Cardiac carnitine deficiency and altered carnitine transport in cardiomyopathic hamsters

The Bio 14.6 hamster has a well-documented cardiomyopathy which leads to congestive heart failure. Previous work demonstrated that hearts from these hamsters have depressed fatty acid oxidation and depressed carnitine concentrations compared to those of normal hamsters. Analyses of tissue carnitine concentrations from 40 to 464 days of age demonstrate that the cardiomyopathic hamsters have a cardiac carnitine deficiency throughout life. Therefore, the carnitine deficiency is not a secondary effect of an advanced stage of the cardiomyopathy. Both the observation that other tissues of the cardiomyopathic hamster have normal or markedly elevated carnitine concentrations and the observation that oral carnitine treatment could not increase the cardiac carnitine concentrations to those of normal hamsters are consistent with the hypothesis that the cardiac carnitine deficiency is the result of a defective cardiac transport mechanism. Cardiac carnitine-binding protein (which may function in the cardiac carnitine transport mechanism) prepared from hearts of cardiomyopathic hamsters had a lower maximal carnitine binding and an increased dissociation constant for carnitine compared to the cardiac carnitine-binding protein prepared from normal hamsters. Thus, several types of data indicate that the cardiomyopathic hamster has an altered cardiac carnitine transport mechanism.     

Coenzyme A and carnitine distribution in normal and ischemic hearts.

The distribution of coenzyme A and carnitine between the mitochondrial and cytosolic compartments was determined in rat heart ventricular muscle. The CoA and carnitine levels of homogenate, mitochondrial, and postmitochondrial fractions were determined in nonperfused hearts and in hearts that were perfused under control and ischemic conditions. Using the mitochondrial marker enzymes, citrate synthase and cytochrome c oxidase, the cellular content of mitochondrial protein was determined to be 53 +/- 1.0 (nonperfused), 53.5 +/- 1.5 (control), and 58.1 +/- 2.2 (ischemic) mg/g of wet heart muscle. These values were used to calculate the contribution of the CoA and carnitine located in the mitochondrial compartment to the total cellular levels of CoA and carnitine. Under both control and ischemic conditions, approximately 95% of the cellular CoA was mitochondrial. The percentage of the total cellular carnitine associated with the mitochondria increased from 8 to 9% in nonperfused and control hearts to 25% during ischemia, indicating that a net transfer of carnitine occurred from the cytosol to the mitochondrial matrix.     

Tissue specific depletion of L-carnitine in rat heart and skeletal muscle by D-carnitine

L-carnitine deficiency in heart and skeletal muscle was induced by intraperitoneal injection of D-carnitine into starved or fed rats. Carnitine levels in kidney were slightly lowered, but liver, brain and plasma were unaffected. L-carnitine deficient hearts were unable to maintain normal cardiac function when perfused in an isolated working heart apparatus with palmitate as the only perfused substrate. These findings indicate that tissue levels of carnitine in heart and skeletal muscle are maintained $\text{in vivo}$ by an exchange transport mechanism. It is postulated that the depletion of L-carnitine from these tissues occurs by an exchange of the D- and L-isomer across the cell membrane. The technique may be useful for estimating the levels of carnitine required for fatty acid oxidation and normal cardiac and skeletal muscle function; however, interpretation of such tests may be complicated by the inhibitory effects of the D-isomer upon carnitine transferase enzymes.     

Effects of L-carnitine and its derivatives on postischemic cardiac function,ventricular fibrillation and necrotic and apoptotic cardiomyocyte death in isolated rat hearts

