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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.

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.

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.Descriptive laboratory investigation.7 volunteers.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.Glucose production increased from 14.1 +/- 1.2 to 21.5 +/- 2.0 mumol/kg/min (p0.05) 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 p0.05). Alanine flux increased from 3.7 +/- 0.5 to 6.9 +/- 0.9 mumol/kg/min (p0.05) 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 (p0.05).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.

The purpose of this study was to assess whether plasma adrenocorticotropin, cortisol, vasopressin, and renin concentrations are higher in resuscitated than in nonresuscitated patients during cardiopulmonary resuscitation, and whether there are possible correlations between these hormones and blood pressure or heart rate in the immediate postresuscitation phase. Of 34 consecutive patients (36-85 yr of age) with out-of-hospital cardiac arrest, 20 could be successfully resuscitated and admitted to hospital, whereas in the remaining 14 patients restoration of spontaneous circulation could not be achieved. During cardiopulmonary resuscitation, median adrenocorticotropin, cortisol, vasopressin, and renin concentrations in the external jugular vein were 237 pg/ml, 32.6 micrograms/dl, 122 pg/ml, and 46.5 ng/l, respectively, in resuscitated patients, and 45 pg/ml (P = 0.018), 18.4 micrograms/dl (P = 0.481), 88 pg/ml (P = 0.049), and 11 ng/l (P = 0.017), respectively, in nonresuscitated patients. Median adrenocorticotropin, cortisol, vasopressin, and renin concentrations were 101 pg/ml, 34.6 micrograms/dl, 22 pg/ml, and 25 ng/l, respectively, 60 min after successful resuscitation. No significant correlations were found between hormone levels and blood pressure or heart rate, but there was a significant negative correlation between the interval from collapse to the start of cardiopulmonary resuscitation and plasma cortisol concentrations during cardiopulmonary resuscitation (Spearman rank correlation coefficient = -0.967, P less than 0.001), indicating an impaired cortisol release from the adrenal cortex. The lower hormone concentrations of the nonresuscitated patients measured during cardiopulmonary resuscitation might indicate an impairment in neuroendocrine response.

To determine the relationship between iv infusion rate, plasma concentrations, and hemodynamic and metabolic actions of norepinephrine.Norepinephrine was administered by using five iv infusion rates (0.01 to 0.2 micrograms/kg/min) for 30 mins each to eight volunteers, for the purpose of constructing cumulative plasma concentration-response curves.Laboratory of the Department of Anesthesiology at a university hospital.Systolic and diastolic BP, heart rate, and the plasma concentrations of norepinephrine, glucose, nonesterified fatty acids, and insulin were measured at the end of each infusion rate. During the highest infusion rate, plasma norepinephrine concentrations increased from 199 +/- 75 to 7475 +/- 1071 pg/mL (1.18 +/- 0.44 to 44.18 +/- 6.33 nmol/L). Typical hemodynamic responses, such as increases in BP and decreases in heart rate, were seen, while the plasma concentrations of glucose and nonesterified fatty acids increased from 92 +/- 10 to 132 +/- 17 mg/dL (5.1 +/- 0.6 to 7.3 +/- 0.9 mmol/L) and 11 +/- 4 to 34 +/- 6 mg/dL (0.11 +/- 0.04 to 0.34 +/- 0.06 g/L), respectively, during the 0.2 micrograms/kg/min infusion rate (p less than .05). Despite the increase in glucose concentration, insulin remained at baseline values. Metabolic and hemodynamic effects occurred at similar plasma concentrations throughout the study.Administration of norepinephrine showed no selective hemodynamic actions. The metabolic responses observed in this investigation were similar to those responses seen during increased endogenous sympathetic nervous system activity, such as stress, exercise, or trauma.

