James Scheuer

Protective Role of Increased Myocardial Glycogen Stores in Cardiac Anoxia in the Rat

To determine whether increased glycogen stores might protect the heart against anoxia, experiments were performed in the isolated perfused rat heart. Marked differences in cardiac glycogen were produced by comparing hearts from rats previously treated with reserpine with hearts from control rats. Lesser differences in cardiac glycogen were produced in hearts by perfusing them for 15 minutes without glucose (0 mM glucose) or with 20 mM glucose. Both groups were then studied during a 5-minute anoxic cycle with 5 mM glucose as the exogenous substrate. Hearts from the reserpine-treated rats had higher left ventricular pressures, maximal rate of left ventricular pressure rise, and lactate output after 2 minutes of anoxia than the hearts from control rats. Similar but less marked mechanical differences were observed between 0 mM glucose and 20 mM glucose hearts. The mechanical differences during anoxia between the two groups were not abolished by simultaneous L-norepinephrine administration. Hearts with greater initial glycogen stores had higher glycogenolytic rates, and proportionately more lactate was produced from glycogen than from glucose. Thus, anaerobic ATP production per mole of hexose was greater in hearts with higher glycogen stores. Calculated ATP production was also greater in hearts from the reserpine-treated rats than in those from control animals. These studies demonstrate that both marked and minor elevations in cardiac glycogen are associated with greater glycolytic reserve and improved mechanical resistance to anoxia. This appears to be mainly due to enhanced glycogenolysis and anaerobic ATP production.

Myocardial metabolism in cardiac hypoxia

Abstract Cardiac substrate metabolism and energyforming pathways have been outlined, with special emphasis on the metabolic shifts that occur in myocardial hypoxia and ischemia. Metabolic control mechanisms provide a fine balance between utilization and formation of energy, oxygen consumption and intra- and extramitochondrial substrate degradation pathways. The mechanical alterations found in myocardial ischemia have been explained by known metabolic abnormalities in the formation of energy. The use of changes in blood lactate and pyruvate as a measure of myocardial hypoxia has been discussed, and several theoretic objections have been raised. Metabolic and hemodynamic abnormalities found in patients with coronary artery disease have been reviewed, and the potential usefulness of metabolic studies in such patients has been reemphasized.

Splanchnic lactic acid metabolism in hyperventilation, metabolic alkalosis and shock

Abstract Hyperlactatemia was induced in dogs by vigorous hyperventilation, shock or bicarbonate infusion, and blood was sampled from the aorta, hepatic vein and lower inferior vena cava. Hyperventilation with air caused elevated arterial lactate levels, an outpouring of lactate and glucose from the splanchnic bed and lactate uptake by hind-limb tissues. lactic acid extration by the splanchnic tissues began soon after cessation of hyperventilation. Hyperventilation was associated with declines in blood pressure, hepatic blood flow and hepatic vein oxygen tension, and increased hepatic vein lactate:pyruvate ratios. Pharmacologic or hemorrhagic shock also caused release of lactic acid from the splanchnic bed which was reversed during recovery. Bicarbonate infusion caused hyperlactatemia not associated with splanchnic output of lactic acid. Experiments with isolated perfused rat liver demonstrated that alkalotic perfusion or ischemia could stimulate hepatic release of lactate. Pyruvate uptake and increased glucose output occurred only in hypoxia. These experiments indicate that the changes in splanchnic lactic acid and glucose metabolism in hyperventilation and shock are due to hepatic ischemia and suggest that the liver may play a major role in the pathogenesis of lactic acidosis.

Effect of physical training on the mechanical and metabolic response of the rat heart to hypoxia.

To study the effects of physical conditioning on cardiac function and metabolism during hypoxia, rats were conditioned by swimming. Their isolated hearts and hearts of sedentary rats were studied under isovolumic conditions and also while performing external work. During isovolumic performance only minimal improvement in hypoxic cardiac performance was observed because of conditioning. While performing external work during hypoxia cardiac output and cardiac work were approximately twice as great in hearts from conditioned rats as in those from sedentary rats. There were also slightly higher peak systolic pressures and mean left ventricular systolic pressures during hypoxia. Oxygen delivery and lactate production during hypoxia were the same in hearts from conditioned and sedentary rats as were myocardial NADH fluorescence, residual high-energy phosphate stores, and myocardial glycogen levels. External efficiency in experiments on working rat hearts was twice as great during hypoxia in hearts from conditioned rats as in those fromsedentary rats. The data suggest that hearts of conditioned rats have enhanced pumping capacity when subjected to hypoxia compared with hearts of sedentary rats. Oxygen delivery and energy formation during hypoxia are not improved in hearts of conditioned animals. The major reason for improved performance appears to be more efficient energy utilization for external cardiac work.