The study aimed to examine whether L-carnitine and its derivatives, acetyl-L-carnitine and propionyl-L-carnitine, were equally effective and able to improve postischemic cardiac function, reduce the incidence of reperfusion-induced ventricular fibrillation, infarct size, and apoptotic cell death in ischemic/reperfused isolated rat hearts. There are several studies indicating that L-carnitine, a naturally occurring amino acid and an essential cofactor, can improve mechanical function and substrate metabolism not only in hypertrophied or failing myocardium but also in ischemic/reperfused hearts. The effects of L-carnitine, acetyl-L-carnitine, and propionyl-L-carnitine, on the recovery of heart function, incidence of reperfusion-induced ventricular fibrillation (VF), infarct size, and apoptotic cell death after 30 min ischemia followed by 120 min reperfusion were studied in isolated working rat hearts. Hearts were perfused with various concentrations of L-carnitine (0.5 and 5 mM), acetyl-L-carnitine (0.5 and 5 mM), and propionyl-L-carnitine (0.05, 0.5, and 5 mM), respectively, for 10 min before the induction of ischemia. Postischemic recovery of CF, AF, and LVDP was significantly improved in all groups perfused with 5 mM of L-carnitine, acetyl-L-carnitine, and propionyl-L-carnitine. Significant postischemic ventricular recovery was noticed in the hearts perfused with 0.5 mM of propionyl-L-carnitine, but not with the same concentration of L-carnitine or L-acetyl carnitine. The incidence of reperfusion VF was reduced from its control value of 90 to 10% (p < 0.05) in hearts perfused with 5 mM of propionyl-L-carnitine only. Other doses of various carnitines failed to reduce the incidence of VF. The protection in CF, AF, LVDP, and VF reflected in a reduction in infarct size and apoptotic cell death in hearts treated with various concentrations of carnitine derivatives. The difference between effectiveness of various carnitines on the recovery of postischemic myocardium may be explained by different membrane permeability properties of carnitine and its derivatives.     

Lack of effect of oral L-carnitine treatment on lipid metabolism and cardiac function in chronically diabetic rats

L-Carnitine is necessary for the transfer of long-chain fatty acids into the mitochondrial matrix where energy production occurs. In the absence of L-carnitine, the accumulation of free fatty acids and related intermediates could produce myocardial subcellular alterations and cardiac dysfunction. Diabetic hearts have a deficiency in the total carnitine pool and develop cardiac dysfunction. This suggested that carnitine therapy may ameliorate alteration in cardiac contractile performance seen during diabetes. In this study, heart function was studied in streptozotocin diabetic rats given L-carnitine orally. Oral L-carnitine treatment (50-250 mg.kg-1.day-1) of 1- and 3-week diabetic rats increased plasma free and total carnitine and decreased plasma acyl carnitine levels. In both groups, myocardial total carnitine levels were increased. However, L-carnitine (200 mg.kg-1.day-1) treatment of diabetic rats for 6 weeks had no effect on plasma carnitine levels. Similarly, plasma lipids remained elevated whereas cardiac function was still depressed. These studies suggest that in the chronically diabetic rat, the route of administration of L-carnitine is an important factor in determining an effect.     

Effects of SM-20550, a selective Na+-H+ exchange inhibitor,on the ion transport of myocardial mitochondria

The study investigated the influence of L-carnitine on the formation of malondialdehyde, an indicator of lipid peroxidation, in isolated Langendorff rat hearts. Earlier investigations of hemodynamic parameters and the recovery of ATP and creatine phosphate, carried out by means of ³¹P-NMR spectroscopy, had demonstrated that, depending on the composition of the perfusates (content of glucose, fatty acids, and carnitine), quite strong differences may occur in the reperfusion period after ischemia.In order to determine a possible relationship between these differences and the addition of carnitine, the study investigated whether carnitine penetrated into the tissue during the experiments, and whether it was able to reduce the concentration of detrimental substances. The concentrations of free and total carnitine as well as the malondialdehyde content as an indicator of ischemia/reperfusion damage were determined in different parts of the cardiac tissue as follows: After the Langendorff-experiments the hearts were dissected, homogenized and reconditioned; then carnitine and malondialdehyde were determined. The study included 63 hearts, which were divided into 8 different perfusion groups.Carnitine concentrations in heart tissue perfused with L-carnitine were much higher than those of the controls. Since exogenous L-carnitine and formed esters could be found in the tissue after the experiment, they must have permeated the cellular membrane rapidly. The concentrations of malondialdehyde behaved in an inverted way; as expected they were lower in carnitine-perfused hearts. The favourable effects of L-carnitine, expressed both by improved cardiac dynamics and ATP and CrP recovery in the reperfusion period, are obviously due to the fact that L-carnitine reduces ischemic damage.     

