RESUMO
HYPOTHESIS: Horseshoe vortices are known to emerge around large-scale obstacles, such as bridge pillars, due to an inertia-driven adverse pressure gradient forming on the upstream-side of the obstacle. We contend that a similar flow structure can arise in thin-film Stokes flow around micro-obstacles, such as used in textured surfaces to improve wettability. This could be exploited to enhance mixing in microfluidic devices, typically limited to creeping-flow regimes. EXPERIMENTS: Numerical simulations based on the Navier-Stokes equations are carried out to elucidate the flow structure associated with the wetting dynamics of a liquid film spreading around a 50 µm diameter micro-pillar. The employed multiphase solver, which is based on the volume of fluid method, accurately reproduces the wetting dynamics observed in current and previous (Mu et al., Langmuir, 2019) experiments. FINDINGS: The flow structure within the liquid meniscus forming at the foot of the micro-pillar evinces a horseshoe vortex wrapping around the obstacle, notwithstanding that the Reynolds number in our system is extremely low. Here, the adverse pressure gradient driving flow reversal near the bounding wall is caused by capillarity instead of inertia. The horseshoe vortex is entangled with other vortical structures, leading to an intricate flow system with high-potential mixing capabilities.
RESUMO
Recent epidemiological studies suggest a rather low dose threshold (below 0.5 Gy) for the induction of a cataract of the eye lens. Some other studies even assume that there is no threshold at all. Therefore, protection measures have to be optimized and current dose limits for the eye lens may be reduced in the future. Two questions arise from this situation: first, which dose quantity is related to the risk of developing a cataract, and second, which personal dose equivalent quantity is appropriate for monitoring this dose quantity. While the dose equivalent quantity H(p)(0.07) has often been seen as being sufficiently accurate for monitoring the dose to the lens of the eye, this would be questionable in the case when the dose limits were reduced and, thus, it may be necessary to generally use the dose equivalent quantity H(p)(3) for this purpose. The basis for a decision, however, must be the knowledge of accurate conversion coefficients from fluence to equivalent dose to the lens. This is especially important for low-penetrating radiation, for example, electrons. Formerly published values of conversion coefficients are based on quite simple models of the eye. In this paper, quite a sophisticated model of the eye including the inner structure of the lens was used for the calculations and precise conversion coefficients for electrons with energies between 0.2 MeV and 12 MeV, and for angles of radiation incidence between 0 degrees and 45 degrees are presented. Compared to the values adopted in 1996 by the International Commission on Radiological Protection (ICRP), the new values are up to 1000 times smaller for electron energies below 1 MeV, nearly equal at 1 MeV and above 4 MeV, and by a factor of 1.5 larger at about 1.5 MeV electron energy.
Assuntos
Algoritmos , Cristalino/fisiologia , Modelos Biológicos , Radiometria/métodos , Adulto , Simulação por Computador , Elétrons , Feminino , Humanos , Cristalino/efeitos da radiação , Masculino , Especificidade de Órgãos , Doses de RadiaçãoRESUMO
Report Committee 26 of the ICRU proposes a set of operational quantities for radiation protection for external radiation, directly based on effective dose and for an extended range of particles and energies. It is accompanied by quantities for estimating deterministic effects to the eye lens and the local skin. The operational quantities are designed to overcome the conceptual and technical shortcomings of those presently in use. This paper describes the proposed operational quantities, and highlights the improvements with respect to the present, legal monitoring quantities.
Assuntos
Cristalino/efeitos da radiação , Exposição à Radiação/efeitos adversos , Lesões por Radiação/prevenção & controle , Monitoramento de Radiação/normas , Proteção Radiológica/normas , Calibragem , Humanos , Agências Internacionais , Doses de Radiação , Lesões por Radiação/etiologiaRESUMO
The effect of fructose infusion (10 gm. every five minutes as a bolus followed by 0.5 gm. per kilogram X hours) on arterial concentrations and hepatic balances of ketones was studied in four juvenile diabetics 24 hours after the withdrawal of insulin. Arterial and hepatic venous concentrations of beta-hydroxybutyrate, acetoacetate, free fatty acids, fructose, and oxygen were measured. Hepatic blood flow was also determined. At constant rates of splanchnic fructose extraction, an 82 per cent diminution of the arterial hepatic venous concentration difference of the ketones was observed but the arteriovenous difference of free fatty acis rose moderately. Since hepatic blood flow was only slightly increased (17 per cent) there was no doubt that total hepatic ketone body formation was reduced. The magnitude of this antiketogenic action became apparent from the continuous fall of the arterial ketone concentrations. Since splanchnic oxygen uptake rose 40 per cent, it is suggested that the antiketogenic effect of fructose was due not only to enhanced re-esterification but also to accelerated oxidation of free fatty acids.
