Pharmacodynamic profile of the M1 agonist talsaclidine in animals and man.

In functional pharmacological assays, talsaclidine has been described as a functionally preferential M1 agonist with full intrinsic activity, and less pronounced effects at M2- and M3 receptors. In accordance with this, cholinomimetic central activation measured in rabbits by EEG recordings occurred at a 10 fold lower dose than that inducing predominantly M3-mediated side effects. This pharmacological profile is also reflected in the clinical situation: Both in healthy volunteers and in Alzheimer patients--unlike after unspecific receptor stimulation through cholinesterase inhibitors--the mainly M3-mediated gastrointestinal effects (like nausea and vomiting) were not dose-limiting. Rather, sweating and hypersalivation, mediated through muscarinic receptors, occurred dose-dependently and were finally dose-limiting. In contrast to talsaclidine, sabcomeline had a less pronounced functional M1 selectivity in pharmacological assays. This was also shown in anaesthetized guinea pigs where sabcomeline alone induced bronchoconstriction, and in the rabbit EEG where central activation and cholinergic side effects occurred in the same dose range. Neither drug, however, showed convincing improvement of cognitive functions in patients with mild-to-moderate Alzheimer's disease. This asks for a reassessment of the muscarinic hypothesis for the treatment of this disease.

Metabolic changes after cardiac surgery.

The metabolic changes that occur after cardiac surgery result from a complex interaction between the effects of surgery and extracorporeal circulation per se, the inflammatory response to surgical trauma and extracorporeal circulation, perioperative use of hypothermia, the cardiovascular and neuroendocrine responses characteristic to cardiac surgery, and the drugs and blood products used to support circulation during and after operation. These changes include among others increased oxygen consumption and energy expenditure and increased secretion of insulin, growth hormone, adrenocorticotrophic hormone, cortisol, epinephrine and norepinephrine. Other changes include decreased total-Trijodthyronine levels, hyperglycemia, hyperlactatemia, increased glutamate, aspartate and free fatty acid concentrations, hypokalemia, an increased production of inflammatory cytokines and increased consumption of complement and adhesion molecules. There is evidence that better control of metabolic abnormalities improves the patients' outcome.

Metabolic effects of vasoactive agents.

After adequate volume resuscitation, the mainstay of therapy in critically ill patients with shock is treatment with vasoactive substances to restore haemodynamics or to improve regional perfusion. These agents include adrenoceptor agonists with inotropic combined with either vasoconstricting or vasodilating effects, and predominantly vasodilating drugs such as prostacyclin and related compounds. However, vasoactive agents not only affect the cardiovascular system, but also have profound metabolic effects. The interdependence of vasoactive drugs with metabolism may be relevant regarding adequate oxygen and substrate delivery to cover actual organ needs. Therefore, the profiles of these metabolic effects have to be considered during their therapeutic administration.

Pharmacokinetics of pinokalant, a new nonselective cation channel blocker in the rat.

The pharmacokinetics of 1-isoquinolineacetamide, 3,4-dihydro-6,7-dimethoxy-alpha-phenyl-N,N-bis [2-(2,3,4-trimethoxyphenyl)ethyl]-, monomethanesulfonate (pinokalant, salt form of the active entity LOE 908 BS, CAS 143482-63-7), a nonselective cation channel blocker, was studied in rats. Drug plasma levels declined rapidly in a polyphasic manner after intravenous bolus administration of 8.8 mg/kg LOE 908 BS. The disposition of LOE 908 BS was governed by a rapid elimination (clearance Cl = 47.7 ml/min/kg) and an extensive distribution into tissues (volume of distribution Vss = 7.21 l/kg). A dose-proportional increase of AUC and steady state concentration up to doses of 194 mg/kg (6 h infusion) was observed suggesting linear pharmacokinetics. The protein binding was very high with 99.4% to 99.7% bound to plasma proteins in the concentration range 0.26 to 2.6 micrograms/ml. The LOE 908 BS concentration-time profile in brain tissue after intravenous infusion (4.4 mg/kg/h over 4 h) paralleled those measured in plasma indicating a rapid but also low penetration of the blood-brain-barrier. The concentration-time profile of drug-related radioactivity after intravenous (bolus) administration of [14C]LOE 908 BS dropped also rapidly to approximately 16% within the first hour compared to the initial 2-min value. The drug exhibited a high biliary excretion (84% during 5 h) and, accordingly, faecal excretion was the main route of excretion (> 90%). The mass balance was complete after 96 h indicating no persistence of radioactivity in the animals. The relevance of these findings with respect to results obtained with LOE 908 BS in animal models for stroke and traumatic brain injury is discussed.

