RESUMEN
Objective: To evaluate the clinical values of 4 types of ceramides (Cer1, Cer2, Cer3, Cer4) in the coronary artery stenosis, clinical diagnosis and risk prediction. Methods: A total of 890 patients with coronary heart disease (CHD) in Beijing Anzhen Hospital between March 2018 and August 2018 were enrolled. The relationships between different degrees of coronary artery stenosis and ceramide levels was investigated. Diagnostic value of ceramides on acute myocardial infarction was analyzed. Meanwhile, Major adverse cardiac and cerebrovascular events (MACCE) in 1 year after discharging were collected to evaluate the predictive value of ceramides on risk of CHD and stroke. Results: This study showed that there were no significant differences of ceramide levels in CHD patients with different degrees of coronary artery stenosis (P>0.05), and the area under receiver operating characteristic (ROC) curve in the diagnosis of acute myocardial infarction patients was 0.725. Conclusions: Ceramide is proved to be helpful in the diagnosis of acute myocardial infarction and MACCE prediction. The relationships between ceramide and degrees of coronary artery stenosis as well as the prognosis of CHD need further elucidation.
Asunto(s)
Enfermedad de la Arteria Coronaria , Estenosis Coronaria , Infarto del Miocardio , Accidente Cerebrovascular , Ceramidas , HumanosRESUMEN
OBJECTIVES AND DESIGN: The effects of the endogenous antioxidant alpha-lipoic acid on guinea pig colon smooth muscle contraction (Gpcc) induced by hydrogen peroxide were examined. Having previously shown that the histone deacetylase (HDAC) benzamide inhibitor MGCD0103 inhibits guinea-pig smooth muscle contraction, as do various sulfur-containing antioxidants, we asked whether hybrid compounds possessing both alpha-lipoic acid-derived antioxidant properties and HDAC inhibitory activity could inhibit Gpcc. MATERIALS AND METHODS: Guinea pig colon (Gpc) was incubated at 37 degrees C with Krebs buffer; the four stimulants-hydrogen peroxide, carbachol, histamine, and sodium fluoride-were added independently. The response to each stimulant alone was compared with that in the presence of each of the test compounds: MGCD0103, alpha-lipoic acid, and two of their hybrids, UCL M084 and UCL M109. RESULTS: NaF (10 mM), carbachol (0.05 microM), histamine (0.1 microM), and hydrogen peroxide (1 microM) produced Gpcc of about 50-60% above basal level. With the exception of MGCD0103 against hydrogen peroxide, all four test compounds at 1 microM-MGCD0103, alpha-lipoic acid, UCL M084, and UCL M109-produced a significant inhibition of 35-60% of Gpcc induced by hydrogen peroxide, NaF, and carbachol, although none reduced histamine or ovalbumin-induced Gpcc. Benzalkonium chloride (Bcl), a G-protein inhibitor, reduced the hydrogen peroxide-induced Gpcc by 35%. CONCLUSIONS: Contraction by stimulants used to induce Gpcc is known to involve G-proteins. All four test compounds-MGCD0103, alpha-lipoic acid and two of their hybrids, UCL M084 and UCL M109-reduced Gpcc induced by NaF and carbachol, suggesting that G-protein pathway involvement is relevant to the action of the test compounds, as is also indicated by the Bcl-induced inhibition of hydrogen peroxide-induced contractions. Additionally, alpha-lipoic acid and the two hybrids showed >30% inhibition of hydrogen peroxide-induced contractions, consistent with the antioxidant properties of the 1,2-dithiolane ring.
