Metabolic and hormonal responses to adrenoceptor antagonists in 48-hour-starved exercising rats.

The influence of 48 hours of starvation on sympathoadrenal regulation of nutrient utilization was investigated in rats. To assess the role of alpha- and beta-adrenoceptors, rats were studied during alpha- and beta-blockade. Energy metabolism was measured using indirect calorimetry before, during, and after moderate swimming exercise (approximately 60% maximal O2 consumption [VO2max]). Additionally, blood samples were taken for determination of nutrient and hormone concentrations. In 48-hour-starved rats, under baseline conditions, there was a reduction in energy expenditure (EE) accompanied by a shift toward fat oxidation (fat-ox) in comparison to fed rats. Exercise-induced responses in EE, fat-ox, and carbohydrate oxidation (CHO-ox) did not differ from those in fed rats. In starved rats, a stronger response to exercise of the sympathoadrenal system was observed. In comparison to control 48-hour-starved rats, blockade of alpha- and beta-adrenoceptors led to a reduction in the exercise-induced increase in EE and fat-ox. The rate of CHO-ox was slightly reduced after blockade of either adrenoceptor type. Alpha-blockade prevented the exercise-induced increase in blood glucose. Plasma free fatty acid (FFA) was not affected. Blood lactate, plasma insulin, norepinephrine (NOR), and epinephrine (EPI) were increased after alpha-blockade. Due to beta-blockade, exercise-induced increases in glucose and FFA were prevented. Blood glucose even declined below the baseline value. EPI showed an exaggerated increase, and NOR showed a smaller increase. Results obtained in starved rats support the idea that alpha-adrenoceptor blockade-induced changes in energy metabolism are the result of a diminished oxygen supply due to diminished circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic and hormonal responses to adrenoceptor antagonists in exercising rats.

alpha- and beta-adrenoceptors play a key role in the regulation of nutrient supply to working muscles during exercise. To assess their influence in the regulation of substrate utilization, rats were studied during alpha- or beta-adrenoceptor blockade. Energy metabolism was studied by means of indirect calorimetry before, during, and after moderate swimming exercise. Blood samples were taken for the determination of nutrient and hormone concentrations. In addition, central venous blood samples were withdrawn for determination of blood gases, pH, and total hemoglobin concentration (c/Hb). alpha- and beta-adrenoceptor blockade decreased the rates of energy expenditure (EE) and fat oxidation (fat-ox) during and after swimming in comparison to swimming without adrenoceptor blockade. The oxidation of carbohydrates (CHO-ox) was increased in both cases. alpha-Blockade prevented the exercise-induced increase in blood glucose, plasma free fatty acids (FFA) were not affected, and plasma insulin, norepinephrine (NOR), epinephrine (EPI), and lactate were markedly increased. beta-adrenoceptor blockade prevented the exercise-induced increases in blood glucose and FFA. EPI increased slightly more than and NOR less than in the control experiment. The exercise-induced decrease in insulin was more pronounced after beta-blockade. alpha-Blockade caused a less pronounced decrease in venous oxygen saturation (SO2) and tension (PO2) than in the control experiment. The exercise-induced increase in carbon dioxide tension (PCO2) was almost absent. After beta-blockade, venous SO2 and PO2 decreased more and PCO2 increased more than in the control experiment. It is concluded that both alpha and beta-blockade restrict the rate of EE during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Co-released adrenaline markedly facilitates noradrenaline overflow through prejunctional beta 2-adrenoceptors during swimming exercise.

