Epinephrine plasma thresholds for lipolytic effects in man: measurements of fatty acid transport with [l-13C]palmitic acid.

To determine the plasma epinephrine thresholds for its lipolytic effect, 60-min epinephrine infusions at nominal rates of 0.1, 0.5, 1.0, 2.5, and 5.0 micrograms/min were performed in each of four normal young adult men while they also received a simultaneous infusion of [1-13C]palmitic acid to estimate inflow transport of plasma free fatty acids. These 20 infusions resulted in steady-state plasma epinephrine concentrations ranging from 12 to 870 pg/ml. Plasma epinephrine thresholds for changes in blood glucose, lactate, and beta-hydroxybutyrate were in the 150--200-pg/ml range reported by us previously (Clutter, W. E., D. M. Bier, S. D. Shah, and P. E. Cryer. 1980. J. Clin. Invest. 66: 94--101.). Increments in plasma glycerol and free fatty acids and in the inflow and outflow transport of palmitate, however, occurred at lower plasma epinephrine thresholds in the range of 75 to 125 pg/ml. Palmitate clearance was unaffected at any steady-state epinephrine level produced. These data indicate that (a) the lipolytic effects of epinephrine occur at plasma levels approximately threefold basal values and (b) lipolysis is more sensitive than glycogenolysis to increments in plasma epinephrine.     

Early metabolic and splanchnic responses to enteral nutrition in postoperative cardiac surgery patients with circulatory compromise

OBJECTIVES: To assess the hemodynamic and metabolic adaptations to enteral nutrition (EN) in patients with hemodynamic compromise. DESIGN AND SETTING: Prospective study in a university hospital surgical ICU, comparing baseline (fasted) with continuous EN condition. PATIENTS: Nine patients requiring hemodynamic support by catecholamines (dobutamine and/or norepinephrine) 1 day after cardiac surgery under cardiopulmonary bypass. INTERVENTION: Isoenergetic EN via a postpyloric tube while catecholamine treatment remained constant. Baseline (fasted) condition was compared to continuous EN condition. MEASUREMENTS AND MAIN RESULTS: Cardiac index (CI), mean arterial pressure (MAP), pulmonary and wedge pressures, indocyanine green (ICG) clearance, gastric tonometry, plasma glucose and insulin, and glucose turnover (6,62H2-glucose infusion) were determined repetitively every 60 min during 2 h of baseline fasting condition and 3 h of EN. During EN CI increased (from 2.9 +/- 0.5 to 3.3 +/- 0.5 l min-1 m-2), MAP decreased transiently (from 78 +/- 7 to 70 +/- 11 mmHg), ICG clearance increased (from 527 +/- 396 to 690 +/- 548 ml/min), and gastric tonometry remained unchanged, while there were increases in glucose (158 +/- 23 to 216 +/- 62 mg/dl), insulin (29 +/- 23 to 181 +/- 200 mU/l), and glucose rate of appearance (2.4 +/- 0.2 to 3.3 +/- 0.2 mg min-1 kg-1). CONCLUSIONS: The introduction of EN in these postoperative patients increased CI and splanchnic blood flow, while the metabolic response indicated that nutrients were utilized. These preliminary results suggest that the hemodynamic response to early EN may be adequate after cardiac surgery even in patients requiring inotropes.     

Vascular and metabolic effects of circulating epinephrine and norepinephrine. Concentration-effect study in dogs.

Vascular and metabolic effects of circulating epinephrine and norepinephrine have been studied in relation to the plasma concentration of these amines in dogs. Intravenous infusion of epinephrine or norepinephrine (0.1, 0.5, and 2.5 nmol x kg-1 x min-1) raised the plasma concentration of the infused amine by 2.5 , 13, and 63 nM from resting levels of 2.4 and 3.6 nM, respectively. Blood flow to isolated adipose tissue; skeletal muscle preparations; and plasma levels of glycerol, glucose, and cyclic AMP were measured. Epinephrine and norepinephrine displayed a distinct selectivity with regard to both vascular and metabolic effects. Epinephrine caused significant vasoconstriction in adipose tissue already at a plasma concentration of 5 nM, whereas no significant effect was seen on skeletal muscle vascular resistance. Norepinephrine, on the other hand, caused significant vasoconstriction in skeletal muscle at 5 nM but had no vasoconstrictor effect in adipose tissue. Epinephrine was more potent than norepinephrine in increasing plasma cyclic AMP and glucose, whereas the converse was true for plasma glycerol. Epinephrine had significant effects on plasma cyclic AMP at 5 nM and on plasma glucose and glycerol at 15 nM. Norepinephrine, on the other hand, had significant effects on plasma glycerol at 5 nM, plasma cyclic AMP at 15 nM and plasma glucose only at 65 nM. It is suggested that these response patterns are related to a preferential action of epinephrine on beta 2-adrenoceptors and a preferential action of norepinephrine on beta 1-adrenoceptors. Our results support the view that both epinephrine and norepinephrine may act as circulating hormones, because vascular and metabolic effects of both amines were seen at plasma concentrations encountered during various kinds of stress in animals and man.     