Asunto(s)
Antioxidantes/farmacología , Colon/efectos de los fármacos , Peróxido de Hidrógeno/farmacología , Músculo Liso/efectos de los fármacos , Oxidantes/farmacología , Animales , Benzamidas/farmacología , Carbacol/farmacología , Proteínas de Unión al GTP/fisiología , Cobayas , Histamina/farmacología , Técnicas In Vitro , Agonistas Muscarínicos/farmacología , Contracción Muscular/efectos de los fármacos , Pirimidinas/farmacología , Receptores Histamínicos H1/efectos de los fármacos , Receptores Histamínicos H1/metabolismo , Fluoruro de Sodio/antagonistas & inhibidores , Fluoruro de Sodio/farmacología , Ácido Tióctico/farmacologíaRESUMEN
OBJECTIVES AND DESIGN: The aim of this study was to investigate the ability of (a) antioxidants, some related to alpha-lipoic acid (LA), (b) histone deacetylase (HDAC) inhibitors, and (c) hybrid compounds possessing both alpha-lipoic acid-derived antioxidant properties and HDAC inhibitory activity to inhibit guinea pig smooth muscle contraction. MATERIALS AND METHODS: Guinea pig isolated tracheal rings (GPTR) were prepared and their isometric tension measured using a transducer. Histamine, carbachol and 5-hydroxytryptamine (5-HT) served as agonists. Tests with antigen (ovalbumin) used GPTR from sensitised guinea pigs or rings from non-sensitised animals that had been incubated for at least 2 h with diluted serum from sensitised animals. RESULTS: All antioxidants tested showed a relaxant effect on resting tension and on tension induced by histamine or carbachol, with EC(50)(s) of 0.2-5.0 mM and a rank order of potency: LA derivatives > glutathione (GSH) > ascorbic acid (AA). However, low concentrations (<50 microM) of GSH, AA and LA potentiated histamine-induced contractions. The benzamide HDAC inhibitor MGCD0103 inhibited mast cell activation and GPTR contraction produced by antigen and certain agonists, although a 2-6 h pre-incubation was required for those effects to be apparent. Two LA-benzamide HDAC hybrid compounds, UCL M084 and UCL M109 inhibited GPTR contraction after 30 min pre-incubation; however, even after long pre-incubation (up to 6 h) those hybrid compounds showed less potent inhibition of agonist-induced contraction than did MGCD0103. CONCLUSIONS: The results showed that GSH more potently inhibited contraction induced by histamine than that induced by 5-HT or carbachol, whereas LA, and especially UCL M084 and UCL M109, more potently blocked contraction induced by carbachol and 5-HT than that induced by histamine. For GSH, and possibly also for LA-type compounds, the inhibition of agonist-induced tracheal smooth muscle contractions may be due to NO formation. This study did not detect a synergistic relaxant effect in two compounds incorporating the structural union of a benzamide HDAC inhibitor terminus with a LA-derived antioxidant moiety.
Asunto(s)
Antioxidantes/farmacología , Músculo Liso/efectos de los fármacos , Músculos Respiratorios/efectos de los fármacos , Ácido Tióctico/análogos & derivados , Ácido Tióctico/farmacología , Tráquea/efectos de los fármacos , Animales , Ácido Ascórbico/farmacología , Benzamidas/farmacología , Carbacol/farmacología , Sinergismo Farmacológico , Glutatión/farmacología , Cobayas , Histamina/farmacología , Antagonistas de los Receptores Histamínicos/farmacología , Técnicas In Vitro , Contracción Isométrica , Agonistas Muscarínicos/farmacología , Contracción Muscular/efectos de los fármacos , Ovalbúmina/farmacología , Pirimidinas/farmacología , Conejos , Serotonina/farmacologíaAsunto(s)
Colon , Inhibidores Enzimáticos/farmacología , Liberación de Histamina/efectos de los fármacos , Inhibidores de Histona Desacetilasas , Mastocitos , Contracción Muscular , Animales , Colon/anatomía & histología , Colon/efectos de los fármacos , Colon/fisiología , Femenino , Cobayas , Masculino , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Ratas , Ratas Sprague-DawleyAsunto(s)
Antígenos/inmunología , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Contracción Muscular , Tráquea , Animales , Antígenos/farmacología , Inhibidores Enzimáticos/química , Humanos , Ratones , Estructura Molecular , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Tráquea/anatomía & histología , Tráquea/efectos de los fármacos , Tráquea/fisiologíaAsunto(s)
Complemento C5a/metabolismo , Depsipéptidos/farmacología , Proteínas de Unión al GTP/metabolismo , Mastocitos/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Péptidos/farmacología , Animales , Depsipéptidos/química , Cobayas , Humanos , Mastocitos/metabolismo , Estructura Molecular , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Músculo Liso/fisiología , Péptidos/química , RatasAsunto(s)
Inhibidores Enzimáticos/farmacología , Genisteína/farmacología , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Animales , Canales de Calcio Tipo L/efectos de los fármacos , Canales de Calcio Tipo L/fisiología , Genisteína/agonistas , Cobayas , Técnicas In Vitro , Masculino , Contracción Muscular/fisiología , Músculo Liso/fisiología , Proteína Quinasa C/efectos de los fármacos , Proteína Quinasa C/metabolismo , Fluoruro de Sodio/farmacología , Tráquea/efectos de los fármacos , Tráquea/fisiologíaAsunto(s)
