RESUMEN
Daptomycin (DAP) is widely used in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection. The emergence of DAP non-susceptible MRSA strains during therapy is a major concern in clinical settings. Recent studies revealed that MRSA spontaneously reverts to a subsequent methicillin-susceptible S. aureus (MSSA) strain. However, it is not clear whether DAP non-susceptible MRSA has the ability to revert to a susceptible strain. We obtained an MRSA strain pair, DAP non-susceptible strain and subsequent DAP susceptible strain, from a patient. To understand the underlying mechanism by which DAP non-susceptible MRSA reverts to a susceptible strain, we performed genetic and phenotypic analysis in the strain pair. Although whole-genome analysis revealed four missense mutations, including L826F in mprF, in both strains, the net cell-surface charge was similar between the DAP non-susceptible and susceptible strains. However, the thickness of the cell wall was higher in the DAP non-susceptible strain, which was decreased to the same level as the control after reversion to the DAP susceptible strain. Moreover, the non-susceptible strain showed higher mRNA expression of the two-component system (TCS), such as VraSR, yycG and GraS, with the up-regulated transcription levels of cell-wall biosynthesis-related genes. The expression levels of those genes were decreased after reversion to the susceptible strain. These results indicated that DAP non-susceptibility due to up-regulation of the TCS and cell-wall biosynthesis-related genes may be reversible by the discontinuation of DAP, leading to reversion to the DAP susceptible phenotype.
Asunto(s)
Antibacterianos/farmacología , Pared Celular/metabolismo , Daptomicina/farmacología , Regulación Bacteriana de la Expresión Génica , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Anciano , Análisis Mutacional de ADN , Femenino , Perfilación de la Expresión Génica , Genotipo , Humanos , Staphylococcus aureus Resistente a Meticilina/genética , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Mutación Missense , FenotipoRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is a general term for fatty liver disease not caused by viruses or alcohol. Fibrotic hepatitis, cirrhosis, and hepatocellular carcinoma can develop. The recent increase in NAFLD incidence worldwide has stimulated drug development efforts. However, there is still no approved treatment. This may be due in part to the fact that non-alcoholic steatohepatitis (NASH) pathogenesis is very complex, and its mechanisms are not well understood. Studies with animals are very important for understanding the pathogenesis. Due to the close association between the establishment of human NASH pathology and metabolic syndrome, several animal models have been reported, especially in the context of overnutrition. In this study, we investigated the induction of NASH-like pathology by enhancing cholesterol absorption through treatment with hydroxypropyl-beta-cyclodextrin (CDX). Female Sprague-Dawley rats were fed a normal diet with normal water (control group); a high-fat (60 kcal%), cholesterol (1.25 %), and cholic acid (0.5 %) diet with normal water (HFCC group); or HFCC diet with 2 % CDX water (HFCC+CDX group) for 16 weeks. Compared to the control group, the HFCC and HFCC+CDX groups showed increased blood levels of total cholesterol, aspartate aminotransferase, and alanine aminotransferase. At autopsy, parameters related to hepatic lipid synthesis, oxidative stress, inflammation, and fibrosis were elevated, suggesting the development of NAFLD/NASH. Elevated levels of endoplasmic reticulum stress-related genes were evident in the HFCC+CDX group. In the novel rat model, excessive cholesterol intake and accelerated absorption contributed to NAFLD/NASH pathogenesis.
Asunto(s)
Hipercolesterolemia , Hiperlipidemias , Enfermedad del Hígado Graso no Alcohólico , Humanos , Ratas , Femenino , Animales , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , 2-Hidroxipropil-beta-Ciclodextrina/metabolismo , 2-Hidroxipropil-beta-Ciclodextrina/uso terapéutico , Ratas Sprague-Dawley , Dieta Alta en Grasa/efectos adversos , Hígado/metabolismo , Colesterol , Hipercolesterolemia/metabolismo , Modelos Animales de EnfermedadRESUMEN
In patients with diabetic kidney disease (DKD), the estimated glomerular filtration rate (eGFR) or creatinine clearance rate (Ccr) is always used as an index of decline in renal function. However, there are few animal models of DKD that could be used to evaluate renal function based on GFR or Ccr. For this reason, it is desirable to develop animal models to assess renal function, which could also be used for the evaluation of novel therapeutic agents for DKD. Therefore, we aimed to develop such animal model of DKD by using spontaneously hypertensive rat (SHR)/NDmcr-cp (cp/cp) rats with the characteristics of obese type 2 diabetes and metabolic syndrome. As a result, we have found that unilateral nephrectomy (UNx) caused a chronic Ccr decline, development of glomerular sclerosis, tubular lesions, and tubulointerstitial fibrosis, accompanied by renal anemia. Moreover, losartan-mixed diet suppressed the Ccr decline in UNx-performed SHR/NDmcr-cp rats (UNx-SHR/cp rats), with improvement in renal anemia and histopathological changes. These results suggest that UNx-SHR/cp rats could be used as a DKD model for evaluating the efficacy of therapeutic agents based on suppression of renal function decline.