Cholinergic Stimulation of Norepinephrine Release in Man: EVIDENCE OF A SYMPATHETIC POSTGANGLIONIC AXONAL LESION IN DIABETIC ADRENERGIC NEUROPATHY

Amplification of endogenous cholinergic activity-produced by the intravenous injection of edrophonium, an acetylcholinesterase inhibitor which does not enter the central nervous system, into normal subjects-resulted in significant and briefly sustained increments in the plasma concentrations of norepinephrine (153+/-15-234+/-29 pg/ml, P < 0.01) and epinephrine (16+/-3-34+/-5 pg/ml, P < 0.01) measured with a single-isotope derivative method. These increments were not attributable to reflex responses to hemodynamic changes and similar increments in plasma norepinephrine occurred in adrenalectomized (epinephrine deficient) patients. Thus, cholinergic activation results in direct stimulation of sympathetic postganglionic neurons, with augmented norepinephrine release, and of the adrenal medullae, with augmented epinephrine release, in man. Four diabetic patients with hypoadrenergic postural hypotension exhibited blunted sympathetic postganglionic neural responses, and normal adrenomedullary responses, to cholinergic stimulation (and to standing) indicative of the presence of a sympathetic postganglionic axonal lesion in diabetic adrenergic neuropathy. Nondiabetic patients with hypoadrenergic postural hypotension due to documented or probable central nervous system lesions exhibited normal responses to cholinergic stimulation produced in this fashion demonstrating the presence of intact sympathetic postganglionic neurons and adrenal medullae in these patients and providing further support for the conceptual soundness of this approach to the study of human adrenergic physiology and pathophysiology.     

Pharmacokinetic studies of 5-fluorouracil and 5'-deoxy-5-fluorouridine in rats

The pharmacokinetics of 5-fluorouracil (FU) and its metabolic prodrug, 5'-deoxy-5-fluorouridine (dFUR), were investigated in 5- to 9-month-old rats without tumors. Intravenous bolus injections and infusions of FU (25-35 mg X kg-1) and dFUR (500-750 mg X kg-1) had activity against transplanted colon tumors in 2- to 4-month-old rats. Blood and plasma concentrations of FU and dFUR were analyzed by high-pressure liquid chromatography using 5-bromouracil as the internal standard. Free fractions of these drugs in plasma were indistinguishable from unity, indicating little or no protein binding. The area under the blood concentration-time profiles and the steady-state concentrations of unchanged dFUR were 40- to 100-fold higher than those of unchanged FU. The respective blood clearances of FU and dFUR were 44 and 18 ml X kg-1 X min-1 after i.v. bolus injections, which were significantly lower than the 108 and 26 ml X kg-1 X min-1 after infusion. FU clearance decreased when its infusion rate was increased from 25 to 50 mg X kg-1 X day-1. Renal clearances of both drugs remained the same after either route of administration. These data suggest that both drugs were eliminated by nonlinear kinetics and that their metabolism was saturated at a more rapid administration rate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic and cardiovascular effects of infusions of low doses of isoprenaline in man

1. The cardiovascular and metabolic responses to low doses of isoprenaline (15 and 5 ng min-1 kg-1 body weight infused over 30 min) were determined in six healthy males. The study was performed to investigate whether there were sustained effects after the termination of the isoprenaline infusion, as has been observed previously after the infusion of adrenaline. 2. The isoprenaline infusions produced dose-dependent increases in heart rate, systolic blood pressure and metabolic rate, but similar increases in calf blood flow and decreases in diastolic blood pressure for the two infusion rates. Finger tremor was increased in amplitude by the 15 ng min-1 kg-1 infusion only. The changes in each of these physiological variables largely resolved within a few minutes of discontinuing the isoprenaline infusions. 3. There were no changes in arterialized venous plasma adrenaline or noradrenaline levels during the isoprenaline infusions. Mean peak plasma isoprenaline levels were 0.16 +/- 0.02 nmol/l during the 5 ng min-1 kg-1 infusion and 0.71 +/- 0.05 nmol/l during the 15 ng min-1 kg-1 infusion. 4. Plasma insulin levels increased with isoprenaline but blood glucose concentrations were unchanged, consistent with a direct effect of isoprenaline on beta 2-adrenoceptors mediating insulin release from pancreatic beta-cells. Blood glycerol concentration also increased with isoprenaline but blood lactate concentration was unaltered. 5. The present study demonstrates pronounced cardiovascular and metabolic effects of low dose isoprenaline infusions. Differences in the rate of resolution of the changes induced by isoprenaline and by adrenaline seen in previous studies may result from a significant difference in their metabolism.     

