RESUMEN

Aromatase is an estrogen synthetic enzyme that plays important roles in brain functions. To quantify aromatase expression in the brain by positron emission tomography (PET), we had previously developed [11C]cetrozole, which showed high specificity and affinity. To develop more efficient PET tracer(s) for aromatase imaging, we synthesized three analogs of cetrozole. We synthesized meta-cetrozole, nitro-cetrozole, and iso-cetrozole, and prepared the corresponding 11C-labeled tracers. The inhibitory activities of these three analogs toward aromatase were evaluated using marmoset placenta, and PET imaging of brain aromatase was performed using the 11C-labeled tracers in monkeys. The most promising analog in the monkey study, iso-cetrozole, was evaluated in the human PET study. The highest to lowest inhibitory activity of the analogs toward aromatase in the microsomal fraction from marmoset placenta was in the following order: iso-cetrozole, nitro-cetrozole, cetrozole, and meta-cetrozole. This order showed good agreement with the order of the binding potential (BP) of each 11C-labeled analog to aromatase in the rhesus monkey brain. A human PET study using [11C]iso-analog showed a similar distribution pattern of binding as that of [11C]cetrozole. The time-activity curves showed that elimination of [11C]iso-cetrozole from brain tissue was faster than that of 11C-cetrozole, indicating more rapid metabolism of [11C]iso-cetrozole. [11C]Cetrozole has preferable metabolic stability for brain aromatase imaging in humans, although [11C]iso-cetrozole might also be useful to measure aromatase level in living human brain because of its high binding potential.

Asunto(s)

Compuestos de Anilina/administración & dosificación , Aromatasa/metabolismo , Encéfalo/diagnóstico por imagen , Radioisótopos de Carbono/administración & dosificación , Tomografía de Emisión de Positrones/métodos , Triazoles/administración & dosificación , Animales , Encéfalo/enzimología , Humanos , Macaca mulatta , Masculino

RESUMEN

Quality of the 68Ga solution eluted from a 68Ge/68Ga generator (Galli Eo®) was evaluated. Elution was performed 488 times from 21 to 484 days (ca. 15 months) after the calibration date. The eluted 68Ga activity was 329 MBq to 1,148 MBq, which decreased with the decay of 68Ge, but no significant change was observed in the elution yields (62.8±2.2%). The half-life of the eluted radioactivity was 67.8±0.1 min, the radionuclide purity of 68Ga was ≥99.9%, the 68Ge breakthrough was 0.000024 ±0.000004%, and the radiochemical purity of 68Ga3+ was 99.7±0.2%. Fe and Zn were detected as metal impurities in the eluent, but both were ≤10 µg/GBq. The endotoxin concentration of the eluate was ≤5 EU/mL, and the eluent passed the sterility test. These results show that the generator can stably provide 68Ga solution over a 15-month period.

Asunto(s)

Radioisótopos de Galio , Generadores de Radionúclidos , Marcaje Isotópico , Control de Calidad , Radioquímica

RESUMEN

Aromatase, an enzyme that converts androgens to estrogens, has been reported to be involved in several brain functions, including synaptic plasticity, neurogenesis, neuroprotection, and regulation of sexual and emotional behaviours in rodents, pathophysiology of Alzheimer's disease and autism spectrum disorders in humans. Aromatase has been reported to be involved in aggressive behaviours in genetically modified mice and in personality traits by genotyping studies on humans. However, no study has investigated the relationship between aromatase in living brains and personality traits including aggression. We performed a positron emission tomography (PET) study in 21 healthy subjects using 11C-cetrozole, which has high selectivity and affinity for aromatase. Before performing PET scans, subjects answered the Buss-Perry Aggression Questionnaire and Temperament and Character Inventory to measure their aggression and personality traits, respectively. A strong accumulation of 11C-cetrozole was detected in the thalamus, hypothalamus, amygdala, and medulla. Females showed associations between aromatase levels in subcortical regions, such as the amygdala and supraoptic nucleus of the hypothalamus, and personality traits such as aggression, novelty seeking, and self-transcendence. In contrast, males exhibited associations between aromatase levels in the cortices and harm avoidance, persistence, and self-transcendence. The association of aromatase levels in the thalamus with cooperativeness was common to both sexes. The present study suggests that there might exist associations between aromatase in the brain and personality traits. Some of these associations may differ between sexes, while others are likely common to both.