Asunto(s)
Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Síndrome Metabólico , Ratas , Animales , Ratas Endogámicas SHR , LosartánRESUMEN
Type 2 diabetes (T2D) is believed to be a non-autoimmune metabolic disorder. However, there are increasing reports that some T2D patients have immune abnormalities. In addition, it is known that there are sex differences in the onset of diabetes and immune responses in humans. Spontaneously Diabetic Torii (SDT) rats, a non-obese T2D model, also have sex differences in the onset of diabetes, but the involvement of immune abnormalities in diabetes is unknown. In this study, we investigated immune abnormalities in SDT rats. Immune cell subset analysis was performed in male and female SDT rats and control Sprague-Dawley (SD) rats at 5, 11, and 17 weeks of age. Male and female SDT rats had swelling of the spleen and lymph nodes and a higher number of T cells and B cells in the blood, spleen, and lymph nodes than SD rats. Only male SDT rats developed diabetes at 17 weeks of age, and the number of classical and non-classical monocytes in the blood and spleen of male SDT rats was higher than that in male SD rats and female SDT rats that did not develop diabetes. Most of these findings were observed before the onset of diabetes (~11 weeks of age), suggesting that classical and non-classical monocytes may contribute to the development of diabetes in male SDT rats. In conclusion, SDT rats may be a useful T2D model involved in immune abnormalities, and further research will help elucidate the pathophysiology of T2D with immune abnormalities and develop new therapeutic agents.
Asunto(s)
Diabetes Mellitus Tipo 2 , Enfermedades del Sistema Inmune , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Caracteres SexualesRESUMEN
It has been postulated that there exists a neuronal mechanism that generates respiratory rhythm and modulates respiratory output pattern in the high cervical spinal cord. Recently, we have found a novel respiratory neuron group in the ventral portion of the high cervical spinal cord, and named it the high cervical spinal cord respiratory group (HCRG). In the present study, we analyzed the detailed anatomical architecture of the HCRG region by double immunostaining of the region using a neuron-specific marker (NeuN) and a marker for motoneurons (ChAT) in the neonatal rat. We found a large number of small NeuN-positive cells without ChAT-immunoreactivity, which were considered interneurons. We also found two and three clusters of motoneurons in the ventral portion of the ventral horn at C1 and C2 levels, respectively. Next, we examined responses of HCRG neurons to respiratory and metabolic acidosis in vitro by voltage-imaging together with cross correlation techniques, i.e., by correlation coefficient imaging, in order to understand the functional role of HCRG neurons. Both respiratory and metabolic acidosis caused the same pattern of changes in their spatiotemporal activation profiles, and the respiratory-related area was enlarged in the HCRG region. After acidosis was introduced, preinspiratory phase-dominant activity was recruited in a number of pixels, and more remarkably inspiratory phase-dominant activity was recruited in a large number of pixels. We suggest that the HCRG composes a local respiratory neuronal network consisting of interneurons and motoneurons and plays an important role in respiratory augmentation in response to acidosis.
Asunto(s)
Acidosis Respiratoria/fisiopatología , Cuello del Útero , Neuronas/metabolismo , Respiración , Médula Espinal/citología , Animales , Animales Recién Nacidos , Colina O-Acetiltransferasa/metabolismo , Proteínas de Unión al ADN , Femenino , Ratones , Proteínas del Tejido Nervioso/metabolismo , Proteínas Nucleares/metabolismo , Ratas , Coloración y EtiquetadoRESUMEN
BACKGROUND/AIMS: Many studies report the role of vascular endothelial growth factor (VEGF) in wound healing, but few describe local VEGF administration to the digestive tract. Leakage from colonic anastomoses, including those due to ischemia, represents a major complication causing increased mortality and morbidity. Angiogenesis is crucial to anastomotic healing and restoration of blood supply, and VEGF is a potent angiogenic factor showing improved healing in various models of reconstruction and anastomosis. Here, we examine the effects of local VEGF-A(165) administration on postoperative rabbit colon anastomosis. METHODS: Two colotomies per animal were made in the sinistral colon on opposite sides of the mesentery. Randomly assigned VEGF (10 microg/0.1 ml) or saline (0.1 ml) was injected into the muscularis propria on both sides of each colonic anastomosis before closing the access laparotomy using single-layer sutures. On postoperative days 3, 4 and 7, the bursting pressure of partially healed anastomoses was measured. On postoperative day 4, anastomotic tissues were examined for the following: hydroxyproline; histopathologically for inflammatory infiltrate and tissue organization and immunohistochemically for capillary proliferation and density; vessel density of midzone collaterals around anastomoses by microangiography. RESULTS: Compared to saline, VEGF administration significantly improved bursting pressure (p = 0.014, paired t test) and increased hydroxyproline (p = 0.027, paired t test) on postoperative day 4. Inflammatory cell infiltration and fibroblast proliferation were prominent, and submucosal capillary vascular counts were significantly higher for VEGF. CONCLUSIONS: Administration of VEGF to colonic anastomosis accelerates wound healing and strengthens the anastomosis by increased angiogenesis.
