Epinephrine, glucose, and lactate infusion in exercising adrenodemedullated rats

The purpose of this study was to determine the metabolic function of the marked increase in plasma epinephrine which occurs in fasted rats during treadmill exercise. Fasted adrenodemedullated (ADM) and sham-operated (SHAM) rats were run on a rodent treadmill (21 m/min, 15% grade) for 30 min or until exhaustion. ADM rats were infused with saline, epinephrine, glucose, or lactate during the exercise bouts. ADM saline-infused rats showed markedly reduced endurance, hypoglycemia, elevated plasma insulin, reduced blood lactate, and reduced muscle glycogenolysis compared with exercising SHAM's. Epinephrine infusion corrected all deficiencies. Glucose infusion restored endurance run times and blood glucose to normal without correcting the deficiencies in blood lactate and muscle glycogenolysis. Infusion of lactate partially corrected the hypoglycemia at 30 min of exercise, but endurance was not restored to normal and rats were hypoglycemic at exhaustion. We conclude that in the fasted exercising rat, actions of epinephrine in addition to provision of gluconeogenic substrate are essential for preventing hypoglycemia and allowing the rat to run for long periods of time.     

Effect of beta-adrenergic blockade on lactate turnover in exercising dogs

Dogs with indwelling catheters in the jugular vein and in the carotid artery ran on the treadmill (slope: 15%, speed: 133 m/min). Lactate turnover and glucose turnover were measured using [U-14C]lactate and [3-3H]glucose as tracers, according to the primed constant-rate infusion method. In addition, the participation of plasma glucose in lactate production (Ra-L) was measured with [U-14C]glucose. Propranolol was given either (A) before exercise (250 micrograms/kg, iv) or (B) in form of a primed infusion administered to the dog running at a steady rate. Measurements of plasma propranolol concentration showed that in type A experiments plasma propranolol fell in 45 min below the lower limit of the complete beta-blockade. In the first 15 min of work Ra-L rose rapidly; then it fell below that of the control (exercise) values. During steady exercise, the elevated Ra-L was decreased by propranolol infusion close to resting values. beta-Blockade doubled the response of glucose production, utilization, and metabolic clearance rate to exercise. In exercising dogs approximately 40-50% of Ra-L arises from plasma glucose. This value was increased by the blockade to 85-90%. It is concluded that glycogenolysis in the working muscle has a dual control: 1) an intracellular control operating at the beginning of exercise, and 2) a hormonal control involving epinephrine and the beta-adrenergic receptors.     

Effects of strenuous maternal exercise on fetal organ weights and skeletal muscle development in rats

The purpose of the present study was to observe the effects of strenuous maternal aerobic exercise throughout gestation on fetal outcome in the rat. The strenuous exercise intensity consisted of a treadmill speed of 30 m.min-1 on a 10 degrees incline, for 120 min.day-1, 5 days.week-1. The rats were conditioned to run on a motor-driven treadmill by following a progressive two-week exercise program, so that by the end of the two weeks the rats were capable of running comfortably at this strenuous intensity in the non-pregnant state. Following the two-week running programme, the rats were paired by weight and randomly assigned to either a pregnant group that continued the running program throughout gestation (pregnant runner), or a pregnant group that did not continue the running program throughout pregnancy (pregnant control). At birth the neonates born to the pregnant running group did not differ in average neonatal body weight values, number per litter or total litter weight values when compared to controls, nor were superficial gross abnormalities observed in neonates born to the pregnant control or pregnant running groups. The strenuous maternal exercise intensity did not alter neonatal organ weight values (brain, heart, liver, lung, kidney), nor neonatal skeletal muscle (gastrocnemius, sternomastoid, diaphragm) when compared to control values. It is suggested that maternal exercise of this intensity throughout gestation does not affect fetal outcome in the rat, and may be due to the animals accustomization to the strenuous exercise protocol prior to pregnancy.     

