Neuronal re-uptake of noradrenaline by sympathetic nerves in humans.

1. Plasma concentrations of [3H]dihydroxyphenylglycol, the intraneuronal metabolite of noradrenaline, were examined during intravenous infusion of [3H]noradrenaline in 43 subjects, to assess the nature of its formation. Noradrenaline re-uptake by sympathetic nerves was estimated in 11 subjects from the effects of neuronal uptake blockade with desipramine on noradrenaline clearance and plasma concentrations of [3H]dihydroxyphenylglycol and endogenous dihydroxyphenylglycol. In seven subjects noradrenaline re-uptake and spillover into plasma were examined before and during mental arithmetic or handgrip exercise. 2. During infusion of [3H]noradrenaline, plasma [3H]dihydroxyphenylglycol increased progressively, indicating its formation from previously stored [3H]noradrenaline leaking from vesicles as well as from [3H]noradrenaline metabolism immediately after removal into sympathetic nerves. Thus, to estimate noradrenaline re-uptake, the amount of [3H]dihydroxyphenylglycol derived from [3H]noradrenaline metabolized immediately after removal into the sympathetic axoplasm must be isolated from that derived from [3H]noradrenaline sequestered into vesicles. 3. At rest in the supine position the rate of noradrenaline re-uptake was 474 +/- 122 pmol min-1 kg-1, 9.5-fold higher than the rate of spillover of noradrenaline into plasma (49.6 +/- 6.4 pmol min-1 kg-1). Noradrenaline re-uptake and spillover into plasma were both increased during mental arithmetic and isometric handgrip exercise.     

Plasma noradrenaline in cirrhosis: a study of kinetics and temporal relationship to ascites formation

The kinetics of plasma noradrenaline (NA) were studied in 14 patients with cirrhosis and ascites and 13 normal subjects. [3H]noradrenaline ([3H] NA) was infused intravenously to steady state and the spillover of NA into plasma and its clearance from plasma calculated. The increase in plasma NA in the cirrhotic patients was due to an increase in NA spillover (14.5 vs 3.9 nmol min-1m-2; P less than 0.001). NA plasma clearance was also increased in the cirrhotic patients (3.5 vs 2.11 min-1m-2; P less than 0.01). Plasma NA and dihydroxyphenylglycol (DHPG), a metabolite of NA of which a portion is formed after re-uptake of NA into sympathetic nerve endings, were then measured in 23 patients with cirrhosis and ascites, 17 patients with cirrhosis who had never had ascites, and 34 normal subjects. Both plasma NA and DHPG were significantly increased in the patients with ascites (NA 4.7, DHPG 14.7 nmol l-1 and in the patients with cirrhosis but no ascites (NA 3.8, DHPG 12.0 nmol l-1) compared with normal subjects (NA 1.9, DHPG 8.8 nmol 1-1). Therefore, the increase in plasma NA in cirrhosis is due to increased activity of the sympathetic nervous system rather than interference with the metabolism of NA or impaired neuronal uptake of NA. This increase appears to precede the development of ascites.     

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)     

Cerebrospinal fluid levels of catechols in patients with neurogenic orthostatic hypotension

In multiple system atrophy (MSA) and pure autonomic failure (PAF), orthostatic hypotension (OH) results from deficient noradrenaline release from sympathetic nerves during standing. Post-mortem findings have indicated loss of central noradrenergic cells in both diseases. The present study sought in vivo neurochemical evidence for central noradrenergic deficiency in patients with OH due to MSA or PAF. A total of 28 patients with OH (18 with MSA; 10 with PAF) had cerebrospinal fluid and blood sampled for levels of noradrenaline and its neuronal metabolite dihydroxyphenylglycol. A control group of 44 subjects included 10 elderly normal volunteers, 10 patients with Alzheimer's disease, 18 patients with dysautonomia (postural tachycardia syndrome or neurocardiogenic syncope) and six patients with MSA in the absence of OH. Patients with OH had lower cerebrospinal fluid concentrations of noradrenaline (0.53+/-0.07 nmol/l) and dihydroxyphenylglycol (6.52+/-0.46 nmol/l) than did control subjects (0.90+/-0.09 and 9.64+/-0.46 nmol/l respectively; P =0.0001). The MSA+OH group had higher plasma levels of both catechols (noradrenaline, 1.31+/-0.16 nmol/l; dihydroxyphenylglycol, 5.08+/-0.43 nmol/l) than did the PAF group (noradrenaline, 0.38+/-0.08 nmol/l; dihydroxyphenylglycol, 2.53+/-0.30 nmol/l; P <0.001), despite similarly low cerebrospinal fluid levels. Among MSA patients, those with OH had lower cerebrospinal fluid levels of noradrenaline and dihydroxyphenylglycol than those without OH (noradrenaline, 1.71+/-0.64 nmol/l; dihydroxyphenylglycol, 10.41+/-1.77 nmol/l respectively; P =0.006). The findings are consistent with central noradrenergic deficiency in both MSA+OH and PAF. In MSA, central noradrenergic deficiency seems to relate specifically to OH.     