The effect of intravenously applied (-)-adrenaline, taken up by and released from sympathetic nerves, on swimming exercise-induced noradrenaline overflow in permanently cannulated adrenal demedullated rats was studied. Adrenaline (100 ng/min) was infused for 2 h, during which a plasma concentration of 500 pg/ml (approximately 2.5 nM) was reached. One hour later plasma adrenaline had returned to undetectable levels. During swimming, adrenaline was released into the plasma in concentrations up to 133 pg/ml and the noradrenaline concentration was markedly enhanced as well. The total catecholamine increase amounted to 178% of control (saline infusion) in the first 3 min of swimming and 165% for the whole 20 min. Cocaine (2.5 mg/kg plus 0.05 mg/kg/min), infused together with adrenaline and continued throughout the experiment, prevented the exercise-induced release of adrenaline and no increase in plasma noradrenaline concentration was observed. Yohimbine (0.25 mg/kg) strongly further enhanced the exercise-induced overflow of both noradrenaline and adrenaline. This further increase was completely blocked by the selective beta 2-adrenoceptor antagonist ICI 118,551 ((+/-)-1-[(2,3-dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methyleth yl) amino]-2-butanol) (1.0 mg/kg). These results demonstrate that adrenaline can be taken up by sympathetic nerve endings through cocaine-sensitive uptake carriers and is released from these nerves during swimming exercise. Neuronally released adrenaline markedly enhances exercise-induced catecholamine overflow through activation of prejunctional beta 2-adrenoceptors.

Effects of long-term d-fenfluramine treatment on energy metabolism in rats.

The effects of chronic intragastric administration of the anorectic agent d-fenfluramine on energy metabolism and nutrient concentrations were investigated at rest and during swimming. Rats were provided with permanent cannulas for blood sampling and intragastric administration of d-fenfluramine or saline. Energy expenditure and nutrient and hormone concentrations were determined. Under baseline conditions, d-fenfluramine increased carbohydrate utilization (14.2 vs. 7.0 mg/kg.min) and decreased fat oxidation (2.8 vs. 5.5 mg/kg.min). Plasma free fatty acid concentration was decreased (0.29 vs. 0.55 mmol/l) and lactate and insulin concentrations were increased after d-fenfluramine treatment (0.64 vs. 0.37 mmol/l and 61 vs. 33 mU/l, respectively). The shift in nutrient utilization also occurred during swimming. The exercise-induced increase in blood glucose was reduced after d-fenfluramine (+0.8 vs. +2.0 mmol/l). During swimming, free fatty acid, lactate and insulin concentrations were similar in the two groups. It is hypothesized that chronic d-fenfluramine treatment increases in the oxidation of carbohydrates and decreases the oxidation of fat as a result of a decrease in the transport of fatty acids over the mitochondrial membrane.

Methods for measurement of energy expenditure and substrate concentrations in swimming rats.

A measuring system is described for the determination of oxygen consumption (Vo2) and carbon dioxide production (Vco2) in swimming rats. Vo2 and Vco2 were measured by means of an O2-analyzer (Ametek S3A) and a mass spectrometer (Balzers QMG 511), respectively, combined with a gas flow meter. The measurements were made in a 5-1 metabolic chamber on top of a swimming pool in which a water flow of 0.22 m/s was maintained. The rats were fitted with an indwelling catheter with its tip at the entrance of the right atrium for the repeated determination of energy substrate and hormone concentrations, before, during, and after swimming. The inaccuracy of the Vo2 and Vco2 measurements was 0.18% and 0.31% of the reading, respectively; the imprecision was 2.15% and 2.59%. This high accuracy and precision of the system was attained by measuring room air for 20 s after each 100 s of measuring air from the metabolic chamber, and by using demineralized water in the swimming pool. Vo2 during steady-state swimming was 1.89 +/- 0.06 mmol/kg.min (ca. 60% Vo2max), indicating moderate exercise. Respiratory quotient (RQ), during steady-state exercise, was 0.80 +/- 0.01. Vo2 and RQ resulted in rates for carbohydrate and fat utilization of 15.6 +/- 0.8 and 15.1 +/- 0.7 mg/kg.min, respectively.

The effect of epinephrine on oxygen consumption, overall energy metabolism, and substrate utilization in rats.

