Metabolic changes in dogs during anaphylactic shock.

Hemodynamic and metabolic parameters were studied in conscious dogs during anaphylactic shock. Mean arterial blood pressure and cardiac output decreased and heart rate increased during shock. FFA flux and O₂ consumption decreased significantly shortly after the challenging injection. RQ was elevated indicating a shift in metabolite utilization towards carbohydrates.     

Effect of NO synthase inhibition on myocardial metabolism during moderate ischemia

Nitric oxide (NO) is involved in the control of myocardial metabolism. In normoperfused myocardium, NO synthase inhibition shifts myocardial metabolism from free fatty acid (FFA) toward carbohydrate utilization. Ischemic myocardium is characterized by a similar shift toward preferential carbohydrate utilization, although NO synthesis is increased. The importance of NO for myocardial metabolism during ischemia has not been analyzed in detail. We therefore assessed the influence of NO synthase inhibition with N(G)-nitro-l-arginine (l-NNA) on myocardial metabolism during moderate ischemia in anesthetized pigs. In control animals, the increase in left ventricular pressure with l-NNA was mimicked by aortic constriction. Before ischemia, l-NNA decreased myocardial FFA consumption (MV(FFA); P < 0.05), while consumption of carbohydrate and O(2) (MVo(2)) remained constant. ATP equivalents [calculated with the assumption of complete oxidative substrate decomposition (ATP(eq))] decreased with l-NNA (P < 0.05), associated with a decrease of regional myocardial function (P < 0.05). In contrast, aortic constriction had no effect on MV(FFA), while MVo(2) increased (P < 0.05) and ATP(eq) and regional myocardial function remained constant. During ischemia, alterations in myocardial metabolism were similar in control and l-NNA-treated animals: MV(FFA) decreased (P < 0.05) and net lactate consumption was reversed to net lactate production (P < 0.05). Regional myocardial function was decreased (P < 0.05), although more markedly in animals receiving l-NNA (P < 0.05). We conclude that the efficiency of oxidative metabolism was impaired by l-NNA per se, paralleled by impaired regional myocardial function. During ischemia, l-NNA had no effect on myocardial substrate consumption, indicating that NO synthases were no longer effectively involved in the control of myocardial metabolism.     

Shift in metabolic substrate uptake by the heart during development of alloxan-induced diabetes

Inhibition of endothelial nitric oxide (NO) synthase (eNOS) is associated with an increase in glucose uptake by the heart. We have already shown that Type I diabetes also causes a decrease in eNOS protein expression and altered NO control of both coronary vascular resistance and oxygen consumption. Therefore, we predict that the increase in plasma glucose and the reduction in eNOS during diabetes together would result in a large increase in cardiac glucose uptake. Arterial (A) and coronary sinus (C) plasma levels of glucose, free fatty acid (FFA), beta-hydroxybutyric acid (beta-HBA), and lactate were measured, and myocardial uptake was calculated before and at week 1, 2, 3, and 4 of alloxan-induced diabetes. The heart of healthy dogs consumed FFA (19.2 +/- 2.6 microeq/min) and lactate (19.7 +/- 3.4 micromol/min). Dogs in the late stage of diabetes (at week 4) had elevated arterial beta-HBA concentrations (1.6 +/- 0.7 micromol/l) that were accompanied by an increased beta-HBA uptake (0.3 +/- 0.2 micromol/min). In contrast, myocardial lactate (-4.8 +/- 3.0 micromol/min) and FFA uptake (2.5 +/- 1.9 microeq/min) were significantly reduced in diabetic animals. Despite a marked hyperglycemia (449 +/- 25 mg/dl), the heart did not take up glucose (-7.9 +/- 4.1 mg/dl). Our results indicate significant changes in the myocardial substrate utilization in dogs only in the late stage of diabetes, at a time when myocardial NO production is already decreased.     

Heart rate and myocardial substrate preference during normal and hypoxic perfusion of the heart in vivo.

