RESUMEN
OBJECTIVE: To investigate the effect of either genistein, or exercise, or both, on parameters that are indicators of cardiovascular health. METHODS: We investigated the effect of genistein treatment (300 mg genisten/kg body weight/day), or exercise training, or combined genistein and exercise training, for a period of 6 weeks on physical characteristics, cardiovascular plasma markers, blood pressure, aortic morphology, cardiac structure and oxidative stress in the ovariectomized (OVX) Sprague-Dawley rat. Comparisons were made with intact rats. RESULTS: Ovariectomy (compared to intact) resulted in significant decreases in uterine weight (6-fold, p < 0.0001), insulin levels (4-fold, p = 0.0214), insulin/glucose ratio (3-fold, p = 0.0029), and tumor necrosis factor-α plasma levels (2-fold, p < 0.0001). Similarly, aortic blood pressure was significantly increased (by 8%, p < 0.0033) in OVX rats, without changes in aortic luminal or wall dimensions. Heart surface area was significantly increased (by 16%, p = 0.0160) in OVX rats and this was without changes in non-protein thiol levels (a marker of oxidative stress). Physical characteristics were not altered by treatment with genistein, or genistein with exercise, with the exception of increased uterine weight in OVX rats treated under these same conditions. There were no effects of genistein or exercise on indices of blood pressure and aortic morphology in the OVX rat. However, right ventricular nuclei count was reduced in sedentary genistein-treated rats compared to non-treated control OVX rats. CONCLUSION: Our results indicate that administration of genistein at this dose, treadmill running, or the combination of both, are not associated with any improvement in cardiovascular function and structure, and risk factors in an ovariectomy model of postmenopause.
Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Genisteína/farmacología , Condicionamiento Físico Animal , Fitoestrógenos/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Suplementos Dietéticos , Modelos Animales de Enfermedad , Femenino , Genisteína/administración & dosificación , Frecuencia Cardíaca/efectos de los fármacos , Ovariectomía , Fitoestrógenos/administración & dosificación , Ratas , Ratas Sprague-Dawley , Factores de RiesgoRESUMEN
AIM: We have demonstrated that short-term angiotensin-converting enzyme (ACE) inhibition in adult spontaneously hypertensive rats produces cardiac changes that persist following cessation of treatment that result in a reduced inflammatory, proliferative and fibrotic response to the nitric oxide synthase inhibitor N(ω) -Nitro-l-arginine methyl ester (L-NAME). The present study examines whether prior ACE inhibition with enalapril also protects against L-NAME-induced cardiac dysfunction. METHODS: Rats were treated with enalapril (Enal + L) or tap water (Con, Con + L) for 2 weeks followed by a 2-week washout period. At this point, Con + L and Enal + L rats were treated with L-NAME for 10 days. Hearts were perfused in the working mode, mean arterial pressure (MAP) was assessed via radiotelemetry, and myocardial injury was evaluated in hematoxylin and eosin-stained sections. RESULTS: L-NAME increased MAP by a similar magnitude in Con + L and Enal + L. L-NAME-induced statistically significant decreases in flow-mediated functional parameters in Con + L rats including cardiac output, stroke volume and coronary flow. This was prevented by prior enalapril treatment. Prior enalapril did not prevent L-NAME-induced myocardial injury, but may have lessened the degree of it. Regardless of treatment, changes in cardiac function did not correlate with myocardial injury. CONCLUSION: Despite equivalent impact on MAP and incidence of myocardial infarction, prior enalapril treatment resulted in the preservation of cardiac function following L-NAME. Understanding the mechanisms by which transient ACE inhibition protects against reductions in cardiac function in the absence of ongoing treatment may reveal novel targets for heart failure treatment.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Gasto Cardíaco/efectos de los fármacos , Enalapril/farmacología , Cardiopatías/prevención & control , Hipertensión/tratamiento farmacológico , NG-Nitroarginina Metil Éster/farmacología , Animales , Presión Arterial/efectos de los fármacos , Presión Arterial/fisiología , Gasto Cardíaco/fisiología , Circulación Coronaria/efectos de los fármacos , Circulación Coronaria/fisiología , Interacciones Farmacológicas , Inhibidores Enzimáticos/farmacología , Cardiopatías/patología , Cardiopatías/fisiopatología , Pruebas de Función Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Hipertensión/inducido químicamente , Hipertensión/fisiopatología , Masculino , Ratas , Ratas Endogámicas SHR , Factores de Tiempo , Remodelación Ventricular/efectos de los fármacos , Remodelación Ventricular/fisiologíaRESUMEN
The objective of this study was to evaluate the effects of genistein and moderate intensity exercise on Achilles tendon collagen and cross-linking in intact and ovariectomized (OVX) female Sprague-Dawley rats. Rats were separated into eight groups (n = 9/group): intact or OVX, treadmill exercised or sedentary, genistein-treated (300 mg/kg/day) or vehicle. After 6 weeks, tendons were assayed for the collagen-specific amino acid hydroxyproline and hydroxylyslpyridinoline (HP). Collagen content was not influenced by exercise (P = 0.40) but was lower (P < 0.001) in OVX-vehicle rats compared with intact vehicle rats (OVX: 894 ± 35 µg collagen/mg dry weight; intact: 1185 ± 72 µg collagen/mg dry weight). In contrast, collagen content in OVX rats treated with genistein was greater (P = 0.010, 1198 ± 121 µg collagen/mg dry weight) when compared with untreated rats and was not different from intact rats (P = 0.89). HP content was lower in OVX genistein-treated rats when compared with intact genistein-treated rats, but only within the sedentary animals (P = 0.05, intact-treated: 232 ± 39 mmol/mol collagen; OVX-treated: 144 ± 21 mmol/mol collagen). Our findings suggest that ovariectomy leads to a reduction in tendon collagen, which is prevented by genistein. HP content, however, may not have increased in proportion to the addition of collagen. Genistein may be useful for improving tendon collagen content in conditions of estrogen deficiency.