Role of oxidative stress in alterations of mitochondrial function in ischemic-reperfused hearts

To study the mechanisms of mitochondrial dysfunction due to ischemia-reperfusion (I/R) injury, rat hearts were subjected to 20 or 30 min of global ischemia followed by 30 min of reperfusion. After recording both left ventricular developed pressure (LVDP) and end-diastolic pressure (LVEDP) to monitor the status of cardiac performance, mitochondria from these hearts were isolated to determine respiratory and oxidative phosphorylation activities. Although hearts subjected to 20 min of ischemia failed to generate LVDP and showed a marked increase in LVEDP, no changes in mitochondrial respiration and phosphorylation were observed. Reperfusion of 20-min ischemic hearts depressed mitochondrial function significantly but recovered LVDP completely and lowered the elevated LVEDP. On the other hand, depressed LVDP and elevated LVEDP in 30-min ischemic hearts were associated with depressions in both mitochondrial respiration and oxidative phosphorylation. Reperfusion of 30-min ischemic hearts elevated LVEDP, attenuated LVDP, and decreased mitochondrial state 3 and uncoupled respiration, respiratory control index, ADP-to-O ratio, as well as oxidative phosphorylation rate. Alterations of cardiac performance and mitochondrial function in I/R hearts were attenuated or prevented by pretreatment with oxyradical scavenging mixture (superoxide dismutase and catalase) or antioxidants [N-acetyl-L-cysteine or N-(2-mercaptopropionyl)-glycine]. Furthermore, alterations in cardiac performance and mitochondrial function due to I/R were simulated by an oxyradical-generating system (xanthine plus xanthine oxidase) and an oxidant (H(2)O(2)) either upon perfusing the heart or upon incubation with mitochondria. These results support the view that oxidative stress plays an important role in inducing changes in cardiac performance and mitochondrial function due to I/R.     

Carnitine deficiency-induced cardiomyopathy

The results of clinical and animal studies suggest that a short term period of moderate secondary carnitine deficiency, in and of itself, does not have a major effect on the cardiac contractile function, although substrate oxidation may be altered. However, with longer durations of carnitine deficiency, alterations occur within the heart that may result in impaired contractile performance, particularly at high workloads. At this point, the mechanisms responsible for the cardiac depression are uncertain. We hypothesize that the alterations in substrate metabolism produced by the carnitine deficient state results in inadequate ATP production under high workload conditions which result in impaired cardiac contractile performance. Carnitine deficiency may also induce a number of changes in gene expression of key enzymes required for normal cardiac contractile function and metabolism.     

Dose-response to cytoskeletal-antigen specific immunoliposome therapy for preservation of myocardial viability and function in langendorff instrumented rat hearts

BACKGROUND: Treatment with Cytoskeketal-antigen Specific ImmunoLiposomes (CSIL) has resulted in the preservation of cell and organ viability and function. The current study investigates whether CSIL-intervention is dose-dependent in Langendorff instrumented adult rat hearts undergoing global ischemia. METHOD AND RESULTS: Rat hearts undergoing experimental global ischemic insult for 25 minutes were treated with CSIL, IgG-liposomes (IgG-L), plain-liposomes (PL) or placebo. Infarct sizes were assessed by histochemical staining method and quantitated by computer planimetry. Mean infarct size of CSIL treated globally ischemic rat hearts was about 5 times smaller than that of control hearts (P 相似文献   

