Elevated plasma noradrenaline concentrations in patients with low-output cardiac failure: dependence on increased noradrenaline secretion rates

1. Plasma noradrenaline concentrations are elevated in patients with congestive heart failure; however, the pathogenesis of these elevated noradrenaline levels is controversial. 2. Possible mechanisms for elevated noradrenaline concentrations in patients with congestive heart failure include increased noradrenaline secretion, decreased clearance of noradrenaline, and a combination of increased secretion and decreased clearance. 3. In the present study, plasma noradrenaline clearance and apparent secretion rates were determined using a whole-body steady-state radionuclide tracer method in six otherwise healthy patients with moderate degrees of low-output cardiac failure and in six normal control subjects. 4. The venous plasma noradrenaline level was elevated in the patients with congestive heart failure as compared with the control subjects (4.18 +/- 1.34 versus 1.54 +/- 0.16 nmol/l, P less than 0.05). There was no stimulation of the adrenal medulla as evident by normal plasma adrenaline levels in both groups (0.19 +/- 0.04 versus 0.18 +/- 0.02 nmol/l, not significant). The apparent secretion rate of noradrenaline was elevated in the patients with congestive heart failure (4.75 +/- 1.95 versus 1.78 +/- 0.18 nmol min-1 m-2, P less than 0.05), whereas the clearance rate of noradrenaline was similar in the two groups (1.26 +/- 0.27 versus 1.16 +/- 0.02 l min-1 m-2, not significant). 5. We conclude that the high peripheral venous plasma noradrenaline concentrations in patients with mildly decompensated low-output cardiac failure are initially due to increased secretion, rather than to decreased metabolic clearance, perhaps in response to diminished effective arterial blood volume.     

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.     

Adrenaline secretion during exercise

By studying six normal subjects during graduated treadmill exercise, we have confirmed that there is very little rise in venous plasma adrenaline levels during mild or moderate exercise. During a second study, adrenaline was infused intravenously in six resting subjects at a rate of 0.025 micrograms min-1 kg-1. This elevated the basal plasma adrenaline level from 0.28 +/- 0.04 nmol/l to 0.92 +/- 0.16, 1.16 +/- 0.20 and 1.28 +/- 0.19 nmol/l at 3, 5 and 7 min after the start of the infusion. The same adrenaline infusion was repeated in the same subjects 7 min after they started moderate exercise at a constant rate on a static exercise bicycle. Just before the start of the infusion, 7 min after the onset of exercise, plasma adrenaline had risen to 0.36 +/- 0.07 nmol/l. This rose to 1.86 +/- 0.30, 1.98 +/- 0.26 and 2.19 +/- 0.29 nmol/l at 3, 5 and 7 min after the start of this second infusion. Five minutes after the end of the infusion, while the subjects were still exercising, the mean level was 0.56 +/- 0.04 nmol/l. The venous plasma level of adrenaline is the result of a balance between the secretion of adrenaline by the adrenal medulla and the clearance of adrenaline from plasma. Our results suggest that the lack of any significant rise in plasma adrenaline during moderate exercise does not result from an accelerated clearance of adrenaline by exercising tissue. The clearance rate of adrenaline from plasma is reduced during exercise. There is no significant increase in secretion by the adrenal medulla in response to the stimulus of mild or moderate exercise.     

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.     

Role of circulating catecholamines in the control of pancreatic polypeptide and gastrin release

The influence of circulating catecholamines on the release of pancreatic polypeptide (PP) and gastrin was studied in volunteers. Physical exercise increased plasma epinephrine by 374 +/- 123% and plasma norepinephrine by 167 +/- 30%, but plasma PP concentrations remained unchanged during standardized bicycle ergometry. Immediately after cessation of exercise catecholamine levels decreased rapidly, whereas PP concentrations increased by 55%. In a second series, epinephrine infusion (5, 25, and 75 ng.kg-1.min-1) increased epinephrine levels by 38 +/- 12, 331 +/- 69, and 1229 +/- 131%, respectively, whilst norepinephrine was unaffected. Neither during nor after catecholamine infusion PP secretion was affected. Gastrin release increased by a maximum of 85 +/- 38% (at epinephrine 75 ng.kg-1.min-1). It is concluded, that (1) changes in circulating adrenaline do not significantly influence PP secretion in man; (2) the PP increase immediately following physical exercise cannot be attributed to a rapid fall of catecholamine levels; (3) endogenous catecholamines are of minor importance in the control of gastrin secretion.     

