RESUMEN
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
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
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
To test the hypothesis that dietary fish oil supplementation decrease systolic blood pressure in hypertensive rats by modifying cardiovascular responsiveness to adrenergic agonists, spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) received either a corn or fish oil diet, 5% (g/kg) for 10 weeks. Mean aortic pressure was lower in fish oil treated (161 +/- 7 mm Hg (1 mmHg = 133.3 Pa)) than corn oil treated (191 +/- 6 mmHg) SHR. Although dietary fish oil supplementation decreased responsiveness to norepinephrine in isolated thoracic aorta from SHR, there was no change in cardiovascular responsiveness to the beta 1 agonist dobutamine or the alpha 1 agonist phenylephrine when these adrenergic agonists were administered in vivo. However, dietary fish oil did decrease the spontaneous basal tone in aorta from both SHR and WKY. This study provides further evidence that dietary fish oil lowers blood pressure in an animal model genetically predisposed to hypertension. However, the mechanism for this decrease in mean aortic pressure in vivo does not appear to be related to modification of cardiovascular responsiveness to alpha 1- or beta 1-adrenergic agonists and may be related to a decrease in basal vasomotor tone.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Agonistas Adrenérgicos beta/farmacología , Sistema Cardiovascular/efectos de los fármacos , Grasas Insaturadas en la Dieta/farmacología , Aceites de Pescado/farmacología , Hipertensión/fisiopatología , Anestesia , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Presión Sanguínea/efectos de los fármacos , Fenómenos Fisiológicos Cardiovasculares , Aceite de Maíz/farmacología , Corazón/efectos de los fármacos , Corazón/fisiología , Hipertensión/tratamiento farmacológico , Masculino , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Contracción Miocárdica/efectos de los fármacos , Norepinefrina/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Receptores Adrenérgicos alfa 1/fisiología , Receptores Adrenérgicos beta 1/efectos de los fármacos , Receptores Adrenérgicos beta 1/fisiología , Estimulación QuímicaRESUMEN
The effect of fish oil on potassium efflux and basal tension in aortas from stroke prone spontaneously hypertensive rats (SHRSP) was evaluated. Four-week-old male Wistar-Kyoto rats (WKY) and SHRSP were divided into two groups: one received a 5% corn oil diet; the other a 5% menhaden oil diet. After 15 weeks, mean systolic blood pressure (mm Hg) was reduced in SHRSP-fish (202 +/- 5) compared to SHRSP-corn (227 +/- 4). Systolic pressure of WKY-fish (146 +/- 3) was not different from WKY-corn (151 +/- 4). Potassium efflux was evaluated with the isotope 86Rb. Basal 86Rb efflux from aorta of SHRSP-corn was evaluated compared to WKY-corn. Diltiazem or sodium nitroprusside decreased 86Rb efflux and basal tension in SHRSP. Basal 86Rb efflux, tension, and the magnitude of this diltiazem- or nitroprusside-induced inhibition were decreased in SHRSP-fish. At maximal diltiazem or nitroprusside concentration, 86Rb efflux from both SHRSP dietary groups was similar but still greater than control aorta. The IC50 values for diltiazem or nitroprusside effects on 86Rb efflux and tension were not altered by diet in SHRSP. Qualitatively similar changes in basal 86Rb efflux and tension were noted in WKY-fish compared to WKY-corn. These experiments demonstrate that dietary fish oil supplementation decreased calcium-sensitive 86Rb efflux and basal tension in vascular smooth muscle and suggest that these changes may contribute to the concomitant antihypertensive effect of dietary fish oil in SHRSP.