RESUMO
Ischemia and reperfusion may be important in the pathogenesis of pressure ulcers. On the basis of this hypothesis, the effects of intermittent pressure and the anti-free radical agents allopurinol and deferoxamine were studied in a pig model in which a pressure of 150 mmHg was applied intermittently to the scapulae. Cutaneous blood flow, transcutaneous oxygen tension, skin and muscle damage, and muscle levels of adenosine triphosphate were quantified. A control group of pigs (n = 6) was untreated, the allopurinol group (n = 6) received oral allopurinol beginning 2 days before the experiment, and the deferoxamine group (n = 6) received an intramuscular injection of deferoxamine 2 hours before the experiment. Pressure (150 mmHg) was applied to the scapulae for 210 minutes, and it was relieved for 30 minutes. This 4-hour cycle was repeated continuously for 48 hours, and it resulted in pressure injuries in all animals. Allopurinol and deferoxamine improved cutaneous blood flow and tissue oxygenation, but only deferoxamine could significantly reduce cutaneous and skeletal muscle necrosis (p < 0.001). This study suggests a future role for anti-free radical agents in the reduction of pressure-induced injury.
Assuntos
Alopurinol/farmacologia , Desferroxamina/farmacologia , Sequestradores de Radicais Livres/farmacologia , Úlcera por Pressão/prevenção & controle , Trifosfato de Adenosina/metabolismo , Administração Oral , Animais , Monitorização Transcutânea dos Gases Sanguíneos , Creatina Quinase/metabolismo , Injeções Intramusculares , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/patologia , Consumo de Oxigênio/efeitos dos fármacos , Peroxidase/metabolismo , Úlcera por Pressão/patologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Pele/irrigação sanguínea , Pele/patologia , SuínosRESUMO
The purpose of the study was to examine the relationship between antioxidant depletion, glycemic control, and development of chronic complications in a controlled population of type 2 diabetic patients. Fifty age-matched type 2 diabetic patients receiving sulfonylureas but not insulin treatment were screened and assigned to two groups based on the presence or absence of proteinuria. A third group of normal subjects without diabetes were also enrolled in the study. All subjects in the three groups were Egyptians who were matched for body weight, and the two diabetic groups were also age-matched. Plasma glucose and fructosamine levels were higher in the two groups of diabetic patients versus the control group, but lipid peroxide levels were higher only in the patients with proteinuria. Compared with the control group, the total antioxidant capacity was depleted in the two diabetic groups, but the depletion was more severe in patients with proteinuria. Thus, the mean Trolox equivalent antioxidant capacity (TEAC) of the control group was 2.7+/-0.45, versus 1.7+/-0.5 (P < .001) in the patients without proteinuria. Furthermore, the TEAC measured in patients with proteinuria, who also had more diabetic complications, was lower (1.4+/-0.5, P < .001) than the TEAC in patients without urinary protein. In conclusion, a depletion of the total antioxidant capacity is associated with a higher incidence of diabetic complications.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Estresse Oxidativo , Adulto , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Incidência , Peroxidação de Lipídeos , Masculino , Pessoa de Meia-Idade , Oxirredução , Proteinúria/etiologia , Proteinúria/metabolismoRESUMO
Hypoxia is characterized by inadequate oxygen delivery to the myocardium with a resulting imbalance between oxygen demand and energy supply. Several adaptive mechanisms occur to preserve myocardial survival during hypoxia. These include both short- and long-term mechanisms, which serve to achieve a new balance between myocardial oxygen demand and energy production. Short-term adaptation includes downregulation of myocardial function along with upregulation of energy production via anaerobic glycolysis following an increase in glucose uptake and glycogen breakdown. Long-term adaptation includes genetic reprogramming of key glycolytic enzymes. Thus, the initial decline in high-energy phosphates following hypoxia is accompanied by a decrease in myocardial contractility and myocardial energy requirements are subsequently met by ATP supplied from anaerobic glycolysis. Thus, a downregulation in cardiac function and/or enhanced energy production via anaerobic glycolysis are the major mechanisms promoting myocardial survival during hypoxia. In contrast to the aforementioned metabolic changes occurring in adult myocardium, the effects of chronic hypoxia on neonatal myocardial metabolism remain undefined. Studies from our laboratory using a novel neonatal piglet model of chronic hypoxia have shown a shift in cardiac myocyte substrate utilization towards the newborn state with a preference for glucose utilization. We have also shown, using this same model, that chronically hypoxic neonatal hearts were more tolerant to ischemia than non-hypoxic hearts. This ischemic tolerance is likely due to adaptive metabolic changes in the chronically hypoxic hearts, such as increased anaerobic glycolysis and glycogen breakdown.