The novel compound LOE 908 attenuates acute neuromotor dysfunction but not cognitive impairment or cortical tissue loss following traumatic brain injury in rats.

Experimental traumatic brain injury (TBI) initiates massive disturbances in Ca2+ concentrations in the brain that may contribute to neuronal damage. Intracellular Ca2+ may be elevated via influx through voltage-operated cation channels, ligand-gated ionotropic channels, and store-operated cation channels (SOCs). In the present study, we evaluated the neurobehavioral and histological effects of acute posttraumatic administration of (R,S)-(3,4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl-N,N-di[2-(2 ,3,4-trimethoxyphenyl)ethyl]-acetamide (LOE 908), a broad spectrum inhibitor of voltage-operated cation channels and SOCs. Male Sprague-Dawley rats (n = 53) were trained in the Morris water maze, anesthetized (60 mg/kg pentobarbital, i.p.), and subjected to lateral fluid percussion brain injury (2.5-2.7 atm; n = 38) or surgery without injury (n = 15). At 15 min postinjury, animals were randomized to receive intravenous administration of either a high dose of LOE 908 (4 mg/kg bolus followed by 160 mg/kg over 24 h; n = 13), a low dose of LOE 908 (2 mg/kg bolus followed by 80 mg/kg over 24 h; n = 12), or vehicle (n = 13). Uninjured controls received the high dose of LOE 908 (n = 8) or vehicle (n = 7). Treatment with either dose of LOE 908 significantly improved neuromotor function at 48 h postinjury when compared to vehicle treatment. Although a significant deficit in visuospatial memory was observed in brain-injured animals at this timepoint when compared to uninjured animals, neither dose of LOE 908 attenuated injury-induced cognitive dysfunction. Histological evaluation revealed that neither dose of LOE 908 affected cortical lesion size at 48 h postinjury. These data suggest that broad spectrum cation channel blockers may be beneficial in the treatment of neurological motor dysfunction when administered in the acute posttraumatic period.

Effect of dobutamine on splanchnic carbohydrate metabolism and amino acid balance after cardiac surgery.

BACKGROUND: As a predominant beta-adrenergic agonist, dobutamine may modify blood flow distribution and increase metabolic demands. The authors investigated the effect of a dobutamine-induced increase in cardiac output on splanchnic and femoral blood flow and metabolism in patients after cardiac surgery. METHODS: Seventeen stable patients were randomized to receive dobutamine or placebo (n = 8 per group, one dropout). After baseline measurement for systemic, splanchnic, and femoral blood flow (by dye dilution); oxygen consumption; gastric mucosal pressure of carbon dioxide (Pco2); total and splanchnic glucose production (by stable isotope tracer dilution); and regional lactate and amino acid balance, patients received either dobutamine, at a dosage (6 microg x kg(-1)min(-1)) sufficient to increase cardiac index by at least 25%, or placebo. A second set of measurements was performed 60 min after the start of dobutamine or placebo infusion. RESULTS: Dobutamine increased cardiac index (3.0+/-0.6 to 4.4+/-1.0 l x min(-1)m(-2), mean +/- SD; P < 0.05), splanchnic blood flow (from 0.8+/-0.2 to 1.0 + 0.2 l x min(-1)m(-2); P < 0.05), femoral blood flow (from 0.2+/-0.1 to 0.3+/-0.1 l x min(-1)m(-2); P < 0.05), and the arterial-gastric mucosal Pco2 gap (from 11.4+/-9.5 to 11.9+/-8.0 mmHg; P < 0.05). Dobutamine increased systemic oxygen consumption (from 132+/-14 to 146+/-13 ml x min(-1) x m(-2); P < 0.05) but not splanchnic or femoral oxygen consumption. Splanchnic glucose production and lactate and amino acid balance did not change. CONCLUSION: After coronary artery bypass surgery, dobutamine increased systemic and regional blood flow and decreased systemic and regional oxygen extraction. Dobutamine did not affect splanchnic glucose production or lactate or amino acid balance. This suggests that dobutamine increases splanchnic blood flow without a concomitant increase in hepatosplanchnic metabolism.