Relationship between infusion rates, plasma concentrations, and cardiovascular and metabolic effects during the infusion of norepinephrine in healthy volunteers.

OBJECTIVE: To determine the relationship between iv infusion rate, plasma concentrations, and hemodynamic and metabolic actions of norepinephrine. DESIGN: 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. SETTING: Laboratory of the Department of Anesthesiology at a university hospital. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.     

Postsynaptic alpha 1- and alpha 2-adrenoceptors in human blood vessels: interactions with exogenous and endogenous catecholamines

The relative efficacy of epinephrine and norepinephrine on vascular alpha 1- and alpha 2-adrenoceptors and also the difference in vasoconstriction induced by exogenous norepinephrine as opposed to neuronally released norepinephrine were studied in the forearm of healthy volunteers. Intra-arterial cumulative dose infusions of epinephrine and norepinephrine (0.6, 1.6 and 4.0 ng kg-1 min-1) were given in the presence of saline, the selective alpha 1-antagonist doxazosin (0.1 microgram kg min-1) the selective alpha 2-antagonist yohimbine (1.0 microgram kg min-1) and the combination of both antagonists. beta-Adrenoceptor-mediated effects were prevented by a concomitant i.a. infusion of propranolol (1.0 microgram kg-1 min-1). Forearm blood flow (FBF) was measured before each infusion and at the end of each dose step. Neuronal norepinephrine was released by i.a. infusion of tyramine in three cumulative doses (0.25, 0.50 and 1.25 micrograms kg-1 min-1) and by lower body negative pressure (LBNP, -40 mmHg for 5 min). Changes in FBF were measured without and with concomitant i.a. infusions of the aforementioned doses of doxazosin and yohimbine. In the LBNP experiment the opposite arm was used as a control. Forearm blood flow was measured by plethysmography. Epinephrine and norepinephrine induced an equal and dose-dependent vasoconstriction, which was significantly inhibited by doxazosin as well as yohimbine and to a greater extent by the combination of the antagonists. No differences were found between epinephrine and norepinephrine in this respect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiac and whole-body [3H]noradrenaline kinetics during adrenaline infusion in man.

1. To investigate the possible role of adrenaline as a modulator of noradrenaline release from the sympathetic nervous system, the responses of cardiac and whole-body noradrenaline kinetics to intravenous infusions of adrenaline (30 ng min-1 kg-1) and matching saline placebo were determined at rest and during supine bicycle exercise in 16 patients undergoing cardiac catheterization, in whom beta-adrenoceptor antagonists had been discontinued for 72 h. 2. At rest and compared with placebo, infusion of adrenaline was associated with a small increase in arterial plasma noradrenaline from 211 +/- 29 pg/ml to 245 +/- 29 pg/ml (P less than 0.05). Increases in whole-body noradrenaline spillover to arterial plasma were larger (from 282 +/- 40 ng min-1 m-2 to 358 +/- 41 ng min-1 m-2, P less than 0.01) and there was a trend towards an increase in whole-body noradrenaline clearance. Cardiac noradrenaline clearance was modestly increased during adrenaline infusion, but cardiac noradrenaline spillover was not altered despite increases in heart rate and coronary sinus plasma flow. Adrenaline infusion was associated with symptomatic myocardial ischaemia in four of 14 patients with coronary heart disease. 3. Supine bicycle exercise was associated with significant increases in peripheral noradrenaline concentrations and in cardiac and whole-body noradrenaline spillover. The increases on exercise were not significantly different for these variables during saline and adrenaline infusions. 4. Infusion of adrenaline to produce 'physiological' increases in plasma adrenaline concentration was associated with an increase in total noradrenaline release, as assessed by whole-body noradrenaline spillover to plasma.(ABSTRACT TRUNCATED AT 250 WORDS)     