Assuntos
Diabetes Mellitus Tipo 1/sangue , Frutose , Corpos Cetônicos/sangue , Acetoacetatos/sangue , Ácidos Graxos não Esterificados/sangue , Humanos , Hidroxibutiratos/sangue , Oxigênio/sangueRESUMO
Inhibitors of ACE/kininase II enhance insulin sensitivity, an action that is mediated in part by bradykinin (BK). We investigated whether insulin interacts with the BK receptor signaling to modulate the inositol 1,4,5-trisphosphate (IP3) response to BK in L8 rat skeletal myoblasts. Stimulation of the cultures with BK (10 nmol/l) for 15 s increased IP3 from a basal level of 75.2 +/- 7.6 to 200.2 +/- 15.7 pmol/mg protein. Treatment of the cultures with 1, 2, and 20 nmol/l of insulin for 90 min before adding BK increased IP3 formation by the same BK dose to 328.2 +/- 19, 434.5 +/- 18, and 460.8 +/-21.3 pmol/mg protein, respectively. When wortmannin was administered to inhibit phosphatidylinositol (PI) 3-kinases at lower concentration (1 nmol/l), it increased IP3 formation stimulated by BK only when insulin was present. At a higher concentration (100 nmol/l), wortmannin significantly enhanced BK-induced IP3 formation in the absence of insulin. Genistein and tyrphostin A-23, tyrosine kinase inhibitors, completely reversed the elevated IP3 formation by BK and insulin. The IP3 response to 10 nmol/l BK was 223.3 +/- 11.8 pmol/mg protein in the absence of insulin and 402.2 +/- 12.0 pmol/mg protein in the presence of 2 nmol/l insulin. However, when exposing the cultures to 1 nmol/l genistein or tyrphostin A-23, the IP3 response to BK in the presence of insulin decreased to 211.8 +/- 46.7 and 187.7 +/- 19.9 pmol/mg protein. Tyrphostin A-1, the inactive analog, was ineffective. Exposing the cells to 1 micromol/ 3,4,5-trimethoxybenzoic acid 8-[diethylamino]octyl ester, an intracellular Ca2+ antagonist, did not change the potentiation by insulin. But, exposing them to 0.1 micromol/l n-[6-aminohexyl]-5-chloro-1-naphthalene-sulfonamide, a calmodulin antagonist, resulted in enhanced IP3 response to BK alone to 292.2 +/- 18.5 pmol/mg protein and to BK in the presence of 1, 2, and 20 nmol/l insulin to 488 +/- 22.2, 625.5 +/- 11.6, and 665.2 +/- 15.9 pmol/mg protein, respectively. In conclusion, insulin potentiates BK-induced IP3 production in L8 rat skeletal myoblasts, and this action of insulin involves a tyrosine kinase. Inhibition of PI 3-kinases potentiated BK-induced IP3 formation in the presence of insulin. Calmodulin blocked the action of insulin. These results support a modulatory effect of insulin on the BK signaling system via a tyrosine kinase in L8 rat skeletal myoblasts that results in increased IP3 formation. Because BK release from skeletal muscle increases during contractions, this action of insulin is likely to play a role in the modulation of the excitation-contraction coupling process of the skeletal muscle.
