Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Linfohistiocitosis Hemofagocítica/inducido químicamente , Melanoma/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Femenino , Humanos , Imidazoles/administración & dosificación , Neoplasias Pulmonares/secundario , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Melanoma/patología , Persona de Mediana Edad , Oximas/administración & dosificación , Pronóstico , Piridonas/administración & dosificación , Pirimidinonas/administración & dosificaciónRESUMEN
OBJECTIVES: To investigate the mechanical effects of mastication on the mandible, we developed computational controlled mastication robot system with human dry skull and analyzed the strain distribution on the mandibular bone surface. DESIGN: In the mastication robot, the mandible was suspended by eight wires, which simulated masticatory muscles. A non-linear spring damper generated viscoelastic properties, and tension sensors for simulation of jaw reflection to avoid unusual biting force were applied as a biological feedback mechanism. By using this robot system, various patterns of muscle loading (change of wire direction and magnitude) were performed. RESULTS: From the results, significant differences in the amount of principal strain and its distribution were demonstrated in each condition (ANOVA, post hoc test, and p < 0.05). The value of maximum principal strain ranged from 79.66 x 10(-6) [at anterior border of ramus (Buccal side), 128 N] to -1.42 x 10(-6) [at foramen mentale (Buccal side), 32 N]. CONCLUSION: These results suggested that the muscle loading generated the mechanical strain on the mandibular bone surface and it was affected by the changes in loading direction and magnitude.
Asunto(s)
Mandíbula/fisiología , Masticación/fisiología , Músculos Masticadores/fisiología , Robótica/instrumentación , Análisis de Varianza , Fuerza de la Mordida , Simulación por Computador , Elasticidad , Humanos , Modelos Biológicos , Contracción Muscular/fisiología , Estrés Mecánico , Viscosidad , Soporte de Peso/fisiologíaRESUMEN
In the current study, we investigated the NO-generation pathway in response to mechanical stimuli in SHR at the prehypertensive stage. To examine the role of NO in coronary autoregulation, we evaluated the effects of L-NAME on the coronary flow in SHR at both the prehypertensive and hypertensive stages. Isolated perfused hearts from 5- and 15-week-old SHR and from age-matched Wistar-Kyoto rats (WKY) were used. After stabilization at 60 mmHg, perfusion pressure was immediately raised to 90 mmHg to record the change in coronary flow for 10 min without (control) or with NO synthesis blockade by Nomega-nitro-L-arginine methyl ester (L-NAME). NOx- (nitrite/nitrate) was measured in coronary effluent. At 5 weeks of age, SHR did not have hypertension, while the coronary autoregulation was enhanced. L-NAME did not affect this enhanced autoregulation in 5-week-old SHR. At perfusion pressures of both 60 and 90 mmHg, 5-week-old SHR showed less coronary NOx- production than age-matched WKY. At 15 weeks, SHR showed a higher blood pressure than WKY. The coronary autoregulation in SHR remained higher than that in WKY, but was below that in 5-week-old SHR. NOx- production in 15-week-old SHR recovered to the level of age-matched WKY. These results indicate that NOx- production induced by mechanical stimulation was markedly reduced in 5-week-old SHR at the prehypertensive stage, which may have enhanced coronary autoregulation. An impaired nitric oxide production may precede the onset of hypertension in SHR.
