Effect of propionyl-L-carnitine on mechanical function of isolated rabbit heart

We studied the acute and chronic effects of propionyl-L-carnitine (PLC) on mechanical function of isolated rabbit heart. Propionyl-L-carnitine was either directly delivered in the perfusate (10^-9 to 10^-3 M) or intraperitoneally injected (250 mg/kg) for 10 days to the animals. When added acutely, propionyl-L-carnitine had no effect on inotropism, heart rate, or coronary perfusion pressure. When added chronically, propionyl-L-carnitine induced a positive inotropic effect, with no changes in heart rate or in coronary perfusion pressure, and it ameliorated the pressure-volume relationship. This effect of propionyl-L-carnitine was independent of the calcium concentration of the perfusion medium, but it was correlated with an increase in the myocardial content of propionyl-L-carnitine. The effect was not apparent after 5 days of treatment, although the tissue content of propionyl-L-carnitine remained unchanged. These data suggest that propionyl-L-carnitine, when given chronically, exerts a positive inotropic effect.     

Effects of human superoxide dismutase on ischemic and reperfused myocardium in isolated perfused rat heart

The effect of human superoxide dismutase (h-SOD) on the ischemic heart was studied in the isolated perfused working rat heart. Myocardial mechanical function expressed as pressure-rate product decreased and completely stopped within 5 min after the onset of global ischemia, and never recovered after reperfusion following 20 min of ischemia. In the ischemic myocardium, the levels of ATP, ADP, and creatine phosphate decreased, and those of AMP and lactate increased. Reperfusion of the ischemic heart did not restore the level of ATP completely. When the heart was treated with h-SOD, the perfusion medium was switched from the buffer containing no h-SOD to that containing h-SOD at either 100, 300 or 1,000 units/ml 5 min before the onset of ischemia. The pressure-rate products of the heart treated with 100, 300, and 1,000 units/ml of h-SOD were restored by reperfusion to 22%, 59%, and 51% of the preischemic level, respectively. The levels of ATP and creatine phosphate in the reperfused heart with 300 and 1,000 units/ml of h-SOD were significantly higher than those without h-SOD. However, a dose-response relationship was not observed when h-SOD was used in concentrations greater than 300 units/ml. These results indicate that a certain amount of h-SOD has some beneficial effects on the ischemic myocardium.     

Effect of iron overload in the isolated ischemic and reperfused rat heart

Summary It has been suggested that iron might play a pivotal role in the development of reperfusion-induced cellular injury through the activation of oxygen free radical producing reactions. The present study examined the effects of myocardial iron overload on cardiac vulnerability to ischemia and reperfusion. Moreover, the effect of the iron chelator deferoxamine in reversing ischemia-reperfusion injury was studied. Animals were treated with iron dextran solution (i.m. injection, 25 mg every third day during a 5 week period). The control group received the same treatment without iron. Isolated rat hearts were perfused at constant flow (11 ml/min) and subjected to a 15 minute period of global normothermic ischemia followed by reperfusion for 15 minutes. The effects of iron overload were investigated using functional and biochemical parameters, as well as ultrastructural characteristics of the ischemic-reperfused myocardium compared with placebo values. The results suggest that (a) a significant iron overload was obtained in plasma and hepatic and cardiac tissues (×2.5, ×16, and ×8, respectively) after chronic intramuscular administration of iron dextran (25 mg); (b) during normoxia, iron overload was associated with a slight reduction in cardiac function and an increase in lactate dehydrogenase (LDH) release (×1.5); (c) upon reperfusion, functional recovery was similar whether the heart had been subjected to iron overload or not. However, in the control group left ventricular end-diastolic pressure remained higher than in preischemic conditions, an effect that was not observed in the iron-overloaded group. Moreover, LDH release was markedly increased in the iron-loaded group (×4.2); (d) iron overload was associated with a significant worsening of the structural alterations observed during reperfusion, particularly at the mitochondrial and sarcomere level; (e) after 15 minutes of reperfusion, the activity of the anti-free-radical enzyme, glutathione peroxidase (GPX), was significantly reduced in ironoverloaded hearts, whereas catalase activity was increased; (e) the overall modifications observed in the presence of iron overload were prevented by deferoxamine. In conclusion, this study underlines the possible role of cardiac iron in the development of injury associated with ischemia and reperfusion, and the possible importance of the use of an iron-chelating agent in antiischemic therapy.     