Assuntos
Animais Recém-Nascidos/metabolismo , Hipóxia/metabolismo , Miocárdio/metabolismo , Adaptação Fisiológica/fisiologia , Envelhecimento/metabolismo , Animais , Metabolismo Energético/fisiologia , Humanos , Valores de ReferênciaRESUMO
BACKGROUND: Transmyocardial laser revascularization (TMR) is an emerging therapy for the treatment of coronary artery disease not amenable to percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass surgery (CABG). OBJECTIVE: To summarize the experimental and clinical experience to date with TMR. Specifically, the history of the technique, preclinical and clinical data, patient selection and perioperative management, as well as future applications of TMR are discussed. DATA SOURCES: All English language articles pertaining to TMR published through March 1999. MEDLINE was searched with the key words 'myocardial revascularization', 'lasers' and 'laser surgery', as well as the text terms 'transmyocardial laser revascularization', 'TMR' and 'TMLR'. Reference lists of articles obtained from MEDLINE were studied for additional references not discovered in computer searches. Pertinent abstracts published within the past two years were reviewed as well. STUDY SELECTION: Studies that produced original experimental or clinical data were selected. DATA SYNTHESIS: Experimental studies demonstrate that TMR channels become occluded in the early postoperative period. However, experimental data indicate that laser injury appears to promote neovascularization with secondary improvements in perfusion in treated regions. Human clinical studies confirm the efficacy of the procedure, with significant improvements in anginal class up to at least one year postoperatively, although documented improvements in myocardial perfusion have been less consistent. Perioperative morbidity and mortality appear to be increased in patients with unstable angina or reduced left ventricular function. CONCLUSIONS: With careful patient selection and peri- operative management, TMR is a safe and effective therapy for severe angina pectoris secondary to end-stage coronary artery disease. Additional studies are required to define the role of TMR in combination with PTCA, CABG and angiogenic growth factors, as well as the safety and efficacy of catheter-based TMR.
Assuntos
Doença das Coronárias/cirurgia , Revascularização Miocárdica/métodos , Angina Pectoris/etiologia , Angina Pectoris/cirurgia , Doença das Coronárias/complicações , Ecocardiografia Transesofagiana , Humanos , Período Intraoperatório , Terapia a Laser , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
This study was designed to investigate the effects of the cardiovascular drug dipyridamole on fatty acid metabolism in isolated cardiac myocytes. Effects of dipyridamole on the oxidation of long-chain (palmitate) fatty acid, medium-chain (octanoate) fatty acid, and the carbohydrate intermediate (pyruvate) were determined by using isolated cardiac myocytes from both normal and diabetic rats. Dipyridamole increased palmitate oxidation in a concentration-dependent manner in both normal and diabetic myocytes. Maximal stimulation of palmitate oxidation (175% of control) was observed with 100 microM dipyridamole. In contrast, oxidation of octanoate and pyruvate was not affected. The stimulation of palmitate oxidation by dipyridamole persisted despite its removal from the incubation medium. In contrast to the effect in myocytes, palmitate oxidation was not affected by dipyridamole in isolated rat heart mitochondria. Palmitate uptake was increased by 2.5- and 1.6-fold when palmitate concentration was adjusted to 0.05 and 0.2 mM, respectively. Dipyridamole did not affect lipolysis in isolated myocytes. When dipyridamole (100 microM) and L-carnitine (5 mM) were added together to the incubation medium, palmitate oxidation was further increased to 223% of the control. The nucleoside transport inhibitor nitrobenzylthioinosine (NBMPR) failed to increase palmitate oxidation in isolated myocytes. Although palmitate oxidation in diabetic cells is much higher than that in normal myocytes, dipyridamole increased palmitate oxidation by 243% in diabetic myocytes over its baseline oxidation rate in normal cells. These results suggest that increased palmitate oxidation in isolated cardiac myocytes after dipyridamole administration occurs independent of effects on either the phosphodiesterase enzyme or nucleoside transport protein, but it may result from increased palmitate transport across the plasma membrane.
