RESUMEN

An 80-year-old male with recurrent thyroid cancer and a percutaneous endoscopic gastrostomy (PEG) tube in situ was referred for radioiodine therapy and was administered 5510 MBq I-131 sodium iodide intravenously. Sequential whole-body images taken over the subsequent 7 days for dosimetric evaluation revealed an area of persistent high uptake in the abdomen. Delayed imaging with single photon emission CT/CT at 15 days post administration revealed this uptake to be at the junction of the PEG tube with the anatomically normal stomach wall. We hypothesise that the PEG tube became contaminated by radioiodine secreted in the gastric mucosa during therapy and this radioactivity subsequently decayed with an increased effective half-life relative to the stomach, leading to the apparent hot spot.

Asunto(s)

Gastrostomía/instrumentación , Radioisótopos de Yodo/metabolismo , Anciano de 80 o más Años , Gastroscopía/métodos , Humanos , Inyecciones Intravenosas , Radioisótopos de Yodo/administración & dosificación , Masculino , Imagen Multimodal , Tomografía de Emisión de Positrones , Yoduro de Sodio/administración & dosificación , Neoplasias de la Tiroides/radioterapia , Tomografía Computarizada por Rayos X

RESUMEN

We performed a multicentre, randomised, double-blind (within-device), placebo- and active-controlled, parallel-group study to compare the efficacy and safety of ipratropium bromide plus fenoterol hydrobromide (IB/FEN; Berodual) delivered via the novel, propellant-free Respimat Soft Mist Inhaler (SMI) and from a chlorofluorocarbon (CFC)-metered-dose inhaler (MDI) in moderate-to-severe chronic obstructive pulmonary disease (COPD) patients. After 2-weeks' run-in (CFC-MDI [IB 20 microg/FEN 50 microg per actuation] two actuations q.i.d. [MDI 40/100]), 892 patients were randomised to Respimat SMI containing IB 10 microg/FEN 25 microg (Respimat SMI 10/25), IB 20 microg/FEN 50 microg (Respimat SMI 20/50) or placebo (one actuation q.i.d.), or a CFC-MDI containing IB 20 microg/FEN 50 microg (MDI 40/100) or placebo (two actuations q.i.d.) for 12 weeks. Analysis of the primary endpoint (change in forced expiratory volume in 1 s [FEV1] in the first 60 min after dosing [area under the curve; AUC0-1h]) on day 85 showed that the efficacy of Respimat SMI 20/50 (but not Respimat SMI 10/25) was not inferior to that of MDI 40/100. The safety profile of Respimat SMI was comparable to CFC-MDI. Switching from MDI 40/100 to Respimat SMI was well tolerated. Respimat SMI enables a 50% reduction of the nominal inhaled dose of IB/FEN in COPD patients while offering similar therapeutic efficacy and safety to the CFC-MDI.

Asunto(s)

Broncodilatadores/administración & dosificación , Fenoterol/administración & dosificación , Ipratropio/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Adulto , Anciano , Anciano de 80 o más Años , Método Doble Ciego , Quimioterapia Combinada , Diseño de Equipo , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Persona de Mediana Edad , Nebulizadores y Vaporizadores/normas , Ápice del Flujo Espiratorio/efectos de los fármacos , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Resultado del Tratamiento , Capacidad Vital/efectos de los fármacos

RESUMEN

Eosinophilia is a feature of airway inflammation associated with asthma. Leukotriene antagonists provide therapeutic benefit in asthma, but their potential antiinflammatory actions have not been fully explored. We have examined the role of eosinophil-derived cysteinyl leukotrienes in the maintenance of eosinophil survival, and the involvement of leukotrienes in the paracrine stimulation of eosinophil survival by mast cells and lymphocytes. We obtained eosinophils and autologous lymphocytes from peripheral blood of asthmatic subjects. Leukotriene (LT)-B(4), LTC(4) and LTD(4), granulocyte-macrophage colony-stimulating factor (GM-CSF), and fibronectin promoted eosinophil survival. LTD(4) (10(-)(6) M) was as effective as GM-CSF (5 ng/ml) and fibronectin (400 ng/ml) in promoting survival. Lymphocytes and conditioned medium from a human mast cell line (HMC-1) induced eosinophil survival. Blockade of cysteinyl leukotriene receptors with SKF 104353 (pobilukast, 3 nM), and inhibition of 5-lipoxygenase (5-LO) with BW A4C (1 microM) and of 5-LO activating protein with MK 886 (1 microM), all increased basal rates of eosinophil apoptosis and reversed GM-CSF-induced eosinophil survival. Fifty percent reversal of GM-CSF- induced survival was achieved with SKF 104353 at 0.3 nM. The potency of SKF 104353 was two orders of magnitude greater than that of the LTB(4) receptor antagonist SB 201146. Mast cell- and lymphocyte-induced eosinophil survival were completely reversed by SB 201146, SKF 104353, BW A4C, and MK 886. These findings provide evidence for the involvement of an autocrine cysteinyl leukotriene pathway that supports eosinophil survival in response to a range of survival stimuli. They also suggest that LTB(4) could act as a paracrine stimulus of eosinophil survival.