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.     

Metabolic effects of low-dose dopamine infusion in normal volunteers

1. Dopamine in 5% (w/v) D-glucose was infused into five healthy male volunteers at doses of 2, 5 and 10 micrograms min-1 kg-1 over three sequential periods of 45 min each. 2. Oxygen consumption, respiratory exchange ratio, blood glucose concentration and plasma levels of free fatty acids, glycerol, lactate, dopamine, adrenaline and noradrenaline were measured. The results were compared with values obtained during infusion over the same time period of the corresponding volumes of 5% (w/v) D-glucose alone. 3. Energy expenditure calculated from the oxygen consumption and the respiratory exchange ratio was higher than control values during infusion of dopamine (P less than 0.001, analysis of variance) specifically at a rate of 10 micrograms min-1 kg-1 (P less than 0.05) when it was 14% higher, but not at a rate 2 of or 5 micrograms min-1 kg-1. The plasma noradrenaline concentration was 74 and 230% and the blood glucose concentration was 21 and 36% higher than control values at 5 and 10 micrograms of dopamine min-1 kg-1, respectively (P less than 0.01). At 10 micrograms of dopamine min-1 kg-1 the plasma free fatty acid concentration was 70% and the plasma glycerol concentration was 80% higher than during the control infusion (P less than 0.01). The respiratory exchange ratio and the plasma lactate concentration were the same in the two groups and did not alter during the dopamine infusion. The plasma adrenaline concentration rose significantly (P less than 0.01), but only transiently, during dopamine infusion at a rate of 2 micrograms min-1 kg-1. 4. Dopamine at low doses has metabolic effects. It increases the blood glucose concentration and the circulating noradrenaline level at an infusion rate of 5 micrograms min-1 kg-1. It increases energy expenditure and circulating free fatty acid and glycerol levels at an infusion rate of 10 micrograms min-1 kg-1, presumably due to stimulation of lipolysis.     

The independent effect of ketone bodies on forearm glucose metabolism in normal man.

Ketone bodies and non-esterified fatty acids (NEFA) inhibit insulin stimulated glucose uptake in muscle in-vitro. In man the infusion of ketone bodies lowers plasma NEFA levels thus confounding the interpretation of individual effects. The aim of this study was to examine the effect of ketone bodies on insulin mediated forearm glucose metabolism independent of the changes in the plasma NEFA levels. Seven healthy men received sodium 3-hydroxybutyrate (15 mumol kg-1 min-1) or sodium bicarbonate (control) for 240 min. Heparin (0.2 U kg-1 min-1) and insulin (0.01 U kg-1 h-1) were infused for 90 min (pre-clamp), followed by insulin alone (0.025 U kg-1 h-1) and euglycaemia was maintained (clamp). Plasma NEFA levels and rates of forearm NEFA uptake (+23 +/- 14 and +49 +/- 21 [mean +/- SEM] nmol 100 ml forearm [FA]-1 min-1) were comparable during the pre-clamp periods, and were suppressed equally during hyperinsulinaemia. Sodium 3-hydroxybutyrate infusion raised the blood ketone body levels from 70 +/- 4 mumol/l to a plateau of 450 +/- 30 mumol/l, while control levels declined from baseline (ketone body vs control; P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic effects of dobutamine in normal man.