Assuntos
Dipiridamol/farmacologia , Ácidos Graxos/metabolismo , Coração/efeitos dos fármacos , Miocárdio/metabolismo , Vasodilatadores/farmacologia , Animais , Diabetes Mellitus Experimental/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Técnicas In Vitro , Masculino , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Palmitatos/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
This study is designed to investigate whether substrate preference in the myocardium during the neonatal period and hypoxia-induced stress is controlled intracellularly or by extracellular substrate availability. To determine this, the effect of exogenous L-carnitine on the regulation of carbohydrate and fatty acid metabolism was determined during cardiac stress (hypoxia) and during the postnatal period. The effect of L-carnitine on long chain (palmitate) and medium chain (octonoate) fatty acid oxidation was studied in cardiac myocytes isolated from less than 24 h old (new born; NB), 2 week old (2 week) and hypoxic 4 week old (HY) piglets. Palmitate oxidation was severely decreased in NB cells compared to those from 2 week animals (0.456+/-0.04 vs. 1.207+/-0.52 nmol/mg protein/30 min); surprisingly, cells from even older hypoxic animals appeared shifted toward the new born state (0.695+/-0.038 nmol/mg protein/30 min). Addition of L-carnitine to the incubation medium, which stimulates carnitine palmitoyl-transferase I (CPTI) accelerated palmitate oxidation 3 fold in NB and approximately 2 fold in HY and 2 week cells. In contrast, octanoate oxidation which was greater in new born myocytes than in 2 week cells, was decreased by L-carnitine suggesting a compensatory response. Furthermore, oxidation of carbohydrates (glucose, pyruvate, and lactate) was greatly increased in new born myocytes compared to 2 week and HY cells and was accompanied by a parallel increase in pyruvate dehydrogenase (PDH) activity. The concentration of malonyl-CoA, a potent inhibitor of CPTI was significantly higher in new born heart than at 2 weeks. These metabolic data taken together suggest that intracellular metabolic signals interact to shift from carbohydrate to fatty acid utilization during development of the myocardium. The decreased oxidation of palmitate in NB hearts probably reflects decreased intracellular L-carnitine and increased malonyl-CoA concentrations. Interestingly, these data further suggest that the cells remain compliant so that under stressful conditions, such as hypoxia, they can revert toward the neonatal state of increased glucose utilization.
Assuntos
Metabolismo dos Carboidratos , Carnitina/fisiologia , Ácidos Graxos/metabolismo , Coração/crescimento & desenvolvimento , Miocárdio/metabolismo , Animais , Animais Recém-Nascidos , Caprilatos/metabolismo , Hipóxia Celular , Glicólise , Malonil Coenzima A/metabolismo , Oxirredução , SuínosRESUMO
The phosphodiesterase (PDE) inhibitor, enoximone, enhances the oxidation of fatty acids in cardiac myocytes. Since carbohydrate oxidation is tightly coupled and inversely related in cardiac tissue to fatty acid oxidation, this study was designed to investigate enoximone's effects on glucose metabolism in the heart. To determine if enoximone alters this reciprocal relationship, the effects of enoximone on [U-14C]glucose and [2-14C]pyruvate oxidation were determined in isolated cardiac myocytes. The effect of PDE inhibitors was also examined on pyruvate dehydrogenase complex (PDH) activity, a key component of oxidative glucose metabolism. Two PDE inhibitors, enoximone and milrinone, decreased PDH activity by 69 and 64%, respectively at 0.5 mM. This inhibition of PDH activity by enoximone was completely reversed after removing enoximone from the myocyte medium. PDH activity was unaffected by agents which alter cyclic nucleotide signaling: cGMP, dibutyryl cyclic AMP, and AMP. The effect of enoximone on [2-14C]pyruvate oxidation was similar to that on PDH. Interestingly, the oxidation of glucose was decreased 35% by 0.5 mM enoximone. In isolated rat heart mitochondria (RHM), enoximone decreased PDH activity by 37%. These studies suggest that PDE inhibitors decrease carbohydrate utilization by inhibiting the PDH complex in the heart. The inhibition of PDH by PDE inhibitors appears unrelated to their effects on cAMP or cGMP. This inhibition of PDH by PDE inhibitors may occur, at least in part, secondary to stimulating fatty acid oxidation.