Asunto(s)

Asma/inmunología , Bencenoacetamidas , Hiperreactividad Bronquial/inmunología , Supervivencia Celular/efectos de los fármacos , Eosinófilos/efectos de los fármacos , Antagonistas de Leucotrieno/farmacología , Leucotrienos/biosíntesis , Hipersensibilidad Respiratoria/inmunología , Acrilatos/farmacología , Adulto , Anciano , Apoptosis/efectos de los fármacos , Medios de Cultivo Condicionados , Ácidos Dicarboxílicos/farmacología , Eosinófilos/inmunología , Femenino , Fibronectinas/fisiología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/fisiología , Humanos , Ácidos Hidroxámicos/farmacología , Indoles/farmacología , Linfocitos/inmunología , Masculino , Mastocitos/inmunología , Persona de Mediana Edad , Piridinas/farmacología

RESUMEN

The objective of the present study was to investigate the effect of tetrandrine (a plant alkaloid isolated from Stephenia tetrandra) on growth factor-induced DNA synthesis and proliferative responses of rat pulmonary artery smooth muscle cells. Male rat and bovine pulmonary artery smooth muscle cells (PASMC) were cultured in Medium 199 containing FBS (10%). DNA synthesis was monitored from [(3)H]-thymidine uptake and cell proliferation by direct cell counting. In the present study FBS (1% v/v) caused a small increase in DNA synthesis above basal levels in rat and bovine PASMC (6% and 11% respectively). Platelet-derived growth factor (PDGF, 50 ng/ml), fibroblast growth factor (FGF, 50 ng/ml) or interleukin-1alpha (IL-1alpha, 100 pg/ml) alone increased rat PASMC proliferation (69-85%) and DNA synthesis above basal levels (76-92%). The addition of these growth factors in combination with FBS (1%) resulted in higher increases in DNA synthesis above basal levels (rat PASMC:PDGF, 465%; FGF, 421%; IL-1alpha, 406%; bovine PASMC:PDGF, 279%). Tetrandrine (10(-5) M) inhibited FBS (10%)-induced rat PASMC proliferation (90.5%) and DNA synthesis (89.0%). Tetrandrine significantly inhibited cell proliferation (86.5-98.5%) and DNA synthesis (79.9-89.0%) induced by FBS (1%) in combination with one of the following mitogens; PDGF (50 ng/ml), FGF (50 ng/ml), IL-1alpha (100 pg/ml). The inhibitory effects of tetrandrine were observed between 10(-6) and 10(-5)M and PASMC viability was not affected by tetrandrine below 3x10(-5) m. In summary, these results suggest that tetrandrine can exert anti-proliferative effects against a range of mitogenic stimuli for vascular smooth muscle cells in vitro. Such effects may contribute to the inhibitory effect of tetrandrine on pulmonary vascular remodelling associated with pulmonary hypertension.

Asunto(s)

Alcaloides/farmacología , Antihipertensivos/farmacología , Bencilisoquinolinas , ADN/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Arteria Pulmonar/efectos de los fármacos , Animales , Bovinos , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , ADN/biosíntesis , Sustancias de Crecimiento/metabolismo , Técnicas In Vitro , Masculino , Músculo Liso Vascular/citología , Nitrendipino/farmacología , Arteria Pulmonar/citología , Conejos , Ratas , Ratas Wistar

RESUMEN

Persistent neutrophilia is a feature of chronic obstructive pulmonary disease (COPD). Leukotriene synthesis inhibitors and cysteinyl leukotriene receptor antagonists have shown efficacy in the treatment of asthma. Antagonism of leukotriene (LT)B(4) receptors is being considered as a mode of treating COPD. We examined the capacity for inhibition of leukotriene synthesis and LTB(4) receptor antagonism to reduce survival of neutrophils from patients with COPD and those from normal subjects. The basal apoptosis level of these cells was 55.4 +/- 2.4% (mean +/- SEM) of total cells. Separate exposure to lipopolysaccharide (LPS), granulocyte-macrophage colony-stimulating factor (GM-CSF), dexamethasone (DEX), and LTB(4) increased neutrophil survival (p < 0. 001). The LTB(4) receptor antagonist SB201146 abolished LPS-induced survival in a concentration-dependent manner (10 pmol to 0.1 microM), with an IC(50) of 1.9 nM. Combined exposure to SB201146 and to the cysteinyl leukotriene antagonist SKF104353 did not have a greater effect on survival than did exposure to SB201146 alone. Inhibition of 5-lipoxygenase (5-LO) with BWA4C and of 5-LO-activating protein (FLAP) with MK886 abolished GM-CSF- and DEX-induced neutrophil survival. BWA4C and MK886 abolished GM-CSF- induced neotrophil survival in a concentration-dependent manner (1 nM to 10 microM), with IC(50) values of 182.0 nM and 63.1 nM, respectively. These findings demonstrate reversal of LPS-, GM-CSF-, and DEX-induced neutrophil survival by LTB(4) receptor antagonism and inhibitors of 5-LO and FLAP. They also suggest a potential additional antiinflammatory mode of action of these compounds through reduction of cell survival.