Assuntos
Bradicinina/farmacologia , Insulina/farmacologia , Músculo Esquelético/efeitos dos fármacos , Androstadienos/farmacologia , Animais , Cálcio/fisiologia , Bloqueadores dos Canais de Cálcio/farmacologia , Calmodulina/fisiologia , Células Cultivadas , Sinergismo Farmacológico , Inibidores Enzimáticos/farmacologia , Ácido Gálico/análogos & derivados , Ácido Gálico/farmacologia , Genisteína/farmacologia , Inositol 1,4,5-Trifosfato/metabolismo , Músculo Esquelético/citologia , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Tirosina Quinases/antagonistas & inibidores , Ratos , Sulfonamidas/antagonistas & inibidores , Sulfonamidas/farmacologia , Tirfostinas/farmacologia , WortmaninaRESUMO
The kallikrein-kinin system has been implicated in the inflammatory process, blood pressure regulation, renal homeostasis, and glucose utilization. The effects of kallikrein and kinin on glucose uptake by the skeletal muscle are well established; however, the occurrence and the cellular distribution of the kinin receptor(s) mediating these effects in the striated muscle are unknown. Using anti-peptide antibodies raised against the predicted intra- and extracellular domains of the B2 receptor and the peroxidase/antiperoxidase system, we have been able to detect the B2 receptor on the plasma membrane of striated skeletal muscle cells of the rat hindlimb. A strong immunostaining appeared as a rim of immunoreactive material located on the periphery of striated muscle cells. Cross-sectioned and longitudinally sectioned cells revealed a similar staining pattern. Alternatively, the immunostaining with specific antibodies to tissue kallikrein and to T-kininogen did not yield a significant staining of the striated muscle cells. Localization of the B2 receptor on the surface of striated muscle cells provides a structural basis for the hypothesized physiological functions of the kinin system in the skeletal muscle.
Assuntos
Músculos/metabolismo , Receptores da Bradicinina/metabolismo , Sequência de Aminoácidos , Animais , Membrana Celular/metabolismo , Técnicas Imunoenzimáticas , Dados de Sequência Molecular , Peptídeos/química , Peptídeos/imunologia , RatosRESUMO
Using the euglycemic-hyperinsulinemic glucose clamp and the human forearm technique, we have demonstrated that the improved glucose disposal rate observed after the administration of an angiotensin-converting enzyme (ACE) inhibitor such as captopril may be primarily due to increased muscle glucose uptake (MGU). These results are not surprising because ACE, which is identical to the bradykinin (BK)-degrading kininase II, is abundantly present in muscle tissue, and its inhibition has been observed to elicit the observed metabolic actions via elevated tissue concentrations of BK and through a BK B2 receptor site in muscle and/or endothelial tissue. These findings are supported by several previous studies. Exogenous BK applied into the brachial artery of the human forearm not only augmented muscle blood flow (MBF) but also enhanced the rate of MGU. In another investigation, during rhythmic voluntary contraction, both MBF and MGU increased in response to the higher energy expenditure, and the release of BK rose in the blood vessel, draining the working muscle tissue. Inhibition of the activity of the BK-generating protease in muscle tissue (kallikrein) with aprotinin significantly diminished these functional responses during contraction. Applying the same kallikrein inhibitor during the infusion of insulin into the brachial artery significantly reduced the effect of insulin on glucose uptake into forearm muscle. This is of interest, because in recent studies insulin has been suggested to elicit its actions on MBF and MGU via the accelerated release of endothelium-derived nitric oxide, the generation of which is also stimulated by BK in a concentration-dependent manner. This new evidence obtained from in vitro and in vivo studies sheds new light on the discussion of whether BK may play a role in energy metabolism of skeletal muscle tissue.
Assuntos
Bradicinina/fisiologia , Músculos/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antebraço , Glucose/metabolismo , Humanos , Insulina/fisiologia , Contração MuscularRESUMO
Insulin resistance of skeletal muscle glucose disposal underlies the pathogenesis of NIDDM and is associated with hypertension, obesity, and dyslipidemia. Angiotensin-converting enzyme (ACE) inhibitors are used primarily in antihypertensive therapy but also are known to improve whole-body insulin-mediated glucose disposal. However, the exact site of action is not well characterized. We have used the isolated epitrochlearis muscle from a well-established animal model of skeletal muscle insulin resistance, the obese Zucker rat, to test the effect of oral administration of ACE inhibitors on insulin-sensitive muscle glucose transport activity. Both acute and chronic administration of a sulfhydryl-containing ACE inhibitor (captopril) or a non-sulfhydryl-containing ACE inhibitor (tran-dolapril) significantly enhanced in vitro insulin-mediated muscle glucose transport activity. In addition, the acute effect of oral captopril administration was completely abolished by pretreatment of the animal with a bradykinin B2 receptor antagonist (HOE 140). These findings indicate that ACE inhibitors may improve whole-body glucose metabolism by acting on the insulin-sensitive skeletal muscle glucose transport system. In addition, bradykinin or one of its metabolites may be involved in the action of the ACE inhibitor captopril on insulin-resistant muscle.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Bradicinina/antagonistas & inibidores , Glucose/metabolismo , Resistência à Insulina , Animais , Transporte Biológico/efeitos dos fármacos , Bradicinina/análogos & derivados , Bradicinina/farmacologia , Antagonistas dos Receptores da Bradicinina , Captopril/farmacologia , Indóis/farmacologia , Insulina/farmacologia , Ratos , Ratos MutantesRESUMO