Asunto(s)

Aromatasa/metabolismo , Encéfalo/enzimología , Personalidad , Adulto , Compuestos de Anilina , Radioisótopos de Carbono , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Triazoles

RESUMEN

The aim of the present study is to investigate the pharmacokinetics of our newly developed aromatase inhibitors (cetrozole and TMD-322) in healthy subjects by a cassette microdose strategy. A cocktail of cetrozole and TMD-322 was administered intravenously or orally (1.98 µg for each drug) to six healthy volunteers in a crossover fashion. Anastrozole (1.98 µg) was also included in the oral cocktail. Total body clearance and bioavailability were 12.1 ± 7.1 mL/min/kg and 34.9 ± 32.3% for cetrozole, and 16.8 ± 3.5 mL/min/kg and 18.4 ± 12.2% for TMD-322, respectively. The area under the plasma concentration-time curves of cetrozole and TMD-322 after oral administration was markedly lower than that of anastrozole because of their high hepatic clearance. Two subjects out of six exhibited 4- and 17-fold larger exposure of cetrozole than the others following intravenous and oral administration, respectively. Such variation was not observed for TMD-322 and anastrozole. Extensive metabolism of cetrozole and TMD-322 was observed in the CYP2C19 expression system among the test CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). We report the first clinical investigation of our aromatase inhibitors by a cassette microdose strategy in healthy Japanese subjects. This strategy offers an optional approach for candidate selection as a phase zero study in drug development.

Asunto(s)

Compuestos de Anilina/farmacocinética , Inhibidores de la Aromatasa/farmacocinética , Aromatasa/metabolismo , Descubrimiento de Drogas , Nitrilos/farmacocinética , Triazoles/farmacocinética , Administración Intravenosa , Administración Oral , Anciano , Anastrozol , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/química , Animales , Inhibidores de la Aromatasa/administración & dosificación , Inhibidores de la Aromatasa/química , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Voluntarios Sanos , Humanos , Japón , Masculino , Estructura Molecular , Nitrilos/administración & dosificación , Nitrilos/química , Ratas , Relación Estructura-Actividad , Triazoles/administración & dosificación , Triazoles/química

RESUMEN

UNLABELLED: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. Although it is hypothesized that brain inflammation is involved in the pathophysiology of CFS/ME, there is no direct evidence of neuroinflammation in patients with CFS/ME. Activation of microglia or astrocytes is related to neuroinflammation. (11)C-(R)-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide ((11)C-(R)-PK11195) is a ligand of PET for a translocator protein that is expressed by activated microglia or astrocytes. We used (11)C-(R)-PK11195 and PET to investigate the existence of neuroinflammation in CFS/ME patients. METHODS: Nine CFS/ME patients and 10 healthy controls underwent (11)C-(R)-PK11195 PET and completed questionnaires about fatigue, fatigue sensation, cognitive impairments, pain, and depression. To measure the density of translocator protein, nondisplaceable binding potential (BP(ND)) values were determined using linear graphical analysis with the cerebellum as a reference region. RESULTS: The BP(ND) values of (11)C-(R)-PK11195 in the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons were 45%-199% higher in CFS/ME patients than in healthy controls. In CFS/ME patients, the BP(ND) values of (11)C-(R)-PK11195 in the amygdala, thalamus, and midbrain positively correlated with cognitive impairment score, the BP(ND) values in the cingulate cortex and thalamus positively correlated with pain score, and the BP(ND) value in the hippocampus positively correlated with depression score. CONCLUSION: Neuroinflammation is present in widespread brain areas in CFS/ME patients and was associated with the severity of neuropsychologic symptoms. Evaluation of neuroinflammation in CFS/ME patients may be essential for understanding the core pathophysiology and for developing objective diagnostic criteria and effective medical treatments.