Asunto(s)

Apoptosis/efectos de los fármacos , Bencenoacetamidas , Proteínas Portadoras/antagonistas & inhibidores , Antagonistas de Leucotrieno/farmacología , Leucotrieno B4/fisiología , Inhibidores de la Lipooxigenasa , Enfermedades Pulmonares Obstructivas/sangre , Proteínas de la Membrana/antagonistas & inhibidores , Neutrófilos/fisiología , Receptores de Leucotrieno B4/antagonistas & inhibidores , Proteínas Activadoras de la 5-Lipooxigenasa , Acrilatos/farmacología , Adulto , Araquidonato 5-Lipooxigenasa/metabolismo , Supervivencia Celular , Dexametasona/farmacología , Ácidos Dicarboxílicos/farmacología , Relación Dosis-Respuesta a Droga , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Humanos , Ácidos Hidroxámicos/farmacología , Técnicas In Vitro , Indoles/farmacología , Leucotrieno B4/biosíntesis , Leucotrieno B4/farmacología , Lipopolisacáridos/farmacología , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Piridinas/farmacología

RESUMEN

1. Airway remodelling occurs in asthma and involves an increase in airway smooth muscle mass through cell proliferation and hypertrophy. Increased eosinophil density in the airways is a feature of asthma. Eosinophils exhibiting activation in the airways of asthmatics also exhibit increased expression of transforming growth factor beta (TGF-beta1). We have examined the capacity of TGF-beta1 and epidermal growth factor (EGF) to influence airway smooth muscle division and the effect of heparin on TGF-beta1. EGF and serum-induced smooth muscle DNA synthesis in confluent airway smooth muscle cells (ASMC) as an indication of entry into S phase preceding mitogenesis. 2. ASMC were obtained from cell populations growing out from explanted bovine trachealis muscle sections. Cell division was monitored in sparse plated cells by direct cell counting following nuclear staining. Cell DNA synthesis in confluent cells was monitored by uptake of [3H]-thymidine. 3. TGF-beta1 (100 microM) inhibited FBS (10%)-induced smooth muscle division in sparsely plated cells (40%). TGF-beta1 (100 pM) increased cell DNA synthesis (200%) in confluent cells in the presence of bovine serum albumin (BSA, 0.25%). EGF (0.7 nM) also increased airway smooth muscle DNA synthesis (69%) in the presence of BSA (0.25%). The facilitatory effect of TGF-beta1 was observed between 1-100 pM, while that of EGF was observed between 20 200 pM. 4. Heparin inhibited serum and TGF-beta1-induced DNA synthesis in confluent ASMC (55%), consistent with our previous observation of inhibition of division in sparsely populated ASMC (Kilfeather et al., 1995a). This action of heparin was observed between concentrations of 1-100 microg ml(-1). Heparin did not inhibit DNA synthesis in response to EGF. An anti-mitogenic effect of heparin was also observed against responses to combined exposure to TGF-beta1 and EGF. 5. There was a clear inhibitory effect of heparin in absolute terms against serum-induced division in cells plated at 10, 20 and 45 x 10(3) cells cm(-2). The inhibitory effect of heparin was also observed at a plating density of 45,000 cells cm(-2) when responses to serum were expressed as fold-stimulation of basal DNA synthesis. 6. These findings demonstrate a potential role of TGF-beta1, EGF and heparin-related molecules in regulation of airway smooth muscle division.

Asunto(s)

Fenómenos Fisiológicos Sanguíneos , Factor de Crecimiento Epidérmico/farmacología , Heparina/farmacología , Músculo Liso/efectos de los fármacos , Inhibidores de la Síntesis del Ácido Nucleico , Factor de Crecimiento Transformador beta/farmacología , Animales , Asma/fisiopatología , Bovinos , División Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Músculo Liso/metabolismo , Tráquea/metabolismo