Quantitative analysis of the contribution of pulmonary and hind limb circulation to the clearance of exogenous catecholamines

The contribution of pulmonary and hind limb circulation to the clearance of exogenous catecholamines was analyzed quantitatively. During infusion of clinical doses of norepinephrine, epinephrine and dopamine in dogs, the plasma level of catecholamine and the plasma flow were measured simultaneously. Percentage of contribution was calculated from the following equation; transorgan difference of plasma catecholamine (nanograms per milliliter) X plasma flow (milliliters per minute) X 100/dose (nanograms per minute). This value means the percentage of the amount of catecholamine cleared by an organ to the amount of catecholamine administered into the body. Small but significant transpulmonary gradients of plasma levels of norepinephrine, epinephrine and dopamine and large translimb gradients of plasma levels of these catecholamines were observed. The plasma flow of pulmonary circulation was increased by infusion of epinephrine and dopamine, whereas it remained unchanged by infusion of norepinephrine. The plasma flow of hind limb circulation showed no significant change by infusion of catecholamines. The calculated contribution values indicate that pulmonary circulation clears 35.7% of norepinephrine (at 0.2 ng X kg-1 X min-1), 27.1% of epinephrine (0.2 ng X kg-1 X min-1) and 21.5% of dopamine (10 micrograms X kg-1 X min-1) administered exogenously, and that the corresponding figures for hind limb circulation are 8.2, 7.8 and 4.5%.     

Neuroendocrine responses to glucose ingestion in man. Specificity, temporal relationships, and quantitative aspects

The mechanisms of postprandial glucose counterregulation—those that blunt late decrements in plasma glucose, prevent hypoglycemia, and restore euglycemia—have not been fully defined. To begin to clarify these mechanisms, we measured neuroendocrine and metabolic responses to the ingestion of glucose (75 g), xylose (62.5 g), mannitol (20 g), and water in ten normal human subjects to determine for each response the magnitude, temporal relationships, and specificity for glucose ingestion. Measurements were made at 10-min intervals over 5 h. By multivariate analysis of variance, the plasma glucose (P < 0.0001), insulin (P < 0.0001), glucagon (P < 0.03), epinephrine (P < 0.0004), and growth hormone (P < 0.01) curves, as well as the blood lactate (P < 0.0001), glycerol (P < 0.001), and β-hydroxybutyrate (P < 0.0001) curves following glucose ingestion differed significantly from those following water ingestion. However, the growth hormone curves did not differ after correction for differences at base line. In contrast, the plasma norepinephrine (P < 0.31) and cortisol (P < 0.24) curves were similar after ingestion of all four test solutions, although early and sustained increments in norepinephrine occurred after all four test solutions. Thus, among the potentially important glucose regulatory factors, only transient increments in insulin, transient decrements in glucagon, and late increments in epinephrine are specific for glucose ingestion. They do not follow ingestion of water, xylose, or mannitol.

Following glucose ingestion, plasma glucose rose to peak levels of 156±6 mg/dl at 46±4 min, returned to base line at 177±4 min, reached nadirs of 63±3 mg/dl at 232±12 min, and rose to levels comparable to base line at 305 min, which was the final sampling point. Plasma insulin rose to peak levels of 150±17 μU/ml (P < 0.001) at 67±8 min. At the time glucose returned to base line, insulin levels (49±12 μU/ml) remained fourfold higher than base line (P < 0.01); thereafter they declined but never fell below base line. Plasma glucagon decreased from 95±14 pg/ml to nadirs of 67±11 pg/ml (P < 0.001) at 84±9 min and then rose progressively to peak levels of 114±17 pg/ml (P < 0.001 vs. nadirs) at 265±12 min. Plasma epinephrine, which was 18±4 pg/ml at base line, did not change initially and then rose to peak levels of 119±20 pg/ml (P < 0.001) at 271±13 min.

These data indicate that the glucose counterregulatory process late after glucose ingestion is not solely due to the dissipation of insulin and that sympathetic neural norepinephrine, growth hormone, and cortisol do not play critical roles. They are consistent with, but do not establish, physiologic roles for the counterregulatory hormones—glucagon, epinephrine, or both—in that process.

     

Hepatic blood flow and metabolism in severe falciparum malaria: clearance of intravenously administered galactose.