血管紧张素Ⅱ预处理对体外大鼠缺血再灌注心肌的保护作用

目的 :研究血管紧张素Ⅱ (AngⅡ )预处理是否对缺血 /再灌注 (I/R)心肌有保护作用 ,其作用是否通过蛋白激酶C(proteinkinaseC ,PKC)及线粒体ATP依赖性钾通道 (KATP)而起作用。方法 :4 0只SD大鼠 ,随机分为 5组 (每组各 8只 ) :AngⅡ预处理组 (APC组 )、缬沙坦加AngⅡ预处理组 (VAPC组 )、PKC阻滞剂chelerythine加AngⅡ预处理组 (CLT组 )、线粒体KATP通道阻滞剂 5 Hydroxydecanoate加AngⅡ预处理组 (5 HD组 )和对照组(C组 )。应用Langendorff主动脉逆行灌流的体外大鼠I/R心脏模型 ,观察各组大鼠I/R后心肌细胞乳酸脱氢酶(LDH)及肌酸激酶 (CK)漏出率、心肌组织三磷酸腺苷 (ATP)含量及心功能指标 (LVSP与±dp/dtmax)。结果 :APC组CK、LDH漏出率较C组明显减少 (P <0 .0 1) ,心肌ATP含量较C组增加 (P <0 .0 1) ,心功能 (LVSP与±dp/dtmax)较C组改善。VAPC组、CLT组及 5 HD组上述各指标 (LDH、CK、ATP、LVSP及±dp/dtmax)分别与C组相应的各指标比较差异无统计学意义 (P >0 .0 5 )。结论 :AngⅡ预处理对I/R心肌有保护作用     

Effects of trimetazidine on the calcium transport and oxidative phosphorylation of isolated rat heart mitochondrial

Trimetazidine (TMZ) added in vitro to isolated cardiac mitochondria at concentrations 10–100 M in the presence of 25–100 nM extramitochondrial Ca²⁺ increased Ca²⁺ uptake and matrix Ca²⁺ concentration. This effect was less evident in the presence of physiologically Na⁺ and Mg²⁺ extramitochondrial concentrations since only 100 M TMZ was able to increase mitochondrial Ca²⁺ entry in the presence of 100 nM Ca²⁺. The drug stimulated a Ca²⁺-cooperative effect on mitochondrial Ca²⁺ transport but did not modify the rate of Ca²⁺ egress stimulated by 10 mM NaCl. An increase in mitochondrial Ca²⁺ level produced by TMZ enhanced oxoglutarate dehydrogenase activity and then ATP synthesis, particularly when 50 nM extramitochondrial Ca²⁺ was used. These data suggest that a possible cardiac mechanism of action of TMZ at mitochondrial level could support ATP synthesis by elevating the mitochondrial Ca²⁺ level.     

Effects of tumor-load and malnutrition on myocardial function in the isolated working rat heart

Marked differences in cardiac associated morbidity and mortality have been reported between patients with and without malnutrition. Tumor-associated cachexia may impair heart function, which further aggravate host wasting and thereby create a vicious circle. The aim of this study was to evaluate to what extent a malignant tumor may influence heart function under well-defined experimental conditions. The perfused working rat heart was used as a model. Study groups of freely-fed sarcoma-bearing rats, starved and protein-calorie malnourished (PCM) non-tumor rats were compared to freely-fed control animals. All groups of malnourished animals (tumor-bearing, starved and PCM) lost significant amounts of body and heart mass compared to freely-fed controls. Loss of heart contractile mass in tumor-bearing rats and malnourished animals did not lead to impaired heart function in any respect. The rate of oxygen uptake was significantly higher under all experimental conditions in perfused hearts from tumor-bearing rats compared with hearts from starved, PCM and freely-fed control rats. Oxygen uptake per left ventricular work was significantly higher in tumor-bearing rats but significantly lower in starved and PCM rats compared with control animals. Norepinephrine at various concentrations (10(-9)-10(-5) mol/l) in the perfusate stimulated the contractility and the left ventricular peak pressure significantly more in hearts from malnourished animals compared with that of freely-fed controls. The results show that adaptive functional changes can be recorded in the isolated perfused rat heart from sarcoma-bearing rats and after a period of comparatively acute undernutrition in non-tumor rats. A malignant tumor or the associated malnutrition does not induce impaired pumping performance despite a reduction in contractile heart mass. Increased oxygen consumption in hearts from tumor-bearing animals may contribute to elevated energy expenditure in a cancer-bearing host.     

