Tissue oxygenation and muscular substrate turnover in two subjects with high hemoglobin oxygen affinity.

Oxygen transport to and substrate turnover in leg muscle were studied at rest and during light and heavy upright bicycle exercise in two brothers with a hereditary hemoglobinopathy associated with high oxygen affinity (P50 = 13 mmHg). Femoral venous oxygen tension was below normal and femoral venous oxygen saturation above normal at rest and during exercise. Thus, the arterial-femoral venous oxygen saturation difference was decreased. Despite a compensatory increase in hemoglobin concentration, the arterial-femoral venous oxygen content difference tended to be below normal at heavy exercise. Approximately 25% of the oxygen was delivered via the abnormal hemoglobin at relative heavy exercise. Arterial lactate levels, lactate release, and muscle lactate concentration were not increased at any level of exercise. Glucose, alanine, pyruvate, and glycerol turnover were essentially normal, but the glycogen and creatine phosphate stores were abnormally depleted at the termination of heavy exercise. The exercise electrocardiogram (ECG) was normal, indicating that myocardial oxygenation was adequate. Muscle-surface oxygen pressure fields were normal at rest (not investigated during exercise). It is concluded that the high oxygen affinity of the hemoglobin in our two subjects did not lead to heart or skeletal muscle hypoxia during heavy exercise, as judged from the ECG and from the leg lactate turnover. Despite the lack of evidence for muscle hypoxia, the subjects experienced leg muscle fatigue and the creatine phosphate and glycogen stores were depleted more than normally.

Glucose metabolism during leg exercise in man.

Arterial concentrations and net substrate exchange across the leg and splanchnic vascular bed were determined for glucose, lactate, pyruvate, and glycerol in healthy postabsorptive subjects at rest and during 40 min of exercise on a bicycle ergometer at work intensities of 400, 800, and 1200 kg-m/min. Rising arterial glucose levels and small decreases in plasma insulin concentrations were found during heavy exercise. Significant arterial-femoral venous differences for glucose were demonstrated both at rest and during exercise, their magnitude increasing with work intensity as well as duration of the exercise performed. Estimated glucose uptake by the leg increased 7-fold after 40 min of light exercise and 10- to 20-fold at moderate to heavy exercise. Blood glucose uptake could at this time account for 28-37% of total substrate oxidation by leg muscle and 75-89% of the estimated carbohydrate oxidation. Splanchnic glucose production increased progressively during exercise reaching levels 3 to 5-fold above resting values at the heavy work loads. Close agreement was observed between estimates of total glucose turnover during exercise based on leg glucose uptake and splanchnic glucose production. Hepatic gluconeogenesis-estimated from splanchnic removal of lactate, pyruvate, glycerol, and glycogenic amino acids-could supply a maximum of 25% of the resting hepatic glucose production but could account for only 6-11% of splanchnic glucose production after 40 min of moderate to heavy exercise. IT IS CONCLUDED THAT: (a) blood glucose becomes an increasingly important substrate for muscle oxidation during prolonged exercise of this type: (b) peripheral glucose utilization increases in exercise despite a reduction in circulating insulin levels: (c) increased hepatic output of glucose, primarily by means of augmented glycogenolysis, contributes to blood glucose homeostasis in exercise and provides an important source of substrate for exercising muscle.

Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect.