Asunto(s)
Tendón Calcáneo/metabolismo , Colágeno/metabolismo , Genisteína/farmacología , Ovariectomía , Condicionamiento Físico Animal/fisiología , Fitoestrógenos/farmacología , Tendón Calcáneo/efectos de los fármacos , Animales , Colágeno/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Ratas , Ratas Sprague-Dawley , Estadística como AsuntoRESUMEN
AIM: pulmonary hypertension (PH) in the rat leads to right ventricular (RV) hypertrophy, inflammation and increased natriuretic peptide (NP) levels in plasma and RV. Because the release of nitric oxide (NO) and atrial natriuretic peptide (ANP) is a function of the oxytocin receptor (OTR), we examined the effect of PH on gene and protein expression of OTR, NP (A, atrial; B, brain) and receptors (NPRs), nitric oxide synthases (NOS), interleukin (IL)-1ß, IL-6 and tumour necrosis factor-α in the hypertrophied RV in a model of PH. METHODS: RV hypertrophy was induced in male Sprague-Dawley rats with monocrotaline (MCT; 60 mg kg(-1) ) and was confirmed by the presence of an increased RV weight and RV-to-[left ventricle (LV) and septum] ratio. RESULTS: in the RV of MCT-treated rats, a approximately 40% reduction in OTR mRNA and protein was observed compared with the RV of control rats. This reduction was associated with increased transcripts of ANP and BNP in both ventricles and a corresponding increase in NP receptor mRNA expression for receptors A, B and C. Protein expression of inducible NOS was increased in the RV, whereas endothelial NOS transcripts were increased only in the LV of MCT-treated rats. In the RV of MCT-treated rats, downregulation of OTR was also associated with increased mRNA expression of IL-1ß and IL-6. CONCLUSION: our results show that downregulation of the OTR in the RV of MCT-treated rats is associated with increased expression of NP and their receptors as well as IL-1ß and IL-6. This reduction in OTR in RV myocardium may have an impact on cardiac function in the MCT-induced model of PH.
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Ventrículos Cardíacos/metabolismo , Hipertensión Pulmonar/metabolismo , Receptores de Oxitocina/biosíntesis , Animales , Western Blotting , Regulación hacia Abajo , Expresión Génica/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Hipertensión Pulmonar/inducido químicamente , Masculino , Monocrotalina/toxicidad , Oxitocina/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Oxitocina/efectos de los fármacos , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The effects of metabolic states of fasting and post-absorption on plasma concentrations of free carnitine (FC), acylcarnitine (AC) and total carnitine (TC) were compared during submaximal exercise in subjects with type 2 diabetes mellitus. Ten sedentary men (54+/-5 years) treated with oral hypoglycaemic agents were tested on two separate occasions: following an overnight fast and 2 h after a 395-kcal standardised breakfast. Exercise was performed at 60% of [Formula: see text]O(2peak) on a cycle ergometer for 60 min. Blood samples were drawn at rest for baseline values and following 60 min of exercise and 30 min of recovery. Our results show that: (1) baseline levels of TC, FC and AC were similar in fasted and postprandial groups, (2) TC and AC levels were increased during exercise in the fasted group only, (3) FC levels were decreased during exercise in both fasted and postprandial state and (4) the AC/FC ratio increased during exercise in the fasted group. Our results indicate that the metabolic state of the diabetic patient is associated with a different plasma carnitine status. These patterns may reflect differences in energy metabolism associated with fasting and postprandial hyperglycaemia.