Ischemic preconditioning exaggerates cardiac damage in PKC-delta null mice

Ischemic preconditioning confers cardiac protection during subsequent ischemia-reperfusion, in which protein kinase C (PKC) is believed to play an essential role, but controversial data exist concerning the PKC-delta isoform. In an accompanying study (26), we described metabolic changes in PKC-delta knockout mice. We now wanted to explore their effect on early preconditioning. Both PKC-delta(-/-) and PKC-delta(+/+) mice underwent three cycles of 5-min left descending artery occlusion/5-min reperfusion, followed by 30-min occlusion and 2-h reperfusion. Unexpectedly, preconditioning exaggerated ischemia-reperfusion injury in PKC-delta(-/-) mice. Whereas ischemic preconditioning increased superoxide anion production in PKC-delta(+/+) hearts, no increase in reactive oxygen species was observed in PKC-delta(-/-) hearts. Proteomic analysis of preconditioned PKC-delta(+/+) hearts revealed profound changes in enzymes related to energy metabolism, e.g., NADH dehydrogenase and ATP synthase, with partial fragmentation of these mitochondrial enzymes and of the E(2) component of the pyruvate dehydrogenase complex. Interestingly, fragmentation of mitochondrial enzymes was not observed in PKC-delta(-/-) hearts. High-resolution NMR analysis of cardiac metabolites demonstrated a similar rise of phosphocreatine in PKC-delta(+/+) and PKC-delta(-/-) hearts, but the preconditioning-induced increase in phosphocholine, alanine, carnitine, and glycine was restricted to PKC-delta(+/+) hearts, whereas lactate concentrations were higher in PKC-delta(-/-) hearts. Taken together, our results suggest that reactive oxygen species generated during ischemic preconditioning might alter mitochondrial metabolism by oxidizing key mitochondrial enzymes and that metabolic adaptation to preconditioning is impaired in PKC-delta(-/-) hearts.     

Contractility and ischemic response of hearts from transgenic mice with altered sarcolemmal K(ATP) channels

The functional significance of ATP-sensitive K(+) (K(ATP)) channels is controversial. In the present study, transgenic mice expressing a mutant Kir6.2, with reduced ATP sensitivity, were used to examine the role of sarcolemmal K(ATP) in normal cardiac function and after an ischemic or metabolic challenge. We found left ventricular developed pressure (LVDP) was 15-20% higher in hearts from transgenics in the absence of cardiac hypertrophy. beta-Adrenergic stimulation caused a positive inotropic response from nontransgenic hearts that was not observed in transgenic hearts. Decreasing extracellular Ca(2+) decreased LVDP in hearts from nontransgenics but not in those from transgenics. These data suggest an increase in intracellular [Ca(2+)] in transgenic hearts. Additional studies have demonstrated hearts from nontransgenics and transgenics have a similar postischemic LVDP. However, ischemic preconditioning does not improve postischemic recovery in transgenics. Transgenic hearts also demonstrate a poor recovery after metabolic inhibition. These data are consistent with the hypothesis that sarcolemmal K(ATP) channels are required for development of normal myocardial function, and perturbations of K(ATP) channels lead to hearts that respond poorly to ischemic or metabolic challenges.     

Energy metabolism and contractile function of the heart in diabetic cardiomyopathy: effect of ischemia and reperfusion]

Physiological parameters, rates of mitochondrial respiration, high energy phosphate levels and creatine phosphokinase (CPK) activity were investigated in the hearts from control and alloxan-induced diabetic rabbits before and after 40-min total ischemia and reperfusion. Diabetic hearts demonstrated significant decreases in the rates of contraction (+dP/dt) and relaxation (-dP/dt), heart rates and cardiac work compared to control hearts. Determination of mitochondrial respiration rates in saponin-skinned fibers showed a low mitochondrial respiratory function in diabetic hearts. It was found that the ATP and ADP levels and the total and mitochondrial isoenzyme activities of CPK in diabetic hearts were lowered in comparison with control. A post-ischemic recovery of cardiac performance for diabetic hearts was better than in controls. After reperfusion diabetic hearts had increased ATP levels. The data obtained demonstrate some abnormalities of both cardiac performance and energy metabolism in the hearts of diabetic animals and a decreased sensitivity of the latter to ischemic injury.     