BIIR 561 CL: a novel combined antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and voltage-dependent sodium channels with anticonvulsive and neuroprotective properties.

Antagonists of glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype, as well as of voltage-gated sodium channels, exhibit anticonvulsive and neuroprotective properties in vivo. One can postulate that a compound that combines both principles might be useful for the treatment of disorders of the central nervous system, like focal or global ischemia. Here, we present data on the effects of dimethyl-(2-[2-(3-phenyl-[1,2, 4]oxadiazol-5-yl)-phenoxy]ethyl)-amine hydrochloride (BIIR 561 CL) on neuronal AMPA receptors and voltage-dependent sodium channels. BIIR 561 CL inhibited AMPA receptor-mediated membrane currents in cultured cortical neurons with an IC50 value of 8.5 microM. The inhibition was noncompetitive. In a cortical wedge preparation, BIIR 561 CL reduced AMPA-induced depolarizations with an IC50 value of 10.8 microM. In addition to the effects on the glutamatergic system, BIIR 561 CL inhibited binding of radiolabeled batrachotoxin to rat brain synaptosomal membranes with a Ki value of 1.2 microM. The compound reduced sodium currents in voltage-clamped cortical neurons with an IC50 value of 5.2 microM and inhibited the veratridine-induced release of glutamate from rat brain slices with an IC50 value of 2.3 microM. Thus, BIIR 561 CL inhibited AMPA receptors and voltage-gated sodium channels in a variety of preparations. BIIR 561 CL suppressed tonic seizures in a maximum electroshock model in mice with an ED50 value of 2.8 mg/kg after s.c. administration. In a model of focal ischemia in mice, i.p. administration of 6 or 60 mg/kg BIIR 561 CL reduced the area of the infarcted cortical surface. These data show that BIIR 561 CL is a combined antagonist of AMPA receptors and voltage-gated sodium channels with promising anticonvulsive and neuroprotective properties.

Metabolic and calorigenic effects of dopexamine in healthy volunteers.

OBJECTIVE: To evaluate metabolic and calorigenic effects of dopexamine in healthy volunteers. DESIGN: Prospective, randomized trial. SETTING: Laboratory of the University Department of Anesthesiology. SUBJECTS: Eight volunteers. INTERVENTIONS: After a control period, dopexamine was administered using four infusion rates (0.75, 1.5, 3.0, and 6.0 microg/kg/min). MEASUREMENTS AND MAIN RESULTS: Blood pressure, heart rate, oxygen consumption (VO2), and the plasma concentration of potassium, glucose, lactate, and norepinephrine were measured. Typical hemodynamic responses were seen. VO2 increased from 122 +/- 11 (SD) to 150 +/- 9 mL/min/m2 during the highest dopexamine infusion rate. Plasma potassium concentration decreased only during the highest infusion rate. Plasma glucose concentration increased during infusion rates of 3 and 6 microg/kg/min of dopexamine, from 90 +/- 5 to 99 +/- 5 mg/dL (5.0 +/- 0.3 to 5.5 +/- 0.3 mmol/L), and from 87 +/- 7 to 103 +/- 11 mg/dL (4.8 +/- 0.4 to 5.7 +/- 0.6 mmol/L), respectively. Lactate did not increase during dopexamine infusion. Plasma norepinephrine concentration increased during all four infusion rates. CONCLUSION: It was not possible to differentiate the adrenergic receptor subtype responsible for the calorigenic and metabolic effects, since the putative beta2 adrenergic-receptor agonist, dopexamine, caused an increase in the plasma concentration of the beta1 adrenergic-receptor agonist, norepinephrine. Since beta2 adrenergic receptor-mediated effects such as hypokalemia were found only at infusion rates > or = 3 microg/kg/min, the effects of dopexamine at infusion rates < 3 microg/kg/min may be mainly mediated by stimulation of dopaminergic receptors and the indirect sympathomimetic action.