Asunto(s)

Síndrome de Fatiga Crónica/diagnóstico por imagen , Isoquinolinas , Adulto , Radioisótopos de Carbono , Citocinas/metabolismo , Síndrome de Fatiga Crónica/metabolismo , Femenino , Humanos , Inflamación/diagnóstico por imagen , Inflamación/metabolismo , Masculino , Cintigrafía

RESUMEN

We have developed an ethanol-free formulation method of [(18) F]florbetapir ([(1) (8) F]AV-45) using a commercially available automated JFE multi-purpose synthesizer. We have also evaluated the radiochemical stability in an ethanol-free solution of [(18) F]AV-45 under visible light irradiation and dark conditions by comparison with a conventional 10% ethanol solution of [(18) F]AV-45. [(18) F]AV-45 was obtained with a radiochemical yield of 55.1 ± 2.2% (decay-corrected to end of bombardment), specific activity of 591.6 ± 90.3 GBq/µmol and radiochemical purity of >99% within a total synthesis time of about 73 min. The radiochemical purity of [(18) F]AV-45 formulated by dissolving the ethanol-free solution was found to decrease as a function of the period of exposure to visible light. In contrast, the visible light photolysis could be suppressed by adding 10% ethanol to the formulation or by avoiding exposure to visible light. In the radiosynthesis of [(18) F]AV-45 formulated by dissolving the ethanol-free solution, [(18) F]AV-45 could be obtained with high radiochemical purity and high stability by avoiding exposure to visible light.

Asunto(s)

Compuestos de Anilina/síntesis química , Glicoles de Etileno/síntesis química , Marcaje Isotópico/métodos , Radiofármacos/síntesis química , Compuestos de Anilina/química , Glicoles de Etileno/química , Radiofármacos/química

RESUMEN

UNLABELLED: The purpose of this study was to determine the safety, distribution, internal dosimetry, and initial human epidermal growth factor receptor 2 (HER2)-positive tumor images of (64)Cu-DOTA-trastuzumab in humans. METHODS: PET was performed on 6 patients with primary or metastatic HER2-positive breast cancer at 1, 24, and 48 h after injection of approximately 130 MBq of the probe (64)Cu-DOTA-trastuzumab. Radioactivity data were collected from the blood, urine, and normal-tissue samples of these 6 patients, and the multiorgan biodistribution and internal dosimetry of the probe were evaluated. Safety data were collected for all the patients after the administration of (64)Cu-DOTA-trastuzumab and during the 1-wk follow-up period. RESULTS: According to our results, the best timing for the assessment of (64)Cu-DOTA-trastuzumab uptake by the tumor was 48 h after injection. Radiation exposure during (64)Cu-DOTA-trastuzumab PET was equivalent to that during conventional (18)F-FDG PET. The radioactivity in the blood was high, but uptake of (64)Cu-DOTA-trastuzumab in normal tissues was low. In 2 patients, (64)Cu-DOTA-trastuzumab PET showed brain metastases, indicative of blood-brain barrier disruptions. In 3 patients, (64)Cu-DOTA-trastuzumab PET imaging also revealed primary breast tumors at the lesion sites initially identified by CT. CONCLUSION: The findings of this study indicated that (64)Cu-DOTA-trastuzumab PET is feasible for the identification of HER2-positive lesions in patients with primary and metastatic breast cancer. The dosimetry and pharmacologic safety results were acceptable at the dose required for adequate PET imaging.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/metabolismo , Compuestos Organometálicos , Tomografía de Emisión de Positrones/métodos , Receptor ErbB-2/metabolismo , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Neoplasias de la Mama/patología , Estudios de Factibilidad , Humanos , Procesamiento de Imagen Asistido por Computador , Persona de Mediana Edad , Metástasis de la Neoplasia , Compuestos Organometálicos/efectos adversos , Tomografía de Emisión de Positrones/efectos adversos , Seguridad , Trastuzumab