The effect of bradykinin on glucose transporter translocation in isolated rat heart was compared with the effect of insulin. Hearts from male obese (fa/fa) Zucker rats were perfused under normoxic conditions and constant pressure in a classic Langendorff preparation with 12 mmol/l glucose as substrate, and a set of functional parameters was measured simultaneously. Bradykinin was administered at a concentration (10(-11) mmol/l) that did not increase coronary flow. Insulin was used at a concentration (8 x 10(-8) mmol/l) known to maximally stimulate glucose transport in this model. After 15 min of perfusion with insulin or bradykinin, subcellular membrane fractions of the heart were prepared, and distribution of glucose transporter protein (GLUT1 and GLUT4) in fractions enriched with surface membranes (transverse tubules [TTs] and sarcolemmal membranes [PMs]) and with low-density microsomal membranes (LDMs) were determined by immunoblotting with the respective antibodies. Both glucose transporter isoforms were translocated after stimulation with insulin (increased transporter protein content in the PM+TT-enriched fraction with a concomitant decrease in the LDM-enriched fraction) and, to a smaller extent, also with bradykinin. These data suggest that in hearts of insulin-resistant obese (fa/fa) Zucker rats, bradykinin interacts with or facilitates the translocation process of both GLUT1 and GLUT4.
Assuntos
Bradicinina/farmacologia , Insulina/farmacologia , Proteínas de Transporte de Monossacarídeos/metabolismo , Proteínas Musculares , Miocárdio/metabolismo , Animais , Transporte Biológico , Membrana Celular/metabolismo , Glucose/metabolismo , Transportador de Glucose Tipo 1 , Transportador de Glucose Tipo 4 , Masculino , Microssomos/metabolismo , Ratos , Ratos Mutantes , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
Insulin resistance of muscle glucose metabolism is a hallmark of NIDDM. The obese Zucker (fa/fa) rat--an animal model of muscle insulin resistance--was used to test whether acute (100 mg/kg body wt for 1 h) and chronic (5-100 mg/kg for 10 days) parenteral treatments with a racemic mixture of the antioxidant alpha-lipoic acid (ALA) could improve glucose metabolism in insulin-resistant skeletal muscle. Glucose transport activity (assessed by net 2-deoxyglucose [2-DG] uptake), net glycogen synthesis, and glucose oxidation were determined in the isolated epitrochlearis muscles in the absence or presence of insulin (13.3 nmol/l). Severe insulin resistance of 2-DG uptake, glycogen synthesis, and glucose oxidation was observed in muscle from the vehicle-treated obese rats compared with muscle from vehicle-treated lean (Fa/-) rats. Acute and chronic treatments (30 mg.kg-1.day-1, a maximally effective dose) with ALA significantly (P < 0.05) improved insulin-mediated 2-DG uptake in epitrochlearis muscles from the obese rats by 62 and 64%, respectively. Chronic ALA treatment increased both insulin-stimulated glucose oxidation (33%) and glycogen synthesis (38%) and was associated with a significantly greater (21%) in vivo muscle glycogen concentration. These adaptive responses after chronic ALA administration were also associated with significantly lower (15-17%) plasma levels of insulin and free fatty acids. No significant effects on glucose transporter (GLUT4) protein level or on the activities of hexokinase and citrate synthase were observed. Collectively, these findings indicate that parenteral administration of the antioxidant ALA significantly enhances the capacity of the insulin-stimulatable glucose transport system and of both oxidative and nonoxidative pathways of glucose metabolism in insulin-resistant rat skeletal muscle.
Assuntos
Antioxidantes/farmacologia , Glucose/metabolismo , Resistência à Insulina , Insulina/farmacologia , Músculos/metabolismo , Ácido Tióctico/farmacologia , Animais , Transporte Biológico , Peso Corporal/efeitos dos fármacos , Feminino , Glicogênio/metabolismo , Músculos/anatomia & histologia , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos MutantesRESUMO
Based upon recent epidemiological studies of ocular exposure, the Main Commission of the International Commission on Radiological Protection (ICRP) in ICRP Publication 118 states that the threshold dose for radiation-induced cataracts is now considered to be approximately 0.5 Gy for both acute and fractionated exposures. Consequently, a reduction was also recommended for the occupational annual equivalent dose to the lens of the eye from 150 mSv to 20 mSv, averaged over defined periods of 5 years. To support ocular dose assessment and optimisation, Committee 2 included Annex F within ICRP Publication 116 . Annex F provides dose coefficients - absorbed dose per particle fluence - for photon, electron, and neutron irradiation of the eye and lens of the eye using two dosimetric models. The first approach uses the reference adult male and female voxel phantoms of ICRP Publication 110. The second approach uses the stylised eye model of Behrens et al., which itself is based on ocular dimensional data given in Charles and Brown. This article will review the data and models of Annex F with particular emphasis on how these models treat tissue regions thought to be associated with stem cells at risk.