1. Hypoglycaemia and lactic acidosis are important manifestations of severe falciparum malaria. To investigate hepatic gluconeogenesis in acute falciparum malaria, liver blood flow and galactose clearance were estimated in seven adult patients with moderately severe infection and seven patients with severe infection (three of whom died later). Nine patients were restudied in convalescence. 2. Liver blood flow, determined from the plasma clearance of Indocyanine Green, was lower in acute illness than in convalescence [16.1 (7.0) versus 23.9 (7.2) ml min-1 kg-1, mean (SD)], but this difference was not statistically significant (P = 0.15). There was a significant inverse correlation between admission venous plasma lactate concentrations and the liver blood flow estimated from the clearance of Indocyanine Green (rs = 0.71, P = 0.004). 3. The plasma clearance of galactose after intravenous injection was similar in the acute [15.4 (4.90) ml min-1 kg-1] and convalescent study [12.8 (2.1) ml min-1 kg-1]. The ratio of galactose clearance to Indocyanine Green clearance was significantly higher in acute disease [1.41 (0.51)] than in convalescence [0.70 (0.34)], largely because of the elevated ratios in severely ill patients [1.48 (0.50)]. 4. The rise in blood glucose concentration after galactose administration was significantly higher during acute illness [1.48 (0.72) mmol/l] than in convalescence [0.67 (0.41) mmol/l, P = 0.022], but the insulin response was similar, indicating reduced tissue insulin sensitivity. There was no significant change in the plasma concentrations of other metabolites (lactate, pyruvate, alanine and triacylglycerol) in either study. 5. These results suggest that the segment of the glycolytic pathway between galactose and glucose is unimpaired in patients with severe falciparum malaria.(ABSTRACT TRUNCATED AT 250 WORDS)     

Association between renal and sympathetic responses to nonhypotensive systemic sepsis

We investigated the association between plasma catecholamines and the renal response to nonhypotensive sepsis. Arterial plasma catecholamines were measured in 16 sheep, before and 24 h after surgical induction of peritonitis. Animals were volume loaded with lactated Ringer's solution (8 L/24 h) before and after surgery; non became hypotensive. For analysis, animals were retrospectively divided into those with increased serum creatinine after 24 h of sepsis (group 1, n = 8) and those without (group 2, n = 8). Group 1 showed increased cardiac index and decreased systemic vascular resistance typical of severe sepsis, with decreased glomerular filtration rate (GFR), oliguria, sodium retention, increased plasma renin activity (PRA), decreased urinary kallikrein excretion, and increased urinary 6-keto-prostaglandin-F1 alpha excretion. Group 2 showed insignificant hemodynamic disturbance, and no significant renal response. Plasma catecholamines were equal in both groups at baseline. In group 1, there were uniform increases after 24 h in plasma norepinephrine (474 +/- 115 to 1183 +/- 158 [SEM] pg/ml; p less than .01) and plasma epinephrine (108 +/- 8 to 309 +/- 70 pg/ml; p less than .05). In group 2, neither plasma norepinephrine (343 +/- 59 to 330 +/- 56 pg/ml) nor plasma epinephrine (116 +/- 16 to 116 +/- 13 pg/ml) changed significantly. Plasma norepinephrine correlated inversely with GFR; plasma epinephrine correlated with PRA. The sympathetic nervous system may be involved in the renal response to nonhypotensive sepsis, both directly and via effects on other vasoactive hormone systems.     

Epinephrine is a Hypophosphatemic Hormone in Man. PHYSIOLOGICAL EFFECTS OF CIRCULATING EPINEPHRINE ON PLASMA CALCIUM, MAGNESIUM, PHOSPHORUS, PARATHYROID HORMONE, AND CALCITONIN

The physiologic effects of epinephrine on mineral metabolism are not known. In six healthy men, insulin-induced hypoglycemia, a potent stimulus to endogenous epinephrine secretion, resulted in a decrement of 0.9+/-0.1 mg/dl (mean+/-SE, P < 0.001) in serum inorganic phosphorus and smaller increments in magnesium and total and ionized calcium. Plasma immunoreactive parathyroid hormone (iPTH) decreased and plasma immunoreactive calcitonin (iCT) increased appropriately with the increments in calcium and magnesium. We wished to determine to what extent these changes in mineral metabolism might be attributable to epinephrine. Therefore, in the same protocol, we infused the hormone over 60 min in these six men, in doses that resulted in steady-state plasma epinephrine concentrations ranging from 52 to 945 pg/ml (levels that span the physiologic range), for a total of 25 studies. Serum ionized calcium, iPTH, and iCT concentrations were unaltered by these physiologic elevations of plasma epinephrine. However, epinephrine resulted in dose-dependent decrements in serum inorganic phosphorus of 0.6+/-0.1 mg/dl (P < 0.005) for the highest epinephrine infusion rate. The plasma epinephrine concentration threshold for this hypophosphatemic effect was approximately 50-100 pg/ml. Thus, the sensitivity of the hypophosphatemic response to epinephrine is comparable to that of the cardiac chronotropic, systolic pressor, and lipolytic responses to epinephrine, and considerably greater than that of the diastolic depressor, glycogenolytic, glycolytic, and ketogenic responses to the hormone in human beings. In view of its rapidity, the hypophosphatemic effect of epinephrine is probably the result of a net shift of phosphate from the extracellular compartment to intracellular compartments. We suggest that it is a direct effect of epinephrine, in that it is not mediated by changes in availability of the primary regulatory hormones PTH and CT, although indirect effects mediated by changes in other hormones, such as insulin, cannot be excluded. The hypophosphatemic response is also not attributable to increments in plasma calcium. These data indicate that epinephrine in physiologic concentrations is a hypophosphatemic hormone in man.     