Objectives To measure plasma catecholamine concentrations after cardiopulmonary resuscitation (CPR) and to correlate catecholamine concentrations with heart rate (HR), BP, and plasma glucose and lactate concentrations. Design Prospective, descriptive study. Setting Emergency medical service at a University Hospital. Patients Ten patients (58 to 85 yrs) with out-of-hospital cardiac arrest. Interventions At 1, 5, 15, 30, and 60 mins after restoration of spontaneous circulation, blood samples were drawn and BP and HR were measured. Plasma catecholamine concentrations were measured by high-pressure liquid chromatography and plasma glucose and lactate concentrations were measured by enzymatic methods. Main results Median plasma epinephrine and norepinephrine concentrations were 136.3 micrograms/L (136,300 pg/mL), range 27.6 to 397.6 micrograms/L (27,600 to 397,600 pg/mL), and 4.7 micrograms/L (4700 pg/mL), range 1.8 to 14.5 micrograms/L (1800 to 14,500 pg/mL), respectively, at 1 min. Median plasma epinephrine and norepinephrine concentrations decreased to 8.7 micrograms/L (8700 pg/mL), range 1.2 to 55.0 micrograms/L (1200 to 55,000 pg/mL) and 1.9 micrograms/L (1900 pg/mL), range 1.3 to 5.8 micrograms/L (1300 to 5800 pg/mL), respectively, at 60 mins after restoration of spontaneous circulation. Epinephrine concentrations decayed with a semilogarithmic decay pattern. The half-life for the alpha phase was 2.2 mins and was 38.7 mins for the beta phase. Mean values of systolic arterial pressure were between 136 +/- 23 mm Hg at 1 min and 120 +/- 15 mm Hg at 30 mins. Median plasma glucose concentrations were between 8.2 mmol/L (147.7 mg/dL; range 5.8 to 11.2 mmol/L [104.5 to 201.8 mg/dL]) at 1 min and 13.9 mmol/L (250.4 mg/dL; range 9.7 to 16.6 mmol/L [174.8 to 299.1 mg/dL]) at 30 mins. Lactate values were between 11.4 mmol/L (range 4.7 to 16.5) at 1 min and 5.2 mmol/L (range 2.7 to 12.5) at 60 mins. No significant correlations were found between circulating catecholamine concentrations and the other variables. Conclusions After CPR, plasma catecholamine concentrations remained at high values but they did not lead to increases in BP, HR, or circulating glucose concentrations.

Background and methods Calcium-channel blockers may attenuate vasospasm after transient ischemia and improve organ blood flow after resuscitation. Our aim was to assess the effect of diltiazem on systemic oxygen delivery and consumption, hemodynamics, electroencephalogram (EEG), and organ blood flow after restoration of spontaneous circulation. After a 3-min period of asphyxial cardiac arrest, 14 pigs (20 to 27 kg) were randomly allocated to treatment with either diltiazem (0.1 mg/kg bolus followed by an iv infusion of 0.025 mg/min/kg over 120 mins) or placebo, given at 5 mins after successful resuscitation. Organ blood flow was measured using tracer microspheres 120 mins after resumption of spontaneous circulation. Results Median systemic oxygen delivery index values at 30, 60, and 120 mins after restoration of spontaneous circulation were 18.2 mL/min/kg (range 14.8 to 20.7), 16.8 mL/min/kg (13.2 to 20.8), and 19.6 mL/min/kg (16.9 to 21.0), respectively, in the diltiazem group and 13.1 mL/min/kg (11.2 to 14.6), 11.9 mL/min/kg (10.3 to 13.3), and 14.7 mL/min/kg (11.4 to 17.2), respectively, in the control group (p less than .05 for all three comparisons). At the same points in time, median systemic oxygen consumption indices were 3.2 mL/min/kg (range 2.2 to 3.7), 2.1 mL/min/kg (1.9 to 3.0), and 2.6 mL/min/kg (1.8 to 3.8) in the diltiazem group and 2.8 mL/min/kg (2.1 to 4.0), 2.7 mL/min/kg (1.7 to 4.3), and 2.3 mL/min/kg (1.6 to 3.8) in the placebo group (NS). Diltiazem enhanced the postarrest recovery of EEG total power. Right and left cerebral blood flow 120 mins after restoration of spontaneous circulation was significantly (p less than .01) higher in the diltiazem group in comparison with the control group. Conclusions Diltiazem causes an increase in systemic oxygen delivery index by promoting vasodilation, but it does not change systemic oxygen consumption index in comparison to placebo treatment. It may be that an impairment in local autoregulation and/or in oxidative metabolism at the cellular or subcellular level was the reason why diltiazem did not improve these derangements. The observed increase in cerebral blood flow and in EEG recovery may be beneficial to the brain after a period of asphyxia.

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.

The objective of the present study was to evaluate the effects of norepinephrine (n = 9) and dobutamine (n = 7) on carbohydrate and protein metabolism in healthy volunteers in comparison with a control group (n = 9). Norepinephrine (0.1 microg/kg min), dobutamine (5 microg/kg min), or placebo was infused for 240 min. The plasma concentration of glucose, lactate, epinephrine, norepinephrine, insulin, and glucagon were determined. Glucose and urea production and leucine flux were measured using a tracer technique. Norepinephrine caused a persisting rise in plasma glucose concentration, whereas the increase in glucose production was only transient. A minor increase in plasma lactate concentration was observed, but it did not exceed the physiological range. No change in leucine flux, urea production, or plasma concentration of insulin, glucagon, or epinephrine was found. Dobutamine slightly decreased glucose production, whereas the plasma concentration of glucose and lactate did not change. The reduction in leucine flux was paralleled by a decrease in urea production. No change in the plasma concentration of insulin, glucagon, or the catecholamines was observed. In conclusion, both norepinephrine and dobutamine have only minor metabolic effects. Because glucose production is enhanced by alpha1- and beta2-adrenoceptor stimulation, we conclude that dobutamine is only a weak agonist at these adrenoceptors. These minor metabolic actions may make both compounds suitable for critically ill patients because no further increase in metabolic rate should be caused.