Contracción Muscular/fisiología , Proteínas Tirosina Quinasas/metabolismo , Receptores Proteinasa-Activados/fisiología , Animales , Carbacol/farmacología , Agonistas Colinérgicos/farmacología , Íleon/efectos de los fármacos , Íleon/fisiología , Técnicas In Vitro , Masculino , Músculo Liso/fisiología , Proteínas Tirosina Quinasas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores Proteinasa-Activados/efectos de los fármacos , Inhibidores de Serina Proteinasa/farmacología , Fluoruro de Sodio/farmacología , Clorometilcetona de Tosilfenilalanila/farmacologíaAsunto(s)
Íleon/fisiología , Músculo Liso/fisiología , Receptores Proteinasa-Activados/efectos de los fármacos , Animales , Calcimicina/farmacología , Quimotripsina/antagonistas & inhibidores , Quimotripsina/farmacología , Cromolin Sódico/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Guanidinas/farmacología , Cobayas , Íleon/efectos de los fármacos , Técnicas In Vitro , Ionóforos , Masculino , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Músculo Liso/efectos de los fármacos , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III , Inhibidores de Serina Proteinasa/farmacología , Clorometilcetona de Tosilfenilalanila/farmacologíaAsunto(s)
Liberación de Histamina/efectos de los fármacos , Íleon/efectos de los fármacos , Mastocitos/metabolismo , Músculo Liso/efectos de los fármacos , Péptidos/farmacología , Animales , Compuestos de Benzalconio/farmacología , Bradiquinina/antagonistas & inhibidores , Bradiquinina/farmacología , Cationes , Calidina/antagonistas & inhibidores , Calidina/farmacología , Masculino , Mastocitos/efectos de los fármacos , Contracción Muscular/efectos de los fármacos , Péptidos/antagonistas & inhibidores , Cavidad Peritoneal/citología , Ratas , Ratas Wistar , Sustancia P/antagonistas & inhibidores , Sustancia P/farmacologíaRESUMEN
We have studied the effect of nitric oxide (NO) and hydrogen peroxide (H(2)O(2)), two reactive oxygen species (ROS) on histamine release (HR) from RBL-2H3 cells, a rat mucosal-type mast cell line. Marked HR was elicited by antigen (DNP-HSA), calcium ionophore A23187, sodium fluoride or phospholipase C, but not with compound 48/80 or 1,2-dioctanoyl-sn-glycerol. The NO-synthase substrate L-arginine and its inactive enantiomer (D-arginine), each on its own, induced a small but significant increase in HR above the basal level. However, the NO-donors (sodium nitroprusside or NaNO(3)) or the NO-synthase inducer lipopolysaccharide did not induce HR. Moreover, methylene blue (MB), which inhibits guanylate cyclase and N(omega)-nitro-L-arginine (L-NA), an inhibitor of NO synthase, were also without effect on either the basal HR or the L-arginine-induced HR. HR induced by A23187, DNP-HSA, sodium fluoride or phospholipase C was markedly reduced by MB, but mildly by L-NA (both at 1-100 microM). H(2)O(2) (0.01-1.0 mM) on its own did not induce HR, but it had a potent inhibitory effect on DNP-HSA- or A23187-induced HR, which was not reversed by L-NA (1-100 microM). Taken together, it seems that neither the stimulatory nor the inhibitory effects of the NO-related compounds on HR can be attributed to NO, but rather to other mechanisms. The inhibition of HR by H(2)O(2) also does not involve NO and suggests a negative feedback regulatory role for the peroxide in the allergic inflammation.
Asunto(s)
Histamina/metabolismo , Peróxido de Hidrógeno/farmacología , Óxido Nítrico/farmacología , Animales , Calcimicina/farmacología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Interacciones Farmacológicas , Inhibidores Enzimáticos/farmacología , Azul de Metileno/farmacología , Nitroarginina/farmacología , Ratas , Fluoruro de Sodio/farmacologíaRESUMEN
The effects of a range of nitric oxide (NO)-related compounds on histamine release from human basophils and rat peritoneal mast cells were studied. Basal and immunologic histamine releases from human basophils were not affected by N(omega)-nitro-L-arginine, N(omega)-nitro-L-arginine methyl ester, aminoguanidine or methylene blue (all inhibitors of NO production), sodium nitroprusside (an NO donor), L-arginine (a substrate for NO synthase) or D-arginine (the inactive enantiomer of L-arginine). In rat peritoneal mast cells, NO donors such as sodium nitroprusside, sodium nitrite and sodium nitrate, and lipopolysaccharide (an inducer of NO synthase) had little effect on basal histamine release, while 3-morpholino-sydnonimine (SIN-1, an NO donor), L-arginine and D-arginine increased this release by up to threefold. None of the inhibitors of NO production had any striking effect on histamine release induced by anti-rat immunoglobulin E (IgE), compound 48/80, sodium fluoride, phospholipase C, 1,2-dioctanoyl-sn-glycerol or ionophore A23187. However, haemoglobin was found to inhibit histamine release by anti-rat IgE or A23187 by ca. 40%. Alone of the NO donors, low concentrations of L-arginine produced a mild inhibition of histamine release induced by anti-IgE, compound 48/80 and A23187, but not other ligands, while sodium nitroprusside dose-dependently inhibited (by a maximum of ca. 30%) histamine release by anti-rat IgE, sodium fluoride or A23187. Stimulation with a variety of secretagogues or treatment with L-arginine, D-arginine, lipopolysaccharide, SIN-1 or sodium nitroprusside had no effect on NO production. Similarly, L-arginine, D-arginine or sodium nitroprusside did not change intracellular cGMP levels. On the basis of these results, it is suggested that NO does not play a significant role in the modulation of histamine release from human basophils or rat peritoneal mast cells. The effects of L-arginine, D-arginine and sodium nitroprusside may involve mechanisms unrelated to NO.