Assuntos
Glucose/metabolismo , Miocárdio/metabolismo , Inibidores de Fosfodiesterase/farmacologia , Animais , Metabolismo dos Carboidratos , Enoximona/farmacologia , Coração/efeitos dos fármacos , Masculino , Oxirredução , Complexo Piruvato Desidrogenase/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Depressed glucose utilization and over-reliance of muscle tissues on fat represents a major metabolic disturbance in diabetes. This study was designed to investigate the relationship between fatty acid oxidation and glucose utilization in diabetic hearts and to examine the role of L-Carnitine on the utilization of these substrates in diabetes. 14CO2 release from [1-14C]pyruvate (an index of PDH activity), [2-14C]pyruvate and [6-14C]glucose (an index of acetyl-CoA flux through the Krebs cycle), [U-14C]glucose (an index of both PDH and acetyl-CoA flux through the Krebs cycle), and [1-14C]palmitate oxidation were studied in cardiac myocystes isolated from normal and streptozotocin-injected rats. Palmitate oxidation was increased twofold in diabetic myocytes compared to normal cells (5.4 +/- 1.45 vs 2.35 +/- 0.055 nmol/mg protein/30 min, p > 0.05). L-Carnitine (5 mM) significantly increased palmitate oxidation (60-70%) in normal cells but had no effect on diabetic cells. The activity of PDH and acetyl-CoA flux through the Krebs cycle was severely depressed in diabetes (58.14 +/- 20.27 and 8.63 +/- 0.62 in diabetes vs 128.75 +/- 11.47 and 24.84 +/- 7.81 nmol/mg protein/30 min in controls, p > 0.05, respectively). The efflux of acetylcarnitine, a by-product of PDH activity was also much lower in diabetic cells than in normal cells but had no effect in diabetes. L-Carnitine also had no effect on 14CO2 release from [U-14C]glucose but significantly decreased that from [6-14C]glucose, which reflects oxidative metabolism suggesting that L-Carnitine decreases oxidative glucose utilization. Thus, these data suggest that the overreliance on fat in diabetes may be in part secondary to a reduction of carbohydrate-generated acetyl-CoA through the Krebs cycle.
Assuntos
Carnitina/farmacologia , Diabetes Mellitus Experimental/metabolismo , Ácidos Graxos/metabolismo , Glucose/metabolismo , Miocárdio/metabolismo , Acetilcoenzima A/metabolismo , Acetilcarnitina/metabolismo , Animais , Radioisótopos de Carbono , Ciclo do Ácido Cítrico , Coração/efeitos dos fármacos , Cinética , Masculino , Oxirredução , Ácido Palmítico/metabolismo , Complexo Piruvato Desidrogenase/metabolismo , Ácido Pirúvico/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
This study was designed to determine if acute (in vitro) or chronic (in vivo) adriamycin inhibits cardiac fatty acid oxidation and if so at what sites in the fatty acid oxidation pathway. In addition, the role of L-carnitine in reversing or preventing this effect was examined. We determined the effects of adriamycin in the presence or absence of L-carnitine on the oxidation of the metabolic substrates [1-14C]palmitate. [1(-14)C] octanoate. [1(-14)C]butyrate, [U-14C]glucose, and [2(-14)C]pyruvate in isolated cardiac myocytes. Acute exposure to adriamycin caused a concentration- and time-dependent inhibition of carnitine palmitoyl transferase 1 (CPT 1) dependent long-chain fatty acid, palmitate, oxidation. Chronic exposure to (18 mg/kg) adriamycin inhibited palmitate oxidation 40% to a similar extent seen in vitro with 0.5 mM adriamycin. Acute or chronic administration of L-carnitine completely abolished the adriamycin-induced inhibition of palmitate oxidation. Interestingly, medium- and short-chain fatty acid oxidation, which are independent of CPT 1, were also inhibited acutely by adriamycin and could be reversed by L-carnitine. In isolated rat heart mitochondria, adriamycin significantly decreased oxidation of the CPT 1 dependent substrate palmitoyl-CoA by 50%. However, the oxidation of a non-CPT 1 dependent substrate palmitoylcarnitine was unaffected by adriamycin except at concentrations greater than 1 mM. These data suggest that after in vitro or in vivo administration, adriamycin, inhibits fatty acid oxidation in part secondary to inhibition of CPT 1 and/or depletion of its substrate, L-carnitine, in cardiac tissue. However, these findings also suggest that L-carnitine plays an additional role in fatty acid oxidation independent of CPT 1 or fatty acid chain length.
