Lipoate ameliorates ischemia-reperfusion in animal modelsFreisleben HJ. Faculty of Medicine, University of Indonesia, Jakarta. firstname.lastname@example.org
Ischemia and reperfusion were studied in isolated working rat hearts and in exarticulated rat hind limbs. Free radicals are known to be generated in ischemia/reperfusion and to propagate complications. To reduce reperfusion injury, conditions were ameliorated including the treatment with antioxidants, lipoate or dihydrolipoate. In isolated working rat hearts, cardiac and mitochondrial parameters are impaired during hypoxia and partially recover in reperfusion. Dihydrolipoate, if added into the perfusion buffer at 0.3 microM concentration, keeps the pH higher (7.15) during hypoxia, as compared to controls (6.98). This compound accelerates and stabilizes the recovery of the aortic flow. With dihydrolipoate, ATP synthesis is increased, ATPase activity (ATP hydrolysis) reduced, intracellular creatine kinase activity maintained and thus phosphocreatine contents are higher than in controls. For exarticulated rat hind limbs, the dihydrolipoate group contained 8.3 microM in the modified reperfusate. Recovery of the contractile function was 49% vs. 34% in controls and muscle flexibility was maintained whereas it decreased by 15% in the controls. Release of creatine kinase from cells was significantly lower with dihydrolipoate. Lipoate/dihydrolipoate effectively reduced reperfusion injury in isolated working rat hearts and in exarticulated rat hind limbs after extended ischemia. Finally, the compound was successfully applied in an in vivo pig hind limb model.
The influence of thioctic acid on metabolism and function of the diabetic heartStrodter D, Lehmann E, Lehmann U, Tritschler HJ, Bretzel RG, Federlin K. Medical Clinic III, University of Giessen, Germany.
Streptozotocin-diabetes as a model for insulin-deficient Type 1 diabetes leads to cardiomyopathy, characterized by a 50% reduced glucose uptake (P < 0.001) and increased lactate and pyruvate levels (P < 0.001), i.e. a reduced glucose utilization by the heart. As thioctic acid (TA) has favourable effects on glucose metabolism, the influence of this drug at two different doses (0.1 mg/ml and 0.5 mg/ml, added to the perfusion medium) was investigated in the heart after 2 weeks of diabetes, using the working rat heart model at physiological workload about 45 min. TA at high doses led to a normalization of glucose uptake (P < 0.001) and glucose utilization, and consequently to a normalization of oxygen uptake (P < 0.001), myocardial ATP levels (P < 0.001) as well as cardiac output (P < 0.05). Whereas a low dose of TA resulted in a normalization of lactate and pyruvate production (P < 0.001), neither a normalization of glucose utilization nor of cardiac output was achieved by this low dosage. Additionally, TA improved at both doses utilization of endogenous glycogen in the diabetic heart (P < 0.001), the latter here already delivering 45% of the utilized glucose. TA acts especially by increasing glucose uptake, glycogen breakdown and glucose oxidation. Thus, metabolic and hemodynamic sequelae of insulin-deficiency in the heart can be corrected by TA. Due to its anti-diabetic effects on cardiac metabolism, TA could be considered an adjuvant therapy in diabetic cardiomyopathy.
Lipoic acid reduces ischemia-reperfusion injury in animal modelsFreisleben HJ. Faculty of Medicine, University of Indonesia, Pascasarjana-Fakultas Kedokteran, Salemba Raya No. 4, Jakarta 10430, Indonesia.