Dose-Response to Cytoskeletal-Antigen Specific Immunoliposome Therapy for Preservation of Myocardial Viability and Function in Langendorff Instrumented Rat Hearts

Background: Treatment with Cytoskeketal-antigen Specific ImmunoLiposomes (CSIL) has resulted in the preservation of cell and organ viability and function. The current study investigates whether CSIL-intervention is dose-dependent in Langendorff instrumented adult rat hearts undergoing global ischemia. Method and Results: Rat hearts undergoing experimental global ischemic insult for 25 minutes were treated with CSIL, IgG-liposomes (IgG-L), plain-liposomes (PL) or placebo. Infarct sizes were assessed by histochemical staining method and quantitated by computer planimetry. Mean infarct size of CSIL treated globally ischemic rat hearts was about 5 times smaller than that of control hearts (P ≤ 0.02). Recovery to normal heart function was achieved with CSIL therapy at 1 mg antimyosin antibody dose, where as significant decreases in functional recovery were seen in hearts treated with 0.5 and 0.2 mg antimyosin antibody doses Dose-dependent preservation of cardiac function, and reduction in infarct sizes in CSIL treated hearts were concordant with ultrastructural evidence. Conclusions: Treatment of globally ischemic rat hearts with CSIL results in significant preservation of function and dramatic decrease in acute myocardial infarct size in a dose dependent process.     

The relative contribution of glucose and fatty acids to ATP production in hearts reperfused following ischemia

High levels of fatty acids decrease the extent of mechanical recovery of hearts reperfused following a transient period of severe ischemia. Glucose oxidation rates during reperfusion are low under these conditions, which can result in a decreased recovery of mechanical function. Stimulation of glucose oxidation with the carnitine palmitoyl transferase I inhibitor, Etomoxir, or by directly stimulating pyruvate dehydrogenase activity with dichloroacetate (DCA) results in an improvement in mechanical function during reperfusion of previously ischemic hearts. Addition of DCA (1 mM) to hearts perfused with 11 mM glucose and 1.2 mM palmitate results in an increase in contribution of glucose oxidation to overall ATP production from 6 to 23%, with a parallel decrease in that of fatty acid oxidation from 90 to 69%. In aerobic hearts, endogenous myocardial triglycerides are an important source of fatty acids for -oxidation. Using hearts in which the myocardial triglycerides were pre-labeled, the contribution of both endogenous and exogenous fatty acid oxidation to myocardial ATP production was determined in hearts perfused with 11 mM glucose, 1.2 mM palmitate and 500 µU/ml insulin. In hearts reperfused following a 30 min period of global no flow ischemia, 91.9% of ATP production was derived from endogenous and exogenous fatty acid oxidation, compared to 87.7% in aerobic hearts. This demonstrates that fatty acid oxidation quickly recovers following a transient period of severe ischemia. Furthermore, therapy aimed at overcoming fatty acid inhibition of glucose oxidation during reperfusion of ischemic hearts appears to be beneficial to recovery of mechanical function.     

Defective sarcolemmal phospholipase C signaling in diabetic cardiomyopathy

Phospholipase C (PLC) activity is known to influence cardiac function. This study was undertaken to examine the status of PLC beta3 in the cardiac cell plasma membrane (sarcolemma, SL) in an experimental model of chronic diabetes. SL membrane was isolated from diabetic rat hearts at 8 weeks after a single i.v. injection of streptozotocin (65 mg/kg body weight). The total SL PLC was decreased in diabetes and was associated with a decrease in SL PLC beta3 activity, which immunofluorescence in frozen diabetic left ventricular tissue sections revealed to be due to a decrease in PLC beta3 protein abundance. In contrast, the SL abundance of Gqalpha was significantly increased during diabetes. These changes were associated with a loss of contractile function (+/- dP/dt). A 2-week insulin treatment of 6-week diabetic animals partially normalized all of these parameters. These findings suggest a defect in PLC beta3-mediated signaling processes may contribute to the cardiac dysfunction seen during diabetes.     