RESUMEN

Theophylline is a bronchodilator and immunomodulator drug which has recently been demonstrated to attenuate the recruitment and activation of inflammatory cells into lungs of asthmatics. This study investigated the effect of chronic treatment with theophylline for its ability to alter airway responsiveness, as indicated by changes in airway sensitivity and reactivity to inhaled methacholine. The subjects studied were mild asthmatics who relied on beta-agonist medication only and who were randomized into two groups, one receiving theophylline (median dose 250 mg twice daily; range 250-375 mg twice daily) and the other placebo. A number of parameters was measured before and after treatment, including baseline forced expiratory volume in one second (FEV1), the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20; sensitivity), dose-response slope (reactivity) and percentage eosinophils, eosinophil cationic protein and T-cell markers in peripheral blood (by flow cytometry). After 2 months of treatment with theophylline there was a significant lowering of airway reactivity (slope) to methacholine and improvement in methacholine sensitivity (PC20). However, such changes were not associated with any significant change in the number or activation status of eosinophils and lymphocytes in peripheral blood. In conclusion, chronic treatment with theophylline reduces the reactivity of the airways to methacholine, which might be beneficial in the treatment of persistent asthma. The cellular mechanisms of this improvement remain to be clarified.

Asunto(s)

Asma/tratamiento farmacológico , Pruebas de Provocación Bronquial , Broncodilatadores/administración & dosificación , Hipersensibilidad Respiratoria/tratamiento farmacológico , Teofilina/administración & dosificación , Adulto , Resistencia de las Vías Respiratorias/efectos de los fármacos , Asma/diagnóstico , Hiperreactividad Bronquial/diagnóstico , Hiperreactividad Bronquial/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Cuidados a Largo Plazo , Masculino , Cloruro de Metacolina , Hipersensibilidad Respiratoria/diagnóstico , Resultado del Tratamiento

RESUMEN

Recent studies have suggested that theophylline, a nonspecific phospho-diesterase inhibitor, has useful anti-inflammatory actions in asthma. Phosphodiesterase 4 (PDE4) represents the predominant PDE isoenzyme present in inflammatory cells. PDE4 inhibitors might, therefore, have beneficial effects in asthma. Side-effects, specifically nausea, have limited the use of existing agents. CDP840 is an orally active, potent and selective PDE4 inhibitor. We have examined the effect of CDP840 on the allergen-induced asthmatic response, its possible modes of action, and its tolerability at therapeutic doses. A total of 54 patients were recruited to three double-blind, placebo-controlled studies. The first study examined the effect of CDP840 (15 mg b.i.d. for 9.5 days) on the allergen-induced asthmatic response in patients with known dual response to allergen. A second study examined the effect of CDP840 (15 mg b.i.d. for 9.5 days) on airway responsiveness to histamine. A third study examined whether single dose CDP840 (15 and 30 mg) had significant bronchodilatory effects. In all studies, CDP840 was well-tolerated, with no patients reporting nausea. CDP840 did not lead to changes in baseline forced expiratory volume in one second (FEV1) as compared to placebo. The late asthmatic response (LAR) to allergen, expressed as area under the curve at 3-8 h (AUC3-8h), was inhibited by 30% (p=0.016), an effect which persisted to the end of the observation period. The early asthmatic response (EAR) was unaffected, and there was no bronchodilatory effect at the doses used. Treatment with CDP840 did not affect bronchial hyperresponsiveness to histamine. In conclusion, CDP840 significantly attenuated the late asthmatic response to allergen challenge in the absence of any bronchodilatory or histamine antagonist effect. This suggests that CDP840 may exert its effects via an anti-inflammatory mechanism.

Asunto(s)

Asma/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/uso terapéutico , Piridinas/uso terapéutico , Adolescente , Adulto , Alérgenos/inmunología , Asma/fisiopatología , Bronquios/efectos de los fármacos , Bronquios/fisiología , Hiperreactividad Bronquial/tratamiento farmacológico , Pruebas de Provocación Bronquial , Método Doble Ciego , Volumen Espiratorio Forzado , Histamina/farmacología , Humanos , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/efectos adversos , Piridinas/administración & dosificación , Piridinas/efectos adversos , Pruebas Cutáneas