Assuntos
Doxorrubicina/efeitos adversos , Ácidos Graxos/metabolismo , Coração/efeitos dos fármacos , Miocárdio/citologia , Animais , Antibióticos Antineoplásicos/farmacologia , Caprilatos/metabolismo , Carnitina/farmacologia , Carnitina O-Palmitoiltransferase/efeitos dos fármacos , Carnitina O-Palmitoiltransferase/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Glucose/metabolismo , Masculino , Mitocôndrias Cardíacas/metabolismo , Miocárdio/metabolismo , Oxirredução , Ácido Palmítico/metabolismo , Ácido Pirúvico/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Long chain free fatty acids (FFA) are the preferred metabolic substrates of myocardium under aerobic conditions. However, under ischemic conditions long chain FFA have been shown to be harmful both clinically and experimentally. Serum levels of free fatty acids frequently are elevated in patients with myocardial ischemia. The proposed mechanisms of the detrimental effects of free fatty acids include: (1) accumulation of toxic intermediates of fatty acid metabolism, such as long chain acyl-CoA thioesters and long chain acylcarnitines, (2) inhibition of glucose utilization, particularly glycolysis, during ischemia and/or reperfusion, and (3) uncoupling of oxidative metabolism from electron transfer. The relative importance of these mechanisms remains controversial. The primary site of FFA-induced injury appears to be the sarcolemmal and intracellular membranes and their associated enzymes. Inhibitors of free fatty acid metabolism have been shown experimentally to decrease the size of myocardial infarction and lessen postischemic cardiac dysfunction in animal models of regional and global ischemia. The mechanism by which FFA inhibitors improve cardiac function in the postischemic heart is controversial. Whether the effects are dependent on decreased levels of long chain intermediates and/or enhancement of glucose utilization is under investigation. Manipulation of myocardial fatty acid metabolism may prove beneficial in the treatment of myocardial ischemia, particularly during situations of controlled ischemia and reperfusion, such as percutaneous transluminal coronary angioplasty and coronary artery bypass grafting.
Assuntos
Ácidos Graxos não Esterificados/metabolismo , Isquemia Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Animais , Ácidos Graxos não Esterificados/antagonistas & inibidores , Glucose/metabolismo , Coração/fisiopatologia , Humanos , Reperfusão Miocárdica , Miocárdio/metabolismoAssuntos
Prótese Vascular/normas , Ponte Cardiopulmonar , Massagem Cardíaca , Veia Safena/fisiologia , Análise de Variância , Anastomose Cirúrgica , Animais , Doença das Coronárias , Cães , Relação Dose-Resposta a Droga , Histamina/farmacologia , Contração Isométrica/efeitos dos fármacos , Contração Isométrica/fisiologia , Microesferas , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Norepinefrina/farmacologia , Perfusão , Veia Safena/cirurgia , Serotonina/farmacologia , Fibrilação Ventricular/cirurgia , Fibrilação Ventricular/terapiaRESUMO
The regulation of fatty acid oxidation in isolated myocytes was examined by manipulating mitochondrial acetyl-CoA levels produced by carbohydrate and fatty acid oxidation. L-carnitine had no effect on the oxidation of [U-14C]glucose, but stimulated oxidation of [1-14C]palmitate in a concentration-dependent manner. L-carnitine (5 mM) increased palmitate oxidation by 37%. The phosphodiesterase inhibitor, enoximone (250 microM), also increased palmitate oxidation by 51%. Addition of L-carnitine to enoximone resulted in a two-fold increase of palmitate oxidation. Whereas, dichloroacetate (DCA, 1 mM), which stimulates PDH activity, decreased palmitate oxidation by 25%. Furthermore, the addition of DCA to myocytes preincubated with either L-carnitine or enoximone, had no effect on the carnitine-induced stimulation of palmitate, and reduced that of enoximone by 50%. Varied concentrations of DCA decreased the oxidation of palmitate and octanoate; but increased glucose oxidation in myocytes. The rate of efflux of acetylcarnitine was highest when pyruvate was present in the medium compared to efflux rates in presence of palmitate or palmitate plus glucose. Although the addition of L-carnitine plus enoximone resulted in a two-fold increase in palmitate oxidation, acetylcarnitine efflux was minimal under these conditions. Acetylcarnitine efflux was highest when pyruvate was present in the medium. These rates were dramatically decreased when myocytes were preincubated with enoximone, despite the stimulation of palmitate oxidation by this compound. These data suggest that: (1) fatty acid oxidation is influenced by acetyl-CoA produced from pyruvate metabolism; (2) L-carnitine may be specific for mitochondrial acetyl-CoA derived from pyruvate oxidation; and (3) it is probable that acetyl-CoA from beta-oxidation of fatty acids is directly channeled into the citric acid cycle.
