused a fall in pHi in both astrocytes and neurons. In the presence of bicarbonate, stimulation with 25 microM 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid elicited a rise in pHi in the astrocytes, while the neurons responded with a small acidification. The astrocytic alkalinization could also be elicited by the specific group I metabotropic glutamate receptor agonist (S)-3-hydroxyphenylglycine but not by the group II agonist (2S,1'S,2'S)-(2-carboxycyclopropyl)glycine or by the group III agonist L(+)-2-amino-4-phosphonobutyric acid. The alkalinization of glial cells could be reduced by preloading the cells with BAPTA, but not by removal of extracellular Ca2+. Depolarization of the astrocytes with potassium elicited a small alkalinization, but stimulation with 100 microM 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid in high potassium medium elicited a further alkalinization. It is concluded that activation of group I metabotropic glutamate receptors leads to an alkalinization of astrocytes by a process that involves an elevation of intracellular Ca2+. The pHi changes that follow activation of the metabotropic glutamate receptors may play a role in initiation of glial proliferation following cerebral injury.
Asunto(s)
Corteza Cerebral/citología , Neuroglía/metabolismo , Neuronas/metabolismo , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/metabolismo , Animales , Animales Recién Nacidos , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Calcio/metabolismo , Células Cultivadas , Corteza Cerebral/efectos de los fármacos , Quelantes/farmacología , Cicloleucina/análogos & derivados , Cicloleucina/farmacología , Ácido Egtácico/análogos & derivados , Ácido Egtácico/farmacología , Inhibidores Enzimáticos/farmacología , Glicina/análogos & derivados , Glicina/farmacología , Concentración de Iones de Hidrógeno , Neuroglía/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
1. Dissociated rat superior cervical ganglion (SCG) neurons have been shown to possess a hyperpolarization-activated inwardly rectifying chloride current. The current was not altered by changes in external potassium concentration, replacing external cations with NMDG (N-methyl-D-glucamine) or by addition of 10 mM caesium or barium ions. 2. The reversal potential of the current was altered by changing external anions. The anion selectivity of the current was Cl- > Br- > I- > cyclamate. All substituted permeant anions also blocked the current. 3. The current was blocked by DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid), 9AC (anthracene-9-carboxylic acid) and NPPB (5-nitro-2-(3-phenylpropylamino)benzoic acid) but was unaffected by SITS (4-acetamido-4'-isothiocyanatostilbene- 2,2'-disulphonic acid) and niflumic acid. The effective blockers were voltage dependent; DIDS and NPPB were more effective at depolarized potentials while 9AC was more effective at hyperpolarized potentials. 4. The current was enhanced by extracellular acidification and reduced by extracellular alkalinization. Reducing external osmolarity was without effect in conventional whole-cell recording but enhanced current amplitude in those perforated-patch recordings where little current was evident in control external solution. 5. The current in SCG neurons was blocked by external cadmium and zinc. ClC-2 chloride currents expressed in Xenopus oocytes were also sensitive to block by these divalent ions and by DIDS but the sensitivity of ClC-2 to block by cadmium ions was lower than that of the current in SCG neurons. 6. Reverse transcriptase-polymerase chain reaction (RT-PCR) experiments showed the presence of mRNA for ClC-2 in SCG neurons but not in rat cerebellar granule cells which do not possess a hyperpolarization-activated Cl- current. 7. The data suggest that ClC-2 may be functionally expressed in rat SCG neurons. This current may play a role in regulating the internal chloride concentration in these neurons and hence their response to activation of GABAA receptors.