Asunto(s)
Carnitina/sangre , Diabetes Mellitus Tipo 2/sangre , Ejercicio Físico/fisiología , Ayuno/fisiología , Consumo de Oxígeno , Periodo Posprandial , Aerobiosis , Índice de Masa Corporal , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/fisiopatología , Ácidos Grasos no Esterificados/sangre , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/sangre , MasculinoRESUMEN
BACKGROUND: Relatively little work has been done on the absorption of trace elements in the mammalian small intestine. Recently, studies have demonstrated that a molybdenum/ascorbic acid complex has shown some promise as a potentially orally administered insulin-mimetic agent. However, the transport mechanism of the molybdenum/ascorbic acid complex is unknown. In this study we examine some aspects of the movement of the complex across the intestinal wall using measurements of elemental molybdenum as an indicator because it is not possible to measure the complex directly. METHODS: Everted rat small intestine sacs were used to determine some aspects of the transport of the complex across the intestine. Intestinal sacs from five rats were incubated in a medium containing 1 g/L of the molybdenum complex. Sacs from a further five rats had 1 mmol/L of 2,4-dinitrophenol, a known inhibitor of oxidative phosphorylation, added to the incubation medium. In a second experiment, everted sacs from five rats were also incubated in media containing one of six concentrations of the molybdenum complex (0.5, 1, 2, 4, 8 or 10 g/L). RESULTS: There was no significant difference between transport rates of groups with or without 2,4-dinitrophenol in the incubation medium, suggesting that the predominant mechanism of molybdenum transport is energy-independent. There was a significant positive, linear increase in the transport rate with increasing concentration of the molybdenum complex. CONCLUSION: These data suggest that the predominant mechanism of this molybdenum/ascorbic acid complex transport in the small intestine is non-saturable and therefore not protein-mediated.
Asunto(s)
Ácido Ascórbico/farmacocinética , Intestino Delgado/metabolismo , Molibdeno/farmacocinética , 2,4-Dinitrofenol/farmacología , Animales , Ácido Ascórbico/química , Transporte Biológico/efectos de los fármacos , Técnicas In Vitro , Masculino , Molibdeno/química , Ratas , Ratas Sprague-Dawley , Desacopladores/farmacología , Vitaminas/química , Vitaminas/farmacocinéticaRESUMEN
The effect of loss of metabolic control, by with-holding insulin treatment, on reperfusion recovery of cardiac function following ischaemia was studied in the spontaneously diabetic "BB" Wor rat. The study involved a group of insulin-treated diabetic BB rats (insulin-treated) and diabetic BB rats in which insulin treatment was withheld 24 h prior to study (insulin-withdrawn). Hearts were isolated and perfused at a constant left atrial filling pressure of 15 cm H(2)O and aortic afterload resistances of 100 and 140 cm H(2)O. Hearts were then subjected to 20 min of ischaemia followed by 30 min of reperfusion. Withdrawing insulin treatment from the BB Wor rat resulted in a dramatic increase in the levels of plasma glucose and free fatty acids. Hearts from these rats perfused under aerobic conditions demonstrated reductions in heart rate, positive and negative dP/dt, cardiac output and left ventricular minute work, whereas diastolic pressure was elevated. Following ischaemia, recovery of cardiac function in the insulin-treated BB Wor rat returned to preischaemic levels, whereas hearts from insulin-withdrawn rats displayed impaired recovery. Throughout reperfusion, heart rate, positive dP/dt, cardiac output and left ventricular minute work remained significantly lower in hearts from insulin-withdrawn rats compared to treated rats. Our results indicate that acute loss of metabolic control increases the sensitivity of the heart to ischaemia, even in the acutely diabetic BB Wor rat.
Asunto(s)
Diabetes Mellitus Tipo 1/fisiopatología , Corazón/fisiopatología , Isquemia Miocárdica/fisiopatología , Animales , Gasto Cardíaco , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diástole , Pruebas de Función Cardíaca , Frecuencia Cardíaca , Hipoglucemiantes/uso terapéutico , Técnicas In Vitro , Insulina/uso terapéutico , Masculino , Daño por Reperfusión Miocárdica/fisiopatología , Ratas , Ratas Endogámicas BB , Reperfusión , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
Clinical and experimental studies have shown that long-term carnitine deficiency is often associated with cardiomyopathy and ischemic failure. The present study was designed to determine whether cardiac dysfunction is seen in an experimental model of short-terrm carnitine deficiency. Carnitine deficiency was induced in Sprague-Dawley rats by supplementing the drinking water with sodium pivalate for a period of 2 weeks. This resulted in a 25% depletion of total myocardial carnitine content. When isolated working hearts from these animals were paced and subjected to increments in left atrial filling pressure, there were no differences in mechanical function compared with control hearts. Following no-flow ischemia, however, recovery of cardiac output and relaxation parameters was depressed in hearts from pivalate-treated animals. Under these conditions, L-carnitine prevented the depressions of function from occurring. Our results show that short-term carnitine deficiency is not associated with cardiac dysfunction under normoxic conditions. However, hearts from pivalate-treated animals are more susceptible to ischemic injury and thus may prove to be useful for the study of metabolic and functional aspects of carnitine deficiency.