Assuntos
Acetilcoenzima A/metabolismo , Ácidos Graxos/metabolismo , Glucose/farmacologia , Miocárdio/metabolismo , Acetilcoenzima A/farmacologia , Animais , Carnitina/farmacologia , Células Cultivadas , Glucose/metabolismo , Masculino , Oxirredução/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
The effects of L-carnitine on 14CO2 release from [1-14C]pyruvate oxidation (an index of pyruvate dehydrogenase activity, PDH), [2-14C]pyruvate, and [6-14C]glucose oxidation (indices of the acetyl-CoA flux through citric acid cycle), and [U-14C]glucose (an index of both PDH activity and the flux of acetyl-CoA through the citric acid cycle), were studied using isolated rat cardiac myocytes. L-carnitine increased the release of 14CO2 from [1-14C]pyruvate, and decreased that of [2-14C]pyruvate in a time and concentration-dependent manner. At a concentration of 2.5 mM, L-carnitine produced a 50% increase of CO2 release from [1-14C]pyruvate and a 50% decrease from [2-14C]pyruvate oxidation. L-carnitine also increased CO2 release from [1-14C]pyruvate oxidation by 35%, and decreased that of [2-14C]pyruvate oxidation 30%, in isolated rat heart mitochondria. The fatty acid oxidation inhibitor, etomoxir, stimulated the release of CO2 from both [1-14]pyruvate and [2-14C]pyruvate. These results were supported by the effects of L-carnitine on the CO2 release from [6-14C]- and [U-14C]glucose oxidation. L-carnitine (5 mM) decreased the CO2 release from [6-14C]glucose by 37%, while etomoxir (50 microM) increased its release by 24%. L-carnitine had no effect on the oxidation of [U-14C]glucose. L-carnitine increased palmitate oxidation in a time- and concentration-dependent manner in myocytes. Also, it increased the rate of efflux of acetylcarnitine generated from pyruvate in myocytes. These results suggest that L-carnitine stimulates pyruvate dehydrogenase complex activity and enhances non-oxidative glucose metabolism by increasing the mitochondrial acetylcarnitine efflux in the absence of exogenous fatty acids.
Assuntos
Carnitina/farmacologia , Glucose/metabolismo , Miocárdio/metabolismo , Acetilcarnitina/metabolismo , Animais , Dióxido de Carbono/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Compostos de Epóxi/farmacologia , Hipoglicemiantes/farmacologia , Masculino , Mitocôndrias/metabolismo , Miocárdio/ultraestrutura , Oxirredução , Palmitatos/metabolismo , Complexo Piruvato Desidrogenase/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
In order to investigate the mechanism by which fatty acid oxidation inhibitors regulate cardiac metabolism, the effects of 2-tetradecylglycidic acid (2-TDGA), and 2-bromopalmitic acid (2-BPA) on the oxidation of [1-14C]palmitate, [1-14C]octanoate and [U-14C]glucose were studied in isolated rat myocytes. Fifty per cent inhibition of palmitate oxidation was achieved at 20 microM 2-TDGA and 60 microM 2-BPA. Octanoate oxidation was also inhibited by 2-BPA. In contrast to their effect on palmitate oxidation, fatty acid inhibitors significantly stimulated the oxidation of glucose in a concentration-dependent manner. Moreover, the oxidation of [2-14C]pyruvate was increased two-fold by these compounds. The rate of uptake of [U-14C]-2-deoxyglucose was also stimulated two-fold by these inhibitors. These studies suggest that the stimulation of glucose utilization via the inhibition of fatty acid oxidation may be mediated through the stimulation of both glucose transport and the oxidation of pyruvate by the pyruvate dehydrogenase complex.