We evaluated a 22-yr-old Swedish man with lifelong exercise intolerance marked by premature exertional muscle fatigue, dyspnea, and cardiac palpitations with superimposed episodes lasting days to weeks of increased muscle fatigability and weakness associated with painful muscle swelling and pigmenturia. Cycle exercise testing revealed low maximal oxygen uptake (12 ml/min per kg; healthy sedentary men = 39 +/- 5) with exaggerated increases in venous lactate and pyruvate in relation to oxygen uptake (VO2) but low lactate/pyruvate ratios in maximal exercise. The severe oxidative limitation was characterized by impaired muscle oxygen extraction indicated by subnormal systemic arteriovenous oxygen difference (a-v O2 diff) in maximal exercise (patient = 4.0 ml/dl, normal men = 16.7 +/- 2.1) despite normal oxygen carrying capacity and Hgb-O2 P50. In contrast maximal oxygen delivery (cardiac output, Q) was high compared to sedentary healthy men (Qmax, patient = 303 ml/min per kg, normal men 238 +/- 36) and the slope of increase in Q relative to VO2 (i.e., delta Q/delta VO2) from rest to exercise was exaggerated (delta Q/delta VO2, patient = 29, normal men = 4.7 +/- 0.6) indicating uncoupling of the normal approximately 1:1 relationship between oxygen delivery and utilization in dynamic exercise. Studies of isolated skeletal muscle mitochondria in our patient revealed markedly impaired succinate oxidation with normal glutamate oxidation implying a metabolic defect at the level of complex II of the mitochondrial respiratory chain. A defect in Complex II in skeletal muscle was confirmed by the finding of deficiency of succinate dehydrogenase as determined histochemically and biochemically. Immunoblot analysis showed low amounts of the 30-kD (iron-sulfur) and 13.5-kD proteins with near normal levels of the 70-kD protein of complex II. Deficiency of succinate dehydrogenase was associated with decreased levels of mitochondrial aconitase assessed enzymatically and immunologically whereas activities of other tricarboxylic acid cycle enzymes were increased compared to normal subjects. The exercise findings are consistent with the hypothesis that this defect impairs muscle oxidative metabolism by limiting the rate of NADH production by the tricarboxylic acid cycle.

Myocardial metabolism before and after valve replacement for aortic stenosis.

AIM: Post ischemic disturbances of myocardial metabolism that may contribute to postoperative heart failure and are accessible to metabolic treatment have been identified early after coronary surgery. Knowledge derived from these studies may not be applicable to other patient groups. Therefore we studied myocardial energy metabolism in patients operated for isolated aortic stenosis. METHODS: Twenty patients undergoing isolated aortic valve replacement (AVR) because of aortic stenosis without significant regurgitation were studied before and immediately after surgery. Myocardial uptake of oxygen and energy substrates was assessed with coronary sinus catheter technique. RESULTS: Free fatty acids (FFA) were the main source of myocardial energy before and after AVR. A significant uptake of lactate was only recorded preoperatively. A significant uptake of glutamate of the same magnitude as previously described in coronary patients was found pre- and postoperatively. Postoperatively a relative decrease of myocardial oxygen extraction ratio (P<0.001) and oxygen consumption (P=0.14) by approximately 20% was observed. CONCLUSION: Preoperative and postoperative metabolic adaptation with substantial uptake of glutamate, previously claimed to be due to chronic or repetitive ischemia, was demonstrated. The results indicate that oxidative metabolism had not fully recovered when the procedure was completed. However, the potentially unfavorable postoperative metabolic state with predominant reliance on FFA as energy source was out-balanced by the unloading effect of AVR with a reduction in myocardial oxygen extraction.

Oxygen supplementation increases glucose tolerance during euglycaemic hyperinsulinaemic glucose clamp procedure in patients with severe COPD and chronic hypoxaemia.

Investigations in chronic obstructive pulmonary disease (COPD) patients have shown impaired glucose tolerance in hypoxic COPD patients, compared with COPD patients with normal arterial blood gases. In healthy subjects, hypoxaemia or stay at altitude, have been shown to alter glucose metabolism. At altitude the effect seems to be dependent on duration of stay. A short stay is associated with insulin resistance, a longer stay gives rise to increased glucose uptake. The euglycaemic hyperinsulinaemic glucose clamp technique is a method to study glucose tolerance and enables determinations of glucose clearance in peripheral tissues. We investigated six COPD patients [forced expiratory volume in 1 s 0.7 +/- 0.2 l (mean +/- SD)] with chronic hypoxaemia (PaO(2) 7.9 +/- 0.6 kPa at rest, breathing air), with and without oxygen supplementation, using the glucose clamp technique. Net peripheral glucose uptake was 5.5 +/- 1.2 and 7.1 +/- 1.6 mg (kg*min)(-1) (+29%) breathing air and supplemental oxygen, respectively (P = 0.03). The tissue sensitivity to insulin increased 32% (P = 0.03) with oxygen supplementation. The results indicate that normalization of oxygen saturation in COPD patients with chronic hypoxaemia may have an immediate effect on glucose tolerance and tissue sensitivity to insulin in these patients.

Metabolic effects in muscle during antihypertensive therapy with beta 1- and beta 1/beta 2-adrenoceptor blockers.