Insulin treatment and myocardial function in isolated, perfused heart from diabetic rat

Difficulty of some patients to maintain adequate cardiac output following the termination of cardiopulmonary bypass remains a significant problem in cardiac surgery. The patients with diabetes mellitus frequently fail to respond to therapy after the cardiopulmonary bypass. However, little is known about the relationship between the control of diabetes mellitus and myocardial performance. The purpose of the present study was to look at the effect of diabetes and insulin treatment upon ventricular function and myocardial microcirculation in isolated perfused rat heart. Experimental diabetes was induced by injecting streptozotocin and some of them were treated by insulin injection. Severe form of ischemia was induced in heart from acute form of diabetes and functional recovery was compared among the control, diabetic and insulin treated groups. In chronic form of diabetes, myocardial function and microcirculation which was measured by local H2 generation method were studied during aerobic perfusion and mild form of ischemic perfusion. The hearts from experimental diabetes were more susceptible to ischemia and insulin pretreatment protected the functional alterations. This beneficial effect of insulin was associated with improved glucose and fatty acid metabolism. Myocardial microcirculation in hearts from diabetes was significantly less than in control, however, this was not correctable by the insulin treatment.     

Effects of hydrogen peroxide on mitochondrial enzyme function studied in situ in rat heart myocytes

Summary Our previous work indicated that energy transduction, as measured by myocyte respiration, was inhibited by hydrogen peroxide, but the mitochondrial membrane potential was relatively unaffected. Therefore, we determined in the present study the critical steps in mitochondrial energy transduction by measuring the sensitivity to hydrogen peroxide of NADH-CoQ reductase, ATP synthase, and adenine nucleotide translocasein situ in myocytes. Adult rat heart cells were isolated using collagenase and incubated in the presence of 0.1–10 mM hydrogen peroxide for 30 min. Activities of NADH-CoQ reductase and oligomycin-sensitive ATP synthase were assayed enzymatically with sonicated myocytes, and adenine nucleotide translocase activities were determined by atractylosideinhibitable [¹⁴C]ADP uptake of myocytes, permeabilized by saponin. The NADH-CoQ reductase and ATP synthase activities were inhibited to 77% and 67% of control, respectively, following an exposure to 10 mM hydrogen peroxide for 30 min. The adenine nucleotide translocase activities were inhibited in a concentration- and time-dependent manner and by 10 mM hydrogen peroxide to 44% of control. The dose-response relationship indicated that the translocase was the most susceptible to hydrogen peroxide among the three enzymes studied. Combined treatment of myocytes with 3-amino-1,2,4-triazole, 1,3-bis(2-chloroethyl)-1-nitrosourea and diethyl maleate (to inactivate catalase, to inhibit glutathione reductase activity, and to deplete glutathione, respectively) enhanced the sensitivity of translocase to hydrogen peroxide, supporting the view that the cellular defense mechanism is a significant factor in determining the toxicity of hydrogen peroxide. The results indicate that hydrogen peroxide can cause dysfunction in mitochondrial energy transduction, principally as the result of inhibition of adenine nucleotide translocase.     

腺苷对大鼠离体心脏功能及心肌细胞凋亡的影响

目的 探讨腺苷预处理对离体灌流大鼠心脏功能及心肌细胞凋亡的影响.方法 将30只雄性Wistar大鼠随机分为对照组、缺血—再灌注（IR）组、腺苷组,各10只.采用戊巴比妥钠腹腔注射麻醉,同时腹腔注射肝素,麻醉后开胸暴露心脏,快速取出心脏.用Langehdorff离体灌注大鼠心脏K-H液,腺苷组、IR组建立心肌缺血—再灌注损伤模型.对照组灌注时间为120 min;IR组灌注K-H液30min,缺血30 min,K-H液60 min;腺苷组灌注K-H液10 min,给予腺苷20 min,缺血30 min,K-H液60 min.记录实验初始和结束时左室发展压（LVDP）和平均冠脉流量（CSF）,测定心肌组织丙二醛（MDA）含量和超氧化物歧化酶（SOD）活性,TUNEL方法检测细胞凋亡.结果 IR组和腺苷组实验结束时LVDP、CSF低于实验初始（P均＜0.01）;实验结束时腺苷组、对照组的CSF均高于IR组,LVDP水平IR组＜腺苷组＜对照组,P均＜0.05.大鼠心肌组织中MDA水平IR组＞腺苷组＞对照组,P均＜0.01,腺苷组及对照组心肌组织SOD活性高于IR组,P均＜0.01.心肌细胞凋亡率IR组＞腺苷组＞对照组P＜0.01.结论 腺苷预处理能改善离体灌流大鼠心功能,其机制可能与减轻缺血-再灌注损伤和抑制心肌细胞凋亡有关.     