Effect of prolonged exercise on the level of triglycerides in the rat liver

This study examined the effect of prolonged exercise on the level of triglycerides (TG) in rat liver. The rats were divided into groups: 1-control, 2-treated with nicotinic acid, 3-fed with glucose during exercise, 4-fasted, 5-adrenalectomized, 6-adrenalectomized and fed with oil. In the control group, there was gradual accumulation of TG in the liver and their level was doubled at exhaustion as compared to the resting value. Nicotinic acid lowered the resting level of TG and prevented their accumulation during exercise. Administration of glucose during exercise partially prevented the increase in TG level in the liver. In rats fasted for 24 h before exercise, the net increase in liver TG level during exercise was similar to that in the controls. Adrenalectomy, like nicotinic acid, lowered TG level at rest and prevented its increase during exercise. Feeding the adrenalectomized rats with oil elevated the plasma free fatty acid level but did not result in accumulation of TG in the liver, either at rest or during exercise. It is concluded that prolonged exercise results in accumulation of TG in the liver and that the process depends on the supply of free fatty acids and glucose and requires the presence of glucocorticoids.     

Effect of dichloroacetate on lactate concentration in exercising humans

The precise mechanism responsible for the increase in plasma lactate concentration during exercise in humans is not known. We have used dichloroacetate to test the hypothesis that a limitation in pyruvate dehydrogenase activity is responsible for the rise in plasma lactate. Dichloroacetate stimulates the activity of pyruvate dehydrogenase, which is normally the regulatory enzyme in the oxidation of glucose when tissue oxygenation is adequate. Six subjects were studied twice according to a randomized, crossover protocol, involving one test with saline infusion and another with dichloroacetate infusion. Exercise load on a bicycle ergometer was increased progressively until exhaustion. Blood samples were drawn each minute throughout exercise and periodically throughout 120 min of recovery. Dichloroacetate significantly lowered the lactate concentration during exercise performed at less than 80% of the average maximal O2 consumption. The peak concentration of lactate at exhaustion was not affected by dichloroacetate treatment, but dichloroacetate did lower lactate concentration throughout recovery. These results suggest that a limitation in pyruvate dehydrogenase activity contributes to the increase in plasma lactate during submaximal exercise and recovery.     

Plasma glucagon and catecholamines during exhaustive short-term exercise

Plasma glucagon and catecholamine levels were measured in male athletes before and after exhaustive 15 min continuous running and strenuous intermittent short-term exercise (3 X 300 m). Blood lactate levels were higher after the intermittent exercise (mean 16.7 mmol X 1(-1)) than after the continuous running (mean 7.1 mmol X 1(-1)). Plasma glucagon concentration increased during continuous running and intermittent exercise by 41% and 55%, respectively, and the increases in plasma noradrenaline concentration were 7.7- and 9.1-fold compared with the respective pre-exercise values. Immediately after the exercises plasma cyclic AMP, blood glucose and alanine levels were elevated significantly. The data suggest that the sympathoadrenal system is of major importance for liver glucose production during high-intensity exercises. Catecholamines directly stimulate liver glucose production and may indirectly stimulate it by enhancing the secretion of glucagon.     

Glucagon responses to exercise in sheep.

Sheep were subjected to moderate (5 km/h) and strenuous (7 km/h) exercise on a treadmill for 45 min. After training, the sheep were again exercised. Glucagon concentrations in plasma increased in all sheep after commencement of exercise. These increases were related directly to the severity of exercise. The glucagon response also was dependent upon training with a lesser increase in trained animals than in untrained animals running at the same speed. Insulin concentrations in plasma decreased significantly only during strenuous exercise in untrained sheep.     

Skeletal muscle metabolism during exercise is influenced by heat acclimation

The influence of heat acclimation on skeletal muscle metabolism during submaximal exercise was studied in 13 healthy men. The subjects performed 30 min of cycle exercise (70% of individual maximal O2 uptake) in a cool [21 degrees C, 30% relative humidity (rh)] and a hot (49 degrees C, 20% rh) environment before and again after they were heat acclimated. Aerobic metabolic rate was lower (0.1 l X min-1; P less than 0.01) during exercise in the heat compared with the cool both before and after heat acclimation. Muscle and plasma lactate accumulation with exercise was greater (P less than 0.01) in the hot relative to the cool environment both before and after acclimation. Acclimation lowered (P less than 0.01) aerobic metabolic rate as well as muscle and plasma lactate accumulation in both environments. The amount of muscle glycogen utilized during exercise in the hot environment did not differ from that in the cool either before or after acclimation. These findings indicate that accumulation of muscle lactate is increased and aerobic metabolic rate is decreased during exercise in the heat before and after heat acclimation; increased muscle glycogen utilization does not account for the increased muscle lactate accumulation during exercise under extreme heat stress; and heat acclimation lowers the aerobic metabolic rate and muscle and blood lactate accumulation during exercise in a cool as well as a hot environment.     