RESUMEN

UNLABELLED: P-glycoprotein (P-gp) plays a pivotal role in limiting the penetration of xenobiotic compounds into the brain at the blood-brain barrier (BBB), where its expression increases with maturation in rats. We investigated developmental changes in P-gp function in the BBB of nonhuman primates using PET with R-(11)C-verapamil, a PET radiotracer useful for evaluating P-gp function. In addition, developmental changes in the brain penetration of (11)C-oseltamivir, a substrate for P-gp, was investigated as practical examples. METHODS: PET studies in infant (age, 9 mo), adolescent (age, 24-27 mo), and adult (age, 5.6-6.6 y) rhesus monkeys (Macaca mulatta) were performed with R-(11)C-verapamil and also with (11)C-oseltamivir. Arterial blood samples and PET images were obtained at frequent intervals up to 60 min after administration of the PET tracer. Dynamic imaging data were evaluated by integration plots using data collected within the first 2.5 min after tracer administration. RESULTS: R-(11)C-verapamil rapidly penetrated the brain, whereas the blood concentration of intact R-(11)C-verapamil decreased rapidly in all subjects. The maximum brain uptake in infant (0.033% ± 0.007% dose/g of brain) and adolescent (0.020% ± 0.002% dose/g) monkeys was 4.1- and 2.5-fold greater, respectively, than uptake in adults (0.0082% ± 0.0007% dose/g). The clearance of brain R-(11)C-verapamil uptake in adult monkeys was 0.056 ± 0.010 mL/min/g, significantly lower than that in infants (0.11 ± 0.04 mL/min/g) and adolescents (0.075 ± 0.023 mL/min/g). (11)C-oseltamivir showed little brain penetration in adult monkeys, with a clearance of R-(11)C-verapamil uptake of 0.0072 and 0.0079 mL/min/g, slightly lower than that in infant (0.0097 and 0.0104 mL/min/g) and adolescent (0.0097 and 0.0098 mL/min/g) monkeys. CONCLUSION: These results suggest that P-gp function in the BBB changes with development in rhesus monkeys, and this change may be closely related to the observed difference in drug responses in the brains of children and adult humans.

Asunto(s)

Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/fisiología , Barrera Hematoencefálica/fisiología , Bloqueadores de los Canales de Calcio , Inhibidores Enzimáticos , Oseltamivir , Radiofármacos , Verapamilo , Envejecimiento/fisiología , Animales , Área Bajo la Curva , Barrera Hematoencefálica/diagnóstico por imagen , Encéfalo/crecimiento & desarrollo , Radioisótopos de Carbono , Inyecciones Intravenosas , Macaca mulatta , Masculino , Neuraminidasa/antagonistas & inhibidores , Tomografía de Emisión de Positrones

RESUMEN

Abnormalities in energy metabolism may play an important role in the development of hypertensive heart failure. However, the transition from compensated hypertrophy to heart failure is not fully understood in terms of energy metabolism. In Dahl salt-sensitive (DS) and salt-resistant (DR) rats, myocardial fatty acid and glucose uptake values were determined using (131)I- or (125)I-labeled 9-methylpentadecanoic acid ((131)I- or (125)I-9MPA), and [(14)C]deoxyglucose ([(14)C]DG), fatty acid beta-oxidation was identified using thin-layer chromatography, and insulin-stimulated glucose-uptake was observed using a euglycemic hyperinsulinemic glucose clamp. Six-week-old rats were fed a diet that contained 8% NaCl, which resulted in development of compensated hypertrophy in DS rats at 12 wk of age and ultimately led to heart failure by 18 wk of age. Uptake of [(14)C]DG increased markedly with age in the DS rats, whereas (131)I-9MPA uptake was marginally but significantly increased only in animals aged 12 wk. The ratio of (125)I-9MPA beta-oxidation metabolites to total uptake in the DS rats was significantly lower (P < 0.05) at 12 (37%) and 18 (34%) wk compared with at 6 (45%) wk. Insulin increased [(14)C]DG uptake more than twofold in the DS rats at 6 wk, although this increase was markedly attenuated at 12 and 18 wk (11 and 8%, respectively). Our data suggest that in a hypertrophied heart before heart failure, fatty acid oxidation is impaired and the capacity to increase glucose uptake during insulin stimulation is markedly reduced. These changes in both glucose and fatty acid metabolism that occur in association with myocardial hypertrophy may have a pathogenic role in the subsequent development of heart failure.

Asunto(s)

Gasto Cardíaco Bajo/etiología , Ácidos Grasos/metabolismo , Glucosa/metabolismo , Hipertensión/complicaciones , Hipertensión/metabolismo , Animales , Cromatografía en Capa Delgada , Desoxiglucosa/farmacocinética , Ácidos Grasos/farmacocinética , Técnica de Clampeo de la Glucosa , Hipoglucemiantes/farmacología , Insulina/farmacología , Yodobencenos/farmacocinética , Masculino , Oxidación-Reducción , Ratas , Ratas Endogámicas Dahl