RESUMEN

AIM: To investigate whether heparin inhibits growth factor-induced mitogenic and proliferative responses of the pulmonary arterial smooth muscle cells (PASMC). METHODS: Rat PASMC were cultured in medium 199 containing 10% fetal bovine serum (FBS). Mitogenesis was monitored from [methyl-3H] thymidine ([methyl-3H] TdR) uptake and cell proliferation was monitored by cell counting. RESULTS: FBS (1%), platelet-derived growth factor (PDGF, 50 micrograms.L-1), fibroblast growth factor (FGF, 50 micrograms.L-1) or interleukin 1 alpha (IL-1 alpha, 100 ng.L-1) alone induced both rat PASMC mitogenesis and proliferation. FBS (10%) and the combination of FBS (1%) with PDGF (50 micrograms.L-1), FGF (50 micrograms.L-1), or IL-1 alpha (100 ng.L-1) increased mitogenesis of rat PASMC. Heparin (100 mg.L-1) inhibited rat PASMC proliferation (28% +/- 6%) and thymidine incorporation (27% +/- 7%) induced by FBS (10%), and also significantly inhibited cell proliferation 25% +/- 6%, 27% +/- 7%, and 20% +/- 4%, and [methyl-3H] TdR incorporation 23% +/- 7%, 26% +/- 6%, 20% +/- 6% induced by FBS (1%) in combination with PDGF (50 micrograms.L-1), FGF (50 micrograms.L-1), or IL-1 alpha (100 ng.L-1) respectively. The PASMC viability was not affected by heparin. CONCLUSION: Proliferation and mitogenesis of rat PASMC induced by PDGF, FGF, and IL-1 alpha was augmented by simultaneous exposure to FBS. Heparin produced an inhibition on the proliferation and mitogenesis of rat PASMC caused by these growth factors.

Asunto(s)

Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Heparina/farmacología , Músculo Liso Vascular/citología , Animales , División Celular/efectos de los fármacos , Células Cultivadas , Interleucina-1/antagonistas & inhibidores , Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Arteria Pulmonar/citología , Ratas , Ratas Wistar

RESUMEN

The effect of a novel leuktriene B4 receptor antagonist N-[5[[8-(1-hydroxy-2- phenyl)ethyl]dibenzofuran-2yl]5-hydroxypentanoyl]pyrrolidine (PF 10042) has been evaluated in comparison with 2-[3(1-hydroxyhexyl)phenoxymethyl]quinoline hydrochloride (PF 5901), a specific inhibitor of the 5-lipoxygenase pathway of arachidonic acid metabolism, against platelet activating factor (PAF) and allergen induced bronchial hyperresponsiveness and pulmonary eosinophil infiltration in the guinea pig. PF 10042 significantly displaced radiolabelled [3H]leukotriene B4 from binding sites on human neutrophils with an EC50 of 3 muM. PF 10042 (100 mg/kg, i.p.) significantly inhibited PAF and allergen induced bronchial hyperresponsiveness without reducing the concomitant eosinophil infiltration, whereas PF 5901 (100 mg/kg, p.o.) significantly inhibited both PAF and allergen induced bronchial hyperresponsiveness and eosinophil infiltration. We suggest from these results that PAF and allergen induced bronchial hyperresponsiveness may be secondary to the release of leukotriene B4, but this lipoxygenase metabolite does not contribute significantly to the observed eosinophil infiltration.

Asunto(s)

Benzofuranos/farmacología , Hiperreactividad Bronquial/inducido químicamente , Antagonistas de Leucotrieno , Inhibidores de la Lipooxigenasa/farmacología , Ovalbúmina/antagonistas & inhibidores , Factor de Activación Plaquetaria/antagonistas & inhibidores , Eosinofilia Pulmonar/inducido químicamente , Quinolinas/farmacología , Animales , Líquido del Lavado Bronquioalveolar/citología , Cobayas , Histamina/farmacología , Humanos , Lipooxigenasa/metabolismo , Masculino , Ovalbúmina/inmunología

RESUMEN

A number of physiological effects have been ascribed to heparin since its discovery almost 80 years ago, many of which are independent from its first-described and best- characterized activity as an anticoagulant. Heparin and heparan sulphate are believed to possess many biological activities that include the ability to modulate embryonic development, neurite outgrowth, tissue homeostasis, wound healing, metastasis, cell differentation, cell proliferation and inflammation. In this review, David Tyrell, Stephen Kilfeather and Clive Page examine some of the activities of heparin (and heparin derivatives) beyond its effects as an anticoagulant, and discuss the therapeutic potential of this old, but certainly not antiquated, drug.

Asunto(s)

Heparina/uso terapéutico , Animales , Secuencia de Carbohidratos , Heparina/química , Heparina/farmacología , Humanos , Datos de Secuencia Molecular , Unión Proteica

RESUMEN

1. The effect of heparin and related glycosaminoglycans on bovine airway smooth muscle proliferation has been investigated. 2. Foetal bovine serum stimulated division of bovine trachealis smooth muscle cells in a concentration-dependent fashion at concentrations between 1 and 30%. 3. Heparin (0.1-100 micrograms ml-1), heparan sulphate (0.1-100 micrograms ml-1) and fragmin (0.1-100 micrograms ml-1) inhibited smooth muscle division in a concentration-dependent fashion between 0.1-100 micrograms ml-1. A heparin disaccharide did not exhibit inhibition of division at 100 micrograms ml-1. 4. Dextran sulphate at molecular weights of 5 x 10(3) and 5 x 10(5) concentration-dependently inhibited division between 0.1-100 micrograms ml-1. Dextran without sulphation did not exhibit inhibition of division at 100 micrograms ml-1. 5. The magnitude of inhibition of proliferation did not reach 100% for any compounds examined at concentrations up to 100 micrograms ml-1 during incubations for 5 and 14 days. IC50 values for inhibition of proliferation ranged between 1-5 micrograms ml-1. 6. These findings suggest that heparin and related glycosaminoglycans inhibit bovine airway smooth muscle cell division.