The hemodynamic and metabolic consequences of long-term antihypertensive treatment with beta 1- and beta 1/beta 2-adrenoceptor blockade was investigated in five young men with mild essential arterial hypertension (World Health Organization stages I and II) at rest and during submaximal exercise in a single-blind crossover study. The drugs (atenolol and alprenolol) were given in equipotent doses as estimated from their effects on blood pressure. Leg blood flow and oxygen uptake were the same during both treatment periods. Muscle glycogen decreased by 40% during exercise, irrespective of the drug. There was a positive relationship between muscle lactate release and concentration, but for a given muscle lactate concentration the release tended to be lower during treatment with alprenolol. A negative correlation was observed between the percentage of slow-twitch fibers versus lactate release and muscle lactate concentration. The results demonstrate that during exercise muscle glycogen breaks down despite beta blockade and is neither reduced when both beta 1- and beta 2-receptors are blocked, nor when only the beta 1-receptors are blocked. It is also shown that beta blockade impairs the translocation of lactate from the muscle cell to the blood and this is greater with alprenolol than with atenolol, probably due to a membrane effect.

Hemodynamics and leg muscle metabolism at rest and during exercise in young healthy men after prenalterol.

In eight young healthy men the effects of short-term treatment with prenalterol, a new beta-adrenergic agonist, on peripheral hemodynamics and leg muscle metabolism were studied at rest and during exercise at a moderate and a heavy workload. At rest prenalterol treatment significantly increased pulmonary oxygen uptake, heart rate, rate pressure product, and leg blood flow and decreased leg arteriovenous oxygen content difference. During exercise fewer hemodynamic effects of prenalterol were observed. At the moderate workload there was a slight increase in heart rate, but at the heavy workload heart rate fell. Prenalterol raised the arterial concentrations of free fatty acids and glycerol at rest by 70% and 40%, but during exercise these alterations were not present. The plasma levels of epinephrine and dopamine in subjects at rest decreased significantly during influence of prenalterol, but these differences were also abolished during exercise. The leg exchange of metabolites and the concentrations of endogenous muscle metabolites were not influenced by prenalterol, although the lactate concentrations in muscle tended to be lower at rest and during exercise. The results at rest demonstrate that prenalterol in this situation acts predominantly as a stimulator of beta 1-adrenoceptors. During heavy exercise, however, when the endogenous sympathetic tone is high, the beta-stimulating effects are no longer overt and instead reduced heart rate indicates a blocking effect on beta-adrenoceptors. The hemodynamic and metabolic results are concordant with the hypothesis that prenalterol acts as a partial beta-receptor agonist.

Influence of alprenolol on hemodynamic and metabolic responses to prolonged exercise in subjects with hypertension.

In 7 young men with essential hypertension, central and regional hemodynamics and leg metabolism were studied at rest, during and after a prolonged exercise, and with and without long-term alprenolol treatment. Alprenolol (200 mg twice daily) lowered arterial blood pressure. Heart rate decreased in relation to plasma levels during and after exercise. Cardiac output was not significantly influenced, but leg blood flow was reduced at rest. Lipolysis was also attenuated by treatment both at rest and during exercise, and the increment in plasma insulin after exercise was decreased. A reduction in the release of leg muscle lactate was noted during exercise.

Metabolic changes in muscle on long-term alprenolol therapy.

Muscle biopsies from the vastus muscle were taken at rest and immediately after upright bicycle exercise at 50% of the individual VO2max, before and during 6 wk of alprenolol treatment (200 to 400 mg twice daily) in 6 untrained patients with essential hypertension. Resting muscle concentrations (mmole - kg-1 - wet weight) of glycogen, glucose, lactate, and high-energy phosphates [adenosine triphosphate (ATP) and creatine phosphate (CP)] were not affected by alprenolol treatment, but after 10 min after exercise the glycogenolysis increased and depletion of ATP and CP was enhanced. The relationship between blood and muscle lactate was altered by alprenolol, indicating that alprenolol prevents lactate translocation from the muscle to the blood. The results show that during moderate exercise, leg muscle metabolism is influenced by long-term antihypertensive therapy.

Measurement of skeletal muscle blood flow in humans: plethysmographic, bolus and continuous infusion technique.