Asunto(s)
Circulación Coronaria , Homeostasis , Óxido Nítrico/biosíntesis , Ratas Endogámicas SHR/fisiología , Animales , Presión Sanguínea/fisiología , Circulación Coronaria/efectos de los fármacos , Circulación Coronaria/fisiología , Endotelio Vascular/fisiología , Masculino , Nitratos/sangre , Donantes de Óxido Nítrico/farmacología , Nitritos/sangre , Nitroprusiato/farmacología , Ratas , Ratas Endogámicas WKY , Vasodilatación/fisiologíaRESUMEN
The aim of this study was to evaluate the possible role of prostacyclin (PGl2) in the onset and development of hypertension and chronic renal failure in 5/6-nephrectomized rats (5/6NX). We measured the systolic blood pressure, 24-h urinary excretion levels of 6-keto-PGF1alpha, which was a stable metabolite of PGI2, and levels of PGI2 synthase (PCS) mRNA in the kidneys. Immunostaining for PCS in the kidneys was also evaluated. Systolic blood pressure was higher in 5/6NX than in sham-operated rats. The 24-h urinary excretion levels of 6-keto-PGF1alpha in 5/6NX at 1 week postsurgery were lower than in sham-operated rats. In renal morphology, tubulointerstitial injury was observed at 2 weeks postsurgery, and glomerulosclerosis at 4 weeks. Levels of PCS mRNA in 5/6NX decreased significantly at 1 and 2 weeks postsurgery compared with those in sham-operated rats, but at 8 weeks these levels showed a tendency to increase. Immunostaining for PCS was positive in a subset of the cortical thick ascending limb of Henle's loop cells, including macula densa in both groups. Moreover, in 5/6NX at 8 weeks postsurgery, mesangial cells also stained positive for PCS. In conclusion, our findings suggest that PCS might play an important role in mitigating glomerular hemodynamic changes associated with reduction of renal mass.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Mesangio Glomerular/enzimología , Oxidorreductasas Intramoleculares/metabolismo , Asa de la Nefrona/enzimología , Nefrectomía/métodos , 6-Cetoprostaglandina F1 alfa/orina , Animales , Presión Sanguínea , Ritmo Circadiano , Sistema Enzimático del Citocromo P-450/genética , Mesangio Glomerular/patología , Corazón/fisiopatología , Frecuencia Cardíaca , Hormonas/sangre , Inmunohistoquímica , Oxidorreductasas Intramoleculares/genética , Riñón/metabolismo , Riñón/patología , Riñón/fisiología , Asa de la Nefrona/patología , Masculino , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Sístole , Tromboxano B2/orinaRESUMEN
Nipradilol (CAS 81486-22-8), a vasodilatory beta-blocker, has been shown to dilate smaller vessels than nitroglycerin does, and the vasodilative effects of nipradilol have been reported to be less mediated by cyclic GMP (guanosine monophosphate) than those of nitroglycerin. To test the hypothesis that cyclic GMP-independent potassium channels have a larger role in nipradilol-induced aortic relaxation than cyclic GMP-dependent mechanisms, the effects of a potassium channel blocker, tetraethylammonium (TEA, CAS 56-34-8), and of a guanylate cyclase inhibitor, methylene blue (MB, CAS 61-73-4), on nipradilol-induced aortic relaxation were investigated and compared with those on nitroglycerin-induced aortic relaxation in isolated rat aortic rings. Relaxation response was expressed as percent relaxation, which is a percentage of the tension developed by 10(-7) mol/l norepinephrine. Nitroglycerin and nipradilol similarly relaxed the aortic ring in a concentration-dependent manner (10(-9)-10(-4) mol/l). In contrast, desnitronipradilol, a nipradilol analogue which has no nitroxy group, induced almost no aortic relaxation. TEA at 10(-3) mol/l, which is selective for calcium-activated potassium channels, inhibited the aortic relaxation induced by nipradilol (10(-5) mol/l) to a significantly greater extent than that induced by nitroglycerin (10(-5) mol/l) (% relaxation: 30.0 +/- 6.8 vs. 51.1 +/- 6.1%, p < 0.05). MB (10(-5) mol/l) suppressed the relaxation by nitroglycerin slightly but not significantly more than that by nipradilol. (% relaxation: 54.7 +/- 9.9 vs. 64.6 +/- 5.7%). The combination of TEA and MB almost completely eliminated the relaxation induced by nipradilol as well as by nitroglycerin. Thus, cyclic GMP-independent calcium activated potassium channels may be more involved in the aortic relaxation by nipradilol than that by nitroglycerin in rats.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Músculo Liso Vascular/efectos de los fármacos , Canales de Potasio Calcio-Activados , Canales de Potasio/fisiología , Propanolaminas/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Guanilato Ciclasa/antagonistas & inhibidores , Técnicas In Vitro , Canales de Potasio de Conductancia Intermedia Activados por el Calcio , Masculino , Relajación Muscular/efectos de los fármacos , Nitroglicerina/farmacología , Bloqueadores de los Canales de Potasio , Canales de Potasio/efectos de los fármacos , Ratas , Ratas Endogámicas WKY , Tetraetilamonio/farmacología , Vasodilatadores/farmacologíaRESUMEN