Asunto(s)

Glicosaminoglicanos/farmacología , Heparina/farmacología , Músculo Liso/efectos de los fármacos , Tráquea/efectos de los fármacos , Animales , Proteínas Sanguíneas/farmacología , Bovinos , Recuento de Células/efectos de los fármacos , División Celular , Células Cultivadas/efectos de los fármacos , Dextranos/farmacología , Relación Dosis-Respuesta a Droga

RESUMEN

Ageing is accompanied by diminishing myocardial tissue beta-adrenoceptor responses. The relative contribution of maturation and senescence to reported age-related changes in cell-surface beta-adrenoceptor dysfunction has not been established, since previous investigation has incorporated young rats lacking full maturity. We have examined myocardial ventricle membrane beta-adrenoceptor function in mature young (6 month) and old (26 month) male Wistar rats and the effect of propranolol infusion for seven days on beta-adrenoceptor function in these groups. beta 1-adrenoceptors comprised 63-72% of total beta-adrenoceptor density in both groups. beta 1-adrenoceptor densities were similar in young and old rats (young, 20.4 +/- 2.3; old, 24.7 +/- 1.4 fmol/mg protein +/- S.E.). beta 2-adrenoceptor densities were higher in older rats (young, 8.2 +/- 0.5, n = 9; old, 13.6 +/- 1.8, n = 9 fmol/mg protein +/- S.E., P < 0.025). Subcutaneous infusion of propranolol for seven days with miniosmotic pumps was accompanied by an increase in beta 1- and beta 2-adrenoceptor densities in young rats only (beta 1-, 38%, P < 0.05; beta 2- 52%, P < 0.025). beta 1-adrenoceptor agonist affinity and adenylate cyclase response to isoprenaline, GTP, Gpp(NH)p, Mn2+ and forskolin were not affected by age or propranolol infusion in either age-group. These findings demonstrate that male Wistar rats do not exhibit changes in myocardial ventricle beta-adrenoceptor-G-protein coupling capacity or adenylate cyclade activation with ageing beyond maturity.(ABSTRACT TRUNCATED AT 250 WORDS)

Asunto(s)

Envejecimiento/fisiología , Propranolol/farmacología , Receptores Adrenérgicos beta/efectos de los fármacos , Factores de Edad , Animales , AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Corazón/efectos de los fármacos , Isoproterenol/farmacología , Masculino , Ratas , Ratas Wistar

RESUMEN

1. PF 10040 displaced [3H]-PAF from binding sites on rabbit platelets with an IC50 = 1.07 x 10(-5) M, which was approximately three orders of magnitude below that of a standard PAF antagonist WEB 2086 (IC50 = 4.23 x 10(-9) M). 2. PF 10040 at doses of 5 and 10 mg (direct intratracheal administration) had no effect on the acute bronchoconstriction induced by PAF in neonatally immunized rabbits (airway resistance RL or dynamic compliance Cdyn). However, the PAF-induced increase in airway responsiveness to inhaled histamine was significantly inhibited (RL and Cdyn) by both doses of PF 10040. 3. PF 10040 (5 and 10 mg) significantly inhibited the total pulmonary cell infiltration and neutrophil influx induced by PAF as assessed by bronchoalveolar lavage. PAF-induced eosinophil infiltration into the airways was significantly inhibited in rabbits that received only 10 mg PF 10040. 4. We suggest from the results of the present study that PF 10040 does not exert an inhibitory effect on PAF-induced airway responses solely via antagonism of the PAF receptor located on platelets, as PF 10040 significantly inhibited PAF-induced airway hyperresponsiveness in the absence of an effect on the acute bronchospasm induced by PAF. 5. We provide further evidence that pulmonary eosinophil infiltration and the development of airway hyperresponsiveness are not causally related events as the lower dose of PF 10040 (5 mg) significantly inhibited PAF-induced airway hyperresponsiveness yet was without effect on the eosinophil influx.