Asunto(s)
Colon/cirugía , Factor A de Crecimiento Endotelial Vascular/administración & dosificación , Cicatrización de Heridas/efectos de los fármacos , Anastomosis Quirúrgica , Angiografía , Animales , Colon/irrigación sanguínea , Colon/metabolismo , Colon/patología , Hidroxiprolina/metabolismo , Masculino , Neovascularización Fisiológica/efectos de los fármacos , Presión , ConejosRESUMEN
We have reported that ischemic preconditioning may limit infarct size by increasing 5'-nucleotidase activity. The present study tested whether alpha 1-adrenoceptor stimulation in ischemic preconditioning mediates the infarct size-limiting effect through augmentation of 5'-nucleotidase activity. The coronary artery was occluded four times for 5 min separated by 5 min of reperfusion (ischemic preconditioning) in 82 dogs. Then the coronary artery was occluded for 90 min followed by 6 h of reperfusion. Infarct size normalized by risk area was smaller after ischemic preconditioning than in the control group (40.6 +/- 2.3 vs 6.7 +/- 2.0%, P < 0.001), even though no difference existed in endomyocardial collateral flow during ischemia (8.7 +/- 1.0 vs 8.9 +/- 1.0 ml/100 g per min). Ectosolic and cytosolic 5'-nucleotidase activity was increased after ischemic preconditioning. However, prazosin blunted the infarct size-limiting effect of ischemic preconditioning (infarct size: 42.8 +/- 3.7%). Intermittent alpha 1-adrenoceptor stimulation by methoxamine mimicked the increase in 5'-nucleotidase activity and the infarct size-limiting effect, which were abolished by alpha, beta,-methyleneadenosine 5'-diphosphate. Identical results were obtained in the conscious model (n = 20). Therefore, we conclude that increases in ectosolic 5'-nucleotidase activity due to alpha 1-adrenoceptor activation may contribute to the infarct size-limiting effect of ischemic preconditioning.
Asunto(s)
5'-Nucleotidasa/metabolismo , Infarto del Miocardio/metabolismo , Isquemia Miocárdica/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Adaptación Biológica , Adenosina/sangre , Animales , Presión Sanguínea , Perros , Endocardio/metabolismo , Esófago/metabolismo , Hemodinámica , Metoxamina/farmacología , Infarto del Miocardio/enzimología , Infarto del Miocardio/patología , Isquemia Miocárdica/enzimología , Perfusión , Prazosina/farmacología , Factores de RiesgoRESUMEN
Retinoic acids (RAs), including all-trans retinoic acid (ATRA) and 9-cis retinoic acid (9-cis RA), play fundamental roles in a variety of physiological events in vertebrates, through their specific nuclear receptors: retinoic acid receptor (RAR) and retinoid X receptor (RXR). Despite the physiological importance of RA, their functional significance under pathological conditions is not well understood. We examined the effect of ATRA on oxygen/glucose-deprivation/reperfusion (OGD/Rep)-induced neuronal damage in cultured rat hippocampal slices, and found that ATRA significantly reduced neuronal death. The cytoprotective effect of ATRA was observed not only in cornu ammonis (CA) 1 but also in CA2 and dentate gyrus (DG), and was attenuated by selective antagonists for RAR or RXR. By contrast, in the CA3 region, no protective effects of ATRA were observed. The OGD/Rep also increased phosphorylated forms of c-jun-N-terminal kinase (P-JNK) and p38 (P-p38) in hippocampus, and specific inhibitors for these kinases protected neurons. ATRA prevented the increases in P-JNK and P-p38 after OGD/Rep, as well as the decrease in NeuN and its shrinkage, all of which were inhibited by antagonists for RAR or RXR. These findings suggest that the ATRA signaling via retinoid receptors results in the inhibition of JNK and p38 activation, leading to the protection of neurons against OGD/Rep-induced damage in the rat hippocampus.