Abnormal lipid metabolism has been proposed to be involved in the pathogenesis of diabetic cardiomyopathy. In this study, we measured myocardial lipid levels, including 1,2-diacylglycerol (1,2-DAG) and ceramide (CM), and myocardial function in diabetic rats. We also evaluated the effects of etomoxir (ETM), a carnitine palmitoyl transferase I inhibitor, on diabetic rat hearts from the viewpoints of alterations in lipid second messengers and myocardial function. Rats were injected with streptozotocin (60 mg/kg) to induce diabetes and were treated 5 weeks later with ETM (18 mg/kg) for 8 days. In diabetic rats, heart rate, systolic blood pressure, and fractional shortening were significantly reduced compared with those in controls. Treatment of diabetic rats with ETM ameliorated myocardial dysfunction other than heart rate. Myocardial 1,2-DAG levels in diabetic rats were significantly elevated compared with those in controls, while myocardial CM levels were not. ETM treatment caused an additional increase in myocardial 1,2-DAG levels in diabetic rats, but the CM levels did not change. There was a marked difference in fatty acid pattern of 1,2-DAG between diabetic and ETM-treated diabetic rat hearts. The fatty acids 18:1 and 18:2 were significantly increased and the fatty acids 16:0, 18:0, 20:4, and 22:6 were significantly reduced in ETM-treated diabetic rat hearts. These data suggest 1,2-DAG is involved in ameliorating myocardial dysfunction in diabetic rats and that its source is different between diabetic and ETM-treated diabetic rats. CM is unlikely to be involved in the pathogenesis of diabetic cardiomyopathy or the improvement of cardiac contractility in diabetic rats by ETM.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Diglicéridos/metabolismo , Inhibidores Enzimáticos/uso terapéutico , Compuestos Epoxi/uso terapéutico , Hipoglucemiantes/uso terapéutico , Disfunción Ventricular Izquierda/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Carnitina/metabolismo , Ceramidas/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/fisiopatología , Ecocardiografía , Ácidos Grasos/análisis , Ácidos Grasos/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Masculino , Miocardio/metabolismo , Miocardio/patología , Ratas , Ratas Wistar , Estreptozocina , Disfunción Ventricular Izquierda/tratamiento farmacológico , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
This study was conducted to (a) assess postischemic vasodilatation by changes in the vascular cross-sectional area using simultaneous intravascular two-dimensional and Doppler ultrasound before and after the infusion of Intralipid (Pharmacia & Upjohn, Peapack, NJ, U.S.A.); (b) evaluate how antioxidant ascorbic acid modifies the effects of Intralipid on postischemic vasodilatation: and (c) clarify the changes in plasma nitrite and nitrate (NOx-) levels after the infusion of Intralipid with and without ascorbic acid. Twenty-eight mongrel dogs were used to measure for vascular cross-sectional area and average instantaneous peak velocity in the iliac arteries after the 5-min occlusion of the arteries. Postischemic vasodilatation was impaired after the infusion of Intralipid (20%, 2 ml/kg) and this impaired response was reversed by the co-administration of ascorbic acid (30 mg/kg). NG-monomethyl-L-arginine completely abolished postischemic vasodilatation. Plasma NOx levels were significantly reduced after the infusion of Intralipid compared with baseline (11.6+/-0.4 vs. 12.9+/-0.3 microM, p = 0.025) and after infusion of Intralipid with ascorbic acid compared with baseline (11.8+/-0.5 vs. 13.1+/-0.4 microM, p = 0.047). We concluded that ascorbic acid reverses the endothelial dysfunction induced by Intralipid without increasing plasma NOx- levels and that deactivation of nitric oxide by oxidative stress is a primary contributor to Intralipid-induced impaired vasodilation.