1. Dobutamine in 5% (w/v) D-glucose was infused at sequential doses of 2, 5 and 10 micrograms min-1 kg-1, 45 min at each dose, into eight healthy male subjects, and the effects were compared with those produced by infusion of the corresponding volumes of 5% (w/v) D-glucose alone. 2. The energy expenditure increased and was 33% higher than control (P less than 0.001) at 10 micrograms of dobutamine min-1 kg-1. The respiratory exchange ratio decreased from 0.85 (SEM 0.02) before infusion to 0.80 (SEM 0.01) at 10 micrograms of dobutamine min-1 kg-1, but did not alter during the placebo infusion (P less than 0.001). 3. Plasma noradrenaline concentrations were lower during the dobutamine infusion compared with during the infusion of D-glucose alone (P less than 0.025). Plasma dopamine concentrations remained below 0.1 nmol/l throughout both infusions. 4. Compared with during the placebo infusion, the blood glucose concentration decreased (P less than 0.001), the plasma glycerol and free fatty acid concentrations increased by 150 and 225%, respectively (both P less than 0.001), and the plasma potassium concentration decreased from 3.8 (SEM 0.07) to 3.6 (SEM 0.04) mmol/l (P less than 0.01) during dobutamine infusion. The plasma insulin concentration increased at 2 and 5 micrograms of dobutamine min-1 kg-1 (P less than 0.001) with no further rise at 10 micrograms of dobutamine min-1 kg-1. 5. Compared with during the placebo infusion, the systolic and diastolic blood pressures and the heart rate increased during dobutamine infusion (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary extraction of circulating noradrenaline in man

Pulmonary plasma kinetics of endogenous noradrenaline (NA) and tritium labelled L-noradrenaline (3H-NA) was studied in fifteen subjects during pulmonary arterial catheterization. Plasma NA concentration in femoral artery ranged from 0.5 to 8.2 nmol l-1, mean 2.3 nmol l-1, which was not significantly different from that of age-matched control subjects. The lungs extracted both endogenous NA and 3H-NA significantly, but no significant pulmonary extraction of endogenous adrenaline was found. The pulmonary arterial-systemic arterial extraction ratio of NA was mean 0.08 (n = 9) as compared to that of 3H-NA: mean 0.07 (n = 8, NS). Likewise mean pulmonary clearances of NA and 3H-NA were not significantly different (97 ml min-1 X M-2 v. 124 ml min-1 X M-2, NS). Estimated whole-body clearance of noradrenaline was mean 0.80 l min-1 X M-2 (n = 6) while the pulmonary clearance amounted to 19% of this value. The small, but significant, pulmonary extraction of circulating noradrenaline implies that whole-body clearance, as estimated from infusion rate and systemic arterial sampling, will be overestimated by approximately 7%. As pulmonary extraction of NA and 3H-NA was almost identical, the results indicate no significant pulmonary contribution to circulating noradrenaline.     

Glutamine: a major gluconeogenic precursor and vehicle for interorgan carbon transport in man.

To compare glutamine and alanine as gluconeogenic precursors, we simultaneously measured their systemic turnovers, clearances, and incorporation into plasma glucose, their skeletal muscle uptake and release, and the proportion of their appearance in plasma directly due to their release from protein in postabsorptive normal volunteers. We infused the volunteers with [U-14C] glutamine, [3-13C] alanine, [2H5] phenylalanine, and [6-3H] glucose to isotopic steady state and used the forearm balance technique. We found that glutamine appearance in plasma exceeded that of alanine (5.76 +/- 0.26 vs. 4.40 +/- 0.33 mumol.kg-1.min-1, P < 0.001), while alanine clearance exceeded glutamine clearance (14.7 +/- 1.3 vs. 9.3 +/- 0.8 ml.kg-1.min-1, P < 0.001). Glutamine appearance in plasma directly due to its release from protein was more than double that of alanine (2.45 +/- 0.25 vs. 1.16 +/- 0.12 mumol.kg-1.min-1, P < 0.001). Although overall carbon transfer to glucose from glutamine and alanine was comparable (3.53 +/- 0.24 vs 3.47 +/- 0.32 atoms.kg-1.min-1), nearly twice as much glucose carbon came from protein derived glutamine than alanine (1.48 +/- 0.15 vs 0.88 +/- 0.09 atoms.kg-1.min-1, P < 0.01). Finally, forearm muscle released more glutamine than alanine (0.88 +/- 0.05 vs 0.48 +/- 0.05 mumol.100 ml-1.min-1, P < 0.01). We conclude that in postabsorptive humans glutamine is quantitatively more important than alanine for transporting protein-derived carbon through plasma and adding these carbons to the glucose pool.     