Study on propionyl-L-carnitine in chronic heart failure

Aims In patients with chronic heart failure, fatigue is independentof haemodynamic and neuroendocrine changes and possibly maybe due to impaired muscle metabolism. Propionyl-L-carnitine,a carnitine derivative, was shown in previous studies to improvemuscle metabolism. The objective of this study was to evaluatethe effect of propionyl-L-carnitine on exercise capacity inmild–moderate chronic heart failure patients, treatedwith ACE inhibitors and diuretics. Methods and Results This was a phase III, double-blind, randomized, parallel, multicentrestudy. The primary objective was the evaluation of the effectof propionyl-L-carnitine vs placebo on maximum exercise durationusing a bicycle exercise test. The primary analysis performedin the intention-to-treat population (271 and 266 patients inpropionyl-L-carnitine and placebo), showed no statisticallysignificant difference between treatments. A difference of 15sin favour of propionyl-L-carnitine was observed in the completer/complierpopulation (P=0·092). An a priori specified subgroupanalysis on patients stratified by baseline maximum exerciseduration showed a trend of improvement in propionyl-L-carnitinepatients with shorter maximum exercise duration. A non a priorispecified analysis in patients stratified by ejection fraction(30% vs 30–40%), showed a statistically significant differencein maximum exercise duration in favour of propionyl-L-carnitinein those patients with a higher ejection fraction (40s,P<0·01).There were no safety issues. Conclusion The study fails to meet the primary objective, but confirmsthe good safety profile of propionyl-L-carnitine. An exploratorynon-prespecified analysis suggests that propionyl-L-carnitineimproves exercise capacity in patients with preserved cardiacfunction. This hypothesis needs to be confirmed by a specifictailored study.     

Iron availability and free radical induced injury in the isolated ischaemic/reperfused rat heart.

OBJECTIVE: A proposal that injury in ischaemic/reperfused rat heart is critically dependent on the availability of free iron rather than on the efficiency of O2-. and H2O2 production was examined. METHODS: Isolated working rat hearts from 152 male Wistar rats (200-250 g weight), subjected to 20-40 min of global ischaemia and reperfused for 30 min, were perfused with 10 mumol.litre-1 Fe[III] or Fe[II] and/or 0.6 mmol.litre-1 desferrioxamine, 10 mmol.litre-1 dimethylthiourea, and 1 mmol.litre-1 allopurinol. Curves relating the recoveries of haemodynamic functions and the reperfusion lactate dehydrogenase release to the duration of the preceding ischaemic period were constructed. Morphological examination was also performed. RESULTS: In the untreated hearts, the duration of ischaemia resulting in 50% loss of cardiac output was 29 min. This time was decreased to 24 min and 20 min by Fe[III] and Fe[II], respectively, and was increased to 36 min and 37 min by desferrioxamine and dimethylthiourea, respectively. Desferrioxamine prevented the effect of Fe[III] but not that of Fe[II], whereas dimethylthiourea prevented the effect of Fe[II]. Neither the effect of Fe[III] nor that of Fe[II] was prevented by allopurinol which, however, proved to be beneficial in the untreated hearts. CONCLUSIONS: The beneficial effect of desferrioxamine and dimethylthiourea suggest that it is intensification of the Fenton reaction by iron which accounts for iron induced aggravation of the reperfusion injury. Thus we speculate that the availability of free iron, rather than O2-. and H2O2, is a limiting factor in the development of injury in an ischaemic/reperfused rat heart. What remains unclear is why allopurinol is unable to prevent iron induced changes.     