In this study the influence of epinephrine (E) on oxygen consumption, overall energy metabolism, and substrate utilization in rats has been investigated. Therefore E was infused at rates of 20, 35, and 50 ng/min for 40 min. Infusion of the solvent, saline, served as control experiment. Before, during, and after the infusion, VO2, as parameter for total metabolism, and RQ, as parameter for substrate utilization, were determined using an open circuit. In addition blood samples were taken for determination of blood glucose, plasma free fatty acids (EFA) and plasma insulin concentrations. The results show a rise in VO2 and blood glucose during infusion of E. Plasma FFA concentrations were elevated during infusion of E and of saline. Plasma insulin decreased when E was administered. RQ values were increased when E was infused at rates of 35 and 50 ng/min. The results suggest that E can influence the ratio in which glucose and FFA are utilized. This influence seems to be excerpted indirectly by influencing the availability of the substrates, rather than directly, by influencing utilization.

Pure gonadal dysgenesis in a triple-x female.

A tall 15 1/2-year-old-girl with an xxx sex chromosome complement, absence of secondary sexual characteristics and histologically verified pure gonadal dysgenesis is described. In contrast to patients with an xxy sex chromosome configuration who--after puberty--are recognisable by typical somatic abnormalities, triple-x females generally show no physical anomalies. Speech and language problems can be features of the triple-x condition; ovarian dysfunction in triple-x females has been described only sporadically. Probably one patient is the second case described having this chromosomal aberration combined with pure gonadal dysgenesis. The presence of three x chromosomes (and thereby possibly extra growth determinants) could be the reason for the extra growth potential in these patients. This contrasts with the reduced growth in patients with the xo sex chromosome configuration who tend to remain small.

The passive coping Roman Low Avoidance rat, a non-obese rat model for insulin resistance.

The aim of the study was develop to an animal model that links coping style to insulin resistance. We hypothesized that the psychogenetically selected Roman Low Avoidance (RLA) rats may serve as such a model. To test this hypothesis, we submitted both RLA and Roman High avoidance (RHA) rats to a series of intravenous glucose tolerance tests (IVGTT). These IVGTT were followed by post mortem metabolic characterization of the selection lines. It was found that plasma insulin levels are markedly elevated in the passively coping RLA rat, both in baseline conditions and during the intravenous glucose tolerance tests. The elevation in plasma insulin was accompanied with increased levels of plasma corticosterone, FFA, leptin and triglycerides but not by changes in body weight. We conclude that the passive, highly emotional RLA rat is metabolically different from both the RHA rat and the standard control Wistar rat and may serve as a non-obese animal model for insulin resistance.

Hyperglycemia suppresses the sympatho-adrenal response to hypoxia, but not to handling stress.

We hypothesized that the ability of prior hyperglycemia to suppress the sympatho-adrenal response would depend on the type of stress. To test this hypothesis, hyperglycemia was induced in chronically catheterized rats, before submitting them to either hypoxia (7.5% O2) or handling stress. Central venous blood samples were drawn for the determination of plasma glucose, epinephrine (EPI), norepinephrine (NOR) and insulin concentrations. Hypoxia caused significant increases in plasma EPI and NOR concentrations (deltaEPI = + 2.95+/-0.68 nmol/l, deltaNOR = + 12.45+/-1.29 nmol/l). Hyperglycemia, antecedent to hypoxia, dose dependently reduced the sympatho-adrenal response. In contrast, the sympatho-adrenal response to handling stress was not affected by even marked antecedent hyperglycemia (deltaEPI = + 2.48+/-0.46 nmol/l, deltaNOR = + 3.12+/-0.69 nmol/l at glucose = 20.7+/-0.6 mmol/l; vs. deltaEPI = + 2.48 + 0.58 nmol/l, deltaNOR= +2.97+/-0.11 nmol/l at glucose = 6.77+/-0.17 mg/dl). Thus, antecedent hyperglycemia suppresses the hypoxia-induced activation of both the sympathetic nerves and the adrenal medulla, but not the activation induced by handling. We conclude that the ability of hyperglycemia to suppress sympathetic activation depends on the stress producing the activation. We therefore speculate that hypoxic stress has a metabolic component to its central activation that handling stress does not.

Central and peripheral adrenoceptors affect glucose, free fatty acids, and insulin in exercising rats.