The effects of uremic compounds on cardiac function and metabolism

Abstract In order to study the effects of some compounds known to be elevated in the uremic syndrome, hearts of normal rats were perfused in an isolated working heart apparatus. High concentrations of urea, creatinine, methyl guanidine, and guanidinosuccinic acid were used alone or in combination. Urea at 20, 10, and 2.5 m m all decreased the cardiac output response to increasing atrial pressure. A combination of urea 20 m m , creatinine 0.88 m m , and guanidinosuccinic acid 0.31 m m caused a depression in coronary flow, cardiac output and maximum left ventricular d P d t . These three agents with methyl guanidine 0.46 m m caused depressions in cardiac output, coronary flow, left ventricular pressure and d P d t , and was associated with a rise in end-diastolic pressure. With these four agents, myocardial oxygen extraction, lactate production and lactate pyruvate ratios were increased. Hearts perfused with methyl guanidine, guanidinosuccinic acid, and creatinine but without urea had the same metabolic and dynamic performance as control hearts. Thus acute exposure to high concentrations of uremic compounds depresses cardiac pumping function in the rat heart. The depressant effect is related to the number of agents present, but is not seen when urea is absent. Depression appears to be partially due to a limitation in oxygen delivery and to the resultant hypoxia.

Effects of High-Energy Phosphate Depletion and Repletion on the Dynamics and Electrocardiogram of Isolated Rat Hearts

To explore the sequence of metabolic, mechanical, and electrocardiographic (ECG) events during myocardial anoxia, isolated rat hearts were paced from the atrium. Anoxic and recovery periods were studied. Adenosine triphosphate (ATP) and creatine phosphate (CP) declined to 50% of control during the first minute and remained at that level for the 5-minute anoxic period. ATP and CP returned to control values after 10 and 20 seconds of recovery. Lactate and potassium efflux from the myocardium closely followed the highenergy phosphate changes. During anoxia, left ventricular systolic pressure increased initially, then fell below the control level after 2 minutes, and recovered within 20 seconds of reoxygenation. In catecholamine-depleted hearts, it fell immediately with anoxia, and recovery was incomplete. The conduction time for the pacing stimulus to reach the ventricle increased with anoxia and decreased with reoxygenation. S-T alterations in the ECG also lagged behind high-energy phosphate reduction and recovery. The study demonstrates that in the isolated heart, ECG evidence of myocardial hypoxia may be absent when high-energy phosphate levels in the myocardium are very low. Mechanical changes are more closely related temporally to high-energy phosphate alterations than are ECG changes. The release of endogenous catecholamines is important to maintain mechanical function in the hypoxic heart.

Experimental observations on the effects of physical training upon intrinsic cardiac physiology and biochemistry

Abstract Hearts of rats conditioned by a moderate swimming program for 8 weeks were compared with hearts of sedentary animals. Hearts of conditioned rats had greater mechanical responses to tachycardia and to increases in preload and afterload, in part because of improved coronary blood flow and oxygen delivery. Energy stores and intermediary metabolism could not account for improved performance of conditioned hearts. Changes in the properties of myocardial contractile proteins with conditioning were characterized by increased adenosine triphosphatase (ATPase) activity and rates of superprecipitation of actomyosin and by alterations in the availability of sulfhydryl groups at the active site of myosin. Hearts of conditioned rats were partially resistant to hypoxia. During hypoxia they converted chemical energy to external work with greater efficiency than hearts of sedentary rats. The studies indicate that a moderate conditioning program in rats improves potential aerobic cardiac performance. Factors in this improvement include increased capacity for coronary flow and oxygen delivery and higher levels of actomyosin and myosin ATPase activity. Conditioning also confers partial resistance to hypoxia, apparently as a result of improved mechanisms of energy utilization.

Early changes in myocardial hypoxia: relations between mechanical function, pH and intracellular compartmental metabolites.