Asunto(s)
Hipocampo/enzimología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Neuronas/enzimología , Tretinoina/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Análisis de Varianza , Animales , Glucemia/metabolismo , Muerte Celular/fisiología , Inhibidores Enzimáticos/metabolismo , Hipocampo/patología , Hipoxia/enzimología , Técnicas In Vitro , Neuronas/patología , Ratas , Ratas Wistar , Receptores de Ácido Retinoico/metabolismo , Daño por Reperfusión/enzimología , Daño por Reperfusión/prevención & control , Transducción de Señal/fisiología , Estadísticas no ParamétricasRESUMEN
Although ischemic stress, including ischemic preconditioning (IP), activates p38 mitogen-activated protein kinase (MAPK), the relationship between p38 MAPK activation and the underlying cellular mechanisms of cardioprotection by IP is not verified in vivo. We examined the effects of the selective p38 MAPK inhibition on the cardioprotective effect of IP in the open-chest dogs. The coronary artery was occluded 4 times for 5 minutes, separated by 5 minutes of reperfusion (IP) followed by 90 minutes of occlusion and 6 hours of reperfusion. We infused SB203580 into the coronary artery during IP and 1 hour of reperfusion, during IP alone, and during sustained ischemia in the IP group. p38 MAPK activity markedly increased during IP but did not additionally increase at the onset of ischemia and was even attenuated at 15 minutes of sustained ischemia, and heat-shock protein (HSP) 27 was phosphorylated and translocated from cytosol to myofibril or nucleus without affecting total protein level at the onset of ischemia compared with the control group. SB203580 treatment (1 micromol/L) only during IP blunted the infarct size limitation by IP (37.3+/-6.3% versus 7.4+/-2.1% in the IP group, P:<0.01) and attenuated either phosphorylation or translocation of HSP27 during IP. Although the SB203580 treatment throughout the preischemic and postischemic periods had no significant effect on infarct size (33.3+/-9.4%) in this model, treatment with SB203580 only during ischemia partially mimicked the infarct size limitation by IP (26.8+/-3.5%). Thus, transient p38 MAPK activation during ischemic preconditioning mainly mediates the cardioprotection followed by HSP27 phosphorylation and translocation in vivo in the canine heart.
Asunto(s)
Precondicionamiento Isquémico Miocárdico , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Infarto del Miocardio/enzimología , Miocardio/enzimología , Animales , Western Blotting , Circulación Coronaria/fisiología , Modelos Animales de Enfermedad , Perros , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/administración & dosificación , Corazón/efectos de los fármacos , Proteínas de Choque Térmico/efectos de los fármacos , Proteínas de Choque Térmico/metabolismo , Hemodinámica/efectos de los fármacos , Imidazoles/administración & dosificación , Infusiones Intravenosas , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Infarto del Miocardio/patología , Fosforilación/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , Piridinas/administración & dosificación , Tasa de Supervivencia , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
BACKGROUND: Phosphodiesterase III inhibitors (PDEIII-Is) improve the hemodynamic status of heart failure via inotropic/vasodilatory effects attributable to the increase in intracellular cAMP level. Direct cardioprotection by PDEIII-Is and its underlying mechanisms, however, have not been identified. We tested the infarct size-limiting effect of PDEIII-Is and the roles of cAMP, protein kinase (PK) A, PKC, and mitogen-activated protein kinase (MAPK) families in open-chest dogs. Methods and Results-- Milrinone, olprinone (PDEIII-Is), or dibutyryl-cAMP (db-cAMP) was injected intravenously 30 minutes before 90-minute ischemia, followed by 6 hours of reperfusion. Olprinone was also examined with an intracoronary cotreatment with a PKA inhibitor (H89), a PKC inhibitor (GF109203X), an extracellular signal-regulated kinase kinase (MEK) inhibitor (PD98059), or a p38 MAPK inhibitor (SB203580) throughout the preischemic period. Either PDEIII-Is or db-cAMP caused substantial hemodynamic changes, which returned to control levels in 30 minutes. Collateral flow and percent risk area were identical for all groups. Both PDEIII-Is and db-cAMP increased myocardial p38 MAPK activity during the preischemic period, which was blocked by H89, but not by GF109203X. Both PDEIII-Is and db-cAMP reduced infarct size (19.1+/-4.1%, 17.5+/-3.3%, and 20.3+/-4.8%, respectively, versus 36.1+/-6.2% control, P<0.05 each). Furthermore, the effect of olprinone was blunted by either H89 (35.5+/-6.4%) or SB203580 (32.6+/-5.9%), but not by GF109203X or PD98059. H89, GF109203X, PD98059, or SB203580 alone did not influence infarct size. CONCLUSIONS: Pretreatment with PDEIII-Is has cardioprotective effects via cAMP-, PKA-, and p38 MAPK-dependent but PKC-independent mechanisms in canine hearts.