Assuntos
Olho/efeitos da radiação , Exposição Ocupacional/prevenção & controle , Doses de Radiação , Radiometria , Catarata/etiologia , Relação Dose-Resposta à Radiação , Feminino , Guias como Assunto , Humanos , Cristalino/efeitos da radiação , Masculino , Proteção RadiológicaRESUMO
We studied whether diabetes mellitus affects the bradykinin (BK)-induced release of norepinephrine (NE) from rat cardiac sympathetic endings in situ. Three groups were studied. Group A (n=12) was rendered diabetic with streptozotocin (STZ), group B (n=13) received STZ and insulin, and group C (n=14) received citrate buffer only. NPH insulin was given to group B from day 7 after STZ. Atria were paced (3Hz) with rectangular voltage pulses at mechanical threshold intensity (0.15 V/cm). The release of NE was assessed through its effects on contractile force in the presence of atropine (1 micromol/L). Intensifying the field stimulation above the neural threshold ( approximately 0.4 V/cm) produced a graded positive inotropic effect that was due to the release of NE from sympathetic nerve endings. The additional effect of 0.1 micromol/L BK on the force of contraction was determined at half-maximal neural stimulation (ie, at approximately 0.65 V/cm). Then, after washing out BK and lowering the stimulation intensity to mechanical threshold, a cumulative dose-response curve for added NE was generated, allowing the positive inotropic effects of neural stimulation (with or without BK) to be expressed in terms of an equivalent inotropic concentration of added NE ([NE(eq)]). Neural stimulation, in the absence of BK, gave an [NE(eq)] of 32+/-3 nmol/L in group A, 44+/-6 nmol/L in group B, and 37+/-6 nmol/L in group C. BK increased [NE(eq)] by a factor of 6.2+/-0.9 in group A, 4.5+/-0.5 in group B, and 3.7+/-0.3 in group C. This factor was greater in group A than in group C but indistinguishable in groups B and C. Atria from normal and diabetic rats were incubated in (3)[H]NE for 60 minutes. Excess tracer was removed, and atria were stimulated during a series of 1-minute episodes at half-maximal neural stimulation to cause exocytotic (3)[H]NE release. BK augmented (3)[H]NE release in normal (n=4) and in diabetic (n=4) atria. This BK-induced increase of (3)[H]NE overflow (expressed as a fraction of tissue (3)[H]NE radioactivity) was 4 times greater in diabetic than in normal preparations. The response to BK in releasing sympathetic neurotransmitter is augmented in diabetic rats, recovering in a manner dependent on insulin.