Synthesis and structure-activity relationships of 6,7-benzomorphan derivatives as antagonists of the NMDA receptor-channel complex.

We have synthesized a series of stereoisomeric 6,7-benzomorphan derivatives with modified N-substituents and determined their ability to antagonize the N-methyl-D-aspartate (NMDA) receptor-channel complex in vitro and in vivo. The ability of the compounds to displace [3H]-MK-801 from the channel site of the NMDA receptor in rat brain synaptosomal membranes and to inhibit NMDA-induced lethality in mice was compared with their ability to bind to the mu opioid receptor. Examination of structure-activity relationships showed that the absolute stereochemistry is critically important for differentiating these two effects. (-)-1R,9 beta,2"S-enantiomers exhibited a higher affinity for the NMDA receptor-channel complex than for the mu opioid receptor. The aromatic hydroxy function was also found to influence the specificity of the compounds. Shift of the hydroxy group from the 2'-position to the 3'-position significantly increased the affinity for the NMDA receptor-channel complex and considerably reduced the affinity for the mu opioid receptor. From this series of 6,7-benzomorphan derivatives, the compound 15cr.HCl [(2R)-[2 alpha, 3(R*),6 alpha]-1,2,3,4,5,6-hexahydro-3-(2-methoxypropyl)-6,11,11-trimethyl -2,6-methano-3-benzazocin-9-ol hydrochloride] was chosen as the optimum candidate for further pharmacological investigations.

[Liver urea and glucose production in patients with alcohol-induced cirrhosis]. / Harnstoff- und Glucoseproduktion der Leber bei Patienten mit alkoholinduzierter Zirrhose.

OBJECTIVE: To use stable isotopes for the analysis of hepatic metabolic pathways (urea synthesis, glucose production), comparing them in alcoholic and normal liver, in order to obtain specific and quantitative information on metabolic functions of the liver. PATIENTS AND METHODS: Urea and glucose production as well as alanine metabolism in the liver were studied by means of stable isotopes in 7 males with alcoholic liver cirrhosis (mean age 46 +/- 4 years; height 173 +/- 5 cm; weight 73 +/- 3 kg) and 7 healthy male volunteers as controls (age 26 +/- 3 years; height 180 +/- 5 cm; weight 75 +/- 6 kg). The plasma concentrations of adrenaline, noradrenaline, insulin, glucagon and amino-acids were also measured. RESULTS: Urea synthesis was lower in the cirrhosis patients than in the controls (3.3 +/- 2.2 mumol/kg.min vs 4.8 +/- 0.9 mumol/kg.min, P < 0.05). But there were no differences in glucose production, alanine metabolism and adrenaline concentrations. The concentrations of glutamine, phenylalanine, tyrosine, insulin, glucagon and noradrenaline were significantly raised in the cirrhotic patients, those of valine and leucine significantly lower. CONCLUSIONS: Contrary to hepatic glucose production, which was within normal limits, urea synthesis was reduced by 30% in the cirrhotic patients. The use of stable isotopes provided detailed information on specific metabolic processes in cirrhotic livers.

In vivo role of the adenosine A3 receptor: N6-2-(4-aminophenyl)ethyladenosine induces bronchospasm in BDE rats by a neurally mediated mechanism involving cells resembling mast cells.

Activation of the adenosine A3 receptor subtype by the agonist N6-2-(4-aminophenyl)ethyladenosine is shown here to induce bronchospasm (increased pulmonary resistance and decreased pulmonary compliance) in BDE strain rats. The effect is substantially reduced by pretreating the rats with compound 48/80, disodium cromoglycate (30 micrograms/kg) or epinastine (10 micrograms/kg), which is compatible with involvement of mast cells. It is also substantially reduced by combined vagotomy and atropinization or by pretreatment with the NK2 receptor antagonist L-659,877, suggesting involvement of neuropeptide-mediated neural pathways. The mechanism by which activation of the adenosine A3 receptor induces bronchospasm is distinct from the mechanism by which activation of the adenosine A1 receptor induces bronchospasm. In particular, the A1 agonist 2-chloro-N6-cyclopentyladenosine can increase pulmonary resistance independently of mast cell activation. These results are in accord with the concept that a pathway exists in vivo by which activation of mast-like cells can activate axon reflexes, that adenosine acting through its A3 receptor can potentially up-regulate this pathway and that antiallergic substances such as disodium cromoglycate and epinastine may interfere with this pathway.