The effect of adrenaline upon cardiovascular and metabolic functions in man

On three separate occasions, at least 1 week apart, seven young healthy male subjects received intravenous infusions of either adrenaline, 50 ng min-1 kg-1 (high A), adrenaline, 10 ng min-1 kg-1 (low A) or sodium chloride solution (saline: 154 mmol of NaCl/l) plus ascorbic acid, 1 mg/ml (control), over 30 min. Venous adrenaline concentrations of 2.19 +/- 0.15 nmol/l, 0.73 +/- 0.08 nmol/l and 0.15 +/- 0.03 nmol/l were achieved during the high A, low A and control infusions respectively. Heart rate rose significantly by 19 +/- 3 beats/min (high A) and by 6 +/- 1 beats/min (low A). Heart rate remained significantly elevated 30 min after cessation of the high A infusion, despite venous plasma adrenaline concentration having fallen to control levels. The diastolic blood pressure fell during the high A and low A infusions, but the systolic blood pressure rose only during the high A infusion. Vasodilatation occurred in the calf vascular bed during both high A and low A infusions. The changes in hand blood flow and hand vascular resistance were not statistically significant, although there was a tendency to vasoconstriction during the infusion of adrenaline. Metabolic rate rose significantly by 23.5 +/- 1.8% (high A) and by 11.8 +/- 1.6% (low A). Metabolic rate remained elevated between 15 and 30 min after termination of the high A infusion. There was an initial transient increase in respiratory exchange ratio (RER) during the adrenaline infusions. During the later stages of the adrenaline infusions and after their cessation, RER fell, probably reflecting increased fat oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Emergency medical service transport-induced stress? An experimental approach with healthy volunteers

This randomized controlled trial was designed to evaluate the effects of simulated emergency medical service (EMS) transport related stress on hemodynamic variables, and catecholamine plasma levels. A total of 32 healthy male volunteers were randomized to being carried by paramedics from a third-floor apartment through a staircase with subsequent high-speed EMS transport with lights and sirens (stress; n = 16); or sitting on a chair for 5 min, and lying on a stretcher for 15 min (control; n = 16). Blood samples and hemodynamic variables were taken in the apartment before transfer, at the ground floor, and at the end of EMS transport in the stress group, and at corresponding time points in the control group. The stress versus control group had both significantly (P < 0.05) higher mean +/- SEM epinephrine (71 +/- 7 versus 37 +/- 3 pg/ml), and norepinephrine (397 +/- 29 versus 299 +/- 28 pg/ml) plasma levels after transport through the staircase. After EMS transport, the stress versus control group had significantly higher epinephrine (48 +/-6 versus 32 +/- 2 pg/ml), but not norepinephrine (214 +/- 20 versus 264 +/- 31 pg/ml) plasma levels. Heart rate increased significantly from 72 +/- 2 to 84 +/- 3 bpm after staircase transport, but not during and after EMS transport. In conclusion, volunteers being carried by paramedics through a staircase had a significant discharge of both epinephrine and norepinephrine resulting in increased heart rate, but only elevated epinephrine plasma levels during EMS transport. Transport through a staircase may reflect more stress than emergency EMS transport.     