Selective utilization of carbohydrates and FFA by the heart was studied on the open-chest dog preparation. The heart was paced at frequencies from 120-240/min, and arterial and coronary venous blood samples were taken at these frequencies both during normal ventilation and hypoxia (arterial PO2 similar to 55 mmHg). The concentrations of glucose, lactate, pyruvate, and FFA were determined, and substrate utilization was calculated from these values and coronary blood flow. It was found that increased heart rate, particularly during hypoxia, increased utilization of both glucose and FFA. However, the relative amount of the energy produced from glucose utilization was minimal during hypoxia and most glucose underwent glycolysis only. Thus, whereas in control conditions of the relation between carbohydrate and FFA was about 60% to 40% during hyposia and high frequency the relation was reversed and almost 90% of all energy produced was supplied by FFA.     

Application of tracers in studying free fatty acid metabolism of various organs in vivo.

A few selected examples are given of the application of radio-labeled fatty acids in studying substrate utilization under in vivo conditions. The flux of free fatty acids (FFA) may be calculated by the constant infusion technique of Armstrong et al. using either labeled palmitic or oleic acid. Utilization of FFA by the myocardium is conveniently studied by the constant infusion of 14C-labeled palmitate or oleate. The extraction ratio of these two fatty acids is very similar both in the case of myocardium and of several other tissues investigated. Using this technique not only the removal and oxidation of FFA may be calculated but also competition between the major substrates (FFA, lactate, ketone bodies) can be studied. Arterial FFA concentration, rate of coronary blood flow, and myocardial work are mentioned as some of the important factors influencing the rate of myocardial FFA utilization. The study of skeletal muscle metabolism employing labeled fatty acids is of great importance since release as well as uptake of FFA takes place across most muscle beds and thus net arteriovenous differences may be misleading. A somewhat similar situation also exists in the splanchnic region. Labeled fatty acids have also been utilized to investigate both the oxidation of FFA and their incorporation into brain lipids. Both the uptake and release of FFA may be followed in the adipose tissue by the use of labeled palmitate or oleate.     

Substrate utilization in leg muscle of men after heat acclimation

Eight men were heat acclimated (39.6 degrees C and 29.2% rh) for 8 days to examine changes in substrate utilization. A heat exercise test (HET), (cycling for 60 min; 50% maximal O2 consumption) was performed before (UN-HET) and after (ACC-HET) the acclimation period. Muscle glycogen utilization (67.0 vs. 37.6 mmol/kg wet wt), respiratory exchange ratio (0.85 +/- 0.002 vs. 0.83 +/- 0.001), and calculated rate of carbohydrate oxidation (75.15 +/- 1.38 vs. 64.80 +/- 1.52 g/h) were significantly reduced (P less than 0.05) during the ACC-HET. Significantly lower (P less than 0.05) femoral venous glucose (15, 30, and 45 min) and lactate (15 min) levels were observed during the ACC-HET. No differences were observed in plasma free fatty acid (FFA) and glycerol concentrations or glucose, lactate and glycerol arteriovenous uptake/release between tests. A small but significant increase (P less than 0.05) above resting levels in FFA uptake was observed during the ACC-HET. Leg blood flow was slightly greater (P greater than 0.05) during the ACC-HET (4.64 +/- 0.13 vs. 4.80 +/- 0.13 l/min). These findings indicate a reduced use of muscle glycogen following heat acclimation. However, the decrease is not completely explained by a shift toward greater lipid oxidation or increased blood flow.     