[The effect of anesthetic method on enflurane air pollution in non-air conditioned operating rooms]. / Einfluss des Narkoseverfahrens auf die Enfluran-Raumluft-belastung in nichtklimatisierten OP-Arbeitsbereichen.

UNLABELLED: Pollution of work areas by volatile anaesthetics and nitrous oxide occurs during general anaesthesia. Short anaesthesia procedures are often carried out in operating theatres that are not equipped with air-conditioning systems. Methods of lowering exposure during short procedures, where mask anaesthesia is the usual procedure, are double masks and the laryngeal mask. The aim of our investigation was to determine the possibility of lowering the pollution of the environment to below national and international thresholds in a non-air-conditioned work area and to find out which method of anaesthesia is the most effective in environmental protection, i.e. which has the lowest leakage rate. METHODS: In our investigation, at two points of the work area the mean enflurane [2-chloro-1-(difluor-omethoxy)-1,1,2-trifluoro-ethane] concentrations were measured under daily routine conditions in a non-ventilated anaesthesiological work area by a gas chromatography. Anaesthesia with single masks, double masks, laryngeal masks or endotracheal intubation was carried out. RESULTS: No differences were found in the mean concentration of enflurane during the anaesthesia procedures. The leakage rates of endotracheal intubation anaesthesia were the lowest. DISCUSSION: In unventilated work areas, it was not possible to lower the exposure of the personnel by changing the method of anaesthesia. The application of procedures like double or laryngeal masks does not avoid the need for installation of air-conditioning systems in all work areas were anaesthesia is performed.

Effects of epinephrine on glucose metabolism in patients with alcoholic cirrhosis.

The cirrhotic liver has been shown to be resistant to the actions of various glucoregulatory hormones. The objective of this study was to investigate the effects of epinephrine on hepatic glucose metabolism in cirrhotic patients. Thirteen cirrhotic and eight healthy subjects were studied. Hepatic glucose production and turnover of alanine and glycerol were measured using stable isotope technique before and during 70 and 150 minutes of epinephrine infusion (0.1 microgram/kg/min). beta-Adrenoreceptor binding sites and affinity in mononuclear leukocyte membranes also were determined. Hepatic glucose production and alanine turnover in normals significantly increased during epinephrine infusion, but did not change in cirrhotics. Glycerol turnover increased after 70 minutes of epinephrine infusion in both groups. Epinephrine induced a significant rise of high-affinity beta-adrenoreceptor binding sites in normals, yielding a significant correlation between hepatic glucose production and receptor density (r = .94, P < .0001). In cirrhotic patients, similar changes in the number of high-affinity beta-adrenoreceptors were observed, but no correlation with hepatic glucose production was detected. The cirrhotic liver did not respond normally to the stimulatory effect of epinephrine on hepatic glucose production. Because this blunted response was not related to changes of beta-adrenoreceptors, our findings suggest that epinephrine resistance in cirrhosis was caused by a postreceptor defect.

[Is infection and septic shock caused by a global oxygen deficiency? An overview in 2 parts. 1: Infection and correlation between DO2 and VO2]. / Liegt der Sepsis und dem septischen Schock ein globaler Sauerstoffmangel zugrunde? Eine Ubersicht in zwei Teilen. Teil 1: Sepsis und Zusammenhang zwischen DO2 und VO2.