Acute Parathyroid Hormone Response to Epinephrine In Vivo

The acute effects of epinephrine, norepinephrine, and isoproterenol on the plasma immunoreactive parathyroid hormone (iPTH) response were studied in 13 550-600 kg cows. Catecholamines were infused for 7.0 min. During epinephrine infusions at 0.08 mumol/min iPTH increased from 0.48+/-0.12 (mean+/-SE, ng/ml) to 1.09+/-0.18 ng/ml (P < 0.02). Small increases in plasma free fatty acids and glucose could be detected with 0.08 mumol/min epinephrine; the iPTH response to epinephrine was as sensitive as the free fatty acid and glucose responses and possibly of physiological importance. Plasma calcium (total and ionized) and magnesium did not change.The responses were more pronounced at 0.8 mumol/min epinephrine with a mean iPTH increase from 0.49+/-0.16 ng/ml to 1.74+/-0.35 ng/ml (P < 0.01). Small decreases in plasma calcium occurred at 0.8 mumol/min epinephrine, but the plasma magnesium remained unchanged. However, when the plasma calcium was lowered with ethylene glycol bis(beta-aminoethyl ether)-N, N'-tetraacetic acid (EGTA), a much more pronounced lowering of the plasma calcium was required to produce comparable increases of the plasma iPTH concentrations than when epinephrine was infused. It appears that epinephrine has a direct effect on the release of iPTH from the parathyroid glands.Simultaneous infusions of calcium and epinephrine suppressed the stimulation by epinephrine. This points towards a common mechanism of the regulation of parathyroid hormone secretion caused by decreases in the extracellular calcium concentration and/or alterations in the distribution of calcium within parathyroid cells following the administration of epinephrine.The iPTH response to epinephrine was suppressed in the presence of propranolol. Isoproterenol was less active in raising iPTH than epinephrine, and norepinephrine was the least active. The stimulation by isoproterenol and the suppression by propranolol suggest beta adrenergic receptor sites within the parathyroid glands.     

Interactions between glucagon and other counterregulatory hormones during normoglycemic and hypoglycemic exercise in dogs.

Somatostatin (ST)-induced glucagon suppression results in hypoglycemia during rest and exercise. To further delineate the role of glucagon and interactions between glucagon and the catecholamines during exercise, we compensated for the counterregulatory responses to hypoglycemia with glucose replacement. Five dogs were run (100 m/min, 12 degrees) during exercise alone, exercise plus ST infusion (0.5 micrograms/kg-min), or exercise plus. ST plus glucose replacement (3.5 mg/kg-min) to maintain euglycemia. During exercise alone there was a maximum increase in immunoreactive glucagon (IRG), epinephrine (E), norepinephrine (NE), FFA, and lactate (L) of 306 +/- 147 pg/ml, 360 +/- 80 pg/ml, 443 +/- 140 pg/ml, 541 +/- 173 mu eq/liter, and 6.3 +/- 0.7 mg/dl, respectively. Immunoreactive insulin (IRI) decreased by 10.2 +/- 4 micro/ml and cortisol (C) increased only slightly (2.1 +/- 0.3 micrograms/dl). The rates of glucose production (Ra) and glucose uptake (Rd) rose markedly by 6.6 +/- 2.2 mg/kg-min and 6.2 +/- 1.5 mg/kg-min. In contrast, when ST was given during exercise, IRG fell transiently by 130 +/- 20 pg/ml, Ra rose by only 3.6 +/- 0.5 mg/kg-min, and plasma glucose decreased by 29 +/- 6 mg/dl. The decrease in IRI was no different than with exercise alone (10.2 +/- 2.0 microU/ml). As plasma glucose fell, C, FFA, and L rose excessively to peaks of 5.4 +/- 1.3 micrograms/dl, 1,166 +/- 182 mu eq/liter and 15.5 +/- 7.0 mg/dl. The peak increment in E (765 +/- 287 pg/ml) coincided with the nadir in plasma glucose and was four times greater than during normoglycemic exercise. Hypoglycemia did not affect the rise in NE. The increase in Rd was attenuated and reached a peak of only 3.7 +/- 0.8 mg/kg-min. During glucose replacement, IRG decreased by 109 +/- 30 pg/ml and the IRI response did not differ from the response to normal exercise. Ra rose minimally by 1.5 +/- 0.3 mg/kg-min. The changes in E, C, Rd, and L were restored to normal, whereas the FFA response remained excessive. In all protocols increments in Ra were directly correlated to the IRG/IRI molar ratio while no correlation could be demonstrated between epinephrine or norepinephrine and Ra. In conclusion, (a) glucagon controlled approximately 70% of the increase of Ra during exercise. This became evident when counterregulatory responses to hypoglycemia (E and C) were obviated by glucose replacement; (b) increments in Ra were strongly correlated to the IRG/IRI molar ratio but not the plasma catecholamine concentration; (c) the main role of E in hypoglycemia was to limit glucose uptake by the muscle; (d) with glucagon suppression, glucose production was deficient but a further decline of glucose was prevented through the peripheral effects of E, (e) the hypoglycemic stimulus for E secretion was facilitated by exercise; and (f) we hypothesize that an important role of glucagons during exercise could be to spare muscle glycogen by stimulating glucose production by the liver.     