Assuntos
Compostos de Epóxi/farmacologia , Ácidos Graxos/metabolismo , Ácidos Graxos/farmacologia , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Mitocôndrias Cardíacas/metabolismo , Palmitatos/farmacologia , Animais , Caprilatos/metabolismo , Masculino , Oxirredução , Palmitatos/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
This study was conducted to determine if the activity of 2,4-dienoyl-CoA reductase limits the rate of cardiac beta-oxidation of highly unsaturated fatty acids. Although growth hormone treatment of hypophysectomized rats caused a 3-fold increase in the activity of 2,4-dienoyl-CoA reductase, beta-oxidation of docosahexaenoate in cardiomyocytes was not stimulated by this treatment. Since cardiomyocytes oxidized oleic acid more rapidly than docosahexaenoic acid, the utilization of energy did not limit beta-oxidation. Respiration measurements with coupled rat heart mitochondria revealed that the rates of beta-oxidation with palmitoyl-CoA and palmitoylcarnitine as substrates were virtually identical but were 3- to 4-fold higher than the rates obtained with either docosahexaenoyl-CoA or docosahexaenoylcarnitine. Although the activity of carnitine palmitoyltransferase I (CPT I) was 5 times higher with palmitoyl-CoA as substrate than with docosahexaenoyl-CoA, this reaction is only one of several that may limit the beta-oxidation of docosahexaenoic acid. Surprisingly, an incremental inhibition of CPT I resulted in a parallel inhibition of respiration supported by either palmitoyl-CoA or docosahexaenoyl-CoA. This observation agrees with the notion that CPT I may also be a regulatory enzyme in cardiac fatty acid oxidation. It is concluded that the reduction of double bonds by 2,4-dienoyl-CoA reductase does not restrict the cardiac beta-oxidation of highly unsaturated fatty acid, like docosahexaenoic acid.
Assuntos
Ácidos Graxos Insaturados/metabolismo , Miocárdio/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Animais , Carnitina O-Palmitoiltransferase/metabolismo , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Graxos Dessaturases/metabolismo , Hormônio do Crescimento/farmacologia , Masculino , Mitocôndrias Cardíacas/metabolismo , Miocárdio/citologia , Ácido Oleico , Ácidos Oleicos/metabolismo , Ratos , Ratos Sprague-DawleyAssuntos
Metabolismo dos Carboidratos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Ácidos Graxos/metabolismo , Miocárdio/citologia , Animais , Relação Dose-Resposta a Droga , Compostos de Epóxi/farmacologia , Glucose/biossíntese , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Masculino , Oxirredução , Palmitatos/metabolismo , Complexo Piruvato Desidrogenase/antagonistas & inibidores , Piruvatos/metabolismo , Ácido Pirúvico , Ratos , Ratos Sprague-DawleyRESUMO
Studies show that insulin deficiency enhances peroxisomal enzyme activities. It is not known, however, whether hyperinsulinemia exerts the opposite effect on peroxisomes. Male Sprague-Dawley rats were infused with normal saline, glucose or galactose for 7 days. Only glucose caused an increase in serum insulin levels. The increase in insulin secretion, in response to glucose, was blocked with diazoxide. Data show an inverse relationship between serum insulin levels and hepatic peroxisomal beta-oxidation (r2 = 0.90, p < 0.01). While hyperinsulinemic rats had diminished peroxisomal beta-oxidation, lowering serum insulin restored peroxisomal enzyme activity to normal levels. These effects were independent of blood glucose levels (r2 = 0.35). In addition to decreasing peroxisomal beta-oxidation, hyperinsulinemia was accompanied by accelerated animal mortality, an effect which was also prevented by lowering serum insulin levels. Peroxisomal deficit may be a potentially lethal consequence of hyperinsulinemia.