Effects of diltiazem on anoxic injury in the isolated rat heart

The effect of diltiazem, a calcium channel blocking agent, on anoxic injury was studied in isolated perfused rat hearts. Anoxia for 60 minutes caused a considerable release of creatine kinase and significant cell injury. Reoxygenation of these anoxic hearts for 20 minutes accelerated the creatine kinase release and caused severe cell injury. Reoxygenation of anoxic hearts with diltiazem at a rate of either 2 or 4.5 mg/liter did not reduce creatine kinase release significantly (probability [p] greater than 0.05). However, the higher dosage of diltiazem (4.5 mg/liter during both anoxic and reoxygenation phases resulted in significant (p less than or equal to 0.05) preservation of healthy tissue. The data suggest that diltiazem in the higher concentration prevents cell injury and reduces mitochondrial damage in anoxic injury.     

Effects of chronic sodium depletion on function of isolated normal and hypertensive hypertrophied rat heart

Since in vivo ejection fraction is said to be reduced in chronically sodium depleted dogs, this study was conducted to investigate the direct effects of sodium deprivation on intrinsic ventricular contractility, independent of haemodynamic or adrenergic influences. Since low sodium diet and/or diuretics are commonly used in the treatment of hypertension, we included a hypertensive group in the study. Normotensive male Sprague-Dawley rats and age matched renovascular hypertensive rats were subdivided into three groups. The first group was fed regular sodium diet (RS) for 6 weeks. The second (LS) and third (LSD) groups received low sodium diet for 6 weeks, and the LSD group also received diuretic (frusemide) treatment to achieve marked sodium depletion (last dose given 2 weeks before the cardiac study). Left ventricular (LV) contractility was investigated in the isolated isovolumetric rat heart (Langendorff preparation) paced at 180 beats-min-1. Results showed that LV +dP/dt max at zero LV end diastolic pressure was higher (p less than 0.01) in the LSD group than in the other groups in normotensive rats [2672 (SEM127) mm Hg.s-1 in LSD, 2267(96) in LS, 2174(111) in RS] and higher in LSD (p less than 0.01) and LS (p less than 0.05) groups than in the RS group in hypertensive rats [2332(110) mm Hg.s-1, 2287(93), 1781(104), respectively]. Calculated LV balloon volume at zero LV end diastolic pressure was not significantly different in any dietary group. These results suggested that after 6 weeks of in vivo sodium depletion, in vitro LV contractility was enhanced rather than depressed under these experimental conditions. This enhancement is contrary to the in vivo findings in the dog model and could not be explained by differences in myocardial flow rate, LV chamber stiffness or myocardial stiffness constant. The mechanism of this accentuated ventricular contractility under these experimental conditions remains to be determined.     

尼可地尔在心肌缺血再灌注中的作用

目的：观察非特异性KAT,通道开放剂尼可地尔在心肌缺血再灌注中的作用及效果。方法：建立在体大鼠心脏缺血再灌注模型,将60只大鼠随机分成3组：缺血再灌（IR）组,尼可地尔（NIC）组,空白对照（CON）组。测定各组血清肌酸激酶（CK）,乳酸脱氢酶（LDH）的浓度,应用罗丹明行线粒体染色,观察各组细胞能量代谢的变化。结果：与IR组比较,尼可地尔组血清CK,LDH浓度显著降低（P〈0．05）,N1C组心肌细胞线粒体的跨膜电位（罗丹明线粒体染色）显著升高,即线粒体能量代谢较强（P〈0．05）。结论：尼可地尔在心肌缺血再灌注中能起到一定的保护作用。     

Effects of gliclazide on myocardial protection of isolated type 2 diabetic rat heart afforded by ischemic preconditioning