Asunto(s)
Carnitina/deficiencia , Corazón/fisiopatología , Isquemia Miocárdica/fisiopatología , Daño por Reperfusión Miocárdica/fisiopatología , Aerobiosis/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Metabolismo Energético/efectos de los fármacos , Masculino , Contracción Miocárdica/efectos de los fármacos , Contracción Miocárdica/fisiología , Isquemia Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Miocardio/metabolismo , Perfusión , Ratas , Ratas Sprague-DawleyRESUMEN
The effects of propionyl-L-carnitine (PLC) on isolated mitochondrial respiration in the ischemic reperfused diabetic heart were studied. Oral PLC treatment of STZ-diabetic rats was initiated for a period of 6 weeks. After treatment, isolated working hearts from diabetic rats were perfused under aerobic conditions then subjected to 25 min of no-flow ischemia followed by 15 min of aerobic reperfusion. At the end of reperfusion, heart mitochondria was isolated using differential centrifugation and respiration measured in the presence of pyruvate, glutamate, and palmitoylcarnitine. Our results indicate that diabetes was characterized by a pronounced decrease in heart function under aerobic conditions as well as during reperfusion following ischemia. Treatment with PLC resulted in a significant improvement in heart function under these conditions. The depressions in state 3 mitochondrial respiration with both pyruvate and glutamate seen in reperfused hearts from diabetic rats were prevented by PLC. State 3 respiration in the presence of palmitoylcarnitine was also improved in the ischemic reperfused diabetic rat heart. Our results show that PLC improves recovery of mechanical function following ischemia in the diabetic rat heart. The beneficial effects of PLC are associated with enhanced mitochondrial oxidation of fuels.
Asunto(s)
Cardiotónicos/farmacología , Carnitina/análogos & derivados , Carnitina/farmacología , Diabetes Mellitus Experimental/metabolismo , Corazón/fisiopatología , Mitocondrias Cardíacas/metabolismo , Reperfusión Miocárdica , Consumo de Oxígeno/efectos de los fármacos , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/fisiopatología , Diástole/efectos de los fármacos , Corazón/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Técnicas In Vitro , Masculino , Mitocondrias Cardíacas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Sístole/efectos de los fármacosRESUMEN
Clinical and experimental data suggest that exercise training (ET) and food restriction (FR) improve cardiovascular function. However, the effects of long-term FR or FR in combination with ET on the recovery of cardiac function following ischemia have not been determined. Male Wistar rats were assigned to ad libitum-fed, FR, ad libitum-exercise, and FR-exercise groups. Mechanical function of isolated working hearts was assessed in response to increases in afterload resistance and following global no-flow ischemia. At low workload, there was a significant FR effect on aortic flow as well as an interaction between FR and ET on systolic pressure. These effects remained when hearts were subjected to increases in aortic afterload resistance. During reperfusion of ischemic hearts, there was a significant FR effect on aortic flow and systolic pressure and a significant ET effect on diastolic pressure. An interaction between FR and ET on heart rate was also seen during reperfusion. In terms of percent recovery of heart function following ischemia, FR continued to affect aortic flow, and we observed an interaction between FR and ET on aortic flow. Our results clearly indicate that the myocardium from the FR animal or the FR, exercise-trained rat is more resistant to ischemia.
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Privación de Alimentos/fisiología , Corazón/fisiología , Isquemia Miocárdica/fisiopatología , Condicionamiento Físico Animal/fisiología , Animales , Hemodinámica , Masculino , Isquemia Miocárdica/rehabilitación , Reperfusión Miocárdica , Ratas , Ratas Wistar , Recuperación de la FunciónRESUMEN
Previous studies have shown that propionyl-L-carnitine (PLC) can exert cardiac antiischemic effects in models of diabetes. In the nonischemic diabetic rat heart, PLC improves ventricular function secondary to stimulation in the oxidation of glucose and palmitate. Whether this increase in the oxidation of these substrates can explain the beneficial effects of PLC in the ischemic reperfused diabetic rat heart has yet to be determined. Diabetes was induced in male Sprague-Dawley rats by an intravenous injection of streptozotocin (60 mg/kg). Treatment was initiated by supplementing the drinking water with propionyl-L-carnitine at the concentration of 1 g/L. After a 6-week treatment period, exogenous substrate oxidation and recovery of mechanical function following ischemia were determined in isolated working hearts. In aerobically perfused diabetic hearts, compared with those of controls, rates of glucose oxidation were lower, but those of palmitate oxidation were similar. Diabetes was also characterized by a pronounced decrease in heart function. Following treatment with by propionyl-L-carnitine, however, there was a marked increase in rates at which glucose and palmitate were oxidized by diabetic hearts and a significant improvement in heart performance. Postischemic recovery of function in diabetic hearts was also improved with PLC. This improvement in contractile function was accompanied by an increase in both glucose and palmitate oxidation. Our findings show that postischemic diabetic rat heart function can be improved following chronic PLC treatment. This beneficial effect of propionyl-L-carnitine can be explained, in part, by an improvement in the oxidation of glucose and palmitate.