Substrate utilization for lactate and energy production by heat-shocked L929 cells

The hypothesis that heat shock protein (HSP) induction depends on inhibition of respiration was tested by examining the effects of heat shock on tricarboxylic acid (TCA) cycle function. In control L929 cell cultures, glucose and exogenous pyruvate were converted primarily to lactate, and glutamine was extensively oxidized, accounting for more than one-half of the calculated ATP production. During heat shock at 42 degrees C, lactate production from all of the labeled substrates and total unlabeled lactate production increased significantly while oxygen consumption increased slightly. TCA cycle oxidation of pyruvate decreased during this period while that of glutamine increased. Uncoupling of oxidative phosphorylation caused large increases in oxygen consumption at both 37 degrees C and 42 degrees C, indicating that the capacity of the respiratory chain is not exceeded during heat shock. The net effect of these alterations in substrate utilization were decreased ATP generation and increased NADH utilization. Both 14CO2 and lactate production declined during the 24-h period after cultures were returned to 37 degrees C. On the basis of these data, we conclude that while inhibition of respiration plays no apparent role, other metabolic consequences of heat shock related to energy metabolism may be involved in HSP induction.     

Impaired myocardial metabolic reserve and substrate selection flexibility during stress in patients with idiopathic dilated cardiomyopathy

Under resting conditions, the failing heart shifts fuel use toward greater glucose and lower free fatty acid (FFA) oxidation. We hypothesized that chronic metabolic abnormalities in patients with dilated cardiomyopathy (DCM) are associated with the absence of the normal increase in myocardial glucose uptake and maintenance of cardiac mechanical efficiency in response to pacing stress. In 10 DCM patients and 6 control subjects, we measured coronary flow by intravascular ultrasonometry and sampled arterial and coronary sinus blood. Myocardial metabolism was determined at baseline, during atrial pacing at 130 beats/min, and at 15 min of recovery by infusion of [(3)H]oleate and [(13)C]lactate and measurement of transmyocardial arteriovenous differences of oxygen and metabolites. At baseline, DCM patients showed depressed coronary flow, reduced uptake and oxidation of FFA, and preferential utilization of carbohydrates. During pacing, glucose uptake increased by 106% in control subjects but did not change from baseline in DCM patients. Lactate release increased by 122% in DCM patients but not in control subjects. Cardiac mechanical efficiency in DCM patients was not different compared with control subjects at baseline but was 34% lower during stress. Fatty acid uptake and oxidation did not change with pacing in either group. Our results show that in DCM there is preferential utilization of carbohydrates, which is associated with reduced flow and oxygen consumption at rest and an impaired ability to increase glucose uptake during stress. These metabolic abnormalities might contribute to progressive cardiac deterioration and represent a target for therapeutic strategies aimed at modulating cardiac substrate utilization.     

Metabolic disturbances in diabetic cardiomyopathy

It has been established that diabetes results in a cardiomyopathy, and increasing evidence suggests that an altered substrate supply and utilization by cardiac myocytes could be the primary injury in the pathogenesis of this specific heart muscle disease. For example, in diabetes, glucose utilization is insignificant, and energy production is shifted almost exclusively towards -oxidation of free fatty acids (FFA). FFA's are supplied to cardiac cells from two sources: lipolysis of endogenous cardiac triglyceride (TG) stores, or from exogenous sources in the blood (as free acid bound to albumin or as TG in lipoproteins). The approximate contribution of FFA from exogenous or endogenous sources towards -oxidation in the diabetic heart is unknown. In an insulin-deficient state, adipose tissue lipolysis is enhanced, resulting in an elevated circulating FFA. In addition, hydrolysis of the augmented myocardial TG stores could also lead to high tissue FFA. Whatever the source of FFA, their increased utilization may have deleterious effects on myocardial function and includes the abnormally high oxygen requirement during FFA metabolism, the intracellular accumulation of potentially toxic intermediates of FFA, a FFA-induced inhibition of glucose oxidation, and severe morphological changes. Therapies that target these metabolic aberrations in the heart during the early stages of diabetes could potentially delay or impede the progression of more permanent sequelae that could ensue from otherwise uncontrolled derangements in cardiac metabolism.     

Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation

Recent human and animal studies have demonstrated that in severe end-stage heart failure (HF), the cardiac muscle switches to a more fetal metabolic phenotype, characterized by downregulation of free fatty acid (FFA) oxidation and an enhancement of glucose oxidation. The goal of this study was to examine myocardial substrate metabolism in a model of moderate coronary microembolization-induced HF. We hypothesized that during well-compensated HF, FFA oxidation would predominate as opposed to a more fetal metabolic phenotype of greater glucose oxidation. Cardiac substrate uptake and oxidation were measured in normal dogs (n = 8) and in dogs with microembolization-induced HF (n = 18, ejection fraction = 28%) by infusing three isotopic tracers ([9,10-(3)H]oleate, [U-(14)C]glucose, and [1-(13)C]lactate) in anesthetized open-chest animals. There were no differences in myocardial substrate metabolism between the two groups. The total activity of pyruvate dehydrogenase, the key enzyme regulating myocardial pyruvate oxidation (and hence glucose and lactate oxidation) was not affected by HF. We did not observe any difference in the activity of carnitine palmitoyl transferase I (CPT-I) and its sensitivity to inhibition by malonyl-CoA between groups; however, malonyl-CoA content was decreased by 22% with HF, suggesting less in vivo inhibition of CPT-I activity. The differences in malonyl-CoA content cannot be explained by changes in the Michaelis-Menten constant and maximal velocity for malonyl-CoA decarboxylase because neither were affected by HF. These results support the concept that there is no decrease in fatty acid oxidation during compensated HF and that the downregulation of fatty acid oxidation enzymes and the switch to carbohydrate oxidation observed in end-stage HF is only a late-stage phenomenon.     

Comparison of local and systemic effects of insulin on myocardial glucose extraction in ischemic heart disease

Physiological increases in circulating insulin level significantly increase myocardial glucose uptake in vivo. To what extent this represents a direct insulin action on the heart or results indirectly from reduction in circulating concentrations of free fatty acids (FFA) is uncertain. To examine this, we measured myocardial glucose, lactate, and FFA extraction in 10 fasting men (ages 49-76 yr) with stable coronary artery disease during sequential intracoronary (10 mU/min, coronary plasma insulin = 140 +/- 20 microU/ml) and intravenous (100 mU/min, systemic plasma insulin = 168 +/- 26 microU/ml) insulin infusion. Basally, hearts extracted 2 +/- 2% of arterial glucose and extracted 27 +/- 6% of FFA. Coronary insulin infusion increased glucose extraction to 5 +/- 3% (P < 0.01 vs. basal) without changing plasma FFA or heart FFA extraction. Conversion to intravenous infusion lowered plasma FFA by approximately 50% and heart FFA extraction by approximately 75%, increasing heart glucose extraction still further to 8 +/- 3% (P < 0. 01 vs. intracoronary). This suggests the increase in myocardial glucose extraction observed in response to an increment in systemic insulin concentration is mediated equally by a reduction in circulating FFA and by direct insulin action on the heart itself. Coronary insulin infusion increased myocardial lactate extraction as well (from 20 +/- 10% to 29 +/- 9%, P < 0.05), suggesting the local action may include stimulation of a metabolic step distal to glucose transport and glycolysis.     

Effects of adenosine, exercise, and moderate acute hypoxia on energy substrate utilization of human skeletal muscle