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Fármacos Cardiovasculares/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Sulfonamidas , 3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Animales , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Bucladesina/farmacología , Proteínas Quinasas Dependientes de Calcio-Calmodulina/antagonistas & inhibidores , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/fisiología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3 , Perros , Inhibidores Enzimáticos/farmacología , Flavonoides/farmacología , Hemodinámica/efectos de los fármacos , Imidazoles/farmacología , Indoles/farmacología , Isoquinolinas/farmacología , Maleimidas/farmacología , Milrinona/farmacología , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/fisiología , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/prevención & control , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/metabolismo , Piridinas/farmacología , Piridonas/farmacología , Fibrilación Ventricular/patología , Fibrilación Ventricular/fisiopatología , Fibrilación Ventricular/prevención & control , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
OBJECTIVES: This study examined the coronary vasoconstrictive action of endogenous neuropeptide Y (NPY) during sympathetic nerve stimulation and its modulation by the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel in vivo. BACKGROUND: Exogenous NPY was characterized by its potent vasoconstrictive effect. However, endogenous NPY has failed to show any vasoconstrictive activity in vivo. METHODS: We studied 70 anesthetized dogs with vagotomy under beta-adrenergic blockade. Ansae subclaviae stimulation and intracoronary administration of the neurotransmitters (NPY and norepinephrine) were done with or without alpha-adrenergic blockade, NPY antagonist BIBP3226 or KATP channel acting agents. We measured coronary vascular resistance (CVR) and the neurotransmitter levels in systemic arteries and the great cardiac vein, and the amount of overflow (venoarterial difference times myocardial blood flow). RESULTS: During nerve stimulation, NPY levels correlated significantly with CVR at the highest r value (r = 0.850, p < 0.0001) obtained for the venous level under alpha-blockade, but norepinephrine showed no correlation. Treatment with BIBP3226 abolished the correlation between NPY level and CVR under alpha-blockade. Without alpha-blockade, norepinephrine levels correlated significantly with CVR; however, NPY showed no correlation. The amount of NPY overflow during the stimulation was nearly 1,000-fold lower than norepinephrine overflow. Exogenous NPY had a 100-fold more potent coronary vasoconstrictive action than that of norepinephrine. The KATP channel antagonist glibenclamide enhanced vasoconstriction of NPY, and the agonist pinacidil suppressed it with a predominant effect in the subepicardial region. CONCLUSIONS: During sympathetic nerve stimulation, the vasoconstrictive actions of NPY are masked by norepinephrine under intact alpha-adrenoceptor conditions, manifest during alpha-blockade and modulated by KATP channel activity.
Asunto(s)
Adenosina Trifosfato/farmacología , Vasos Coronarios/efectos de los fármacos , Neuropéptido Y/farmacología , Canales de Potasio/fisiología , Vasoconstricción/fisiología , Antagonistas Adrenérgicos alfa/farmacología , Antagonistas Adrenérgicos beta/farmacología , Animales , Arginina/análogos & derivados , Arginina/farmacología , Vasos Coronarios/fisiología , Perros , Femenino , Masculino , Norepinefrina/farmacología , Canales de Potasio/efectos de los fármacos , Receptores de Neuropéptido Y/antagonistas & inhibidores , Resistencia Vascular/efectos de los fármacos , Vasoconstricción/efectos de los fármacosRESUMEN
OBJECTIVES: This study was undertaken to examine whether nitric oxide released in ischemic myocardium decreases the coronary vascular resistance and attenuates the severity of contractile and metabolic dysfunction. BACKGROUND: Endothelium-derived relaxing factor, recently identified as nitric oxide, is a potent relaxant of coronary smooth muscle. METHODS: The left anterior descending coronary artery was perfused through an extracorporeal bypass tube placed in the carotid artery in 56 open chest dogs. After hemodynamic stabilization, we occluded this bypass tube to decrease coronary blood flow to one third of the control flow. Thereafter, we maintained a constant coronary perfusion pressure (40.9 +/- 3.1 mm Hg). RESULTS: Under ischemic conditions, the coronary arteriovenous differences in nitrate and nitrite (end products of nitric oxide) increased (from 3.5 +/- 0.4 [mean +/- SEM] to 12.9 +/- 2.1 mumol/liter, p < 0.01). NG-Monomethyl L-arginine (3 micrograms/kg body weight per min, intracoronary) decreased the coronary arteriovenous differences in nitrate and nitrite (5.0 +/- 0.9 mumol/liter, p < 0.05) and coronary blood flow (from 29.8 +/- 0.5 to 18.1 +/- 1.1 ml/100 g per min, p < 0.001). Fractional shortening (from 3.7 +/- 1.0 to -1.3 +/- 0.7%, p < 0.001) and lactate extraction ratio (from -44.0 +/- 4.1 to -59.2 +/- 4.9%, p < 0.005) of the perfused area also decreased. These values were restored by the concomitant administration of L-arginine. Blood flow to the endomyocardium was decreased relative to the epimyocardium. A reduction in coronary blood flow and worsening of myocardial contractile and metabolic functions due to the administration of NG-monomethyl L-arginine during ischemia were observed in denervated hearts. A reduction in coronary blood flow in ischemic myocardium was observed with the administration of NW-nitro-L-arginine methyl ester as well, although neither NW-nitro-L-arginine methyl ester nor NG-monomethyl L-arginine changed coronary blood flow and myocardial contractile and metabolic functions in the nonischemic myocardium. The cyclic guanosine monophosphate content of epicardial coronary artery increased due to myocardial ischemia; this increase was attenuated with NG-monomethyl L-arginine treatment. CONCLUSIONS: We conclude that endogenous nitric oxide predominantly decreases the coronary vascular resistance of ischemic endomyocardium, thereby improving myocardial contractility and metabolic function.