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)     

Catecholamine Levels and Pacing Behavior of QT-Driven Pacemakers During Exercise

It is thought that increasing catecholamine levels in the heart are partly responsible for shortening of the repolarization time and so indirectly for the pacing behavior of the QT driven pacemaker. Adrenaline and noradrenaline (NA) plasma levels were determined at rest, during symptom-limited exercise, and during recovery more than 1 month after the implantation of a 919 or a Rhythmyx pacemaker (Vitatron, The Netherlands) in eight patients (age 54-85 yrs). Significant increases were detected in NA level (from 0.57 +/- 0.23 ng/mL to 2.15 +/- 0.76 ng/mL), but not in the circulating adrenaline level. The correlation coefficient of the mean pacing rate and the mean NA level during exercise and recovery was 0.963 (P less than 0.0001), the correlation coefficient with the mean oxygen consumption was 0.888 (P less than 0.01). No correlation with the adrenaline level was observed. The correlation coefficient of the changes of pacing rate and the changes of NA level during exercise and recovery was 0.882 (P less than 0.005). The pacing rate of the new generation of QT driven pacemakers is closely correlated with the noradrenaline spillover in the plasma, not with the adrenaline level. A short delay (less than 1 minute) is observed in the adaptation.     

Physiological control of splanchnic blood flow by adrenaline: studies during acute hypoglycaemia in man.

Superior mesenteric artery blood flow (SMABF) increases significantly during and after the hypoglycaemia reaction in healthy humans. To investigate the mechanisms controlling this phenomenon, SMABF and plasma catecholamines were measured in healthy human volunteers. In 10 controls, hypoglycaemia was induced by insulin infusion (2.5 m-units.min-1.kg-1). In six subjects, beta-blockade by propranolol infusion (0.7 microgram.min-1.kg-1) preceded insulin infusion and was continued throughout the study. Following the hypoglycaemia reaction, the glucose nadir was similar in both groups. In controls, increases in SMABF [42.4+/-6.1% (mean+/-S.E.M.); P<0. 001], cardiac output (34.3+/-2.3%; P<0.001) and pulse rate (from 63. 9+/-2.7 to 82.5+/-3.1 beats/min; P<0.001) occurred. Superior mesenteric artery resistance fell by 32.4+/-3.3% (P<0.001). Under beta-blockade, decreases in SMABF (34.8+/-2.9%; P<0.001) and pulse rate (from 59.5+/-0.2 to 51.8+/-2.2 beats/min; P<0.001) occurred. Superior mesenteric artery resistance increased (peak +30.8+/-12.3%; not significant). Subjects showed greater increases in adrenaline (P<0.006) and noradrenaline (P<0.022) concentrations than controls. Mesenteric hyperaemia associated with hypoglycaemia in man appears to be mediated by a beta-adrenergic mechanism that is activated by increased circulating levels of adrenaline.     

The role of opioid peptides in the hormonal responses to acute exercise in man

Opioid involvement in the physiological and hormonal responses to acute exercise was investigated in six normal male subjects. Each was exercised to 40% (mild exercise) and 80% (severe exercise) of his previously determined maximal oxygen consumption on two occasions, with and without an infusion of high-dose naloxone. The exercise task was a bicycle ergometer; mild and severe exercise were performed for 20 min each, followed by a recovery period. Exercise produced the expected increases in heart rate, blood pressure, ventilation, tidal volume, respiratory rate, oxygen consumption and carbon dioxide production. After severe exercise, naloxone infusion increased ventilation from 94.8 +/- 4.9 litres/min to 105.7 +/- 5.0 litres/min (P less than 0.05), but had no effect on any of the other physiological variables. Exercise-induced changes in several hormones and metabolites were noted, including elevations in circulating lactate, growth hormone (GH), prolactin, cortisol, luteinizing hormone (LH), follicle stimulating hormone (FSH), adrenaline noradrenaline, plasma renin activity (PRA) and aldosterone. There was no change in plasma met-enkephalin. Naloxone infusion produced the expected increases in LH and cortisol, but also significantly enhanced the elevations in prolactin, adrenaline, noradrenaline, plasma renin activity and aldosterone (P less than 0.05). Psychological questionnaires revealed minor mood changes after exercise, but no evidence was found for the suggested 'high' or euphoria of exercise. Effort was perceived as greater during the naloxone infusion than the saline infusion in every subject.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of aminophylline on plasma and urinary catecholamine levels during heavy leg exercise in healthy young men