Asunto(s)
Ácido Ascórbico/farmacología , Arteria Ilíaca/fisiología , Isquemia/fisiopatología , Aceite de Soja/farmacología , Vasodilatación/efectos de los fármacos , Animales , Colesterol/sangre , Circulación Coronaria/efectos de los fármacos , Perros , Inhibidores Enzimáticos/farmacología , Emulsiones Grasas Intravenosas/farmacología , Femenino , Arteria Ilíaca/anatomía & histología , Infusiones Intravenosas , Masculino , Nitratos/sangre , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III , Nitritos/sangre , Aceite de Soja/administración & dosificación , Triglicéridos/sangre , omega-N-Metilarginina/farmacologíaRESUMEN
This study evaluated the role of adrenomedullin in patients with vasospastic angina pectoris. Adrenomedullin may be involved in regulating a basal tone of the coronary artery in these patients.
Asunto(s)
Angina Pectoris Variable/sangre , Péptidos/sangre , Vasodilatadores/sangre , Acetilcolina , Adrenomedulina , Anciano , Angina Pectoris Variable/etiología , Péptido Relacionado con Gen de Calcitonina/sangre , Estudios de Casos y Controles , Circulación Coronaria , Femenino , Humanos , Masculino , Péptidos/fisiología , Proyectos PilotoRESUMEN
OBJECTIVES: We sought to elucidate the long-term prognostic importance of angiographic no-reflow phenomenon after percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial infarction (AMI). BACKGROUND: Angiographic no-reflow phenomenon, a reduced coronary antegrade flow (Thrombolysis in Myocardial Infarction [TIMI] flow grade < or =2) without mechanical obstruction after recanalization, predicts poor left ventricular (LV) functional recovery and survival in the early phase of AMI. We hypothesized that angiographic no-reflow phenomenon also predicts long-term clinical outcome. METHODS: We studied 120 consecutive patients with their first AMI treated by PTCA without flow-restricting lesions. The patients were classified as either no-reflow (n = 30) or reflow (TIMI-3) (n = 90) based on post-PTCA cineangiograms to follow up (5.8 +/- 1.2 years) for cardiac death and nonfatal events. RESULTS: Patients with no-reflow had congestive heart failure (p < 0.0001), malignant arrhythmia (p = 0.038), and cardiac death (p = 0.002) more often than did those with reflow. Kaplan-Meier curves showed lower cardiac survival and cardiac event-free survival (p < 0.0001) in patients with no-reflow than in those with reflow. Multivariate analyses disclosed that no-reflow phenomenon was an independent predictor of long-term cardiac death (relative risk [RR] 5.25, 95% confidence interval [CI] 1.85 to 14.9, p = 0.002) and cardiac events (RR 3.71, 95% CI 1.79 to 7.69, p = 0.0004). At follow-up, survivors with no-reflow had higher end-diastolic and end-systolic LV volume indices and plasma brain natriuretic peptide levels, and lower LV ejection fractions (p = 0.0002, p < 0.0001, p = 0.002, p < 0.0001, respectively) than did those with reflow, indicating that no-reflow may be involved in LV remodeling. CONCLUSIONS: Angiographic no-reflow phenomenon strongly predicts long-term cardiac complications after AMI; these complications are possibly associated with LV remodeling.