Assuntos
Insulina/sangue , Fígado/metabolismo , Microcorpos/metabolismo , Animais , Diazóxido/farmacologia , Galactose/farmacologia , Glucose/farmacologia , Fígado/ultraestrutura , Masculino , Oxirredução , Ratos , Ratos Sprague-DawleyRESUMO
The phosphodiesterase inhibitor, enoximone, was previously shown to cause paradoxical effects on cardiac lipid metabolism. The present study was undertaken to elucidate the effects of enoximone on the hepatic mitochondrial pathway of fatty acid oxidation. Results presented here show that in isolated rat liver mitochondria, palmitate oxidation was inhibited progressively by increasing concentrations of enoximone. Maximum inhibition (35%) of mitochondrial oxygen uptake was attained at 250 microM enoximone. At this concentration, enoximone did not affect the oxidation of either palmitoyl-CoA or palmitoyl carnitine. Also, enoximone did not inhibit the oxidation of the short-chain fatty acid, hexanoate, neither did it affect the respiratory chain in the mitochondria. These data suggest that enoximone specifically inhibits long-chain acyl-CoA synthetase activity. This was confirmed experimentally when the activity of this enzyme was determined in the absence and presence of enoximone. Discovering inhibitors of specific steps in lipid metabolism should provide a useful tool to investigate mechanisms regulating this pathway.
Assuntos
Coenzima A Ligases/antagonistas & inibidores , Enoximona/farmacologia , Mitocôndrias Hepáticas/efeitos dos fármacos , Proteínas Repressoras , Proteínas de Saccharomyces cerevisiae , Animais , Caproatos/metabolismo , Fracionamento Celular , Malatos/metabolismo , Masculino , Mitocôndrias Hepáticas/enzimologia , Oxirredução , Consumo de Oxigênio/efeitos dos fármacos , Palmitatos/metabolismo , Piruvatos/metabolismo , Ácido Pirúvico , Ratos , Ratos Sprague-Dawley , Succinatos/metabolismo , Ácido SuccínicoRESUMO
Direct mechanical ventricular actuation (DMVA) uses a pressure regulated heart cup, fabricated from silicone rubber (SR) for mechanical massage of the heart. Because DMVA has demonstrated potential for long-term circulatory support, investigations are currently exploring the use of more durable materials for fabricating DMVA heart cups. This study assessed the acute effects of heart cups fabricated from SR versus polyurethane (PU) on the myocardium. Dogs (n - 18) received DMVA for 4 hr of ventricular fibrillation (VF) using either SR (n = 10) or PU (n = 8) cups. Microspheres were used to determine perfusion during sinus rhythm (control) and at 2 and 4 hr of support. After support, myocardial biopsies were assayed for high energy phosphate content. Results demonstrated that PU cups required relatively frequent adjustments in drive line parameters that were likely due to material softening during PU cup support. Both PU and SR cups achieved similar hemodynamics during 4 hr of support. Myocardial perfusion, however, demonstrated a marked hyperemia at 4 hr of PU versus SR cup support. Regional high energy phosphate content was significantly decreased in hearts supported by PU versus SR cups. These results suggest that the relatively compliant characteristics of SR materials are important for achieving effective DMVA support without injuring the myocardium.
Assuntos
Materiais Biocompatíveis , Coração Auxiliar , Coração/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Materiais Biocompatíveis/efeitos adversos , Engenharia Biomédica , Cães , Elasticidade , Estudos de Avaliação como Assunto , Coração Auxiliar/efeitos adversos , Hemodinâmica/fisiologia , Teste de Materiais , Microesferas , Miocárdio/metabolismo , Poliuretanos/efeitos adversos , Elastômeros de Silicone/efeitos adversos , Estresse Mecânico , Função Ventricular Esquerda/fisiologiaRESUMO
The study of the regulation of glucose utilization by inhibition of fatty acid oxidation is greatly enhanced by the availability of specific inhibitors of fatty acid oxidation. This study examines the regulation of cardiac glucose utilization by inhibition of fatty acid oxidation at different sites. The effects of Etomoxir and 4-bromocrotonic acid (4-BCA) on the oxidation of [1-14C]palmitate, [1-14C]-octanoate and [U-14C]glucose were studied in isolated rat myocytes. Fifty percent inhibition of palmitate oxidation was achieved at 8 microM Etomoxir and 40 microM 4-BCA. Octanoate oxidation was inhibited only by 4-BCA. In contrast to their effect on palmitate oxidation, these inhibitors significantly stimulated the oxidation of glucose in a concentration-dependent manner. Moreover, the oxidation of [2-14C]pyruvate was increased two-fold by these compounds. The rate of utilization of [U-14C]-2-deoxyglucose was also stimulated 2-3 times by these inhibitors. These studies suggest that the stimulation of glucose utilization via the inhibition of fatty acid oxidation may be mediated through the stimulation of both glucose transport and the oxidation of pyruvate by the pyruvate dehydrogenase complex.