Asunto(s)

Resistencia de las Vías Respiratorias/efectos de los fármacos , Hiperreactividad Bronquial/inducido químicamente , Isoquinolinas/farmacología , Factor de Activación Plaquetaria/antagonistas & inhibidores , Administración por Inhalación , Animales , Sitios de Unión , Plaquetas/efectos de los fármacos , Líquido del Lavado Bronquioalveolar/citología , Broncoconstricción/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Eosinófilos/efectos de los fármacos , Femenino , Histamina , Inmunización , Isoquinolinas/metabolismo , Masculino , Neutrófilos/efectos de los fármacos , Factor de Activación Plaquetaria/metabolismo , Conejos

RESUMEN

The haemodynamic and neuroendocrine responses and beta adrenoceptor distribution associated with aortic cross clamping and release were quantified in 14 patients undergoing elective abdominal aortic aneurysm surgery using a high-dose opiate-oxygen-isoflurane anaesthetic technique. These changes were correlated with neutrophil beta adrenoceptor distribution. Aortic cross clamp application was associated with increased systemic vascular resistance (SVR), and decreased cardiac index (CI). Left ventricular stroke work index remained constant during the period of cross clamp application and following release. Cross clamp release was associated with increased CI and decreased SVR. Plasma cortisol concentrations did not change during the study period. Plasma catecholamine concentrations, although elevated prior to surgery, remained unchanged during aortic cross clamping and following release. The percentage of internalised beta adrenoceptors was elevated before surgery and was unaffected by surgical intervention. This study suggests that a high-dose fentanyl-oxygen-isoflurane anaesthetic technique in a patient population with high circulating catecholamine levels and downregulation of beta adrenoceptors is associated with cardiovascular stability and attenuated neuroendocrine responses.

Asunto(s)

Anestesia General/métodos , Aneurisma de la Aorta Abdominal/cirugía , Epinefrina/sangre , Hemodinámica/fisiología , Hidrocortisona/sangre , Isoflurano , Norepinefrina/sangre , Receptores Adrenérgicos beta/análisis , Anciano , Aorta Abdominal/fisiología , Constricción , Femenino , Fentanilo , Humanos , Masculino , Neutrófilos/química

RESUMEN

We investigated the association of age with supine and ambulant plasma osmolality (pOSM) and arginine vasopressin (AVP). Twenty-eight healthy-status-defined subjects were studied. Following an overnight fast, blood samples were withdrawn after one hour supine rest and two hours' ambulation. Neither supine nor ambulant pOSM nor AVP varied significantly with age. The results suggest that in healthy subjects age does not influence plasma osmolality or AVP.

Asunto(s)

Envejecimiento/sangre , Arginina Vasopresina/sangre , Equilibrio Hidroelectrolítico/fisiología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valores de Referencia

RESUMEN

A decline in the function of the renin angiotensin aldosterone system may induce adaptive changes in response to angiotensin II (ANG II) with age. We have examined platelet ANG II receptor density, blood pressure and aldosterone responses to ANG II [Asn1, Val5-ANG II] (Hypertensin, Ciba Geigy, Horsham, Sussex, England) infusion in 8 young, 24 to 30 years, and 8 older, 54 to 65 years, healthy volunteers. To measure circulating ANG II, we established a new method for specific and simultaneous measurement of exogenous [Asn1, Val5] (Hypertensin) and endogenous [Asp1,Ile5] ANG II in plasma by using isocratic HPLC and radioimmunoassays with cross-reacting antibodies and compared results with immunoreactive ANG II which was measured conventionally using monoclonal antibodies. Baseline endogenous ANG II (Asp1,Ile5-ANG II) levels in venous plasma were marginally, but not significantly, lower in the old [mean (95% confidence limits): 3.4 (< 0.1 to 7.7) v 3.7 (1.2 to 6.2), fmol/mL] and during suppression by the Hypertensin infusion appeared consistently, but not significantly, lower in the old [0.9 (0 to 3.1) v 2.1 (0.6 to 3.7), after 3 ng/kg/min], while the same infusion rate in young and old resulted in similar plasma Hypertensin levels. Baseline systolic blood pressure (SBP) was similar in both groups but the percentage increases in SBP at infusion rates of 1, 3.0, and 10 ng/kg/min were greater in the old than in the young (9.1 v 2.8, P < .05; 16.3 v 8.0, P < .01; 30.4 v 14.0%, P < .001, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Asunto(s)

Envejecimiento/fisiología , Angiotensina II/farmacología , Presión Sanguínea/efectos de los fármacos , Hormonas/sangre , Adulto , Anciano , Aldosterona/sangre , Angiotensina Amida/sangre , Angiotensina Amida/farmacología , Angiotensina II/administración & dosificación , Angiotensina II/sangre , Plaquetas/metabolismo , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Radioinmunoensayo , Receptores de Angiotensina/efectos de los fármacos , Receptores de Angiotensina/metabolismo