Asunto(s)
Circulación Coronaria/fisiología , Isquemia Miocárdica/fisiopatología , Óxido Nítrico/fisiología , Resistencia Vascular/fisiología , Animales , Presión Sanguínea , Perros , Frecuencia Cardíaca , Contracción Miocárdica , Miocardio/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/biosíntesisRESUMEN
1. Inhibitory effects of water-soluble glucocorticoids administered intravenously were examined on skin and airway reactions caused by antigen challenge or chemical mediators in guinea-pigs. 2. Methylprednisolone suleptanate (U-67590A) which is an analogue of methylprednisolone, produced immediate inhibition of 3-h and 7-day homologous passive cutaneous anaphylaxis (PCA) reactions, but not of histamine- or bradykinin-induced cutaneous vascular permeability, when administered 10 min before antigen challenge. In contrast, methylprednisolone succinate (MP) or dexamethasone (DXM) administered 10 min before antigen challenge failed to show an immediate inhibitory effect on the PCA or mediator-induced reactions. When administered 1 to 5 h before antigen challenge, all the steroids used in this study reduced both PCA and mediator-induced reactions. 3. Pretreatment with cycloheximide almost completely abolished the late inhibition of 3-h PCA and histamine reactions produced by U-67590A or MP, but it did not affect the immediate inhibition of 3-h PCA produced by U-67590A. 4. U-67590A also demonstrated immediate inhibitory effects on antigen-induced bronchoconstriction in guinea-pigs actively sensitized with ovalbumin even when administered 10 min before antigen challenge, whereas MP and DXM failed to show the immediate inhibitory effect. When administered 3 h before antigen challenge, all the steroids used in this study reduced the response to antigen. 5. The late inhibitory effect of U-67590A administered 3 h before antigen challenge was almost completely abolished by treatment with cycloheximide or 17 alpha-methyltestosterone, whereas the immediate inhibition produced by U-67590A administered 10 min before challenge was not affected by this treatment. 6. U-67590A administered 10 min or 3 h before challenge did not affect the bronchoconstriction induced by histamine or leukotriene D4.7. Release of histamine from lung fragments of sensitized guinea-pigs in vitro was inhibited by U-67590A.8. The present experiments indicate that U-67590A demonstrated dual, immediate and late, inhibitory effects. The former are independent of protein synthesis and may be associated with non-genomic direct action on the mediator-releasing process without affecting mediator-induced reactions. The latter share common inhibitory actions with other glucocorticoids which are dependent on protein synthesis through gene expression.
Asunto(s)
Anafilaxia/prevención & control , Metilprednisolona/análogos & derivados , Anafilaxis Cutánea Pasiva/efectos de los fármacos , Resistencia de las Vías Respiratorias/efectos de los fármacos , Animales , Bradiquinina/farmacología , Permeabilidad Capilar/efectos de los fármacos , Cicloheximida/farmacología , Dexametasona/análogos & derivados , Dexametasona/farmacología , Cobayas , Histamina/farmacología , Liberación de Histamina/efectos de los fármacos , Inmunoglobulina E/inmunología , Inmunoglobulina G/inmunología , Técnicas In Vitro , Masculino , Metilprednisolona/farmacología , Hemisuccinato de Metilprednisolona/farmacología , Receptores de Glucocorticoides/efectos de los fármacos , Receptores de Glucocorticoides/metabolismo , Sistema Respiratorio/efectos de los fármacos , Sistema Respiratorio/inmunología , Piel/efectos de los fármacos , Piel/inmunologíaRESUMEN
The effect of gonadal steroids on basal and GnRH-stimulated hCG release was studied using collagenase-dispersed trophoblast cells from early pregnancy. Both GnRH and a GnRH superagonist, Buserelin, stimulated hCG release with a similar dose dependency. Progesterone (0.1 to 10 micrograms/ml) inhibited GnRH-stimulated hCG release in a dose dependent manner as well as basal hCG release. Relatively high concentrations of estradiol (10 micrograms/ml) stimulated both basal and GnRH-mediated hCG release and antagonized the inhibitory effect of progesterone on hCG release at 1 micrograms/ml as well as RU486 (1 microgram/ml). These results indicate that progesterone has an important role in both basal and GnRH-mediated hCG regulatory system in the placenta.