Dihydroxyphenylglycol and intraneuronal metabolism of endogenous and exogenous norepinephrine in the rat vas deferens

To elucidate the origin and significance of dihydroxyphenylglycol (DHPG) as a metabolite of norepinephrine (NE), the isolated rat vas deferens was preloaded with tracer amounts of tritiated NE and examined for the release of radioactive and endogenous NE and DHPG before and during electrical stimulation or stimulation with excess K+. Tissues were incubated with desipramine or reserpine to determine the effects of blockade of neuronal uptake and of interference with vesicular translocation of NE. Radioactive NE appeared to distribute differently from endogenous NE into at least two pools, but for the most part endogenous NE and DHPG behaved similarly in response to pharmacological manipulations. Desipramine blocked completely the increased appearance of both radioactive and endogenous DHPG in the medium during electrical stimulation or K+ stimulation; DHPG responses to stimulation are thus dependent on recapture of NE at the synapse. Basal release of DHPG was increased by reserpine, and this increase was not affected by desipramine; therefore, reserpine-induced release of DHPG is independent of neuronal uptake consistent with formation of DHPG from NE leaking into the cytosol from vesicular stores. Reserpine enhanced the release of DHPG during stimulation, and concomitant desipramine treatment blocked this effect; thus, interference with NE translocation into storage vesicles increases the availability of recaptured NE for intraneuronal metabolism. During stimulation of NE release between 70 to 80% of the recaptured NE was estimated to be sequestered into storage vesicles for rerelease. Combined measurement of endogenous and labeled NE and DHPG provides a useful tool for examining neuronal uptake and intraneuronal disposition of NE.     

Effect of alpha-ketoglutarate infusions on organ balances of glutamine and glutamate in anaesthetized dogs in the catabolic state.

1. The salt complex of L-(+)-ornithine and alpha-ketoglutarate (2-oxoglutarate) has recently been proposed for the treatment of patients in the catabolic state. As yet, it is unclear which of the two substrates (ornithine or alpha-ketoglutarate) is responsible for the anticatabolic effect. We infused alpha-ketoglutarate into anaesthetized post-operative dogs in order to investigate whether infusion of alpha-ketoglutarate affects the flux of glutamine and glutamate between skeletal muscle and the splanchnic bed. We used three infusion rates: 3, 10 and 20 mumol min-1 kg-1. A steady state of alpha-ketoglutarate concentration in arterial whole-blood was attained only when the infusion rate was 3 mumol min-1 kg-1. 2. Arterial whole-blood concentrations of alpha-ketoglutarate were 8.8 +/- 1.2 mumol/l in the basal period and rose to 208 +/- 41, 344 +/- 61 and 1418 +/- 315 mumol/l after 60 min infusions of alpha-ketoglutarate at 3, 10 and 20 mumol min-1 kg-1, respectively. 3. alpha-Ketoglutarate uptake was measured in skeletal muscle, liver, gut and kidneys in the basal period and during the infusion of alpha-ketoglutarate. The net uptake of infused alpha-ketoglutarate was highest in the skeletal muscle, followed by kidneys, liver and gut. 4. The alpha-ketoglutarate load increased the muscular tissue content of alpha-ketoglutarate from 49.5 +/- 5 to 142 +/- 15 nmol/g of dry substance (P less than 0.001), but did not alter the muscular glutamate or glutamine contents.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of the dopamine D2 receptor agonist quinpirole on renal sympathetic nerve activity and renal norepinephrine spillover in anesthetized rabbits.

Cardiovascular and sympathetic nervous system effects of the dopamine D2 receptor-selective agonist quinpirole were studied in anesthetized rabbits. Sodium nitroprusside was administered for comparison. The animals received a tracer infusion of [3H] norepinephrine i.v. Arterial and renal venous concentrations of endogenous norepinephrine and epinephrine and [3H]norepinephrine, the firing rate of the renal sympathetic nerves and renal blood flow were determined. Quinpirole (100 micrograms kg-1 + 5 micrograms kg-1 min-1 i.v.) lowered blood pressure and renal vascular resistance. The firing rate of the renal sympathetic nerves was increased, but there was no reflex tachycardia. Despite the increase in renal sympathetic firing, the renal spillover of norepinephrine into blood was decreased. The increase in total body norepinephrine spillover during quinpirole-induced hypotension was less than expected from baroreflex activation. Effects of quinpirole were antagonized by domperidone (1000 micrograms kg-1 + 200 micrograms kg-1 h-1). The distinguishing feature of this study is the simultaneous measurement of sympathetic firing and norepinephrine spillover in the same organ, the kidney, under conditions of intact sympathetic impulse traffic. Quinpirole activated presynaptic D2 receptors and thus reduced the released norepinephrine per action potential. Consequences of the presynaptic inhibition were reductions of blood pressure and renal vascular resistance and absence of reflex tachycardia.     