Asunto(s)
Cardiotónicos/farmacología , Carnitina/análogos & derivados , Carnitina/farmacología , Diabetes Mellitus Experimental/fisiopatología , Corazón/fisiopatología , Isquemia Miocárdica/fisiopatología , Animales , Diabetes Mellitus Experimental/metabolismo , Glucosa/metabolismo , Corazón/efectos de los fármacos , Masculino , Isquemia Miocárdica/metabolismo , Miocardio/metabolismo , Palmitatos/metabolismo , Ratas , Ratas Sprague-Dawley , Recuperación de la FunciónRESUMEN
Several investigators have reported that carbohydrate metabolism is suppressed in blood vessels from diabetic (Db) rats. However, it is not known if metabolites from the reciprocal increase in oxidation of long-chain fatty acids that accompanies insulin-deficiency exacerbates the suppression of this pathway in the Db blood vessels. Such inhibition may have particularly deleterious consequences in vascular smooth muscle since aerobic glycolysis is believed to preferentially fuel the sarcolemmal Na/K ATPase in this tissue. Therefore, this study evaluated the effect of physiological (0.4 mM) and elevated (1.2 mM) concentrations of the long-chain fatty acid palmitate on both carbohydrate utilization and Na/K-ATPase activity in aorta from insulin-deficient Db rat. Thoracic aorta were removed from 10 week Db (streptozotocin 60 mg/Kg , i.v.) or control (C) rats and intima-media aortic preparations were incubated in the absence or presence of palmitate. Glycolysis (microM/g dry wt/h) and glucose oxidation (microM/g dry wt/h) were quantified using 3H-glucose and 14C-glucose, respectively. Na/K-ATPase activity was estimated by the measurement of 86rubidium uptake in the absence and presence of 2 mM ouabain. In the absence of exogenous palmitate, glycolysis (p < 0.05), glucose oxidation (p < 0.01) and the estimated ATP production from exogenous glucose were decreased in aorta from Db rat. However, despite this diminished rate of glycolysis, Na/K ATPase activity was similar in Db and C aorta. Palmitate (0.4 mM) inhibited Na/K ATPase activity and glucose oxidation to a similar extent in both Db and C but had no effect on glycolysis in either group. Elevation of palmitate to 1.2 mM had no additional inhibitory effect on glucose oxidation, Na/K ATPase activity or glycolysis in either the Db or C aorta. The metabolism of exogenous palmitate restored the ATP production in Db to control values. These data demonstrate that, despite the diminished glycolysis and glucose oxidation demonstrated in the Db tissue, Na/K ATPase activity was comparable in the C and Db aorta, in the absence or presence of exogenous long-chain fatty acid. Therefore, the accelerated oxidation of palmitate in diabetic vascular smooth muscle had no additional inhibitory effect on glycolysis or Na/K ATPase activity. These data suggest that Na/K ATPase activity in vascular smooth muscle is not impaired by the altered pattern of substrate utilization that occurs in insulin-deficient Db rats.
Asunto(s)
Metabolismo de los Hidratos de Carbono , Diabetes Mellitus Experimental/metabolismo , Músculo Liso Vascular/efectos de los fármacos , Ácido Palmítico/farmacología , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/enzimología , Aorta Torácica/metabolismo , Diabetes Mellitus Experimental/enzimología , Técnicas In Vitro , Masculino , Músculo Liso Vascular/enzimología , Músculo Liso Vascular/metabolismo , Oxidación-Reducción , Ratas , Ratas Sprague-Dawley , EstreptozocinaRESUMEN
Whole-body heat stress (HS) in rats leads to the accumulation of myocardial heat shock proteins and subsequent protection against ischemic injury in glucose-perfused hearts. We determined whether HS treatment would confer protection against ischemia in hearts perfused with high levels of fatty acids. In addition, since fatty acids can potentiate ischemic injury by inhibiting glucose metabolism, the effects of HS on glucose utilization were also determined. Anesthetized rats were subjected to whole-body hyperthermia by raising body temperature to 41-42 degrees C 15 min. Twenty four hours later, their hearts were perfused with buffer containing either 11 mM glucose alone or 11 mM glucose and 1.2 mM palmitate, and then subjected to ischemic conditions followed by reperfusion. In hearts perfused with glucose only, HS improved aortic flow (expressed as percent change from preischemic aortic flow) late into the reperfusion period. Rates of overall glucose utilization under these conditions were similar between control and HS hearts. When hearts were perfused with 1.2 mM palmitate, the benefits of HS on aortic flow occurred at the onset of the reperfusion period. This beneficial effect was associated with a significant increase in glucose oxidation. Our results show that HS induces a faster rate of recovery in fatty acid perfused hearts but does not offer more protection against ischemic damage when compared with hearts perfused with glucose as a sole substrate.