Assuntos
Sistema Nervoso Autônomo/fisiologia , Bradicinina/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Átrios do Coração/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Animais , Função Atrial , Denervação , Relação Dose-Resposta a Droga , Estimulação Elétrica , Átrios do Coração/fisiopatologia , Técnicas In Vitro , Insulina/farmacologia , Contração Miocárdica/efeitos dos fármacos , Norepinefrina/metabolismo , Norepinefrina/farmacocinética , Norepinefrina/farmacologia , Ratos , Ratos Sprague-Dawley , Sistema Nervoso Simpático/metabolismo , Trítio , Tiramina/farmacologiaRESUMO
Alpha-lipoic acid (ALA), a naturally occuring compound and a radical scavenger was shown to enhance glucose transport and utilization in different experimental and animal models. Clinical studies described an increase of insulin sensitivity after acute and short-term (10 d) parenteral administration of ALA. The effects of a 4-week oral treatment with alpha-lipoic acid were evaluated in a placebo-controlled, multicenter pilot study to determine see whether oral treatment also improves insulin sensitivity. Seventy-four patients with type-2 diabetes were randomized to either placebo (n = 19); or active treatment in various doses of 600 mg once daily (n = 19), twice daily (1200 mg; n = 18), or thrice daily (1800 mg; n = 18) alpha-lipoic acid. An isoglycemic glucose-clamp was done on days 0 (pre) and 29 (post). In this explorative study, analysis was done according to the number of subjects showing an improvement of insulin sensitivity after treatment. Furthermore, the effects of active vs. placebo treatment on insulin sensitivity was compared. All four groups were comparable and had a similar degree of hyperglycemia and insulin sensitivity at baseline. When compared to placebo, significantly more subjects had an increase in insulin-stimulated glucose disposal (MCR) after ALA treatment in each group. As there was no dose effect seen in the three different alpha-lipoic acid groups, all subjects receiving ALA were combined in the "active" group and then compared to placebo. This revealed significantly different changes in MCR after treatment (+27% vs. placebo; p < .01). This placebo-controlled explorative study confirms previous observations of an increase of insulin sensitivity in type-2 diabetes after acute and chronic intravenous administration of ALA. The results suggest that oral administration of alpha-lipoic acid can improve insulin sensitivity in patients with type-2 diabetes. The encouraging findings of this pilot trial need to be substantiated by further investigations.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Sequestradores de Radicais Livres/uso terapêutico , Resistência à Insulina , Ácido Tióctico/uso terapêutico , Administração Oral , Antropometria , Feminino , Sequestradores de Radicais Livres/efeitos adversos , Técnica Clamp de Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estereoisomerismo , Ácido Tióctico/efeitos adversosRESUMO
BACKGROUND: Hypertensive patients frequently show resistance to insulin-stimulated glucose uptake and hyperinsulinemia. Diuretics and beta-adrenoceptor blocking agents have been found to decrease insulin sensitivity, whereas alpha 1-blockers and angiotensin converting enzyme inhibitors seem to improve it. OBJECTIVE: To compare the effects of a 3 months' antihypertensive treatment with carvedilol, a non-selective beta-adrenoceptor blocker with alpha 1-blocking properties, with the beta 1-selective receptor blocker metoprolol on insulin sensitivity in non-diabetic hypertensive patients. DESIGN: A multicenter double-blind randomized study. SUBJECTS AND METHODS: Seventy-two non-diabetic hypertensive patients were randomly assigned to treatment with either carvedilol or metoprolol. An isoglycemic, hyperinsulinemic glucose clamp was conducted before and after 12 weeks of treatment; the metabolic clearance rate for glucose was taken as an indicator of insulin sensitivity. RESULTS: The two groups did not differ in age, sex, body mass index, blood pressure or lipids, and treatment effectively lowered blood pressure. In both groups, insulin sensitivity was impaired at baseline. After metoprolol treatment, insulin sensitivity further decreased significantly by about 14%, whereas it increased after carvedilol. There was also a decrease in high-density lipoprotein and an increase in triglycerides levels in patients in the metoprolol-treated group, whereas these parameters remained unchanged in patients in the carvedilol-treated group. CONCLUSION: This study confirms previous findings of a reduction in insulin sensitivity after chronic metoprolol treatment. Carvedilol treatment, however, resulted in a small amelioration of insulin resistance and a better lipid profile [corrected]. We thus demonstrate that a beta-blocker with alpha 1-blocking properties has favorable effects on glucose metabolism, suggesting a potentially important role of peripheral blood flow in regulating glucose uptake. These findings imply that beta-blocker treatment, when combined with alpha 1-blocking activity has advantageous effects on insulin sensitivity and lipids and could therefore be suitable for patients with the metabolic syndrome.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Carbazóis/farmacologia , Insulina/farmacologia , Metoprolol/farmacologia , Propanolaminas/farmacologia , Adulto , Idoso , Pressão Sanguínea/efeitos dos fármacos , Carvedilol , Método Duplo-Cego , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Resistência à Insulina , Lipídeos/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
31p nuclear magnetic resonance (NMR) spectroscopy represents a unique instrument to noninvasively monitor myocardial metabolism in humans. The technique has been used to study the metabolism in myocardial hypertrophy in humans with hypertension, aortic stenosis, aortic incompetence, mitral regurgitation, and hypertrophic cardiomyopathy, as well as after maintenance dialysis or long-term physical exercise in elite cyclists. A primary aim is the determination of the phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio, which reflects the energetic state of the myocardium. Recent investigations take advantage of proton decoupling in 31p NMR spectroscopy, which, besides the PCr/ATP ratio, also allows the determination of the inorganic phosphate/ PCr and the phosphomonoester/PCr ratios as additional indicators for alterations in myocardial metabolism. Abnormal myocardial metabolism was found in humans with aortic stenosis, mitral regurgitation, hypertrophic cardiomyopathy, and in patients who undergo maintenance dialysis. A trend toward a lower PCr/ATP ratio was reported in hypertension and aortic incompetence patients. Several studies have revealed a dependence of the metabolic abnormalities on the degree of heart failure, and one study claimed that a correlation with the extent of hypertrophy exists. No metabolic abnormalities were found in elite cyclists.