Asunto(s)
Basófilos/metabolismo , Histamina/metabolismo , Mastocitos/metabolismo , Óxido Nítrico/fisiología , Animales , Anticuerpos/farmacología , Arginina/farmacología , Basófilos/citología , Basófilos/efectos de los fármacos , Calcimicina/farmacología , Relación Dosis-Respuesta a Droga , Guanidinas/farmacología , Hemoglobinas/farmacología , Humanos , Inmunoglobulina E/inmunología , Masculino , Mastocitos/citología , Mastocitos/efectos de los fármacos , Azul de Metileno/farmacología , Molsidomina/análogos & derivados , Molsidomina/farmacología , NG-Nitroarginina Metil Éster/farmacología , Nitratos/farmacología , Óxido Nítrico/biosíntesis , Donantes de Óxido Nítrico/farmacología , Nitroarginina/farmacología , Nitroprusiato/farmacología , Cavidad Peritoneal/citología , Ratas , Ratas Sprague-Dawley , Fluoruro de Sodio/farmacología , Nitrito de Sodio/farmacología , p-Metoxi-N-metilfenetilamina/farmacologíaAsunto(s)
Ciclosporina/farmacología , Liberación de Histamina/efectos de los fármacos , Inmunosupresores/farmacología , Músculo Liso/efectos de los fármacos , Tráquea/efectos de los fármacos , Animales , Asma/metabolismo , Asma/fisiopatología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Adyuvante de Freund/toxicidad , Cobayas , Leucotrieno C4/metabolismo , Leucotrieno D4/metabolismo , Leucotrieno E4/metabolismo , Masculino , Contracción Muscular/efectos de los fármacos , Ovalbúmina/toxicidad , Radioinmunoensayo , Tráquea/metabolismoAsunto(s)
Ciclosporinas/farmacología , Liberación de Histamina/efectos de los fármacos , Inmunosupresores/farmacología , Mastocitos/efectos de los fármacos , Cavidad Peritoneal/citología , Animales , Ciclosporina/farmacología , Leucemia Basofílica Aguda , Masculino , Mastocitos/metabolismo , Ratas , Ratas Sprague-DawleyAsunto(s)
Ciclosporina/farmacología , Mastocitos/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Animales , Femenino , Cobayas , Humanos , Íleon/efectos de los fármacos , Técnicas In Vitro , Pulmón/efectos de los fármacos , Masculino , Mastocitos/metabolismo , Contracción Muscular/efectos de los fármacos , Tráquea/efectos de los fármacosRESUMEN
Deoxycholic acid (DA) caused a dose-related release of histamine (HR) from mast cells of rat peritoneum (RPMC) and mucosal cells of guinea pig rectocolon (RCMC). In both cell populations, DA-induced HR was: (1) accompared by a parallel release of lactate dehydrogenase (LDH), (2) not affected by metabolic inhibitors, (3) dependent on time of incubation, temperature and pH, and affected by Ca++ concentration in RPMC but not in RCMC. DA-induced HR from RCMC may be involved in certain functional disorders of the colon.
Asunto(s)
Ácido Desoxicólico/farmacología , Liberación de Histamina/efectos de los fármacos , Mucosa Intestinal/citología , Mastocitos/fisiología , Cavidad Peritoneal/citología , Animales , Colon/citología , Femenino , Cobayas , Concentración de Iones de Hidrógeno , Cinética , L-Lactato Deshidrogenasa/metabolismo , Masculino , Mastocitos/efectos de los fármacos , Ratas , Ratas Endogámicas , Recto/citología , TemperaturaRESUMEN
Compound 48/80-induced histamine release (HR) from the isolated perfused rat heart was markedly and significantly inhibited by picumast (PIC), possibly by acting as a calmodulin antagonist (CMA) or membrane stabilizer. Trifluoperazine (TFP, another CMA in clinical use) had a similar effect. However, an action as CMA being the basis of inhibition of HR could not be confirmed in another 'allergy' model, namely HR from rat peritoneal mast cells (RPMC). PIC, TFP and two other CMA, W7 and N-(4-aminobutyl)-5-chloro-1-naphthalenesulfonamide) failed consistently to inhibit 48/80-induced HR from RPMC, and when used on their own at high concentration these compounds caused HR. PIC and TFP also potentiated the heat-induced haemolysis of rat erythrocytes, i.e. lacked membrane stabilizing effect in this model.