Asunto(s)
Glucosa/metabolismo , Corazón/fisiología , Hipertermia Inducida , Isquemia Miocárdica/metabolismo , Miocardio/metabolismo , Animales , Ácidos Grasos/administración & dosificación , Masculino , Reperfusión Miocárdica , Oxidación-Reducción , Ratas , Ratas Sprague-DawleyRESUMEN
This study was designed to determine whether L-propionylcarnitine (LPC) treatment is beneficial in preventing the depression in cardiac function from occurring in chronic diabetes. Diabetes was induced by tail vein injection of streptozotocin (60 mg/kg). Two weeks later, treatment was initiated by supplementing the drinking water with LPC at the concentration of 1 mg/ml. Following a 6-week treatment period, myocardial substrate utilization and cardiac function were determined in isolated working hearts. In a separate group of hearts, the effects of LPC treatment on mitochondrial respiration were also determined. The results showed that diabetic hearts, compared with those of controls, oxidized glucose at a much lower rate, but oxidized palmitate at a similar rate. The effect of diabetes compared a controls was also characterized by a pronounced decrease in cardiac pump function. Following treatment with LPC, however, there was a marked increase in the rates at which glucose and palmitate were oxidized by diabetic hearts, and a significant improvement in cardiac pump performance. In addition, the depression of cardiac mitochondrial respiration seen in diabetes was prevented with LPC treatment. Our findings show that the depression of cardiac pump function by diabetes can be prevented with chronic LPC treatment. Possible mechanisms for this beneficial effect include an energetically favorable shift in glucose and fatty acid metabolism.
Asunto(s)
Cardiotónicos/farmacología , Carnitina/análogos & derivados , Diabetes Mellitus Experimental/metabolismo , Corazón/efectos de los fármacos , Mitocondrias Cardíacas/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Análisis de Varianza , Animales , Fenómenos Biomecánicos , Carnitina/metabolismo , Carnitina/farmacología , Ciclo del Ácido Cítrico/efectos de los fármacos , Masculino , Miocardio/metabolismo , Oxidación-Reducción , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVES: Increasing myocardial carnitine content can improve heart function in patients with carnitine deficiency. We were interested in determining the effects of L-carnitine on cardiac function and substrate metabolism in a rat model of carnitine deficiency. METHODS: Carnitine deficiency was induced in male Sprague-Dawley rats by supplementing the drinking water with 20 mM sodium pivalate. Control animals received an equimolar concentration of sodium bicarbonate. Following treatment, cardiac function and myocardial substrate utilization were determined in isolated working hearts perfused with glucose and relevant levels of fatty acids. To increase tissue levels of carnitine, hearts were perfused with 5 mM L-carnitine for a period of 60 min. RESULTS: Hearts from sodium pivalate-treated animals demonstrated a 60% reduction in total heart carnitine content, depressions in cardiac function and rates of palmitate oxidation, and elevated rates of glycolysis compared to control hearts. Treatment with L-carnitine increased total carnitine content and reversed the depression in cardiac function seen in carnitine-deficient hearts. However, this was not associated with any improvement in palmitate oxidation. Rates of glycolysis and glucose oxidation, on the other hand, were increased with L-carnitine. CONCLUSIONS: Our findings indicate that acute L-carnitine treatment is of benefit to cardiac function in this model of secondary carnitine deficiency by increasing overall glucose utilization rather than normalizing fatty acid metabolism.
Asunto(s)
Carnitina/deficiencia , Ácidos Grasos/metabolismo , Glucosa/metabolismo , Miocardio/metabolismo , Animales , Carnitina/farmacología , Glucólisis , Masculino , Oxidación-Reducción , Ácidos Pentanoicos , Perfusión , Ratas , Ratas Sprague-Dawley , Estimulación QuímicaRESUMEN
Long-term treatment with sodium pivalate, a compound conjugated to carnitine and excreted in the urine, results in carnitine deficiency and cardiac dysfunction. Since L-propionylcarnitine (LPC) is generally of benefit to cardiac function, it was of interest to determine whether it is effective in preventing the reductions in both heart carnitine content and function from occurring in carnitine deficiency. Secondary carnitine deficiency was induced in male Sprague-Dawley rats by supplementing the drinking water with 20 mM sodium pivalate for 26 weeks. Control animals received an equimolar concentration of sodium bicarbonate. At 13 weeks into treatment, a subgroup of control and sodium pivalate animals were given 80 mg/kg of LPC in their drinking water. Following treatment, isolated working hearts were perfused with buffer containing 11 mM glucose and 0.4 mM palmitate. Hearts from sodium pivalate treated animals demonstrated a severe reduction in tissue carnitine. When mechanical function was measured in these hearts, heart rate, rate-pressure product, and aortic flow were significantly depressed. Treatment with LPC, however, prevented the depletion in cardiac carnitine content and improved these cardiac parameters. Our results demonstrate that LPC treatment is beneficial in preventing the depression in cardiac function from occurring in this model of secondary carnitine deficiency.