Asunto(s)
Angioplastia Coronaria con Balón/efectos adversos , Angiografía Coronaria , Circulación Coronaria/fisiología , Infarto del Miocardio/terapia , Función Ventricular Izquierda/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Angioplastia Coronaria con Balón/mortalidad , Causas de Muerte , Cineangiografía , Angiografía Coronaria/métodos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/mortalidad , Infarto del Miocardio/fisiopatología , Estudios Retrospectivos , Factores de Riesgo , Volumen Sistólico , Tasa de SupervivenciaRESUMEN
The expression of mRNAs of creatine kinase (CK)-B and CK-M has been show to be affected by insulin, and myocardial CK-MB activity is suppressed in insulin-deficient rats. We investigated the dose-related effect of insulin on CK-MB activity in cardiac and skeletal muscles. Male Wistar rats were divided into three groups: (1) control group, (2) diabetic group, injected with 65 mg/kg streptozotocin for 4 weeks, and (3) atenolol group, administered 30 mg/kg per day atenolol. Each group was further divided into three subgroups and administered either saline, or 20 (Ins 20) or 30 (Ins 30) U/kg per day insulin. After 3 weeks, the isoenzyme activity of CK and lactate dehydrogenase (LDH) in the left ventricle of the heart (LV) and the major pectoral muscle (PM) was measured. Serum insulin increased and plasma glucose decreased in Ins 20 and Ins 30, dose-dependently, in all three groups. Both CK-MB and -BB activity in LV increased dose-dependently with insulin treatment in the control, diabetes, and atenolol groups, although these changes did not occur in skeletal muscles. CK-MB in LV correlated with the serum insulin levels in all rats, while no correlation was found in the skeletal muscles. These findings suggest that insulin possibly regulates the distribution of CK isoenzymes in rat heart muscle, and that the effect of insulin is not due to the sympathetic drive induced by hypoglycemia.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Atenolol/farmacología , Creatina Quinasa/metabolismo , Diabetes Mellitus Experimental/enzimología , Corazón/efectos de los fármacos , Insulina/fisiología , Miocardio/enzimología , Antagonistas Adrenérgicos beta/administración & dosificación , Animales , Atenolol/administración & dosificación , Glucemia/análisis , Interpretación Estadística de Datos , Diabetes Mellitus Experimental/sangre , Insulina/administración & dosificación , Insulina/sangre , Insulina/farmacología , L-Lactato Deshidrogenasa/sangre , L-Lactato Deshidrogenasa/metabolismo , Masculino , Músculo Esquelético/enzimología , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Our objective was 1) to assess postischemic vasodilatation using simultaneous intravascular two-dimensional and Doppler ultrasound, and 2) to clarify whether plasma nitrite and nitrate (NOx-) levels change during postischemic vasodilatation. The vascular cross-sectional area (CSA) was evaluated in 18 mongrel dogs, and the average instantaneous peak velocity (APV) in the iliac arteries after the 5-min occlusion of blood flow was determined. Plasma NOx- levels were measured at the baseline, during the occlusion of blood flow, and 1.5, 3, and 10 min after recanalization. The %CSA significantly increased from 30 s to 7 min after the recanalization, and maximal vasodilatation was observed at 1.5 min after the recanalization (14.1 +/- 0.9 to 15.8 +/- 1.0 mm2, p< 0.0001 vs. baseline). Plasma NOx- levels were significantly reduced during the occlusion of blood flow and remained reduced at 1.5, 3, and 10 min after recanalization compared with the baseline values. We concluded that simultaneous intravascular two-dimensional and Doppler ultrasound is useful for assessment during postischemic vasodilatation, and that plasma NOx- levels assayed with the Griess reagent do not significantly increase, even when maximal vasodilatation is observed.