Lack of both oxygen and glucose contributes to I/R-induced changes in cardiac SR function

Although ischemia-reperfusion(I/R) has been shown to depress cardiac performance and sarcoplasmicreticulum (SR) function, the mechanisms underlying these alterationsare poorly understood. Because lack of oxygen and substrate deprivationare known to occur during the ischemic phase, we examined theeffects of reperfusion on cardiac performance and SR function in heartssubjected to hypoxia and substrate lack. For this purpose, isolated rathearts were perfused with hypoxic and/or glucose-free medium for 30 min and then reperfused with normal medium for 1 h; the SR vesicles were isolated for studying the Ca²⁺-transport activities.Reperfusion with normal medium of hearts deprived of oxygen or glucoseshowed no changes in cardiac performance and SR function. However,reperfusion of hearts perfused with hypoxic glucose-free medium showed~45% decrease in cardiac contractile activities as well as 23 and64% reduction in SR Ca²⁺-uptake andCa²⁺-release activities, respectively, without any changein the level of SR Ca²⁺-cycling proteins. Depressed SRfunction in these hearts was associated with a reduction inCa²⁺/calmodulin-dependent protein kinase (CaMK)phosphorylation of the SR Ca²⁺-cycling proteins and 34%decrease in SR CaMK activity. These changes in cardiac performance, SRfunction, and SR CaMK activity in the hypoxic, glucose-deprived,reperfused hearts were similar to those observed in hearts subjected to30 min of global ischemia and 60 min of reperfusion. Theresults therefore suggest that the lack of both oxygen and substrateduring the ischemic phase may contribute to the I/R-inducedalterations in cardiac performance and SR function. Furthermore, theseabnormalities were associated with reduced SR CaMK activity.

     

Attenuation of extracellular ATP response in cardiomyocytes isolated from hearts subjected to ischemia-reperfusion

Extracellular ATP is known to augment cardiac contractility by increasing intracellular Ca2+ concentration ([Ca2+]i) in cardiomyocytes; however, the status of ATP-mediated Ca2+ mobilization in hearts undergoing ischemia-reperfusion (I/R) has not been examined previously. In this study, therefore, isolated rat hearts were subjected to 10-30 min of global ischemia and 30 min of reperfusion, and the effect of extracellular ATP on [Ca2+]i was measured in purified cardiomyocytes by fura-2 microfluorometry. Reperfusion for 30 min of 20-min ischemic hearts, unlike 10-min ischemic hearts, revealed a partial depression in cardiac function and ATP-induced increase in [Ca2+]i; no changes in basal [Ca2+]i were evident in 10- or 20-min I/R preparations. On the other hand, reperfusion of 30-min ischemic hearts for 5, 15, or 30 min showed a marked depression in both cardiac function and ATP-induced increase in [Ca2+]i and a dramatic increase in basal [Ca2+]i. The positive inotropic effect of extracellular ATP was attenuated, and the maximal binding characteristics of 35S-labeled adenosine 5'-[gamma-thio]triphosphate with crude membranes from hearts undergoing I/R was decreased. ATP-induced increase in [Ca2+]i in cardiomyocytes was depressed by verapamil and Cibacron Blue in both control and I/R hearts; however, this response in I/R hearts, unlike control hearts, was not affected by ryanodine. I/R-induced alterations in cardiac function and ATP-induced increase in [Ca2+]i were attenuated by treatment with an antioxidant mixture and by ischemic preconditioning. The observed changes due to I/R were simulated in hearts perfused with H2O2. The results suggest an impairment of extracellular ATP-induced Ca2+ mobilization in I/R hearts, and this defect appears to be mediated through oxidative stress.     

STAT subtype specificity and ischemic preconditioning in mice: is STAT-3 enough?