Asunto(s)
Cardiotónicos/farmacología , Carnitina/análogos & derivados , Carnitina/deficiencia , Carnitina/metabolismo , Corazón/efectos de los fármacos , Miocardio/metabolismo , Animales , Aorta/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Carnitina/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Técnicas In Vitro , Masculino , Ácidos Pentanoicos/farmacología , Perfusión , Ratas , Ratas Sprague-DawleyRESUMEN
Carnitine-deficiency syndromes are often associated with alterations in lipid metabolism and cardiac function. The present study was designed to determine whether this is also seen in an experimental model of carnitine deficiency. Carnitine deficiency was induced in male Sprague-Dawley rats supplemented with sodium pivalate for 26 to 28 weeks. This treatment resulted in nearly a 60% depletion of myocardial total carnitine content as compared with control hearts. When isolated working hearts from these animals were perfused with 5.5 mmol/L glucose and 1.2 mmol/L palmitate and subjected to incremental increases in left-atrial filling pressures, cardiac function remained dramatically depressed. The effects of carnitine deficiency on glucose and palmitate utilization were also assessed in hearts perfused at increased workload conditions. At this workload, function was depressed in carnitine-deficient hearts, as were rates of 1.2-mmol/L [U-14C]-palmitate oxidation, when compared with control hearts (544 +/- 37 vs 882 +/- 87 nmol/g dry weight.min, P < .05). However, glucose oxidation rates from 5.5 mmol/L [U-14C]-glucose were slightly increased in carnitine-deficient hearts. To determine whether the depressed fatty acid oxidation rates were a result of reduced mechanical function in carnitine-deficient hearts, the workload of hearts was reduced. Under these conditions, mechanical function was similar among control and carnitine-deficient hearts. Palmitate oxidation rates were also similar in these hearts (526 +/- 69 v 404 +/- 47 nmol/g dry weight.min for control and carnitine-deficient hearts, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Carnitina/deficiencia , Ácidos Grasos/metabolismo , Corazón/fisiopatología , Adenosina Trifosfato/biosíntesis , Animales , Glucemia/análisis , Carnitina/metabolismo , Ésteres/metabolismo , Glucosa/metabolismo , Lípidos/sangre , Masculino , Miocardio/metabolismo , Oxidación-Reducción , Palmitatos/metabolismo , Ácidos Pentanoicos , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: Stimulation of glucose oxidation by L-carnitine improves mechanical recovery of ischaemic hearts from non-diabetic rats perfused with high levels of fatty acids. The aim of this study was to determine whether L-carnitine also increases glucose oxidation and function in diabetic rat hearts, which have suppressed glucose metabolism. METHODS: Isolated working hearts from six week streptozotocin diabetic and control rats were perfused with 11 mM (5-3H/U-14C)-glucose, 1.2 mM palmitate. Hearts were paced at 260 beats.min-1 during 60 min of low flow ischaemia, and were then subjected to 30 min of aerobic reperfusion. Total myocardial carnitine content in these hearts was first increased by a 60 min aerobic perfusion with 10 mM L-carnitine. RESULTS: Steady state glucose oxidation rates (measured as 14CO2 production) were depressed in diabetic rat hearts compared to control hearts during the initial aerobic period. However, L-carnitine treatment dramatically increased glucose oxidation rates in the diabetic rat hearts, as well as in control hearts. Glycolysis was also lower in diabetic rat hearts compared to control hearts, although L-carnitine treatment significantly increased glycolysis only in the diabetic animals. During reperfusion, steady state rates of glucose oxidation and glycolysis returned to preischaemic values in both the control and diabetic groups. L-carnitine treatment stimulated glucose oxidation during reperfusion in control and diabetic rat hearts. Mechanical function of control hearts returned to 38(SEM 9)% of preischaemic values, whereas in L-carnitine treated hearts function returned to 90(7)% of preischaemic values. Recovery of function was 80(15)% of preischaemic in the diabetic rat hearts, and was increased to 100% of preischaemic function with L-carnitine. CONCLUSIONS: Carnitine improves recovery of function of ischaemic non-diabetic rats by stimulating glucose oxidation during reperfusion, whereas it may be beneficial in diabetic rat hearts by stimulating both glycolysis during ischaemia and glucose oxidation during reperfusion.