Asunto(s)
Gonadotropina Coriónica/metabolismo , Hormonas Esteroides Gonadales/fisiología , Hormonas Liberadoras de Hormona Hipofisaria/fisiología , Trofoblastos/metabolismo , Buserelina/farmacología , Células Cultivadas , Estradiol/fisiología , Estrenos/farmacología , Femenino , Humanos , Mifepristona , Hormonas Liberadoras de Hormona Hipofisaria/antagonistas & inhibidores , Embarazo , Progesterona/antagonistas & inhibidores , Progesterona/fisiologíaRESUMEN
To investigate whether QT dispersion increases in borderline and mild hypertension during a longitudinal observation of > 3 years and whether it is improved with medications, left ventricular geometric patterns and QT dispersion were studied with special regard to their longitudinal changes in 85 male borderline and mild hypertensive subjects with left ventricular mass index < 125 g/m2. These subjects were followed for > 3 years without medication. Thirty-two patients with a left ventricular mass index > 125 g/m2 at the end of follow-up period were further observed using antihypertensive drugs for an additional 3 years. Echocardiograms and electrocardiograms were obtained at the beginning and end of the follow-up period. At the end of the follow-up period, subjects were classified into four groups based on ventricular geometric patterns determined by left ventricular mass index and relative wall thickness in diastole. The QT dispersion was greater in patients with concentric hypertrophy (56+/-18 msec) than in patients with normal geometry (41+/-17 msec) (P < .05) and increased significantly in the former group during the follow-up period. After medication, the left ventricular mass index regressed and the QT dispersion decreased (from 55+/-21 to 50+/-26 msec, P < .01) in these patients. Thus, these findings suggest that changes in the QT dispersion reflect both concentric evolution and regression of left ventricular hypertrophy.
Asunto(s)
Ecocardiografía , Electrocardiografía , Hipertensión/diagnóstico por imagen , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/fisiopatología , Adulto , Presión Sanguínea/fisiología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Análisis de Regresión , Estudios RetrospectivosRESUMEN
BACKGROUND AND PURPOSE: Conventional X-ray angiography lacks the sensitivity and spatial resolution needed to detect small amounts of iodinated contrast material and to quantitate diameters of the small vessels in the brain. The purpose of this study was to ascertain whether digitized synchrotron radiation microangiography, with the use of a high-definition TV camera system, can accurately show small cerebral vessels. METHODS: Six anesthetized dogs were exposed to monochromatic synchrotron radiation with an energy level of 33.3 keV optimized for iodine detection while iodinated contrast material was injected into the brachiocephalic and vertebral arteries. The images were detected with a high-definition TV camera system with a spatial resolution of 30 microm. In all, 26 cerebral angiograms of the circle of Willis with its branches were obtained, and the images were digitized at a workstation. RESULTS: The small branches of the circle of Willis were clearly visible on all images. Vasodilatation of the circle of Willis and its large and small branches induced by CO2 inhalation was quantitatively confirmed on the images: for example, the diameter of one small branch was increased from 0.24 +/- 0.04 mm to 0.38 +/- 0.12 mm. Temporal subtraction improved the image quality. CONCLUSION: The synchrotron radiation angiographic system is useful for visualizing large and small vessels deep in the brain as well as for quantitating their diameters.