The effects of intravenously and intrahypothalamically administered alpha- and beta-adrenoceptor antagonists on exercise-induced alterations in blood glucose, plasma free fatty acids (FFA), and insulin were investigated in rats. Exercise consisted of strenuous swimming against a counter current for 15 min. Before, during, and after swimming, blood samples were withdrawn through a permanent heart catheter. Intravenous administration of the alpha-blocker phentolamine led to a reduction in glucose and a substantial increase in insulin levels. Infusion of phentolamine through permanent bilateral cannulas into either the ventromedial or lateral area of the hypothalamus (VMH and LHA, respectively) completely prevented the increase in glucose while the decline in insulin was unaffected. Infusion of phentolamine into the VMH caused much higher plasma FFA levels than in controls. The beta-blocker timolol given intravenously caused a delayed increase in glucose and prevented the increase in FFA. Infusion of timolol into either VMH or LHA caused a delay in the increase in both glucose and FFA. The results suggest that 1) both peripheral and hypothalamic adrenoceptors are involved in energy metabolism during exercise and 2) FFA, glucose, and insulin concentrations in blood are independently regulated by VMH and LHA.

Parasympathetic inhibition of sympathetic neural activity to the pancreas.

The present study tested the hypothesis that activation of the parasympathetic nervous system could attenuate sympathetic activation to the pancreas. To test this hypothesis, we measured pancreatic norepinephrine (NE) spillover (PNESO) in anesthetized dogs during bilateral thoracic sympathetic nerve stimulation (SNS; 8 Hz, 1 ms, 10 mA, 10 min) with and without (randomized design) simultaneous bilateral cervical vagal nerve stimulation (VNS; 8 Hz, 1 ms, 10 mA, 10 min). During SNS alone, PNESO increased from the baseline of 431 +/- 88 pg/min to an average of 5,137 +/- 1,075 pg/min (P < 0.05) over the stimulation period. Simultaneous SNS and VNS resulted in a significantly (P < 0.01) decreased PNESO response [from 411 +/- 61 to an average of 2,760 +/- 1,005 pg/min (P < 0.05) over the stimulation period], compared with SNS alone. Arterial NE levels increased during SNS alone from 130 +/- 11 to approximately 600 pg/ml (P < 0.05); simultaneous SNS and VNS produced a significantly (P < 0.05) smaller response (142 +/- 17 to 330 pg/ml). Muscarinic blockade could not prevent the effect of VNS from reducing the increase in PNESO or arterial NE in response to SNS. It is concluded that parasympathetic neural activity opposes sympathetic neural activity not only at the level of the islet but also at the level of the nerves. This neural inhibition is not mediated via muscarinic mechanisms.

Meal-induced insulin secretion in dogs is mediated by both branches of the autonomic nervous system.

We investigated the relationship between autonomic activity to the pancreas and insulin secretion in chronically catheterized dogs when food was shown, during eating, and during the early absorptive period. Pancreatic polypeptide (PP) output, pancreatic norepinephrine spillover (PNESO), and arterial epinephrine (Epi) were measured as indexes for parasympathetic and sympathetic nervous activity to the pancreas and for adrenal medullary activity, respectively. The relation between autonomic activity and insulin secretion was confirmed by autonomic blockade. Showing food to dogs initiated a transient increase in insulin secretion without changing PP output or PNESO. Epi did increase, suggesting beta(2)-adrenergic mediation, which was confirmed by beta-adrenoceptor blockade. Eating initiated a second transient insulin response, which was only totally abolished by combined muscarinic and beta-adrenoceptor blockade. During absorption, insulin increased to a plateau. PP output showed the same pattern, suggesting parasympathetic mediation. PNESO decreased by 50%, suggesting withdrawal of inhibitory sympathetic neural tone. We conclude that 1) the insulin response to showing food is mediated by the beta(2)-adrenergic effect of Epi, 2) the insulin response to eating is mediated both by parasympathetic muscarinic stimulation and by the beta(2)-adrenergic effect of Epi, and 3) the insulin response during early absorption is mediated by parasympathetic activation, with possible contribution of withdrawal of sympathetic neural tone.