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.

As we have shown earlier (-)125Iodocyanopindolol (125ICYP) binding to beta-adrenoceptors (beta-AR) in human mononuclear leucocytes (MNL) yields evidence for the existence of high affinity (Bhiaff) and low affinity (Bloaff) binding sites. We studied the regulation of these 2 classes of binding sites during 240 min of (-)-epinephrine (EPI) infusion (0.1 microgram/kg/min) (n = 8) in male healthy volunteers. Saturation experiments were performed on MNL membranes with 125ICYP over a large concentration range (1-550 pmol/l). Binding parameters were calculated by computer analysis assuming 2 classes of binding sites. We found a preinfusion value of 830 +/- 50 [sites/cell] (KD = 1.5 +/- 0.2 pmol/l) of Bhiaff binding sites and 5210 +/- 510 [sites/cell] (KD = 420 +/- 80 pmol/l) of Bloaff. During EPI infusion we observed biphasic modulation of the Bhiaff and an inverse modulation of the Bloaff. After 40 min of EPI Bhiaff increased to 1970 +/- 280 [sites/cell] (KD = 4.2 +/- 0.8 pmol/l), whereas Bloaff decreased to 2720 +/- 280 [sites/cell] (KD = 140 +/- 70 pmol/l); despite constant plasma epinephrine concentration (PEC) after 240 min of EPI Bhiaff changed to 1310 +/- 240 [sites/cell] (KD = 2.8 +/- 1.0 pmol/l) vs. 4370 +/- 760 [sites/cell] (KD = 190 +/- 100 pmol/l) Bloaff. These results suggest an interdependent inverse modulation of the 2 classes of binding sites for 125ICYP on MNL during EPI infusion.

BACKGROUND AND METHODS This study was designed to assess the effect of epinephrine during cardiopulmonary resuscitation (CPR) on left ventricular myocardial blood flow, systemic oxygen delivery and consumption, and on plasma glucose and lactate concentrations. Fourteen pigs were allocated to receive either 0.9% saline (n = 7), or 45 micrograms/kg epinephrine (n = 7) after 5 mins of ventricular fibrillation, and 3 mins of open-chest CPR. Left ventricular myocardial blood flow was measured with radiolabeled microspheres. Plasma catecholamine concentrations were measured by high-pressure liquid chromatography. RESULTS During open-chest CPR, mean (+/- SD) values of left ventricular myocardial blood flow before, 90 secs, and 5 mins following drug administration were 49 +/- 10, 46 +/- 12, 43 +/- 15 mL/min/100 g, respectively, in the control group, and 52 +/- 12, 118 +/- 21, 84 +/- 28 mL/min/100 g, respectively, in the epinephrine group (p less than .05 at 90 secs and 5 mins). At the same time points, mean (+/- SD) oxygen delivery indices were 7.7 +/- 3.0, 6.0 +/- 2.1, 6.5 +/- 2.7 mL/min/kg in the control group and 7.6 +/- 2.5, 5.3 +/- 2.1, 5.5 +/- 1.9 mL/min/kg in the epinephrine group (nonsignificant). Mean oxygen consumption indices were 5.8 +/- 2.4, 4.6 +/- 1.6, 5.2 +/- 2.6 mL/min/kg in the control group and 5.4 +/- 1.6, 4.2 +/- 1.6, 4.4 +/- 1.4 mL/min/kg in the epinephrine group (nonsignificant). During CPR and before epinephrine administration, arterial plasma epinephrine concentrations increased from prearrest values of 0.77 +/- 0.70 to 62.1 +/- 48.7 micrograms/L, and plasma norepinephrine concentrations increased from 0.28 +/- 0.32 to 104.3 +/- 57.1 micrograms/L. After administered epinephrine, there was an additional increase to 271 +/- 83 micrograms/L at 90 secs in arterial plasma epinephrine, but no important alteration in the plasma norepinephrine concentration. At no time point could we find a clinically important difference in plasma glucose or lactate concentrations between the two groups. CONCLUSIONS At a dose of 45 micrograms/kg, epinephrine caused an increase in left ventricular myocardial blood flow after a total of 8 mins of cardiac arrest, including 3 mins of CPR, while not altering systemic oxygen delivery and consumption, plasma glucose, or lactate concentrations.