Assuntos
Metabolismo Energético , Hipertrofia Ventricular Esquerda/metabolismo , Espectroscopia de Ressonância Magnética , Miocárdio/metabolismo , Trifosfato de Adenosina/metabolismo , Humanos , Fosfatos/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Isótopos de Fósforo , Reprodutibilidade dos TestesRESUMO
Disturbed myocardial energy metabolism may occur in patients with primary hypertrophic cardiomyopathy (HCM). A noninvasive way to gain insight into cardiac energy metabolism is provided by in vivo 31P nuclear magnetic resonance (NMR) spectroscopy. 31P NMR spectroscopy with proton decoupling was performed in 13 patients aged 13-36 years with HCM on a 1.5 T Magnetom with a double resonant surface coil. A 2D chemical shift imaging (CSI) sequence in combination with slice selective excitation was used to acquire spectra of the anteroseptal region of the left ventricle (volume element: 38 mL). The chemical shifts of the phosphorus metabolites, intracellular pHi, and coupling constants J(alphabeta) and J(gammabeta) were calculated. Peak areas of 2,3-diphosphoglycerate (DPG), Pi, and adenosine triphosphate (ATP) were determined and corrected for blood contamination, saturation, and differences in nuclear Overhauser enhancements (NOE). The maximum thickness of the interventricular septum (IVSmax) was determined from tomographic long-axis images and expressed as number of standard deviations above the mean of the normal population (Z score). The patients were then divided into 2 groups: 6 patients with moderate HCM (HCMm, Z score < or = 5) and 7 patients with severe HCM (HCMs, Z score > 5). No differences between both groups and a control group of healthy volunteers (n = 16) were found with respect to phosphocreatine (PCr)/gamma-ATP ratio, pHi, or the coupling constants. Only the PCr/Pi ratio differed significantly from the control group (HCM(all), alpha < 0.05, HCMs, alpha < 0.02, 2-sided U test). The decrease of the PCr/Pi ratio in patients with HCM is probably caused by ischemically decreased oxygen supply in the severely hypertrophied myocardium.
Assuntos
Trifosfato de Adenosina/metabolismo , Cardiomiopatia Hipertrófica/metabolismo , Magnésio/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Miocárdio/metabolismo , Fosfocreatina/metabolismo , Adolescente , Adulto , Humanos , Concentração de Íons de Hidrogênio , Isótopos de Fósforo , PrótonsRESUMO
The International Commission on Radiological Protection (ICRP) in its Publication 60 introduced important changes in the concept of risk-related quantities. For external neutron radiation in particular the introduction of the equivalent dose with the radiation weighting factor wR instead of the dose equivalent concept with the quality factor Q(L) has many consequences. The value of wR is defined by the external neutron radiation field, while the radiation quality in the phantom depends on the radiation field at the position of interest and hence on the size of and the position in the phantom. It has been investigated to what extent the size of the phantom influences the mean radiation quality in the phantoms. For incident monoenergetic neutrons, mean photon dose contributions and mean quality factors have been calculated. Results are presented for various phantoms which characterize the conditions for a mouse, a rat, the ICRU sphere and a human body.