A global hypoxia resulting in an oxygen debt is assumed to be present in patients who suffer from the different stages and degrees of sepsis including septic shock and ARDS. As a consequence, the therapeutic concept of optimal values for cardiac output and oxygen delivery for these patients was proposed. This article reviews the literature with the objective of determining whether investigations dealing with oxygen delivery and consumption and with the plasma lactate concentration support the idea of the global hypoxia in septic patients. The finding of a pathologic oxygen supply dependency and an increase in plasma lactate concentration were taken as evidence for a global hypoxia. Between 1983 and 1991, oxygen supply dependency in septic patients was reported in an increasing number of publications. The increase in plasma lactate concentration was interpreted as lactic acidosis without presentation of plasma pH values and taken as evidence of global hypoxia and oxygen debt. From 1989 on, the number of publications that failed to show oxygen supply dependency even in the presence of an increased plasma lactate concentration increased. The problem in the method of determination of oxygen supply dependency became evident. Deducing both oxygen consumption and oxygen delivery from cardiac output from a common shared variable subject to measurement error may produce errors in the calculation of the regression between oxygen delivery and consumption. Oxygen supply dependency was not demonstrated in most investigations in which oxygen delivery and consumption were measured independently of each other. No decrease in mortality could be shown in prospective randomized studies for patients with sepsis and septic shock who were treated according to the concept of the optimal values. The lactate plasma concentration was below 5 mmol/l in most studies, which represents the borderline value for a clinically significant lactic acidosis. The term acidosis is not justified without a decrease in plasma pH or a decrease in the bicarbonate plasma concentration. An increased lactate plasma concentration can be merely the result of a hypermetabolism which is often found in septic patients. There is no proven evidence for global tissue hypoxia in septic patients from the investigations of oxygen delivery and consumption. This is also true for patients in septic shock after plasma volume expansion. The dogmatic proposal to increase cardiac output and oxygen delivery to certain levels cannot be sustained. However, regional hypoperfusion (e.g., of the splanchnic vascular bed) cannot be excluded. New approaches like gastric mucosal tonometry, measurement of splanchnic blood flow, and determination of regional metabolism are currently under investigation.

Glycerol metabolism in patients with alcohol-induced liver cirrhosis.

The clearance rate of glycerol has been found to be impaired in alcoholic liver disease. However it remains unclear, if this can be ascribed to a defect of hepatic gluconeogenesis. Thus, the purpose of this work was to investigate glycerol clearance and hepatic glucose production in patients with liver cirrhosis. 13 patients with alcohol-induced Child B cirrhosis and 8 healthy volunteers were studied. Rates of appearance (R(a)) of glycerol, glucose and alanine were determined using stable isotope techniques. In addition indocyanine green clearance (ICGC) and plasma substrate concentrations were measured. Clearance rates were calculated as R(a) divided by the corresponding substrate concentration. R(a) of glycerol in patients was not different from controls, but glycerol clearance was significantly reduced (29 +/- 3 vs. 41 +/- 4 ml/kg/min). No differences in R(a) of glucose and alanine and corresponding plasma concentrations were observed. ICGC in patients was about 35% lower than reference values. Diminished glycerol clearance in patients with liver cirrhosis was not due to impaired hepatic gluconeogenesis. Since glycerol is almost completely extracted by the liver decreased glycerol clearance possibly simply reflected compromised liver perfusion as seen by reduced ICGC.

Pramipexole binding and activation of cloned and expressed dopamine D2, D3 and D4 receptors.

Pramipexole (SND 919; 2-amino-4,5,6,7-tetrahydro-6-propylamino-benzthiazole-dihydrochlor ide) is a potent dopamine autoreceptor agonist. We have carried out an analysis of the binding affinities of dopamine D2L, D2S, D3, and D4 receptors for pramipexole using both [3H]pramipexole and [3H]spiperone as radioligands at cloned and heterologously expressed receptors. Studies were carried out using rat and human D2L, D2S and D3 receptors with equivalent results. When the binding of pramipexole to the high affinity, guanine nucleotide-sensitive state of each receptor was analyzed, pramipexole is most selective for D3 compared to D2 and D4 receptors. These results indicate a 5-fold selectivity of pramipexole for D3 receptors, while quinpirole and bromocriptine are non-selective or more D2/D4 receptor selective. Two measurements of receptor activation for dopamine D2, D3, and D4 receptors also show that pramipexole is most potent for activation of D3 receptors. The dopamine D3 receptor selectivity of pramipexole may explain the previously described properties of this drug, including its potent autoreceptor preference.

Are the effects of noradrenaline, adrenaline and dopamine infusions on VO2 and metabolism transient?