In this report a number of practical methods for the measurement of skeletal muscle blood flow in humans are presented and discussed. Special attention has been paid to the problems concerning representativeness for muscle blood flow (muscle vs other tissues and small muscle segments vs skeletal musculature of the total body) as well as the demand for steady state.

Metabolic and hemodynamic effects of intravenous glutamate infusion early after coronary operations.

Amino acids, particularly glutamate, have been proposed to play an important role in the recovery of cardiac oxidative metabolism after ischemia. In this investigation, the metabolic and hemodynamic effects of glutamate infusion after coronary operations were studied. From 220 to 240 ml 0.1 mol/L l-glutamic acid solution was infused in 10 patients during 1 hour starting 2 hours after operation. A control group of 10 patients received an infusion of 240 ml saline solution. During glutamate infusion, there were significant increases in the uptake of glutamate (from 0.7 +/- 0.2 micromol/min in the basal state to a peak of 5.7 +/- 1.2 micromol/min at 20 minutes) and lactate (from 4.9 +/- 2.0 micromol/min in the basal state to 14.1 +/- 4.4 micromol/min at 60 minutes; p < 0.01), whereas the uptake and release of other substrates remained essentially unaffected. Arterial glutamate levels (in whole blood) increased from 103 +/- 10 micromol/L to 394 +/- 20 micromol/L at 60 minutes. Thirty minutes after discontinuation of the glutamate infusion, arterial levels had decreased to 129 +/- 17 micromol/L. The markedly improved utilization of lactate and the unchanged release of alanine together suggest that the oxidative metabolism of the heart was stimulated by glutamate. The metabolic changes were associated with improved myocardial performance. Left ventricular stroke work index increased from 26.8 +/- 2.1 gm x beat(-1) x m(-2) body surface area to 31.3 +/- 3.1 gm x beat(-1) x m(-2) body surface area during glutamate infusion. Metabolic support with amino acids may provide a means to improve recovery of metabolic and hemodynamic function of the heart early after cardiac operations.

The influence of ethanol on splanchnic and skeletal muscle metabolism in man.

Splanchnic and leg exchange of ethanol, acetate, glucose, lactate, pyruvate, glycerol, and free fatty acids was studied in five healthy volunteers before and after a 60-min infusion of ethanol. Leg and splanchnic blood flows were determined simultaneously using a modified indicator dilution technique. The blood alcohol concentration obtained was 1.88 mmoles/liter and splanchnic uptake of ethanol was calculated to be 1.18 mmoles/min. All subjects showed an acetate uptake over the legs with a mean of 0.25 mmole/min. Splanchnic glucose production was attenuated in four of five subjects after ethanol treatment, and glucose uptake by the legs was significantly reduced. The normal splanchnic uptake of lactate was changed by ethanol to a release, and the arterial concentration was nearly doubled. Net leg release of lactate decreased significantly. Splanchnic blood flow and oxygen uptake were uninfluenced by ethanol, whereas leg blood flow decreased from a mean of 0.77 to 0.65 liter/min. It is concluded that, following ethanol treatment, (1) a major part of acetate released from the splanchnic region is taken up by the muscles, (2) leg glucose uptake is decreased by a reduction of the same magnitude as the actate uptake, and (3) leg blood flow is reduced, probably owing to a constriction of muscle vessels.

Impaired oxidative metabolism increases adenine nucleotide breakdown in McArdle's disease.

Two patients with muscle phosphorylase deficiency [McArdle's disease (McA)] were studied during bicycle exercise at 40 (n = 2) and 60 W (n = 1). Peak heart rate was 170 and 162 beats/min, corresponding to approximately 90% of estimated maximal heart rate. Muscle samples were taken at rest and immediately after exercise from the quadriceps femoris. Lactate content remained low in both muscle and blood. Acetylcarnitine, which constitutes a readily available form of acetyl units and thus a substrate for the tricarboxylic acid cycle, was very low in McA patients both at rest and during exercise, corresponding to approximately 17 and 11%, respectively, of that in healthy subjects. Muscle NADH was unchanged during exercise in McA patients in contrast to healthy subjects, in whom NADH increases markedly at high exercise intensities. Despite low lactate levels, arterial plasma NH3 and muscle inosine 5'-monophosphate increased more steeply relative to work load in McA patients than in healthy subjects. The low postexercise levels of lactate, acetylcarnitine, and NADH in McA patients support the idea that exercise performance is limited by the availability of oxidative fuels. Increases in muscle inosine 5'-monophosphate and plasma NH3 indicate that lack of glycogen as an oxidative fuel is associated with adenine nucleotide breakdown and increased deamination of AMP. It is suggested that the early onset of fatigue in McA patients is caused by an insufficient rate of ADP phosphorylation, resulting in transient increases in ADP.