Asunto(s)
Ecocardiografía , Daño por Reperfusión Miocárdica/fisiopatología , Ultrasonografía Intervencional , Vasodilatación , Animales , Presión Sanguínea/efectos de los fármacos , Cardiología/métodos , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/fisiopatología , Perros , Inhibidores Enzimáticos/farmacología , Femenino , Inyecciones Intraarteriales , Masculino , Daño por Reperfusión Miocárdica/sangre , Nitratos/sangre , Óxido Nítrico/fisiología , Nitritos/sangre , Factores de Tiempo , omega-N-Metilarginina/farmacologíaRESUMEN
During postischemic reperfusion, free radicals are produced and have deleterious effects in isolated rat hearts. We investigated whether melatonin (MEL) reduces the production of hydroxyl radical (*OH) in the effluent and aids in recovery of left ventricular (LV) function. Hearts were subjected to 30 min of ischemia followed by 30 min of reperfusion. Salicylic acid (SAL) was used as the probe for *OH, and its derivatives 2,5- and 2,3-dihydroxybenzoic acid (DHBA) were quantified using HPLC. In addition, thiobarbituric acid reactive substances (TBARS) in the myocardium was measured. Plateaus in the measurement of 2,5- and 2,3-DHBA were seen from 3 to 8 min after reperfusion in each group. The group that received 100 microM MEL+ SAL had significantly reduced amounts of 2,5- and 2,3-DHBA by multiple folds, compared to the SAL group. TBARS was significantly decreased in the 100 microM MEL group (1.20+/-0.36 vs 1.85+/-0.10 micromol/g of drug-free group, p<0.001). More importantly, the 100 microM MEL group significantly recovered in LV function (LV developed pressure, +dp/dt, and -dp/dt; 63.0%, 60.3%, and 59.4% in the 100 microM MEL group; 30.2%, 29.7%, and 31.5% in the drug-free group, respectively; p<0.05). Duration of ventricular tachycardia or ventricular fibrillation significantly decreased in the 100 microM MEL group (100 microM MEL, 159+/-67 sec; drug-free, 1244+/-233 sec; p<0.05). As a result of scavenging *OH and reducing the extent of lipid peroxidation, MEL is an effective agent for protection against postischemic reperfusion injury.
Asunto(s)
Depuradores de Radicales Libres/uso terapéutico , Radical Hidroxilo/metabolismo , Melatonina/uso terapéutico , Isquemia Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Animales , Arritmias Cardíacas/etiología , Depuradores de Radicales Libres/farmacología , Técnicas In Vitro , Peroxidación de Lípido/efectos de los fármacos , Masculino , Melatonina/farmacología , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatología , Daño por Reperfusión Miocárdica/metabolismo , Sustancias Protectoras/farmacología , Sustancias Protectoras/uso terapéutico , Ratas , Ratas Sprague-DawleyRESUMEN
An accumulation of recent evidence suggests that the mechanism in ischemic preconditioning (IPC) may involve the activation of protein kinase C (PKC) regulatory pathway. In this study, we examined whether the content of 1,2-diacylglycerol (1,2-DAG) and ceramide, which are intracellular second messengers regulating PKC activity, change during IPC in isolated perfused rat hearts, and whether the observed change in 1,2-DAG is accompanied with alteration in its fatty acid composition. Hearts subjected to IPC, consisting of 5-min transient global ischemia followed by 5-min reperfusion, presented a significant functional recovery during subsequent 40-min reperfusion following 40-min global ischemia compared with non-preconditioned hearts. An increase in 1,2-DAG content was observed in hearts subjected to 5-min transient ischemia compared with non-ischemic control hearts, however this was not seen in hearts harvested after 5-min reperfusion following 5-min ischemia. While fatty acid composition in 1,2-DAG was virtually unchanged in hearts subjected to 5-min ischemia, saturated 1,2-DAG decreased and monounsaturated/polyunsaturated 1,2-DAG increased in hearts reperfused for 5-min following 5-min ischemia compared with the non-ischemic control hearts. Ceramide mass did not change significantly, suggesting that the contribution of ceramide may be small in IPC. These data are in concert with the hypothesis that 1,2-DAG is a second messenger in IPC and the changes in fatty acid composition of 1,2-DAG may add new insight concerning signal transduction pathway in IPC.