Assuntos
Nêutrons , Fótons , Animais , Humanos , Camundongos , Doses de Radiação , RatosRESUMO
We have used an animal model of insulin resistance-the obese Zucker (fa/fa) rat-to test whether oral administration of the non-sulfhydryl-containing angiotensin-converting enzyme (ACE) inhibitor, trandolapril, alone or in combination with the Ca2+-channel blocker, verapamil, can induce a beneficial effect on insulin-stimulated glucose transport and metabolism in skeletal muscle. Insulin-stimulated 2-deoxyglucose (2-DG) uptake in the isolated epitrochlearis muscle was less than 50% as great in obese animals compared with lean (Fa/-) controls (P < .05), but was significantly improved in the obese group by both short-term (6 hours, +33%) and long-term (14 days,+70%) oral treatment with trandolapril. Verapamil treatment alone did not alter insulin-stimulated 2-DG uptake in muscle, but simultaneous administration of verapamil and trandolapril resulted in the most pronounced effect on insulin-stimulated 2-DG uptake (+106%). Long-term treatment with trandolapril alone and in combination with verapamil significantly increased muscle glycogen (+26% to 27%), glucose transporter GLUT-4 protein (+27% to 31%), and hexokinase activity (+21% to 49%), and decreased plasma insulin levels (-23% to -29%). Muscle citrate synthase activity was enhanced only when trandolapril and verapamil were administered in combination (+24%). We conclude that the long-acting, non-sulfhydryl-containing ACE inhibitor, trandolapril, alone and in combination with the Ca2+-channel blocker, verapamil, can significantly improve insulin-stimulated glucose transport activity in skeletal muscle of the insulin-resistant obese Zucker rat, and that this improvement is associated with favorable adaptive responses in GLUT-4 protein levels, glycogen storage, and activities of relevant intracellular enzymes of glucose catabolism.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Glucose/metabolismo , Indóis/farmacologia , Resistência à Insulina , Músculo Esquelético/efeitos dos fármacos , Verapamil/farmacologia , Animais , Transporte Biológico , Feminino , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Obesidade/metabolismo , Ratos , Ratos ZuckerRESUMO
The systemic effect of low-dose bradykinin infusion on total body glucose production and arterial substrate concentrations was examined during D5W infusion (1.0 mg/kg/min) in five normal-weight postsurgical subjects and compared to the response in four saline infused control patients, well matched for age, weight, and degree of postoperative stress. The primed-constant infusion of 6,6-d2-glucose was used to determine the rate of endogenous glucose production. After a basal period of 90 minutes, subjects in the study group were infused with bradykinin at increasing rates of 2.0 and 4.0 micrograms/kg/h, each infusion rate lasting for 90 minutes, whereas in controls corresponding amounts of saline were given. After 75 minutes of bradykinin, endogenous glucose production was significantly reduced as compared to basal values (1.63 +/- 0.21 mg/kg/min, P less than .0125 v 2.20 +/- 0.35 basal). This was accompanied by a significant reduction in arterial concentrations of glucose, lactate, pyruvate, and alanine. Corresponding concentrations of insulin, glucagon, glycerol, free fatty acids, and ketone bodies, as well as mean arterial blood pressure and heart rate was not affected by bradykinin. In the control group no significant changes in substrate and hormone concentrations, or the rate of glucose production were observed. The higher bradykinin infusion rate did not further affect substrate metabolism or systemic hemodynamics. These results demonstrate the inhibitory effect of low-dose bradykinin on glucose production in surgically stressed patients. The stimulation of hepatic prostaglandin synthesis by bradykinin may explain the results since prostaglandins are known to exert an inhibitory effect on hormone stimulated gluconeogenesis and glycogenolysis in liver tissue.
Assuntos
Bradicinina/farmacologia , Glucose/biossíntese , Estresse Fisiológico/metabolismo , Adulto , Inibidores de Ciclo-Oxigenase , Gluconeogênese , Humanos , Fígado/metabolismo , Procedimentos Cirúrgicos OperatóriosRESUMO
To evaluate the effect of the glucose-induced insulin release on peripheral substrate metabolism, we studied muscle metabolism in seven patients after elective surgery and in four healthy volunteers combining the forearm and the euglycemic glucose clamp technique (insulin infusion, 0.2 mU/kg per minute). Arterial and deep venous concentrations of substrates and hormones were determined in the basal period and during steady state of the infusion period. After 90 minutes of insulin infusion, the whole-body glucose infusion rate was significantly lower in patients who had elective surgery, although plasma insulin concentrations were comparable. In both groups this was related to a reduced supply of free fatty acids and ketones in muscle. In controls the resulting lack of substrates in muscle appeared to be compensated by an enhanced uptake of glucose, not seen in the patients who had elective surgery. Surprisingly, as indicated by the significantly reduced lactate production (-0.15 +/- 0.05 vs -0.62 +/- 0.32 mumol/100 g per minute basal), in this group the glucose taken up was oxidized aerobically to a greater extent. However, the total resulting energy gain was small. Thus, a peripheral energy deficit might arise favoring increased oxidation of amino acids. To avoid this undesired side effect, only those substrates should be administered that minimize pancreatic insulin release.