Effects of dichloroacetate on hemodynamic responses to dynamic exercise in dogs.

To determine whether lactic acid production contributes significantly to the cardiac responses to muscular dynamic exercise, we administered intravenous sodium dichloroacetate (32 mumol.kg-1.min-1), a pyruvate dehydrogenase activator that facilitates lactate metabolism via the tricarboxylic cycle, in 12 dogs during two graded levels of treadmill exercise. Similar exercise was carried out in nine normal dogs receiving equimolar doses of NaCl. In the latter group, arterial lactate increased progressively from 0.80 +/- 0.11 (SE) mmol/l at rest to 2.13 +/- 0.28 mmol/l by the end of exercise. In contrast, arterial lactate did not change significantly (0.98 +/- 0.12 to 0.95 +/- 0.11 mmol/l) during exercise in dogs receiving dichloroacetate infusion. Dichloroacetate infusion also reduced the increases in plasma norepinephrine, heart rate, and left ventricular contractile indexes that occurred during exercise, suggesting that the sympathetic cardiac stimulation occurring during exercise may be related to the production of lactic acid. However, dichloroacetate affected neither the net increase in cardiac output nor the relationship between total body oxygen consumption and cardiac output that occurred during exercise. Thus we conclude that lactic acid production is not essential to the increase in cardiac output that occurs during mild-to-moderate exercise.     

Effect of carbohydrate ingestion on metabolism during running and cycling.

The effects of carbohydrate or water ingestion on metabolism were investigated in seven male subjects during two running and two cycling trials lasting 60 min at individual lactate threshold using indirect calorimetry, U-14C-labeled tracer-derived measures of the rates of oxidation of plasma glucose, and direct determination of mixed muscle glycogen content from the vastus lateralis before and after exercise. Subjects ingested 8 ml/kg body mass of either a 6.4% carbohydrate-electrolyte solution (CHO) or water 10 min before exercise and an additional 2 ml/kg body mass of the same fluid after 20 and 40 min of exercise. Plasma glucose oxidation was greater with CHO than with water during both running (65 +/- 20 vs. 42 +/- 16 g/h; P < 0.01) and cycling (57 +/- 16 vs. 35 +/- 12 g/h; P < 0.01). Accordingly, the contribution from plasma glucose oxidation to total carbohydrate oxidation was greater during both running (33 +/- 4 vs. 23 +/- 3%; P < 0.01) and cycling (36 +/- 5 vs. 22 +/- 3%; P < 0.01) with CHO ingestion. However, muscle glycogen utilization was not reduced by the ingestion of CHO compared with water during either running (112 +/- 32 vs. 141 +/- 34 mmol/kg dry mass) or cycling (227 +/- 36 vs. 216 +/- 39 mmol/kg dry mass). We conclude that, compared with water, 1) the ingestion of carbohydrate during running and cycling enhanced the contribution of plasma glucose oxidation to total carbohydrate oxidation but 2) did not attenuate mixed muscle glycogen utilization during 1 h of continuous submaximal exercise at individual lactate threshold.     

Effects of training on glucose metabolism of gluconeogenesis-inhibited short-term-fasted rats