A mathematical model for measuring blood flow in skeletal muscle with the microdialysis ethanol technique.

A theoretical analysis of the microdialysis ethanol technique in skeletal muscle is presented, and a model governing the transport of ethanol from the microdialysis probe to the capillaries in the muscle tissue is proposed. The model is derived under the assumption of a steady-state situation, and an analytical solution is found for the outflow-to-inflow ratio of ethanol in the perfusate. Theoretically calculated results are compared with experiments, and for at least one of the two probe types used good agreement is achieved in a wide range of blood flow and perfusate flow rates. The main uncertainty factor in the theoretical calculations is the diffusivity of ethanol in muscle tissue, and the value for best agreement between theory and experiments has been used. Error estimates show that for a constant relative error in the outflow-to-inflow ratio of ethanol in the perfusate, low perfusate flow rates give better predictions of the blood flow.

Intravenous aspartate infusion after a coronary operation: effects on myocardial metabolism and hemodynamic state.

BACKGROUND: In a previous study glutamate infusion after coronary artery bypass grafting was associated with beneficial effects on myocardial metabolism and myocardial performance. It has been claimed that aspartate is more important than glutamate for the recovery of myocardial metabolism after cardioplegic arrest. Therefore, the metabolic and hemodynamic effects of aspartate were studied after coronary artery bypass grafting. METHODS: Fifty to 240 mL of a 0.1 mol/L aspartic acid solution was infused intravenously during 60 minutes in 10 patients early after coronary artery bypass grafting. Myocardial metabolism was studied using the coronary sinus catheter technique. RESULTS: Aspartate infusion caused a significant increase in the arterial levels of both aspartate and glutamate. This was associated with a significant increase in myocardial uptake of aspartate and a decrease in myocardial uptake of glutamate. Myocardial exchange of other substrates remained unaffected. There were no changes in hemodynamic state except an increase of heart rate and pulmonary vascular resistance. CONCLUSIONS: Interactions with glutamate metabolism, compatible with competitive inhibition of myocardial glutamate uptake, which may have outweighed potential effects of aspartate, were observed. Recognition of these amino acid interactions is important as they are used together as additives in cardioplegic solutions.

Use of ethanol as marker substance to increase patient safety during transurethral prostatic resection. Screening investigation of irrigating fluid absorption in four hospitals and comparison of experienced and inexperienced urologists.

Of 472 patients at four different hospitals electively undergoing transurethral resection of the prostate (TURP), 192 received Sorbitur as an irrigating fluid with 2% ethanol (w/v) as a marker. Using a breath analyzer (Alcol-meter), the amount of ethanol in expired air was measured regularly during the operation to detect the absorption of irrigating fluid. The ethanol concentration in expired air was plotted against time. The time-ethanol concentration product was used as a measurement of absorbed ethanol marked irrigating fluid. A unit of more than 2.5 was considered to be a major absorption with possible clinical significance. This criterion was fulfilled in 24 percent of the patients. Postoperative serum sodium was shown to decrease more in patients with major absorption than in patients with minor absorption in comparison to preoperative values. The weight of resected tissue and the bleeding per resected gram of tissue was higher in the patients with major absorption, but the resected tissue per operating time was the same in both groups. The experienced urologists had as many patients with absorption as did the inexperienced ones. Ethanol-marked irrigating fluid is a simple, safe, noninvasive, rapid, and cheap method of detecting absorption of irrigating fluid thus increasing patient safety during TURP. This method indicates absorption before clinical signs and symptoms of the TUR syndrome occur. It also provides an easy method for estimating the frequency of absorption of irrigating fluid routinely in clinical work.

Absorption of irrigating fluid during transurethral prostatic resection as measured by ethanol, radioisotopes, and regular-interval monitoring.