Asunto(s)
Ceramidas/análisis , Diglicéridos/análisis , Precondicionamiento Isquémico , Miocardio/química , Animales , Ácidos Grasos/análisis , Corazón/fisiopatología , Masculino , Ratas , Ratas WistarRESUMEN
OBJECTIVE: This study was designed to compare the effects of prostacyclin synthase (PCS) gene transfer with those of a systemic infusion of beraprost sodium (BPS), a prostacyclin analogue, on vascular smooth muscle cell (VSMC) proliferation and neointimal formation after arterial injury. METHODS: PCS gene (3 or 30 micrograms) was transfected into rat balloon-injured carotid arteries by a non-viral lipotransfection method. BPS (100 or 300 micrograms/kg/day) was subcutaneously infused with osmotic pumps after the injury. LacZ gene (30 micrograms) was used as a control. VSMC proliferation was estimated by the bromodeoxyuridine (BrdU) index (BrdU-positive nuclei/total nuclei) at day 7. Neointimal formation was evaluated at day 14. Each treatment group had six rats. RESULTS: PCS gene transfer prevented the increase in intimal/medial area ratio (3 micrograms: 46.6%, 30 micrograms: 61.1% reduction; P < 0.05, P < 0.01, respectively), as did BPS 300 micrograms/kg/day (49.8% reduction; P < 0.05). BPS 100 micrograms/kg/day, however, had no effects on the ratio. PCS gene transfer and BPS 300 micrograms/kg/day significantly suppressed the BrdU index. BPS 300 micrograms/kg/day group had more frequent hematoma and longer bleeding time. There were no significant differences in blood pressure, heart rate, or urinary volume among all groups. CONCLUSION: Both PCS gene transfer and BPS 300 micrograms/kg/day reduced neointimal formation after arterial injury by inhibiting VSMC proliferation. PCS gene transfer may be a safer therapeutic modality against neointimal formation than a systemic infusion of BPS because the former method resulted in fewer bleeding complications.
Asunto(s)
Sistema Enzimático del Citocromo P-450/genética , Epoprostenol/análogos & derivados , Técnicas de Transferencia de Gen , Oxidorreductasas Intramoleculares/genética , Músculo Liso Vascular/patología , Inhibidores de Agregación Plaquetaria/farmacología , Análisis de Varianza , Animales , Western Blotting , Cateterismo , División Celular/efectos de los fármacos , Epoprostenol/farmacología , Músculo Liso Vascular/efectos de los fármacos , Ratas , Túnica Íntima/patologíaRESUMEN
Carvedilol (CAR) is a vasodilating beta-blocker which also has antioxidant properties. CAR produces dose-related reduction in mortality in patients with congestive heart failure. In the present study, we tested the hypothesis that CAR protects against doxorubicin (DOX)-induced cardiomyopathy in rats. Sprague-Dawley rats were treated with DOX, CAR, CAR+DOX, or atenolol (ATN)+DOX. DOX (cumulative dose, 15 mg/kg) was administered intraperitoneally, and CAR (30 mg/kg daily) or ATN (150 mg/kg daily) was administered orally. Three weeks after the completion of these treatments, cardiac performance and myocardial lipid peroxidation were assessed. Mortality was observed in the DOX (25%) and ATN+DOX (12.5%) groups. Compared with control rats, DOX significantly decreased systolic blood pressure (104+/-4 vs. 120+/-4 mmHg, P<0.05) and left ventricular fractional shortening (38.8+/-3.1 vs. 55.4+/-1.3%, P<0.01), and resulted in a significant accumulation of ascites (14.4+/-4.9 vs. 0 ml, P<0.01). CAR significantly prevented the cardiomyopathic changes caused by DOX, while ATN did not. The myocardial thiobarbituric acid reactive substances (TBARS) content was significantly higher in DOX-treated rats than in control rats (80.4+/-7.1 vs. 51.5+/-1.2 nmol/g heart, p<0.01). CAR prevented the increase in TBARS content (48.8+/-3.0 nmol/g heart, P<0.01 vs. DOX group), whereas ATN had no significant effect (74.3+/-5.2 nmol/g heart). CAR also significantly prevented the increase in both myocardial and plasma cholesterol concentrations caused by DOX. These data indicate that CAR protects against DOX-induced cardiomyopathy and that this effect may be attributed to the antioxidant and lipid-lowering properties of CAR, not to its beta-blocking property.