Glucose metabolism increases in hypoxia and can be influenced by endogenous adenosine, but the role of adenosine for regulating glucose metabolism at rest or during exercise in hypoxia has not been elucidated in humans. We studied the effects of exogenous adenosine on human skeletal muscle glucose uptake and other blood energy substrates [free fatty acid (FFA) and lactate] by infusing adenosine into the femoral artery in nine healthy young men. The role of endogenous adenosine was studied by intra-arterial adenosine receptor inhibition (aminophylline) during dynamic one-leg knee extension exercise in normoxia and acute hypoxia corresponding to ～3,400 m of altitude. Extraction and release of energy substrates were studied by arterial-to-venous (A-V) blood samples, and total uptake or release was determined by the product of A-V differences and muscle nutritive perfusion measured by positron emission tomography. The results showed that glucose uptake increased from a baseline value of 0.2 ± 0.2 to 2.0 ± 2.2 μmol·100 g(-1)·min(-1) during adenosine infusion (P < 0.05) at rest. Although acute hypoxia enhanced arterial FFA levels, it did not affect muscle substrate utilization at rest. During exercise, glucose uptake was higher (195%) during acute hypoxia compared with normoxia (P = 0.058), and aminophylline had no effect on energy substrate utilization during exercise, despite that arterial FFA levels were increased. In conclusion, exogenous adenosine at rest and acute moderate hypoxia during low-intensity knee-extension exercise increases skeletal muscle glucose uptake, but the increase in hypoxia appears not to be mediated by adenosine.     

Substrate utilization by the inactive leg during one-leg or arm exercise.

Substrate utilization by the nonexercising leg was studied in healthy subjects during one-leg exercise at an average work load of 105 W for 40 min (n equals 8) or during arm exercise at 65 W for 20 min (n equals 5). During one-leg exercise both the blood flow and the A-FV difference of oxygen for the non exercising leg rose, resulting in an approximately five fold increment in oxygen uptake. EMG activity of the leg was increased above basal. Despite unchanged or falling arterial levels of insulin, the A-FV difference for glucose across the nonexercising leg rose during exercise and the estimated glucose uptake increased approximately fourfold. Release of lactate in the basal state reverted to a significant net uptake of lactate by the nonexercising leg. During arm exercise there was a 20-70% rise in leg blood flow and the leg oxygen uptake rose 25-45% in spite of minimal EMG activity from the thigh muscles. There was a large uptake of lactate by the legs during arm exercise. We conclude that several important metabolic alterations take place in the nonexercising leg tissues during physical exertion: 1) blood flow and oxygen uptake rise, partly as a consequence of motor activation; 2) substrate utilization shifts from a predominant FFA uptake in the basal state to a greater utilization of carbohydrate; 3) nonexercising muscle, and possibly adipose tissue, play an important role in the removal of lactate during exercise.     

Impact of low-flow ischemia on substrate oxidation and glycolysis in the isolated perfused rat heart

Interventions that stimulate carbohydrate oxidation appear to be beneficial in the setting of myocardial ischemia or infarction. However, the mechanisms underlying this protective effect have not been defined, in part because of our limited understanding of substrate utilization under ischemic conditions. Therefore, we used (1)H and (13)C NMR spectroscopy to investigate substrate oxidation and glycolytic rates in a global low-flow model of myocardial ischemia. Isolated male Sprague-Dawley rat hearts were perfused for 30 min under conditions of normal flow (control) and low-flow ischemia (LFI, 0.3 ml/min) with insulin and (13)C-labeled lactate, pyruvate, palmitate, and glucose at concentrations representative of the physiological fed state. Despite a approximately 50-fold reduction in substrate delivery and oxygen consumption, oxidation of all exogenous substrates plus glycogen occurred during LFI. Oxidative metabolism accounted for 97% of total calculated ATP production in the control group and approximately 30% in the LFI group. For controls, lactate oxidation was the major source of ATP; however, in LFI, this shifted to a combination of oxidative and nonoxidative glycogen metabolism. Interestingly, in the LFI group, anaplerosis relative to citrate synthase increased sevenfold compared with controls. These results demonstrate the importance of oxidative energy metabolism for ATP production, even during very-low-flow ischemia. We believe that the approach described here will be valuable for future investigations into the underlying mechanisms related to the protective effect of increasing cardiac carbohydrate utilization and may ultimately lead to identification of new therapeutic targets for treatment of myocardial ischemia.     