Asunto(s)
Carnitina/farmacología , Diabetes Mellitus Experimental/metabolismo , Glucosa/metabolismo , Isquemia Miocárdica/metabolismo , Miocardio/metabolismo , Animales , Diabetes Mellitus Experimental/fisiopatología , Glucólisis/efectos de los fármacos , Corazón/efectos de los fármacos , Corazón/fisiopatología , Técnicas In Vitro , Masculino , Isquemia Miocárdica/fisiopatología , Oxidación-Reducción/efectos de los fármacos , Perfusión , Ratas , Ratas Sprague-DawleyRESUMEN
The contribution of metabolic control to in vivo myocardial contractile function in response to beta 1-adrenergic stimulation was determined in the spontaneously diabetic BB Wor rat. The study involved a group of insulin-dependent BB Wor rats showing marked variations in metabolic control, assessed by the level of glycosylated hemoglobin (gHb). These diabetic BB rats were divided into moderate and severe (%gHb > 14), diabetic groups. A group of Wistar rats and diabetes-resistant BB Wor rats served as controls. In vivo myocardial contractile function was measured under basal conditions and after i.v. dobutamine infusions in anesthetized rats, using a catheter-tip pressure transducer inserted into the left ventricle. No dramatic differences in heart rate with dobutamine stimulation were observed between the moderate, severe diabetic, and diabetes-resistant groups. However, heart rate was lower in Wistar control rats compared with these groups. Systolic left ventricular pressure was depressed in severe diabetic rats compared with Wistar controls. In addition, positive dP/dt was significantly less in the severe diabetic group at the highest doses of stimulation, whereas negative dP/dt was depressed under basal conditions and remained so with increasing doses of dobutamine. In the diabetic group maximal systolic left ventricular pressure, rate-pressure product, and negative dP/dt responses to dobutamine were all inversely correlated with gHb. These results indicate that changes in metabolic control of the insulin-dependent BB diabetic rat can contribute to a depressed myocardial contractile function.
Asunto(s)
Diabetes Mellitus Tipo 1/fisiopatología , Dobutamina/farmacología , Hemoglobina Glucada/metabolismo , Corazón/fisiopatología , Agonistas de Receptores Adrenérgicos alfa 1 , Animales , Glucemia/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Corazón/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Ratas , Ratas Endogámicas BB , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
BACKGROUND: We have previously shown that increasing myocardial carnitine levels in fatty acid-perfused isolated working rat hearts dramatically increases glucose oxidation rates. Since high levels of fatty acids depress reperfusion recovery of ischemic hearts by inhibiting glucose oxidation, we determined what effect carnitine has on glucose oxidation during reperfusion of ischemic hearts. METHODS AND RESULTS: Isolated working rat hearts were perfused with 11 mM [5-3H/ul-14C]glucose, 1.2 mM palmitate, and 100 microU/ml insulin and subjected to a 35-minute period of global ischemia followed by aerobic reperfusion. Rates of glycolysis and glucose oxidation were determined by measuring tritiated water and 14CO2 production, respectively. Before ischemia, myocardial carnitine content was first increased by perfusing hearts during a 60-minute baseline aerobic perfusion with 10 mM L-carnitine. This resulted in a significant increase in total myocardial carnitine from 4,804 +/- 358 to 9,692 +/- 2,090 nmol/g dry wt (mean +/- SD). Glycolysis rates in carnitine-treated hearts were not significantly altered compared with control hearts during the aerobic perfusion (2,482 +/- 1,173 versus 1,840 +/- 1,365 nmol glucose.g dry wt-1 x min-1, respectively). In contrast, glucose oxidation rates in carnitine-treated hearts were significantly increased before ischemia compared with control hearts (471 +/- 209 versus 158 +/- 75 nmol glucose.g dry wt-1 x min-1, respectively). During reperfusion of previously ischemic hearts, glycolytic rates returned to preischemic values in both carnitine-treated and control hearts. Glucose oxidation rates also recovered to preischemic values in these hearts and remained significantly elevated in carnitine-treated hearts compared with control hearts (283 +/- 113 versus 130 +/- 27 nmol glucose.g dry wt-1 x min-1, respectively). Mechanical recovery in control hearts returned to 44% of preischemic values (measured as heart rate-peak systolic pressure product), whereas in carnitine-treated hearts, mechanical recovery returned to 71% of preischemic values. CONCLUSIONS: These results suggest that the beneficial effects of carnitine in the ischemic heart can be explained by the actions of this compound on overcoming fatty acid inhibition of glucose oxidation.