To evaluate the effects of endurance training on gluconeogenesis and blood glucose homeostasis, trained as well as untrained short-term-fasted rats were injected with mercaptopicolinic acid (MPA), a gluconeogenic inhibitor, or the injection vehicle. Glucose kinetics were assessed by primed-continuous venous infusion of [U-14C]- and [6-3H]glucose at rest and during submaximal exercise at 13.4 m/min on level grade. Arterial blood was sampled for the determination of blood glucose and lactate concentrations and specific activities. In resting untrained sham-injected rats, blood glucose and lactate were 7.6 +/- 0.2 and 1.3 +/- 0.1 mM, respectively; glucose rate of appearance (Ra) was 71.1 +/- 12.1 mumol.kg-1.min-1. MPA treatment lowered blood glucose, raised lactate, and decreased glucose Ra. Trained animals had significantly higher glucose Ra at rest and during exercise. At rest, trained MPA-treated rats had lower blood glucose, higher blood lactate, and similar glucose Ra and disappearance rates (Rd) than trained sham-injected animals. Exercising sham-injected untrained animals had increased blood glucose and glucose Ra compared with rest. Exercising trained sham-injected rats had increased blood glucose and glucose Ra and Rd but no change in blood lactate compared with untrained sham-injected animals. In the trained animals during exercise, MPA treatment increased blood lactate and decreased blood glucose and glucose Ra and Rd. There was no measurable glucose recycling in trained or untrained MPA-treated animals either at rest or during submaximal exercise. There was no difference in running time to exhaustion between trained and untrained MPA-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of beta-adrenergic blockade on plasma lactate concentration during exercise at high altitude

When unacclimatized lowlanders exercise at high altitude, blood lactate concentration rises higher than at sea level, but lactate accumulation is attenuated after acclimatization. These responses could result from the effects of acute and chronic hypoxia on beta-adrenergic stimulation. In this investigation, the effects of beta-adrenergic blockade on blood lactate and other metabolites were studied in lowland residents during 30 min of steady-state exercise at sea level and on days 3, 8, and 20 of residence at 4300 m. Starting 3 days before ascent and through day 15 at high altitude, six men received propranolol (80 mg three times daily) and six received placebo. Plasma lactate accumulation was reduced in propranolol- but not placebo-treated subjects during exercise on day 3 at high altitude compared to sea-level exercise of the same percentage maximal oxygen uptake (VO2max). Plasma lactate accumulation exercise on day 20 at high altitude was reduced in both placebo- and propranolol-treated subjects compared to exercise of the same percentage VO2max performed at sea level. The blunted lactate accumulation during exercise on day 20 at high altitude was associated with reduced muscle glycogen utilization. Thus, increased plasma lactate accumulation in unacclimatized lowlanders exercising at high altitude appears to be due to increased beta-adrenergic stimulation. However, acclimatization-induced changes in muscle glycogen utilization and plasma lactate accumulation are not adaptations to chronically increased beta-adrenergic activity.     

Influence of fasting on glycogen depletion in rats during exercise

We recently observed that a 24-h fasted group of rats could run longer than an ad libitum fed control group before becoming exhausted. Because of the demonstrated importance of glycogen levels and free fatty acid availability during endurance exercise, we have investigated several parameters of carbohydrate and lipid metabolism in exercised and nonexercised rats that were either fed ad libitum or fasted for 24 h. A 24-h fast depleted liver glycogen, lowered plasma glucose concentration, decreased muscle glycogen levels, and increased free fatty acid and beta-hydroxybutyrate concentrations in plasma. During exercise the fasted group had lower plasma glucose concentration, higher plasma concentration of free fatty acids and beta-hydroxybutyrate, and a lower muscle glycogen depletion rate than did the ad libitum fed group. Since fasted rats were able to continue running even when plasma glucose had dropped to levels lower than those of fed-exhausted rats, it seems unlikely that blood glucose level, per se, is a factor in causing exhaustion. These results suggest that fasting increases fatty acid utilization during exercise and the resulting "glycogen sparing" effect may result in increased endurance.     

Exercise in rats does not alter hypothalamic AMP-activated protein kinase activity

Recent studies have demonstrated that AMP-activated protein kinase (AMPK) in the hypothalamus is involved in the regulation of food intake. Because exercise is known to influence appetite and cause substrate depletion, it may also influence AMPK in the hypothalamus. Male rats that either rested or ran for 30 or 60 min on a treadmill (22 m/min, 10% slope) were sacrificed immediately after exercise or after 60 min recovery either in the fasted state or after oral gavage with glucose (3g/kg body weight). Exercise decreased muscle and liver glycogen substantially. Hypothalamic total or alpha2-associated AMPK activity and phosphorylation state of the AMPK substrate acetyl-CoA carboxylase were not changed significantly immediately following treadmill running or during fed or fasted recovery. Plasma ghrelin increased (P<0.05) by 40% during exercise whereas the concentration of PYY was unchanged. In recovery, glucose feeding increased plasma glucose and insulin concentrations whereas ghrelin and PYY decreased to (ghrelin) or below (PPY) resting levels. It is concluded that 1h of strenuous exercise in rats does not elicit significant changes in hypothalamic AMPK activity despite an increase in plasma ghrelin. Thus, changes in energy metabolism during or after exercise are likely not coordinated by changes in hypothalamic AMPK activity.     