The PPAR-alpha activator fenofibrate fails to provide myocardial protection in ischemia and reperfusion in pigs

Rodent studies suggest that peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activation reduces myocardial ischemia-reperfusion (I/R) injury and infarct size; however, effects of PPAR-alpha activation in large animal models of myocardial I/R are unknown. We determined whether chronic treatment with the PPAR-alpha activator fenofibrate affects myocardial I/R injury in pigs. Domestic farm pigs were assigned to treatment with fenofibrate 50 mg.kg(-1).day(-1) orally or no drug treatment, and either a low-fat (4% by weight) or a high-fat (20% by weight) diet. After 4 wk, 66 pigs underwent 90 min low-flow regional myocardial ischemia and 120 min reperfusion under anesthetized open-chest conditions, resulting in myocardial stunning. The high-fat group received an infusion of triglyceride emulsion and heparin during this terminal experiment to maintain elevated arterial free fatty acid (FFA) levels. An additional 21 pigs underwent 60 min no-flow ischemia and 180 min reperfusion, resulting in myocardial infarction. Plasma concentration of fenofibric acid was similar to the EC50 for activation of PPAR-alpha in vitro and to maximal concentrations achieved in clinical use. Myocardial expression of PPAR-alpha mRNA was prominent but unaffected by fenofibrate treatment. Fenofibrate increased expression of carnitine palmitoyltransferase (CPT)-I mRNA in liver and decreased arterial FFA and lactate concentrations (each P < 0.01). However, fenofibrate did not affect myocardial CPT-I expression, substrate uptake, lipid accumulation, or contractile function during low-flow I/R in either the low- or high-fat group, nor did it affect myocardial infarct size. Despite expression of PPAR-alpha in porcine myocardium and effects of fenofibrate on systemic metabolism, treatment with this PPAR-alpha activator does not alter myocardial metabolic or contractile responses to I/R in pigs.     

Albiglutide, a long lasting glucagon-like peptide-1 analog, protects the rat heart against ischemia/reperfusion injury: evidence for improving cardiac metabolic efficiency

Background

The cardioprotective effects of glucagon-like peptide-1 (GLP-1) and analogs have been previously reported. We tested the hypothesis that albiglutide, a novel long half-life analog of GLP-1, may protect the heart against I/R injury by increasing carbohydrate utilization and improving cardiac energetic efficiency.

Methods/Principal Findings

Sprague-Dawley rats were treated with albiglutide and subjected to 30 min myocardial ischemia followed by 24 h reperfusion. Left ventricle infarct size, hemodynamics, function and energetics were determined. In addition, cardiac glucose disposal, carbohydrate metabolism and metabolic gene expression were assessed. Albiglutide significantly reduced infarct size and concomitantly improved post-ischemic hemodynamics, cardiac function and energetic parameters. Albiglutide markedly increased both in vivo and ex vivo cardiac glucose uptake while reducing lactate efflux. Analysis of metabolic substrate utilization directly in the heart showed that albiglutide increased the relative carbohydrate versus fat oxidation which in part was due to an increase in both glucose and lactate oxidation. Metabolic gene expression analysis indicated upregulation of key glucose metabolism genes in the non-ischemic myocardium by albiglutide.

Conclusion/Significance

Albiglutide reduced myocardial infarct size and improved cardiac function and energetics following myocardial I/R injury. The observed benefits were associated with enhanced myocardial glucose uptake and a shift toward a more energetically favorable substrate metabolism by increasing both glucose and lactate oxidation. These findings suggest that albiglutide may have direct therapeutic potential for improving cardiac energetics and function.     