OBJECTIVE: To determine whether noradrenaline, adrenaline and dopamine have persistent actions on VO2 and metabolism. DESIGN: Descriptive laboratory investigation. SETTING: Laboratory of the Department of Anaesthesiology at a University Hospital. SUBJECTS: 9 volunteers. INTERVENTION: VO2 and the plasma concentration of glucose and free fatty acids were measured prior to and during a 4 h infusion of saline (control), noradrenaline (0.14 microgram/kg min) adrenaline (0.08 microgram/kg min) or dopamine (7 micrograms/kg min), n = 9 each. VO2 was measured using an open circuit gas exchange system. MEASUREMENTS AND MAIN RESULTS: VO2 increased from 250 +/- 22 ml/min to 280 +/- 38 ml/min during noradrenaline, to 298 +/- 30 ml/min during adrenaline and to 292 +/- 39 ml/min during dopamine infusion. The plasma glucose concentration increased from 6.2 +/- 0.6 mmol/l to 8.8 +/- 0.8 mmol/l, 13.2 +/- 1.4 and 7.3 +/- 0.4 mmol/l during infusion of noradrenaline, adrenaline or dopamine, respectively. The plasma free fatty acid concentration increased from 0.28 +/- 0.10 mmol/l to 0.79 +/- 0.21 mmol/l during noradrenaline and to 0.52 +/- 0.09 mmol/l during dopamine. In contrast, free fatty acid values averaged baseline values at the end of the adrenaline infusion after an initial increase to 0.72 +/- 0.31 mmol/l. CONCLUSIONS: Administration of noradrenaline, adrenaline or dopamine resulted in persistent increases in VO2 in volunteers. With the exception of the transient adrenaline effect on fatty acids the metabolic actions were steady during 4 h of adrenergic stimulation. Since the adrenergic effect on VO2 is persistent over time a similar action in patients (e.g. septic shock) during treatment with adrenoceptor agonists may be important. Thus, an increase in VO2 during therapy may not only reflect an oxygen debt but also a pharmacodynamic action of adrenoceptor mediated calorigenic and metabolic induction.

Glucose and urea production and leucine, ketoisocaproate and alanine fluxes at supraphysiological plasma adrenaline concentrations in volunteers.

OBJECTIVE: To determine the magnitude and time course of adrenergic effects on metabolism in volunteers and possible implications for the use of sympathomimetics in the critically ill. DESIGN: Descriptive laboratory investigation. SUBJECTS: 7 volunteers. INTERVENTION: Primed continuous infusions of stable isotope tracers ([15N2]-urea, [6,6-D2]-glucose, [methyl-D3]-L-leucine, [15N]-L-alanine) were used. After isotopic steady state had been reached an infusion of adrenaline (0.1 microgram/kg/min) was administered (4 h). Isotopic enrichment was measured using gas chromatography-mass spectrometry and the corresponding rates of appearance were calculated. MEASUREMENTS AND MAIN RESULTS: Glucose production increased from 14.1 +/- 1.2 to 21.5 +/- 2.0 mumol/kg/min (p < 0.05) after 80 min of adrenergic stimulation and then decreased again to 17.9 +/- 1.2 mumol/kg/min after 240 min. Leucine and ketoisocaproate (KIC) fluxes were 2.3 +/- 0.2 and 2.6 +/- 0.2 mumol/kg/min, respectively, at baseline and gradually decreased to 1.8 +/- 0.2 and 2.2 +/- 0.1 mumol/kg/min, respectively, after 240 min of adrenaline infusion (both p < 0.05). Alanine flux increased from 3.7 +/- 0.5 to 6.9 +/- 0.9 mumol/kg/min (p < 0.05) after 80 min of adrenergic stimulation. Urea production slightly decreased from 4.8 +/- 0.9 to 4.3 +/- 0.8 mumol/kg/min during adrenaline (p < 0.05). CONCLUSIONS: Adrenaline induced an increase in glucose production lasting for longer than 240 min. The decrease in leucine and KIC flux suggests a reduction in proteolysis, which was supported by the decrease in urea production. The increase in alanine flux is therefore most likely due to an increase in de-novo synthesis. The ammonia donor for alanine synthesis in peripheral tissues and the target for ammonia after alanine deamination in the liver remain to be investigated. These results indicate that adrenaline infusion most probably will not promote already enhanced proteolysis in critically ill patients. Gluconeogenesis is an energy consuming process and an increase may deteriorate hepatic oxygen balance in patients.