Metabolic and physiological response of the rabbit to continuous and intermittent treadmill exercise

Our knowledge of the effects of exercise on the heart is limited by the predominant use of rats as an animal model. The rabbit has many advantages over the rat as an animal model to study. However, little work has characterized its capacity to exercise. The purposes of the present study were to determine if the rabbit could (i) learn to run on a motor-driven treadmill at relatively high speeds using different exercise protocols, and (ii) characterize the various physiological and metabolic responses of the rabbit to acute bouts of exercise. We found that female New Zealand white rabbits had the capacity to run continuously on the treadmill for up to 21 min at 20 m/min until exhausted. Continuous, endurance-type exercise resulted in significant elevations in body temperature, heart rate, and plasma lactate levels. Plasma triglyceride concentration decreased as a function of this type of running whereas plasma glucose levels were unchanged. Twenty-four hours after a bout of running, plasma creatine phosphokinase activity was significantly elevated. The rabbits also had the capacity to learn to run using an intermittent, higher speed protocol. These physically untrained animals could achieve speeds of up to 70 m/min for 10 bouts of 15 s run/30 s rest. Their metabolic and physiological responses to this protocol were similar to those of continuous running with the following exceptions. The decrease in plasma triglyceride was less marked and the increase in plasma lactate was greater after intermittent exercise. Glycogen content of the rabbit vastus lateralis muscle was also significantly depleted after exhaustive, intermittent exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Possible inhibitory role of prolactin-releasing peptide for ACTH release associated with running stress

Exercise around the lactate threshold induces a stress response, defined as "running stress." We have previously demonstrated that running stress is associated with activation of certain regions of the brain, e.g., the paraventricular hypothalamic nucleus (PVN) and supraoptic nucleus, that are hypothesized to play an integral role in regulating stress-related responses, including ACTH release during running. Thus we investigated the role of prolactin-releasing peptide (PrRP), found in the ventrolateral medulla and the nucleus of the solitary tract, which is known to project to the PVN during running-induced ACTH release. Accumulation of c-Fos in PrRP neurons correlated with running speeds, reaching maximal levels under running stress. Intracerebroventricular injection of neutralizing anti-PrRP antibodies led to increased plasma ACTH level and blood lactate accumulation during running stress, but not during restraint stress. Exogenous intracerebroventricular administration of low doses of PrRP had the opposite effects. Therefore, our results suggest that, during running stress, PrRP-containing neurons are activated in an exercise intensity-dependent manner, and likewise the produced endogenous PrRP attenuates ACTH release and blood lactate accumulation during running stress. Here we provide a novel perspective on understanding of PrRP in the endocrine-metabolic response associated with running stress.     

Epinephrine inhibits exogenous glucose utilization in exercising horses.

This study examined the effects of preexercise glucose administration, with and without epinephrine infusion, on carbohydrate metabolism in horses during exercise. Six horses completed 60 min of treadmill exercise at 55 +/- 1% maximum O(2) uptake 1) 1 h after oral administration of glucose (2 g/kg; G trial); 2) 1 h after oral glucose and with an intravenous infusion of epinephrine (0.2 micromol. kg(-1). min(-1); GE trial) during exercise, and 3) 1 h after water only (F trial). Glucose administration (G and GE) caused hyperinsulinemia and hyperglycemia ( approximately 8 mM). In GE, plasma epinephrine concentrations were three- to fourfold higher than in the other trials. Compared with F, the glucose rate of appearance was approximately 50% and approximately 33% higher in G and GE, respectively, during exercise. The glucose rate of disappearance was approximately 100% higher in G than in F, but epinephrine infusion completely inhibited the increase in glucose uptake associated with glucose administration. Muscle glycogen utilization was higher in GE [349 +/- 44 mmol/kg dry muscle (dm)] than in F (218 +/- 28 mmol/kg dm) and G (201 +/- 35 mmol/kg dm). We conclude that 1) preexercise glucose augments utilization of plasma glucose in horses during moderate-intensity exercise but does not alter muscle glycogen usage and 2) increased circulating epinephrine inhibits the increase in glucose rate of disappearance associated with preexercise glucose administration and increases reliance on muscle glycogen for energy transduction.     