SPONTANEOUS AND OUABAIN-INDUCED EFLUX OF CATECHOLAMINES AND DIHYDROXYPHENYLGLYCOL IN TWO CANINE BLOOD VESSELS

Summary— The spontaneous efflux of endogenous noradrenaline, dopamine, dihydroxyphenylglycol (DOPEG) from adrenergic nerve endings of 2 canine blood vessels (the mesenteric artery and the saphenous vein) were studied during 8 successive incubation periods of 15 min each. Extraneuronal uptake and 0-methylation were minimized by the presence of adequate concentrations of tropolone and hydrocortisone.
Both vessels had an efflux characterized by a decline in the 3 catechols, which was most marked for noradrenaline; the mesenteric artery lost larger amounts than the saphenous vein. Ouabain caused a large increase in the efflux of noradrenaline and dopamine and a reduction of DOPEG efflux. Cocaine had only a modest effect, more evident in the case of the mesenteric artery, increasing noradrenaline and reducing DOPEG effluxes. The combination of ouabain and cocaine had no additive effects, and the effects of ouabain were even reduced (on some parameters) by cocaine.
Accordingly, the noradrenaline: DOPEG ratio was markedly increased by ouabain, but not by cocaine; cocaine significantly reduced the effects of ouabain. The ratio dopamine: noradrenaline was decreased by cocaine and by ouabain. Comparison of tissue content and efflux allowed us to conclude that apparently no significant de novo synthesis of noradrenaline occurred during the incubation period.
We conclude that a fast and early component of spontaneous efflux is due to loss from the neurons and that its greater magnitude in the mesenteric artery may be due to differences in neuronal [Na+] and/or to differences in neuronal membrane adenosine triphosphatase activity. The results also suggest that neuronal reuptake plays only a minor role in the handling of spontaneously released noradrenaline.     

Effect of yohimbine on renal sympathetic nerve activity and renal norepinephrine spillover in anesthetized rabbits.

The function of presynaptic alpha-2 adrenergic autoinhibition of norepinephrine release was studied in anesthetized rabbits (alfadolone + alfaxalone) with uninterrupted sympathetic impulse traffic. The animals received a tracer infusion of [3H]norepinephrine i.v. Arterial and renal venous concentrations of endogenous norepinephrine and [3H]norepinephrine, the firing rate of the renal sympathetic nerves and renal blood flow were determined. The results were used to calculate the renal fractional [3H]norepinephrine extraction, the renal removal and spillover of norepinephrine, the total body [3H]norepinephrine clearance and total body norepinephrine spillover. Sodium nitroprusside (10-80 micrograms kg-1 min-1 i.v.), which was infused to modulate sympathetic activity through the baroreceptors, caused hypotension and increased the renal sympathetic firing rate and the renal as well as total body norepinephrine spillover. Increases of total body norepinephrine spillover were much higher than increases of renal spillover. Yohimbine (1 mg kg-1 + 0.2 mg kg-1 hr-1 i.v.) caused slight central sympathoexcitation. In addition, it enhanced the renal and total body spillover of norepinephrine at any given firing rate of the renal sympathetic nerves. The distinguishing feature of this study is the measurement of sympathetic firing rate and norepinephrine spillover in one and the same organ, the kidney. The results demonstrate that the alpha-2 adrenergic autoinhibition of norepinephrine release normally operates in the kidney with intact sympathetic impulse traffic. They also suggest its operation in other peripheral sympathetically innervated tissues.     

Persistent glucose production during glucose infusion in the neonate.