Hypoxia and reoxygenation were studied in rat hearts and ischemia and reperfusion in rat hindlimbs. Free radicals are known to be generated through these events and to propagate complications. In order to reduce hypoxic/ischemic and especially reoxygenation/reperfusion injury the (re)perfusion conditions were ameliorated including the treatment with antioxidants (lipoate or dihydrolipoate). In isolated working rat hearts cardiac and mitochondrial parameters are impaired during hypoxia and partially recover in reoxygenation. Dihydrolipoate, if added into the perfusion buffer at 0.3 microM concentration, keeps the pH higher (7. 15) during hypoxia as compared to controls (6.98). The compound accelerates the recovery of the aortic flow and stabilizes it during reoxygenation. With dihydrolipoate, ATPase activity is reduced, ATP synthesis is increased and phosphocreatine contents are higher than in controls. Creatine kinase activity is maintained during reoxygenation in the dihydrolipoate series. Isolated rat hindlimbs were stored for 4 h in a moist chamber at 18 degrees C. Controls were perfused for 30 min with a modified Krebs-Henseleit buffer at 60 mmHg followed by 30 min Krebs-Henseleit perfusion at 100 mmHg. The dihydrolipoate group contained 8.3 microM in the modified reperfusate (controlled reperfusion). With dihydrolipoate, recovery of the contractile function was 49% (vs. 34% in controls) and muscle flexibility was maintained whereas it decreased by 15% in the controls. Release of creatine kinase was significantly lower with dihydrolipoate treatment. Dihydrolipoate effectively reduces reoxygenation injury in isolated working rat hearts. Controlled reperfusion, including lipoate, prevents reperfusion syndrome after extended ischemia in exarticulated rat hindlimbs and in an in vivo pig hindlimbs model.
Effect of alpha-lipoic acid and dihydrolipoic acid on ischemia/reperfusion injury of the heart and heart mitochondriaSchonheit K, Gille L, Nohl H. Institute of Pharmacology and Toxicology, Veterinary University of Vienna, Austria.
The aim of the present study was to evaluate a possible interference of alpha-lipoic acid (LA) or its reduced form (dithiol dihydrolipoic acid = DHLA) in the cardiac ischemia/reperfusion injury both at the level of the intact organ and at the subcellular level of mitochondria. In order to follow the effect of LA on the ischemia/reperfusion injury of the heart the isolated perfused organ was subjected to total global ischemia and reperfusion in the presence and absence of different concentrations of LA. Treatment with 0.5 microM LA improved the recovery of hemodynamic parameters; electrophysiological parameters were not influenced. However, application of 10 microM LA to rat hearts further impaired the recovery of hemodynamic functions and prolonged the duration of severe rhythm disturbances in comparison to reperfusion of control hearts. Treatment of isolated mitochondria with any concentration of DHLA could not prevent the impairment of respiratory-linked energy conservation caused by the exposure of mitochondria to 'reperfusion' conditions. However, DHLA was effective in decreasing the formation and the existence of mitochondrial superoxide radicals (O2.-). Apart from its direct O(2.-)-scavenging activities DHLA was also found to control mitochondrial O2.- formation indirectly by regulating redox-cycling ubiquinone. It is suggested that impairment of this mitochondrial O2.- generator mitigates postischemic oxidative stress which in turn reduces damage to hemodynamic heart function.
Effects of lipoic acid on reperfusion induced arrhythmias and myocardiac action potential alterations induced by free radical generating systemGao TL, Huang YZ. Department of Biology, Beijing University.
By means of Langendorff method the isolated rat heart was perfused with Krebs Henseleit solution. Following ligation of the left descending coronary artery for 10 min the heart was reperfused for 3 min. The incidence of ventricular fibrillation in the reperfusion period was 100%, and the normal sinus rhythm time was shortened to 29 s within 3 min of reperfusion. Administration of lipoic acid (6.8 X 10(-6)-1.7 X 10(-4) mol/L) to the perfusate significantly reduced the incidence of ventricular fibrillation to 33-50% and prolonged the normal sinus rhythm time to 97-107 s. APA, RP, and Vmax recorded from the guinea pig papillary muscle were depressed due to the deleterious effect of xanthine oxidase and hypoxanthine free radical generating system. Under the treatment of lipoic acid (3.5 X 10(-5) mol/L), the depression of APA, RP, and Vmax were significantly relieved. This confirms that lipoic acid treatment, owing to its free radical scavenger effect, is able to protect myocardium from free radical induced electrophysiological abnormalities, and consequently decrease the incidence of malignant arrhythmias.
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