RESUMEN

UNLABELLED: Although various noninvasive methods have been used to detect vasospasm, none of them are sensitive enough for patients with sporadic attacks. Because abnormal fatty acid metabolism and cardiac adrenergic neuronal damage are observed in ischemic myocardium, (123)I-15-(p-iodophenyl)-3-R,S-methyl pentadecanoic acid (BMIPP) and (123)I-metaiodobenzylguanidine (MIBG) have recently been proposed as useful tracers for detection of myocardial damage. This study investigated the relationships among the coronary vasospastic regions, abnormal left ventricular regional wall motion, fatty acid metabolism, and sympathetic nerve functions and their changes during treatment in patients with vasospastic angina. METHODS: We evaluated 50 patients with vasospastic angina (25 with clinically documented vasospasm [group A] and 25 with vasospasm induced by ergonovine provocation [group B]) and 25 control subjects who had chest pain but had normal coronary arteries without ergonovine provocation of spasm. Sixteen patients in group A were reevaluated 6 mo after medical treatment. The territorial regions of the vasospasm-induced coronary artery, wall motion determined by left ventriculography, and BMIPP and MIBG uptake were compared. RESULTS: Regions exhibiting a positive reaction to the ergonovine provocation were observed in the right coronary artery in 41 patients, the left anterior descending artery in 33, and the left circumflex artery in 21. Provocation occurred in multiple vessels in 29 patients (58%). Reduction of wall motion was observed in 19 patients (38%). Sensitivity and specificity for the identification of vasospastic angina were 86% (43/50 patients) and 88% (22/25 control subjects), respectively, for BMIPP scintigraphy and 100% (50/50 patients) and 56% (14/25 control subjects), respectively, for MIBG scintigraphy. In the region exhibiting a reduction in left ventricular wall motion, BMIPP or MIBG uptake was decreased. The sensitivity and specificity of determination of vasospasm-induced coronary arteries were 71% (67/95 arteries) and 95% (71/75 arteries), respectively, for BMIPP scintigraphy and 96% (91/95 arteries) and 55% (41/75 arteries), respectively, for MIBG scintigraphy. After 6 mo, during treatment, vasospasm was reinduced by ergonovine provocation in 6 patients (group I) and was not reinduced in 10 patients (group II). Improvements of decreased BMIPP and MIBG uptake were lower in group I (25% +/- 4% and 16% +/- 4%, respectively) than in group II (69% +/- 4% and 50% +/- 3%, respectively; both P < 0.01). The regions in which vasospasm was reinduced exhibited decreased BMIPP and MIBG uptake. CONCLUSION: Abnormal fatty acid metabolism and cardiac sympathetic denervation were observed more frequently than were wall motion abnormalities in the vasospastic region in patients with vasospastic angina. BMIPP and MIBG scintigraphy are highly accurate and noninvasive techniques for determining the presence and location of vasospasm.

Asunto(s)

Angina de Pecho/fisiopatología , Vasoespasmo Coronario/fisiopatología , Ácidos Grasos/metabolismo , Sistema Nervioso Simpático/fisiopatología , Función Ventricular Izquierda , 3-Yodobencilguanidina , Adulto , Anciano , Angina de Pecho/diagnóstico por imagen , Angina de Pecho/metabolismo , Circulación Coronaria , Vasoespasmo Coronario/diagnóstico , Vasoespasmo Coronario/diagnóstico por imagen , Vasoespasmo Coronario/metabolismo , Vasos Coronarios/efectos de los fármacos , Ergonovina , Femenino , Corazón/diagnóstico por imagen , Corazón/inervación , Humanos , Radioisótopos de Yodo , Yodobencenos , Masculino , Persona de Mediana Edad , Contracción Miocárdica , Miocardio/metabolismo , Ventriculografía con Radionúclidos , Radiofármacos , Tomografía Computarizada de Emisión de Fotón Único