RESUMEN

Plasma renin activity (PRA) declines with age in normal individuals, but the effect of age on plasma angiotensin II (ANG II) is less clear. A decline in plasma ANG II with age could result in altered platelet ANG II receptor density since plasma hormone levels influence their target organ receptors. To investigate this possibility, PRA, plasma ANG II, and platelet ANG II receptor density were examined in 17 young, 12 middle-aged, and 14 elderly healthy normotensive volunteers. To assess whether hypertension altered receptor density, these variables were also examined in 23 hypertensive patients. In normotensives, there was a negative correlation between age and PRA (r = -0.43, P < .05), no significant change in basal plasma ANG II with age, and a weak positive correlation between age and ANG II receptor density (r = 0.34, P < .05). Multiple regression analysis revealed that the relationship between age and ANG II receptor density was independent of the associated rise in mean arterial pressure with age (P < .05). Platelet ANG II receptor density was not significantly related to PRA or plasma ANG II. ANG II receptor affinity did not change with age. Neither PRA nor ANG II receptor density or affinity differed between hypertensives and normotensives of similar mean age, but plasma ANG II was significantly lower in hypertensives compared with normotensives. We concluded that aging is associated with a decline in supine PRA. The small decrease in plasma ANG II was not significant. Platelet ANG II receptor density increased with age primarily due to a small group of elderly subjects with elevated receptor density. There was no change in ANG II receptor density or affinity in hypertensives despite apparently lower plasma ANG II in these patients.

Asunto(s)

Envejecimiento/sangre , Angiotensina II/sangre , Plaquetas/metabolismo , Hipertensión/sangre , Receptores de Angiotensina/análisis , Adulto , Anciano , Humanos , Persona de Mediana Edad , Valores de Referencia , Análisis de Regresión

RESUMEN

Age-related changes in regulation of receptor response have been observed in several tissues and include regulation of beta-adrenergic receptor (beta-receptor) responses. The role of cellular aging in age-related changes in receptor response is not clear. We have examined the effect of aging in vitro on human fibroblast beta-receptor function. MRC-5 (embryonic lung) fibroblasts were aged by replication to produce cells of early, middle and late stages corresponding to the following cumulative population doublings: 15-20, 35-45 and greater than 50, respectively. Fibroblast membrane beta-receptor responses to isoproterenol (ISO, 0.1 mM) did not differ between the three stages. Adenylate cyclase responses to prostaglandin E1 (PGE1, 1 microM), guanosine triphosphate (GTP, 0.1 mM) and 5'-guanylimidodiphosphate (Gpp(NH)p, 0.1 mM) were also similar between the stages. Beta-receptor density (Bmax) was unaffected by in vitro aging. Beta-receptor agonist affinity, an indication of the capacity for beta-receptor coupling to the nucleotide binding protein (NS), was also unaffected by cell aging. These findings suggest that cellular aging in fibroblasts alone is not accompanied by changes in beta-receptor function.

Asunto(s)

Envejecimiento/metabolismo , Fibroblastos/metabolismo , Receptores Adrenérgicos beta/metabolismo , Adenilil Ciclasas/metabolismo , Alprostadil/farmacología , Línea Celular , Senescencia Celular , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Guanosina Trifosfato/farmacología , Guanilil Imidodifosfato/farmacología , Humanos , Isoproterenol/farmacología , Pulmón/citología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pindolol/metabolismo , Receptores Adrenérgicos beta/efectos de los fármacos

RESUMEN

Previous studies have indicated that Ca2+ is a trigger for apoptosis (programmed cell death) in thymocytes and related cell lines. Recently we have shown that levels of apoptosis in leukaemic cells are diminished in Ca(2+)-deficient conditions, indicating that Ca2+ may be important in the mechanism of apoptosis in these cells. In the present study we investigated the possibility that Ca2+ serves as a trigger for apoptosis in the human leukaemic cell line, HL-60. Using fura-2 to measure cytosolic free Ca2+ concentrations, [Ca2+]i, in cell suspensions, and by using ratio imaging of fura-2 in single cells, we did not observe an early significant increase in [Ca2+]i in HL-60 cells undergoing apoptosis. The latter stages of apoptosis were, however, accompanied by increasing [Ca2+]i; these increases were apparently a result of, rather than a cause of, apoptosis. Furthermore, apoptosis could be induced in HL-60 cells under conditions of vastly reduced [Ca2+]i achieved by loading these cells with fura-2 in the presence of EGTA. These results indicate that elevation of [Ca2+]i is not a prerequisite for apoptosis in HL-60 cells and that apoptosis can occur in these cells in the presence of low [Ca2+]i.

Asunto(s)

Calcio/metabolismo , Citosol/metabolismo , Leucemia Promielocítica Aguda/patología , Calcimicina/farmacología , Muerte Celular/efectos de los fármacos , Muerte Celular/efectos de la radiación , ADN de Neoplasias/análisis , Electroforesis en Gel de Agar , Etanol/farmacología , Fura-2/metabolismo , Humanos , Peróxido de Hidrógeno/farmacología , Leucemia Promielocítica Aguda/metabolismo , Células Tumorales Cultivadas , Rayos Ultravioleta