Determinants of the variability in respiratory exchange ratio at rest and during exercise in trained athletes

We examined the variability and determinants of the respiratory exchange ratio (RER) at rest and during exercise in 61 trained cyclists. Fasting (10-12 h) RER was measured at rest and during exercise at 25, 50, and 70% of peak power output (W(peak)), during which blood samples were drawn for [lactate] and [free fatty acid] ([FFA]). Before these measurements, training volume, dietary intake and muscle fiber composition, [substrate], and enzyme activities were determined. There was large interindividual variability in resting RER (0.718-0.927) that persisted during exercise of increasing intensity. The major determinants of resting RER included muscle glycogen content, training volume, proportion of type 1 fibers, [FFA] and [lactate], and %dietary fat intake (adjusted r(2) = 0.59, P < 0.001). Except for muscle fiber composition, these variables also predicted RER at 25, 50, and 70% W(peak) to different extents. The key determinant at 25% W(peak) was blood-borne [substrate], at 50% was muscle [substrate] and glycolytic enzyme activities, and at 70% was [lactate]. Resting RER was also a significant determinant of RER at 25 (r = 0.60) and 50% (r = 0.44) W(peak).     

Interaction between glucose utilization and left ventricular heart function in type I-diabetics

The aim of the present study was to check whether equal, therapeutically relevant, positively inotropic doses of different adrenergic agents elicit equal inotropic and metabolic effects in 6 type I-diabetics as in 6 matched nondiabetic subjects. The effects of increasing doses of norepinephrine (NE)- and orciprenaline (0.12, 0.20, 0.33 microgram/kg min) on heart function (systolic time interval, heart rate, blood pressure) and on serum fatty acid (NEFA), glucose, lactate, pyruvate and insulin concentrations were recorded. In the therapeutic dose range, NE, and orciprenaline elicited in diabetics without clinical signs of any cardiovascular disease a diminished myocardial inotropic response (20-40%), less marked vascular effects (vasoconstriction, vasodilatation), but greater metabolic changes in right atrial blood (NEFA, pyruvate, lactate) compared to matched controls (p less than 0.05). The smaller increase of cardiac performance in diabetics to exogenous catecholamines cannot be explained by sympathetic cardiac denervation, since chronotropic beta 1-beta 2-stimulation with orciprenaline provoked nearly equal dose-dependent changes in diabetics and controls. It is suggested that the smaller positive inotropic effect during NE and orciprenaline infusion in type I-diabetics is a result first of all of alterations in myocardial energy turnover in diabetes due to reduced myocardial glucose utilization. It seems necessary to secure continuous myocardial glucose utilization and subnormal NEFA concentrations in the serum during the therapeutic application of inotropic adrenergic agents in severe cardiac failure and cardiogenic shock in diabetics.     

Platelets, lysosomal enzymes and anaphylactic shock in the rat

1. Rat serum levels in beta-glucuronidase and beta-galactosidase are higher than plasma levels. Rat platelets release these lysosomial enzymes during blood coagulation in vitro. 2. After anaphylactic shock, in the sensitized rat, there is no increase in beta-galactosidase and beta-glucuronidase plasma levels. The tissues of the sensitized rat do not release these enzymes during the antigen-antibody reaction. The blood platelet level is diminished after anaphylactic shock and the serum levels of the lysosomial enzymes are decreased. 3. In thrombopenic rat, anaphylactic shock is identical as in control animals. Rat platelets do not play a significant role in the anaphylactic shock.     

Glucagon effect on myocardial transport and utilization of energy-metabolites from the coronary microcirculation in the perfused rabbit heart

Effect of glucagon on energy-metabolite transport into cardiac muscle was studied during a single transit through the isolated rabbit heart using a rapid paired-tracer dilution method. Kinetic experiments revealed that 1.5 microM glucagon stimulated the influx of palmitate bound to 30 g/litre albumin, by increasing the V 2.3 times and increasing the Km for transport 2.4 times. Tracer uptake of D-glucose, as the only exogenous substrate provided, was increased by 80% by 1.5 microM glucagon. Myocardial utilization of [3H]-or [14C]-labelled short-chain monocarboxylic acids (L-lactate, pyruvate and acetate) was significantly reduced by glucagon, to the same degree as their unidirectional sarcolemmal transport. Inhibition of L-[14C]lactate uptake was dose-dependent and in positive correlation with myocardial lactate production. It is concluded that glucagon may regulate sarcolemmal permeability and myocardial utilization for energy-metabolites from the coronary circulation.