The myocardial protection afforded by ischemic preconditioning(IPC) can alleviate ischemia-reperfusion injury in normal rat heart.However,this myocardial protection is seldom studied in the type 2 diabetic rat with myocardial ischemia disease.In this study,we aimed to evaluate the effects of ATP-sensitive potassium channels(KATP channels) on IPC in the isolated type 2 diabetic rat heart and the role of the sulfonylurea gliclazide.Methods Streptozotocin(STZ)-induced type 2 diabetic male Wistar rats with or without gliclazide(64 mg /kg body weight,orally) and age-matched non-diabetic control rats were used for all studies.The isolated hearts were perfused with Langendorff’s system under the constant flow,pressure and temperature conditions with Kreb’s-Henseleit solution(K-H).After 5 minutes of balance perfusion,these rats were randomly divided into six groups:non-diabetic control rats without IPC(CIR);non-diabetic control rats with IPC(CIP);diabetic rats without IPC(DIR);diabetic rats with IPC(DIP);gliclazide-treated diabetic rats without IPC(GIR);and gliclazide-treated diabetic rats with IPC(GIP).Groups CIR,DIR,and GIR were subjected to 30-min global ischemia and 60-min reperfusion for induction of ischemia /reperfusion injury.Groups CIP,DIP,and GIP were given three cycles of 5-min ischemia and 5-min reperfusion as IPC,and then ischemia /reperfusion injury program was implemented.Extent of ischemia /reperfusion injury was measured in terms of the release of lactate dehydrogenase(LDH),creatine kinase(CK),and creatin kinase-MB(CKMB) in coronary effluent.After perfusion,Kir6.2 and SUR2A mRNA expressions in the myocardial tissue were characterized by fluorescent quantitative real-time PCR method,and Kir6.2 and SUR2A protein expressions were assessed by immunohistochemistry.Result In non-diabetic control rats,the release of LDH,CK,and CK-MB in coronary effluent markedly decreased with IPC compared with No-IPC(P < 0.05),but not in diabetic rats.However,in gliclazide-treated diabetic rats,IPC-induced decrease in the release of LDH,CK,and CK-MB was restored compared with No-IPC(P < 0.05).The expressions of Kir6.2 both at mRNA and protein levels in CIP were significantly higher than those in CIR.There was no significant difference in the expression of Kir6.2 and SUR2A both at mRNA and protein levels between DIP and DIR.However,the expression of Kir6.2 both at mRNA and protein levels was significantly higher in GIP than in GIR.No significant difference was detected in the mRNA expression level of SUR2A between the six groups.The expression of SUR2A at protein level was significantly higher in CIP than in CIR and in GIP than in GIR.Conclusions The cardioprotective effect of IPC is abolished in the isolated type 2 diabetic rats compared with non-diabetic control rats.However,to some extent,gliclazide can improve the myocardial protection of IPC against ischemia /reperfusion injury,thus suggesting that it is mediated mainly by KATP channels at mRNA or protein level,which provides a basis for further investigating the effects of KATP channels on IPC.     

The effect of calcium antagonists on the activities of lipid metabolizing enzymes in the isolated ischaemically perfused and reperfused rat heart

Isolated rat hearts were perfused with various external Ca2+ concentrations and with various Ca2+ uptake antagonists. Compared to control activities (at 1.2 mM Ca2+), 0.6 mM Ca2+ and Ca2+ antagonists inhibited triglyceride lipase (TGL) and stimulated glycerol 3-phosphate acyltransferase (GPAT). Raising external Ca2+ concentration above the control value had no effect on TGL activity but GPAT activity was greatly reduced. Therefore, it appears that GPAT, but not TGL, will respond to increases in [Ca2+]. During ischaemia the activity of TGL is increased and that of GPAT is inhibited by beta-adrenergic activation. On reperfusion, TGL activity returns to pre-ischaemic values but GPAT activity is further reduced. In this study pre-perfusion of hearts with the Ca2+ antagonist diltiazem (10(-6) M) produced the following effects on enzyme activity during ischaemia and reperfusion: after 10 min ischaemia, TGL activity was increased and GPAT activity decreased to the same extent as seen during ischaemia in control hearts; however, on reperfusion of diltiazem-perfused hearts, the activities of both TGL and GPAT returned to pre-ischaemic values. These results suggest that Ca2+ entry on reperfusion is responsible for the reperfusion-induced decrease in GPAT activity.     

Effects of dichloroacetate on the mechanical function of the isolated ischemic heart

The effects of sodium dichloroacetate (DCA) on the activity of the pyruvate dehydrogenase complex (PDH) and the mechanical function of the isolated ischemic rat heart were investigated. Ischemia was induced by restriction of coronary flow. Perfusion with DCA caused a decrease in the tension developed (DT) and the maximal rate of tension development (+ dT/dt max), and an increase in the resting tension (RT) at low flow rates (0.6 and 0.15 ml/min). However, it did not affect the DT or +dT/dt max of normoxic hearts (3 ml/min) or hearts at zero flow rate. DCA increased PDH activity in hearts at all flow rates. It was concluded that this effect of DCA was associated with a decrease in lactate production, rather than an increase in the lactate/pyruvate ratio.