The role of other STAT subtypes in conferring ischemic tolerance is unclear. We hypothesized that in STAT-3 deletion alternative STAT subtypes would protect myocardial function against ischemia-reperfusion injury. Wild-type (WT) male C57BL/6 mice or mice with cardiomyocyte STAT-3 knockout (KO) underwent baseline echocardiography. Langendorff-perfused hearts underwent ischemic preconditioning (IPC) or no IPC before ischemia-reperfusion. Following ex vivo perfusion, hearts were analyzed for STAT-5 and -6 phosphorylation by Western blot analysis of nuclear fractions. Echocardiography and postequilibration cardiac performance revealed no differences in cardiac function between WT and KO hearts. Phosphorylated STAT-5 and -6 expression was similar in WT and KO hearts before perfusion. Contractile function in WT and KO hearts was significantly impaired following ischemia-reperfusion in the absence of IPC. In WT hearts, IPC significantly improved the recovery of the maximum first derivative of developed pressure (+dP/dtmax) compared with that in hearts without IPC. IPC more effectively improved end-reperfusion dP/dtmax in WT hearts compared with KO hearts. Preconditioned and nonpreconditioned KO hearts exhibited increased phosphorylated STAT-5 and -6 expression compared with WT hearts. The increased subtype activation did not improve the efficacy of IPC in KO hearts. In conclusion, baseline cardiac performance is preserved in hearts with cardiac-restricted STAT-3 deletion. STAT-3 deletion attenuates preconditioning and is not associated with a compensatory upregulation of STAT-5 and -6 subtypes. The activation of STAT-5 and -6 in KO hearts following ischemic challenge does not provide functional compensation for the loss of STAT-3. JAK-STAT signaling via STAT-3 is essential for effective IPC.     

Alterations of heart function and Na+-K+-ATPase activity by etomoxir in diabetic rats.

To examine the role of changes in myocardial metabolism in cardiac dysfunction in diabetes mellitus, rats were injected with streptozotocin (65 mg/kg body wt) to induce diabetes and were treated 2 wk later with the carnitine palmitoyltransferase inhibitor (carnitine palmitoyltransferase I) etomoxir (8 mg/kg body wt) for 4 wk. Untreated diabetic rats exhibited a reduction in heart rate, left ventricular systolic pressure, and positive and negative rate of pressure development and an increase in end-diastolic pressure. The sarcolemmal Na+-K+-ATPase activity was depressed and was associated with a decrease in maximal density of binding sites (Bmax) value for high-affinity sites for [3H]ouabain, whereas Bmax for low-affinity sites was unaffected. Treatment of diabetic animals with etomoxir partially reversed the depressed cardiac function with the exception of heart rate. The high serum triglyceride and free fatty acid levels were reduced, whereas the levels of glucose, insulin, and 3,3',-5-triiodo-L-thyronine were not affected by etomoxir in diabetic animals. The activity of Na+-K+-ATPase expressed per gram heart weight, but not per milligram sarcolemmal protein, was increased by etomoxir in diabetic animals. Furthermore, Bmax (per g heart wt) for both low-affinity and high-affinity binding sites in control and diabetic animals was increased by etomoxir treatment. Etomoxir treatment also increased the depressed left ventricular weight of diabetic rats and appeared to increase the density of the sarcolemma and transverse tubular system to normalize Na+-K+-ATPase activity. Therefore, a shift in myocardial substrate utilization may represent an important signal for improving the depressed cardiac function and Na+-K+-ATPase activity in diabetic rat hearts with impaired glucose utilization.     

Observation of the in situ contracting heart of guinea pigs infected with Pichinde virus

The in situ beating hearts from anesthetized control and Pichinde virus-infected strain 13 guinea pigs, between days 7 and 19 postinoculation, were directly observed and video recorded. Although some hearts from Pichinde virus-infected animals were visually depressed and had altered contraction patterns, such a pronounced cardiac dysfunction was not associated with any marked histopathological changes in the cardiac tissue. The manifestations of cardiac dysfunction were limited mainly to the right side of the heart and occurred only from days 11 to 19 postinoculation. We suggest that certain biochemical "lesions" in the heart after lethal Pichinde virus infection may be present, which may have been caused by the actions of endogenous pathogenic mediators and an overall metabolic deficiency of the infected body.