Noradrenaline and adrenaline were infused IV at 5 different rates (0.01-0.2 micrograms.kg.min-1) for 30 min to volunteers. The plasma catecholamine concentrations were determined by HPLC and electro-chemical detection. At the highest infusion rate, the arterial and venous plasma concentrations of noradrenaline increased from 1.18 to 44.1 nmol.l-1 and from 1.14 to 31.9 nmol.l-1, respectively, and of adrenaline from 0.29 to 23.9 nmol.l-1 and from 0.28 to 19.3 nmol.l-1, respectively. The peripheral venous plasma concentration of noradrenaline averaged 76% of the arterial concentration, and of adrenaline it was 73%. There was a linear relationship between the peripheral venous and arterial plasma noradrenaline and adrenaline concentrations at therapeutic doses.

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.

In contrast to its preserved stimulatory effect on lipolysis epinephrine failed to enhance hepatic glucose production in cirrhotic patients. Since this blunted response was not related to changes of s-adrenoreceptors our findings suggest that epinephrine resistance in cirrhosis was due to a postreceptor defect.

To determine the relationships between plasma concentrations of norepinephrine, epinephrine, and dopamine and oxygen consumption (VO2) during infusion of these catecholamines.Prospective, randomized variable dose, pharmacologic study in which a noncumulative infusion-rate design was used.Laboratory of the Department of Anesthesiology at a University Hospital.Twenty-one normal volunteers.After a control period of 20 mins, norepinephrine (three infusion rates; 0.06 to 0.2 microgram/kg/min; n = 7), epinephrine (four infusion rates; 0.02 to 0.2 microgram/kg/min; n = 7), or dopamine (three infusion rates; 3 to 12 micrograms/kg/min; n = 7) was administered to normal volunteers (n = 21) for the purpose of constructing plasma concentration/VO2 response curves.Systolic and diastolic blood pressure, heart rate, plasma concentrations of norepinephrine, epinephrine, and dopamine, and VO2 were measured at the end of the control period and at the end of each catecholamine infusion. VO2 was measured using a ventilated canopy system and a differential oxygen sensor. Typical hemodynamic responses to vasopressors were seen during adrenergic receptor agonist infusions. VO2 increased from 132 +/- 7 to 153 +/- 10 mL/min/m2 during the highest infusion rate of norepinephrine, from 133 +/- 7 to 182 +/- 11 mL/min/m2 during the highest infusion rate of epinephrine, and from 132 +/- 13 to 163 +/- 8 mL/min/m2 during the highest infusion rate of dopamine (p.05; paired t-test). Increases in VO2 were correlated with the logarithms of the corresponding plasma catecholamine concentrations. Effects on VO2 and hemodynamic responses occurred at similar plasma concentrations for each of the three catecholamines.Administration of norepinephrine, epinephrine, or dopamine results in marked increases in VO2 in volunteers. In patients, the administration of catecholamines or sympathomimetics to attain optimal values of cardiac index, oxygen delivery (DO2), and VO2 may increase the oxygen demand and thus obscure the DO2-VO2 relationship.

We have studied the effects of bremazocine on the peripheral sympathetic nervous system and the arterial blood pressure of pithed rabbits with electrically (2 Hz) stimulated sympathetic outflow, and compared them with the effects of Leu-enkephalin and fentanyl. The 3H-noradrenaline plasma clearance and the plasma concentration of noradrenaline were used to calculate the rate of spillover of endogenous noradrenaline into the plasma; the spillover rate reflects the overall release of noradrenaline from postganglionic sympathetic neurones. Bremazocine (10 and 100 micrograms kg-1, followed by an infusion of 2 and 20 micrograms kg-1 h-1, respectively, i.v.) persistently decreased the noradrenaline spillover rate as well as blood pressure. Both effects were antagonized by naloxone. Leu-enkephalin (70 and 350 micrograms kg-1 min-1 i.v.) caused only transient hypotension. Fentanyl decreased blood pressure only at a very high dose (250 micrograms kg-1, followed by an infusion of 500 micrograms kg-1 h-1 i.v.). The effects of Leu-enkephalin and fentanyl were also antagonized by naloxone. When the blood pressure of pithed rabbits was raised by an intravenous infusion of noradrenaline, rather than by electrical stimulation, bremazocine, Leu-enkephalin, and fentanyl failed to produce hypotension. The results indicate that bremazocine inhibits the release of noradrenaline and, in consequence, lowers arterial pressure by activation of peripheral, probably prejunctional, opioid receptors. The receptors appear to be of the kappa-type.