Abstract In order to study the events associated with decreased contractility during decreased oxygen delivery, isolated rat hearts were perfused through the aorta with a bicarbonate buffer containing 5 m m glucose during full oxygenation (95% O2, 5% CO2) and during impaired oxygenation (20% O2, 5% CO2). Mechanical activity and epicardial NADH fluorescence were monitored. Extracellular space was estimated with H3-sorbitol. Intracellular pH was determined by the CO2 method. The reactants of the glutamic dehydrogenase (GDH) and lactate dehydrogenase (LDH) systems were measured in an attempt to calculate changes in the ratios of free cytoplasmic and mitochondrial NAD + NADH . With decreased oxygenation there was a simultaneous decrease in mechanical activity and an increase in fluorescence at 8 s. pH decreased and the lactate/pyruvate ratio increased between 15 and 30 s. The glutamate/α-ketoglutarate-ammonium ratio rose between 1 and 5 min. These studies suggest that in simulated hypoxia: (1) Epicardial NADH fluorescence correlates relatively well with changes in the cytoplasmic free NAD + NADH ratio, but that the mitochondrial system (GDH) may not be sufficiently active to reflect rapid changes in mitochondrial redox state in heart, and (2) a fall in intracellular pH may not be responsible for the earliest mechanical change.

Myocardial Metabolism in Cyanotic Congenital Heart Disease

Eight normal subjects and 7 cyanotic patients, 5 with tetralogy of Fallot, and 2 with Eisenmenger’s syndrome, were studied with coronary sinus catheterization. In the resting state mean coronary flows were lower and myocardial oxygen extractions higher in cyanotic patients so that myocardial oxygen consumption was the same in the 2 groups. Coronary flows appeared to be inversely related to hematocrit in the cyanotic group. Myocardial lactate balance was similar in the 2 groups, but coronary sinus lactate/ pyruvate ratios were frequently higher than arterial ratios in the cyanotic group. The subjects were stressed with supine leg exercise or with an isoproterenol infusion. In cyanotic subjects exercise caused a fall in arterial oxygen and myocardial oxygen extraction so that oxygen delivery tended to be more dependent upon coronary flow. Myocardial oxygen delivery appeared adequate during stress in cyanotic patients and lactate and pyruvate analysis failed to show evidence of myocardial hypoxia. Between the 3rd and 8th min of exercise, cyanotic patients continued to have falling arterial oxygen values and rising arterial lactate and lactate/pyruvate ratios indicating that they had not reached steady metabolic state. Myocardial glucose and free fatty acid uptake were similar in the 2 groups. These results indicate that although the mechanisms of oxygen delivery to the myocardium may differ in normals and some patients with cyanotic congenital heart disease, left ventricular myocardial oxidative metabolism is intact even in the presence of hypoxemia.

The effect of alkalosis upon the mechanical and metabolic response of the rat heart to hypoxia

Abstract In order to study the effects of alkalosis on cardiac function and metabolism during hypoxia, isolated rat hearts were studied in a working rat heart apparatus. Hearts were subjected to hypoxia by perfusing with a bicarbonate buffer equilibrated with 50% oxygen. Respiratory alkalosis (pH 7.8) was caused by lowering the pCO2, and metabolic alkalosis (pH 7.8) by increasing the bicarbonate content of the perfusion medium. During hypoxia metabolic alkalosis was associated with improved left ventricular pressure and rate of pressure rise as compared with hearts perfused at pH 7.4. Improved function continued into the recovery period (95% O2, pH 7.4) in hearts that had been alkalotic during hypoxia. During hypoxia respiratory alkalosis was associated with early protection of pressure and velocity characteristies, but this was not sustained. The major protective effects of respiratory alkalosis were on cardiac output, external cardiac work, and external efficiency. Recovery was not improved by prior respiratory alkalosis. Neither respiratory or metabolic alkalosis during hypoxia were associated with increased oxygen consumption or lactate production. However, the lactate-pyruvate ratio in the effluent medium was lower in both sets of hypoxic alkalotic hearts than in controls. These results suggest that alkalosis does protect cardiac function during hypoxia. The protection does not appear to be due to improved energy delivery, but to enhanced utilization. There appears to be a qualitative difference between the effects of respiratory and metabolic alkalosis on the responses of hypoxic hearts.