Asunto(s)
Antibióticos Antineoplásicos/toxicidad , Antioxidantes/farmacología , Carbazoles/farmacología , Cardiomiopatías/prevención & control , Doxorrubicina/toxicidad , Propanolaminas/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Cardiomiopatías/inducido químicamente , Carvedilol , Colesterol/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Miocardio/metabolismo , Ratas , Ratas Sprague-Dawley , Triglicéridos/metabolismoRESUMEN
We investigated whether the apolipoprotein E (apoE) and the angiotensin-converting enzyme (ACE) genotypes contribute to the variance in low-density lipoprotein (LDL) particle size in Japanese subjects (n = 136; M/F= 106/30). ACE polymorphism was associated with neither LDL size nor individual lipid levels. In contrast, the subjects with the epsilon2 allele of the apoE genotype had significantly lower levels of total cholesterol (P = 0.002) and LDL cholesterol (P = 0.004) compared with those without the epsilon2 allele. The subjects with the epsilon4 allele had a significantly smaller LDL particle size than those without the epsilon4 allele (P = 0.012). Separate analyses of the male subjects showed similar associations. A stepwise regression analysis revealed the epsilon4 allele to be an independent contributing variable that could affect LDL particle size. Our results suggest that the apoE genotype is associated with the development of atherosclerotic disease, since the epsilon2 and epsilon4 alleles relate to a decrease in LDL cholesterol levels and a decrease in LDL particle size, respectively.
Asunto(s)
Apolipoproteínas E/genética , Lipoproteínas LDL/química , Peptidil-Dipeptidasa A/genética , Adulto , Anciano , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Japón , Masculino , Persona de Mediana Edad , Tamaño de la Partícula , Polimorfismo GenéticoRESUMEN
OBJECTIVE: The aim of this study was to evaluate the possible role of prostacyclin (PGI2) in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR). METHODS: Measurement of mRNA and protein levels of PGH synthase (PGHS)-1, PGI2 synthase and the PGI2 receptor, in the thoracic aorta was performed in SHR aged 5, 10, 20, and 40 weeks old and in age-matched normotensive Wistar-Kyoto (WKY) rats with a competitive polymerase chain reaction method and immunoblotting. Aortic production of 6-keto-PGF1 alpha, the main metabolite of PGI2, was also measured. RESULTS: Compared with age-matched WKY rats, PGHS-1 mRNA and protein levels in the thoracic aorta of SHR increased with age, reaching three- and twofold higher than WKY rats at 40 weeks old, respectively. PGI2 synthase mRNA and protein levels in SHR were significantly higher than in WKY rats at 20 and 40 weeks old. In contrast, PGI2 receptor mRNA levels in SHR were consistently lower than in WKY rats at all ages. CONCLUSIONS: These results provide evidence that hypertension elicits alterations in levels of arachidonic acid metabolites, including PGH2 and PGI2. They also suggest that the decreased expression of PGI2 receptor mRNA in prehypertensive SHR could be one of the causes of hypertension in SHR.