RESUMEN

UNLABELLED: Metaiodobenzylguanidine (MIBG) is a reliable marker for the detection of cardiac adrenergic neuronal damage in heart failure. The cardioprotective properties of carvedilol, a vasodilating beta-adrenoceptor-blocking agent, were studied in a rat model of dilated cardiomyopathy after autoimmune myocarditis. METHODS: Twenty-eight days after immunization, surviving rats (41/55, or 75%) were divided into 2 groups treated with carvedilol, 2 mg/kg/d (group C, n = 19), or vehicle alone (0.5% methylcellulose, group V, n = 22). After oral administration for 2 mo, heart weight, heart rate, left ventricular end-diastolic pressure (LVEDP), and myocardial fibrosis were measured and compared with those in untreated rats (group N, n = 19). Myocardial uptake of (125)I-MIBG (differential absorption ratio) in the left ventricle was measured by autoradiography at 10, 30, or 240 min after tracer injection. RESULTS: Four (18%) of 22 rats in group V died between days 28 and 84 after immunization. None of the rats in group C or N died. Heart weight, heart rate, LVEDP, and area of myocardial fibrosis in group C (1.14 +/- 0.04 g, 345 +/- 16 beats per minute, 7.6 +/- 1.5 mm Hg, and 12% +/- 1%) were significantly lower than those in group V (1.34 +/- 0.04 g, 389 +/- 10 beats per minute, 12.3 +/- 1.3 mm Hg, and 31% +/- 2%). Although the differential absorption ratio was lower at all time points in group V than in group N, uptake after treatment increased in group C, compared with group V, at 10 min (12.5 +/- 1.0 vs. 7.6 +/- 0.8, not significant), 30 min (10.1 +/- 1.1 vs. 6.3 +/- 0.9, not significant), and 240 min (6.5 +/- 0.5 vs. 2.5 +/- 0.2, P < 0.05). The late washout ratio from myocardial radioactivity between 30 and 240 min in group C was lower than that in group V (36% vs. 60%). CONCLUSION: These observations indicated that carvedilol has beneficial effects and protects cardiac adrenergic neurons in dilated cardiomyopathy.

Asunto(s)

Fibras Adrenérgicas/efectos de los fármacos , Antagonistas Adrenérgicos beta/uso terapéutico , Carbazoles/uso terapéutico , Cardiomiopatía Dilatada/patología , Corazón/inervación , Corazón/fisiopatología , Propanolaminas/uso terapéutico , Vasodilatadores/uso terapéutico , 3-Yodobencilguanidina , Fibras Adrenérgicas/diagnóstico por imagen , Animales , Enfermedades Autoinmunes/complicaciones , Autorradiografía , Cardiomiopatía Dilatada/diagnóstico por imagen , Cardiomiopatía Dilatada/tratamiento farmacológico , Cardiomiopatía Dilatada/fisiopatología , Carvedilol , Fibrosis , Hemodinámica , Masculino , Miocarditis/complicaciones , Miocardio/patología , Tamaño de los Órganos , Cintigrafía , Radiofármacos , Ratas , Ratas Endogámicas Lew

RESUMEN

One of the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in the treatment of heart failure may derive from sympathoinhibition and the prevention of beta-adrenergic desensitization. However, the roles of these properties in the overall effects of ACE inhibitor are not clear. We studied the effects of chronic enalapril treatment (20 mg/L in drinking water for 12 weeks) on left ventricular (LV) function, cardiac norepinephrine (NE), sympathetic neuronal function assessed by 131I-metaiodobenzylguanidine (MIBG), beta-receptors, and isometric contraction of papillary muscle in rats with myocardial infarction (MI) induced by coronary artery ligation. Decreased LV function in the MI rats was associated with reduced cardiac NE content and MIBG uptake, and severely blunted responses of non-infarcted papillary muscle to isoproterenol, forskolin, and calcium. Enalapril attenuated LV remodeling in association with a reduction of the ventricular loading condition and restored baseline developed tension of non-infarcted papillary muscle to the level of sham-operated rats. However, enalapril did not improve cardiac NE content, MIBG uptake, or inotropic responsiveness to beta-agonists. These results suggest that the major effect of the ACE inhibitor enalapril in the treatment of heart failure is not due to sympathoinhibition or restoration of beta-adrenergic pathway in this model of heart failure.

Asunto(s)

Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Enalapril/farmacología , Insuficiencia Cardíaca/fisiopatología , Infarto del Miocardio/fisiopatología , Sistema Nervioso Simpático/efectos de los fármacos , Animales , Hemodinámica/efectos de los fármacos , Masculino , Contracción Miocárdica , Miocardio/metabolismo , Norepinefrina/metabolismo , Músculos Papilares/fisiología , Ratas , Ratas Wistar , Receptores Adrenérgicos beta/fisiología , Sistema Nervioso Simpático/fisiología , Función Ventricular Izquierda , Remodelación Ventricular