Ethanol monitoring is a novel noninvasive method for immediate detection of absorption of irrigating fluid during transurethral prostatic resection. Its accuracy was evaluated during thirteen resections using 5% mannitol +2% ethanol as the irrigating fluid. The ethanol concentration in the expired breath correlated strongly with the degree of absorption of intravascular irrigating fluid as determined by a radioisotope technique, and fluid volume measurements, and with the changes in the serum sodium concentration. Extravascular absorption of the irrigating fluid resulted in prolonged elevation of the ethanol concentration and gave smaller changes in the serum sodium concentration.

High incidence of scintigraphic myocardial uptake defects at rest and during exercise in male elite runners.

OBJECTIVE: To evaluate the usefulness of myocardial perfusion scintigraphy (MIBI-SPECT) as a diagnostic tool in well trained men. DESIGN: The study was prospective, involving 2 d stress-rest myocardial scintigraphy (MIBI-SPECT), polar map reconstruction with and without uniform attenuation correction, and comparison with a healthy male group (local Swedish) and with a commonly used reference group (American, Emory University Hospital). SETTING: University Hospital, Stockholm, Sweden. SUBJECTS: 16 healthy, male elite runners (mean (SD) age 26.1 (3.1) years). Peak oxygen uptake 73 (4) ml O2/kg/min. RESULTS: Uptake defects on polar maps were found in the majority of the runners compared with both reference groups (local Swedish 13/16, American 10/16). Most defects (91%) were fixed. Defects were located in the anterior, lateral, and posterior regions of the left ventricle. Application of a uniform attenuation correction algorithm enhanced rather than reduced perfusion defect size, probably because this correction method is imperfect in SPECT studies of the thoracic cavity. CONCLUSIONS: If myocardial perfusion scintigraphy is used for evaluating well trained men, existing normal reference files for semiquantitative evaluation appear to be inadequate.

Exchange of free fatty acids and glucose in leg tissues before and immediately after surgery.

The present study was undertaken to investigate whether there is an augmented uptake of free fatty acids (FFA) in the leg tissues immediately after surgery when the energy expenditure of the leg is increased considerably. Eight patients were studied before and after cholecystectomy. Blood and plasma flow were determined in one leg, as well as arterio-venous concentration differences for oxygen, glycose, lactate and the total fraction of FFA. To determine uptake and release of FFA, 1-(14C)-oleic acid was infused intravenously and the arterio-venous differences for (14C)-FFA were determined. The mean oxygen uptake in the leg increased from 0.72+/-0.06 mmol/min to 1.78+/-0.41 mmol/min. The uptake of free fatty acids in the leg did not increase significantly after cholecystectomy when compared to before operation in spite of the marked increase in oxygen uptake. Postoperatively there was, however, a positive linear relationship between the uptake of FFA and that of oxygen in the leg. The glucose uptake, after correction for released lactate, corresponded to 7% of the oxygen uptake before surgery and 13% after surgery. The arterial FFA concentration did not change. This study indicates that the combined possible contribution of glucose and free fatty acids to the oxidative energy metabolism of the leg tissues exceeded the oxygen uptake before, but not after surgery. In the postoperative state there was a positive correlation between oxygen uptake and FFA uptake in the leg.

Effect of starvation on work capacity and voluntary skeletal muscle function in man.

Post-operative fatigue is a well-known clinical problem even after uncomplicated surgery. In the multifaceted post-operative state, several factors other then the surgical trauma may influence muscular function, such as an insufficient nutritional intake. The aim of this study was to investigate the effect of fasting on work capacity and voluntary skeletal muscle function. Eight healthy lean volunteers, age range 25-43 years, were studied the day before starvation, at the end of the fasting period of 5 days, and after another 3-4 days on a normal diet. Hand grip strength was assessed as maximum voluntary contraction (MVC) and physical working capacity was investigated with successively increased work load on a cycle ergometer until near exhaustion. After 5 days of total starvation, MVC remained unchanged but physical working capacity was reduced from 220 +/- 18 watt to 199 +/- 22 watt (p < 0.05). Corresponding heart rate, estimated effort and leg tiredness were not changed. A poor nutritional intake per se may therefore be a less important factor causing post-operative muscle fatigue than the operation itself.