In adults, glucose infusion results in a decreased glucose production rate (GPR) as a mechanism for maintaining euglycemia. To document the development of glucose homeostasis, we derived the GPR in 23 preterm appropriate for gestational age infants, 14 term appropriate for gestational age infants, and in 6 adults. After a 3-h fast, the average plasma glucose and insulin concentration was measured and the GPR was derived. During glucose infusion (5.6 +/- 0.3 mg X kg-1 min-1), compared with saline controls, the preterms had a rise in plasma glucose and plasma insulin, and the GPR was 1.4 mg X kg-1 min-1 (range, 0-4.4) vs. 3.0 mg X kg-1 min-1 (range, 1.8-4.1) (saline controls). In the term infants, only the plasma insulin concentration was elevated when the glucose infused (5.7 +/- 0.3 mg X kg-1 min-1) infants were compared with the saline controls and GPR was 0.4 X kg-1 min-1 (range, 0-2.6) vs. 3.4 mg X kg-1 min-1 (range, 2.8-5.7) (saline controls). In comparison to saline infused adults, glucose infusion (3.2 +/- 0.1 mg X kg-1 min-1) resulted in a significant rise in plasma glucose and in plasma insulin; and the GPR was reduced to 0.1 mg X kg-1 min-1 (range, 0-0.3) from 2.0 mg X kg-1 min-1 (range, 1.5-2.4). 5 of 13 preterms and 2 of 7 term infants had persistent GPR during glucose infusion; in contrast, the GPR in all adults was unmeasurable. There was no correlation between the plasma glucose concentration and the GPR in the newborn or in the adult. Both newborns and adults did have a correlation between plasma insulin concentration and the GPR; however, there was considerable variability in the neonate. We conclude that there are significant developmental differences in neonatal glucose homeostasis and that insulin is important in neonatal hormonal control of glucose production.     

Adrenergic mechanisms contribute to the late phase of hypoglycemic glucose counterregulation in humans by stimulating lipolysis.

Three studies were performed on nine normal volunteers to assess whether catecholamine-mediated lipolysis contributes to counterregulation to hypoglycemia. In these three studies, insulin was intravenously infused for 8 h (0.30 mU.kg-1.min-1 from 0 to 180 min, and 0.40 mU.kg-1.min-1 until 480 min). In study I (control study), only insulin was infused; in study II (direct + indirect effects of catecholamines), propranolol and phentolamine were superimposed to insulin and exogenous glucose was infused to reproduce the same plasma glucose (PG) concentration of study I. Study III (indirect effect of catecholamines) was the same as study II, except heparin (0.2 U.kg-1.min-1 after 80 min), 10% Intralipid (1 ml.min-1 after 160 min) and variable glucose to match PG of study II, were also infused. Glucose production (HGO), glucose utilization (Rd) [3-3H]glucose, and glucose oxidation and lipid oxidation (LO) (indirect calorimetry) were determined. In all three studies, PG decreased from approximately 4.8 to approximately 2.9 mmol/liter (P = NS between studies), and plasma glycerol and FFA decreased to a nadir at 120 min. Afterwards, in study I plasma glycerol and FFA increased by approximately 75% at 480 min, but in study II they remained approximately 40% lower than in study I, whereas in study III they rebounded as in study I (P = NS). In study II, LO was lower than in study I (1.69 +/- 0.13 vs. 3.53 +/- 0.19 mumol.kg-1.min-1, P less than 0.05); HGO was also lower between 60 and 480 min (7.48 +/- 0.57 vs. 11.6 +/- 0.35 mumol.kg-1.min-1, P less than 0.05), whereas Rd was greater between 210 and 480 min (19 +/- 0.38 vs. 11.4 +/- 0.34 mumol.kg-1.min-1, respectively, P less than 0.05). In study III, LO increased to the values of study I; between 4 and 8 h, HGO increased by approximately 2.5 mumol.kg-1.min-1, and Rd decreased by approximately 7 mumol.kg-1.min-1 vs. study II. We conclude that, in a late phase of hypoglycemia, the indirect effects of catecholamines (lipolysis mediated) account for at least approximately 50% of the adrenergic contribution to increased HGO, and approximately 85% of suppressed Rd.     