Effect of increased plasma free fatty acid concentrations on muscle metabolism in exercising men

The effect of increasing plasma concentrations of free fatty acids on substrate utilization in muscle during exercise was investigated in 11 healthy young males. One hour of dynamic knee extension at 80% of knee-extensor maximal work capacity was performed first with one leg and then with the other leg during infusion of Intralipid and heparin. Substrate utilization was assessed from arterial and femoral venous blood sampling as well as from muscle biopsies. Intralipid infusion increased mean plasma free fatty acid concentrations from 0.54 +/- 0.08 to 1.12 +/- 0.09 (SE) mM. Thigh glucose uptake during rest, exercise, and recovery was decreased by 64, 33, and 42%, respectively, by Intralipid, whereas muscle glycogen breakdown and release of lactate, pyruvate, and citrate were unaffected. Concentrations of glucose, glucose 6-phosphate, and lactate in muscle before and at termination of exercise were unaffected by Intralipid. During exercise, net leg uptake of plasma free fatty acids was not measurably increased by Intralipid, whereas uptake of ketone bodies was. Local respiratory quotient across the leg was not changed by Intralipid (control 0.87 +/- 0.02, Intralipid 0.86 +/- 0.02). Arterial concentrations of insulin, norepinephrine, and epinephrine were similar in the two trials. It is concluded that at rest and during exercise at a moderate intensity (requiring approximately equal contributions from fat and carbohydrate metabolism), muscle carbohydrate metabolism is affected only with regard to uptake of glucose when plasma concentrations of lipid and lipid metabolites are increased. This effect may be by direct inhibition of glucose transport rather than by the classic glucose-fatty acid cycle.     

Changes in plasma glucose and lipid concentrations during treadmill exercise in domestic fowl

• 1.1. Plasma glucose, non-esterified fatty acid, triglyceride, cholesterol and lactate concentrations were measured during 90 min treadmill exercise at a work intensity of 55–60% maximum.
• 2.2. After 90 min exercise plasma glucose fell by 35% whilst the non-esterified fatty acid concentration rose to as much as 3–4 times resting.
• 3.3. Exercise had no significant effect on plasma cholesterol, triglyceride or lactate concentrations.
• 4.4. The findings indicate a progressive increase in fat utilization during prolonged exercise. Possible hormonal mechanisms underlying exercise-induced changes in lipid and carbohydrate metabolism are discussed.

     

Ventilatory and treadmill endurance during acute semistarvation

Little is known about respiratory muscle function in acute undernutrition, although an inadequate caloric intake is common in numerous disease states. Twelve young-adult, healthy female volunteers performed two familiarization experiments and were then studied after 7 days of consuming 40% of normal daily caloric intake as well as after 1 wk of normal caloric intake. In each experiment subjects performed tests of resting pulmonary function, inspiratory muscle strength, and ventilatory endurance, the last of which involved two 60-s and two 6-min isocapnic maximum voluntary ventilation maneuvers. Subjects then walked to exhaustion in 8-20 min on a treadmill. The caloric restriction did not affect performance of any breathing test but did lower endurance time in severe treadmill exercise (P less than 0.05). Basal metabolic rate was lowered, resting blood levels of free fatty acids and beta-hydroxybutyrate elevated, and glucose lowered following the caloric restriction (P less than 0.05). Blood lactate levels were lower during and after exercise following caloric restriction (P less than 0.05). We conclude that ventilatory muscle strength and endurance are fully preserved in caloric restriction severe enough to cause mild ketoacidosis and hypoglycemia, lowered basal metabolic rate, and decreased endurance in severe treadmill exercise.