Increased insulin action and clearance in hyperthyroid newly diagnosed IDDM patient. Restoration to normal with antithyroid treatment

In a patient with hyperthyroidism and newly diagnosed insulin-dependent diabetes mellitus (IDDM), insulin action and clearance were studied before the initiation of antithyroid treatment and at 3-mo intervals for 1 yr thereafter. The sequential euglycemic clamp technique (5 mM) was used with insulin infusion rates of 0.5, 1.0, 2.0, and 5.0 mU.kg-1.min-1 in four steps of 2 h. The data were compared with nine control subjects and nine newly diagnosed euthyroid IDDM patients treated with insulin for 0.5 mo. Insulin sensitivity was increased in the patients (ED50 40 vs. 52 mU/L, range 43-70, in controls and 70 mU/L, range 59-120, in IDDM subjects). Insulin responsiveness was markedly elevated; the steady-state glucose infusion rate (SSGIR) of step 4 was 104 vs. 64 mumol.kg-1.min-1 (range 50-79) in controls and 61 mumol.kg-1.min-1 (range 47-69) in IDDM subjects. Insulin clearance was elevated in all steps (1-3, 20-23 vs. 9-15 ml.kg-1.min-1; 4, 18 vs. 6-12 ml.kg-1.min-1 in control and IDDM subjects). Parallel to the normalization of thyroid metabolism, insulin action (ED50 60 mU/L, SSGIR in step 4, 51 mumol.kg-1.min-1) and insulin clearance (steps 1-3, 11-14 ml.kg-1.min-1; step 4, 7 ml.kg-1.min-1) returned to the normal range in 6 mo. Both remained within the normal range until 12 mo. In the patient with newly diagnosed IDDM, the initial marked increases of insulin action and clearance were due to coexistent hyperthyroidism. With the amelioration of the hyperthyroid state, both processes became normal. The parallelism between insulin action and clearance suggests a functional relationship.     

Epinephrine, norepinephrine and dopamine infusions decrease propofol concentrations during continuous propofol infusion in an ovine model

OBJECTIVE: To determine the effects of exogenous ramped infusions of epinephrine, norepinephrine and dopamine on arterial and effluent brain blood concentrations of propofol under steady state intravenous anesthesia. DESIGN: Prospective, randomized animal study. SETTING: University research laboratory. SUBJECTS: Five adult female merino sheep. INTERVENTIONS: Induction (5 mg/kg) and continuous infusion of propofol (15 mg/min) with controlled mechanical ventilation to maintain PaCO2 40 mmHg. After 1 h of continuous anesthesia, each animal randomly received ramped infusions of epinephrine, norepinephrine (10, 20, 40 microg/min) and dopamine (10, 20, 40 microg x kg x min) in 3 x 5 min intervals followed by a 30-min washout period. MEASUREMENTS: Arterial and sagittal sinus whole blood for determination of propofol concentrations using high-pressure liquid chromatography. Cardiac output using a thermodilution method. Level of consciousness using an observational scale. MAIN RESULTS: All three drugs significantly and transiently increased cardiac output in a dose-dependent fashion to a maximum of 146-169% of baseline. Baseline arterial and sagittal sinus propofol concentrations were not statistically different prior to catecholamine infusions. All three drugs significantly reduced mean arterial propofol concentrations (95 % CI, p < 0.05): epinephrine to 41.8% of baseline (11.4-72), norepinephrine to 63 % (27-99) and dopamine to 52.9 % (18.5-87.3). There were parallel reductions of concentrations in sagittal sinus blood leaving the brain. The lowest blood concentrations were associated with emergence from anesthesia. Arterial concentrations were inversely related to the simultaneously determined cardiac output (r2 = 0.74, p < 0.0001). Comparison of the data with the predictions of a previously developed recirculatory model of propofol disposition in sheep showed the data were consistent with a mechanism based on increased first pass dilution and clearance of propofol secondary to the increased cardiac output. CONCLUSIONS: Catecholamines produced circulatory changes that reversed propofol anesthesia. These observations have potential clinical implications for the use of propofol in hyperdynamic circulatory conditions, either induced by exogenous catecholamine infusions or pathological states.