Insulin action in insulin-dependent diabetics after short-term thiazide therapy

The influence of short-term thiazide treatment on peripheral tissue and liver sensitivity to insulin in insulin-dependent diabetes mellitus was determined by the euglycemic insulin clamp technique. A sequential three-step hyperinsulinemic clamp was performed in six insulin-dependent diabetics before and after 2 wk of hydroflumethiazide (HFT) administration in a daily dose of 75 mg. Insulin was infused at rates of 0.5, 2.0, and 4.0 mU X kg-1 X min-1, and each dose was given for at least 120 min. Glucose uptake during the last 30 min of each step was almost identical in the two situations (2.7 +/- 0.6 vs. 2.4 +/- 0.5 mg X kg-1 X min-1, 9.6 +/- 0.9 vs. 9.7 +/- 1.2 mg X kg-1 X min-1, and 12.0 +/- 1.3 vs. 12.6 +/- 1.5 mg X kg-1 X min-1). Serum insulin levels were also similar, and blood glucose was kept at 100 +/- 3, 99 +/- 4, and 97 +/- 3 mg/dl before thiazides and at 93 +/- 6, 93 +/- 6, and 94 +/- 6 mg/dl after thiazides. Another five insulin-dependent diabetics were infused with tritiated glucose followed by insulin infusion at two rates: 0.45 and 1.0 mU X kg-1 X min-1. Basal glucose output was comparable before and after thiazides (3.63 +/- 0.24 vs. 2.97 +/- 0.26 mg X kg-1 X min-1), as was the liver response to increasing insulin concentrations. The metabolic state as assessed by HbA1c and fasting blood glucose did not differ in the two experiments.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of two indices for forearm noradrenaline release in humans

Although there is as yet no method which measures directly the neuronal release of noradrenaline in humans in vivo, the isotope dilution technique with [(3)H]noradrenaline has been applied to estimate forearm neuronal noradrenaline release into plasma. Two different equations have been developed for this purpose: one to estimate the spillover of noradrenaline into the venous effluent, and a modified formula (often referred to as the appearance rate) which may reflect more closely changes in the neuronal release of noradrenaline into the synaptic cleft, particularly during interventions that alter forearm blood flow. The present study was performed to compare the effects of two interventions known to exert contrasting actions on neuronal forearm noradrenaline release and forearm blood flow. Intra-arterial infusion of sodium nitroprusside at doses without systemic effect increases forearm blood flow, but not neuronal noradrenaline release. In contrast, lower-body negative pressure at -25 mm Hg causes forearm vasoconstriction by stimulating neuronal noradrenaline release. During sodium nitroprusside infusion, forearm noradrenaline spillover increased from 1.1+/-0.3 to 2.2+/-1.0 pmol x min(-1) x 100 ml(-1) (P<0.05), whereas the forearm noradrenaline appearance rate was unchanged. Lower-body negative pressure did not affect the forearm noradrenaline spillover rate, but increased the forearm noradrenaline appearance rate from 3.4+/-0.4 pmol x min(-1) x 100 ml(-1) at baseline to 5.0+/-0.9 pmol x min(-1) x 100 ml(-1) (P<0.05). These results indicate that the noradrenaline appearance rate provides the better approximation of changes in forearm neuronal noradrenaline release in response to stimuli which alter local blood flow.     

Simultaneous assay of noradrenaline and its deaminated metabolite, dihydroxyphenylglycol, in plasma: a simplified approach to the exclusion of phaeochromocytoma in patients with borderline elevation of plasma noradrenaline concentration

Abstract. The fate of noradrenaline released from sympathetic endings differs from that of noradrenaline secreted directly into the bloodstream. This has been used to establish a single sample test for the exclusion of phaeochromocytoma in patients with borderline elevation of plasma noradrenaline concentration. This test is based on the measurement of the ratio in plasma of noradrenaline to its deaminated metabolite, dihydroxyphenylglycol (DHPG). The latter was shown to reflect mainly nervous release of noradrenaline and its plasma concentration was not increased during intravenous noradrenaline infusion. In seventeen phaeochromocytoma patients the ratio in plasma of noradrenaline to DHPG was greater than 2 (range 2·05–3·57); in nineteen non-phaeochromocytoma patients the reverse was found, the ratio of DHPG to noradrenaline being greater than 2 (range 2·08–2·74). Since DHPG can be measured simultaneously with noradrenaline, measurement of the plasma ratio of these two catechols may prove a simple method of differentiating phaeochromocytoma from non-phaeochromocytoma patients.