Asunto(s)
Angiografía de Substracción Digital , Círculo Arterial Cerebral/diagnóstico por imagen , Sincrotrones , Angiografía de Substracción Digital/métodos , Animales , Angiografía Cerebral , Medios de Contraste , Perros , Procesamiento de Imagen Asistido por Computador , MicrorradiografíaRESUMEN
Newborn rats were intracranially inoculated with human adenovirus type 12 within 24 hours after birth and their brains were sequentially investigated by conventional histological techniques and autoradiography to clarify the early process of tumor growth. At the end of the 2nd week atypical cells having bizarre configuration first appeared singly in the tapetum. From the end of the 3rd week small clusters of slightly atypical subependymal cells ("abnormal clusters") appeared in the subependymal area. From the end of the 4th week a few "microtumors" showing compact nodular growth of atypical glial cells were observed among the "abnormal clusters". These early neoplastic changes in the rat brains had close relationship to subependymal cells. The perinatal subependymal cells showed most dense distribution in the subependymal area of lateral ventricle with open ventricular space ("open ventricular area") especially in the region of anterior horn. In contrast, the microtumors and the enlarged tumors were recognized much more in number in the subependymal area of bulbus olfactorius and tapetum where ventricular cavities closed in the young period of maturation ("closed ventricular area"). "Abnormal clusters" were located in both of the areas with more preponderence in the open ventricular area. The reasons for this discrepancy of occurrence were discussed from the viewpoint of environmental factors. Subsequent investigation revealed that the average number of microtumors, after reaching its peak at the end of the 5th week, diminished gradually and, finally, only one or two enlarged tumors were found per each tumor-bearing animal. The mechanisms for this phenomenon are open to further investigation.
Asunto(s)
Infecciones por Adenovirus Humanos/patología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/virología , Adenovirus Humanos , Animales , Ratas , Ratas Sprague-DawleyRESUMEN
We proposed a mathematical model to describe the early filling process of the left ventricle and applied the model to in vivo experiments. The solution of a second-order differential equation indicated that the pressure difference between the left atrium and ventricle during ventricular filling (PD) could be explained by a transient response, i.e. decremental oscillation, in an LCR circuit. Thereafter, we analysed the sequence of PD during vagal stimulation with two catheter-tip manometers in 12 anaesthetised dogs and evaluated changes in the parameters of the system under various haemodynamic conditions. The values of omega n and zeta were quite stable among beats within an episode of vagal stimulation, between episodes and even among dogs, despite the changes in haemodynamic variables. Pericardiotomy and partial discommunication of the mitral valve with the left ventricular free wall by cutting the mitral chordal tendons decreased omega n and increased zeta, mainly because of the increase in CLV. Occlusion of the coronary vascular beds with large numbers of microspheres increased omega n and decreased zeta, mainly because of the decrease in CLV. Mitral obstruction with an inflated balloon (increase in R) abolished the oscillatory changes and produced an exponential decay sequence of PD. In conclusion, both the logical and experimental approaches indicated that the sequence of PD could be considered as decremental oscillation in the LCR circuit and the parameters omega n and zeta could be good indices of the diastolic property of the left ventricle.
Asunto(s)
Presión Sanguínea/fisiología , Modelos Cardiovasculares , Función Ventricular Izquierda/fisiología , Animales , Función Atrial , Adaptabilidad , Perros , Electricidad , MatemáticaRESUMEN
The left ventricle was removed from 76 dogs and was cast in silicone, in vitro, under three fixing pressure levels to simulate various end-diastolic pressures. This cast was designated as a silicone cast. The waxen cast was constructed by adding attachments which protrude inside the LV cavity, such as the papillary muscles and trabeculae carneae to the silicone cast. The cast volumes were compared with the volume calculated by the area-length method, including ellipsoid and paraboloid models, and by Chapman's method in which silhouettes of the silicone casts projected on 4 planes were used. Under a lower fixing pressure, the volume of papillary muscles and trabeculae carneae accounted for about 35% of the LV volume which was independent of either size of heart or weight of the dog. This ratio was reduced at higher fixing pressure levels. The relationship between the cast volume and the volume calculated by the silhouette method was linearly proportional. However, the deviation increased with higher fixing pressure levels and with larger ventricular volumes in all calculation methods, indicating the shape of the left ventricle cannot be represented by any ideal symmetrical spherical model. The calculated volume agreed with its corresponding cast volume with an error of less than 10% if either the fixing pressure level was below 5 mmHg, or the volume was less than 50 ml.
Asunto(s)
Corazón/anatomía & histología , Modelos Anatómicos , Animales , Perros , Ventrículos Cardíacos/anatomía & histología , MatemáticaRESUMEN
A case of priapism following epidural anesthesia was reported. A 67 year old man received epidural anesthesia for the transurethral resection of a malignant bladder tumor. Epidural anesthesia which he had wanted to receive was given through the L3 to L4 intervertebral space with 18 ml of 2% lidocaine. The penile erection occurred while he was prepared and draped. Additional 8 ml of 1% lidocaine failed to overcome it and the operation cancelled. After this episode, he had anesthesia on 5 occasions in 2 years. General anesthesia was given 3 times without penile erection, but epidural block was tried on 2 occasions, which was followed by penile erection. For the penile erection, intracavernous injection of etilefrine hydrochloride was effective and surgical procedure could be done smoothly. The mechanism of priapism remained unclear but imbalance of the autonomic nervous system may be a involved. This case suggests that intracavernous injection of etilefrine hydrochloride is effective for treatment of penile erection during transurethral surgery.