1. Methylxanthines have been shown to elevate the basal plasma level and/or urinary excretion of noradrenaline (NA) and adrenaline (ADR) in healthy subjects. The present study addressed the hypothesis that the methylxanthine aminophylline also augments plasma and urinary catecholamines during increased sympathoadrenal activity. 2. Eleven healthy young men performed a maximal 2 h bicycle exercise twice, after double-blind intravenous administration of placebo or aminophylline. Femoral venous plasma and urinary concentrations of NA and ADR were analysed in samples representing basal state, exercise and recovery, using liquid chromatography with electrochemical detection. 3. Leg exercise induced eight- and six-fold increases in the plasma concentrations of NA and ADR, respectively, and seven- and four-fold increases in the urinary concentrations of NA and ADR, respectively, indicating that sympathoadrenal activity was considerably elevated. 4. After aminophylline (mean plasma concentration 20-35 mumol/l), the plasma concentrations of NA (P less than 0.001) and ADR (P less than 0.05) were independently higher at rest, during exercise and during recovery, in comparison to after placebo; the mean exercise plasma level of NA was increased by the drug from 13 +/- 1 to 21 +/- 2 nmol/l and the corresponding level of ADR from 2.1 +/- 0.4 to 2.9 +/- 0.5 nmol/l. Also urinary NA (P less than 0.01) and ADR (P less than 0.05) were elevated by aminophylline; the exercise concentrations of NA in the urine were 75 +/- 8 and 97 +/- 10 mumol/mol of creatinine after placebo and aminophylline, respectively, and the corresponding levels of ADR were 12 +/- 3 and 16 +/- 3 mumol/mol of creatinine, respectively.     

Dose-response study of the redistribution of intravascular volume by angiotensin II in man.

1. The response of systemic and regional haemodynamic indices to increasing infusion rates of angiotensin II (1, 3 or 10 ng min-1 kg-1) or placebo [5% (w/v) D-glucose] was studied in eight normal male subjects. 2. As compared with placebo, angiotensin II infusion caused an incremental rise in the serum angiotensin II level [14.5 +/- 7.7 (placebo) to 187.2 +/- 36.1 (10 ng of angiotensin II min-1 kg-1) pmol/l; mean +/- 95% confidence interval] associated with a stepwise increase in total peripheral resistance [880 +/- 42 (placebo) to 1284 +/- 58 (10 ng of angiotensin II min-1 kg-1) dyn s cm-5] and a progressive reduction in cardiac output [8.3 +/- 0.4 (placebo) to 7.0 +/- 0.4 (10 ng of angiotensin II min-1 kg-1) litres/min]. 3. A stepwise fall in renal blood flow was observed with increasing angiotensin II infusion rate [1302 +/- 65 (placebo) to 913 +/- 64 (10 ng of angiotensin II min-1 kg-1) ml/min]. In contrast, calf blood flow was unaffected by 1 ng or 3 ng of angiotensin II min-1 kg-1 and was significantly increased by 10 ng of angiotensin II min-1 kg-1 (P less than 0.01). 4. Calf venous capacitance was uninfluenced by 1 ng of angiotensin II min-1 kg-1, but was significantly increased by both 3 ng (P less than 0.005) and 10 ng (P less than 0.001) of angiotensin II min-1 kg-1.(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.     

Effect of low dose adrenaline and noradrenaline infusions on airway calibre in asthmatic patients

Airway, cardiovascular and metabolic responses were measured in six asthmatic patients with stable asthma during separate adrenaline, noradrenaline and control infusions. Four incremental infusion rates (4, 10, 25 and 62.5 ng min-1 kg-1) produced circulating catecholamine concentrations within the physiological range. Specific airways conductance and maximal expiratory flow rates measured from complete and partial flow-volume curves increased significantly (P less than 0.05) during adrenaline infusion, in a dose-response manner. No changes in specific airways conductance or maximal expiratory flow rates were seen during the noradrenaline or control infusion. The highest adrenaline infusion rate caused a rise in systolic blood pressure (P less than 0.05) and plasma glucose (P less than 0.05) and a fall in plasma potassium (P less than 0.05). Noradrenaline infusion caused a slight increase in diastolic blood pressure (P less than 0.05) but no metabolic changes. No cardiovascular or metabolic changes occurred during the control infusion. Infused adrenaline, producing circulating concentrations within the physiological range, caused dose-related bronchodilatation in asthmatic patients. Circulating noradrenaline does not appear to have a role in the control of basal airway tone in asthmatic patients.     

The effects of low dose insulin infusions on the renin angiotensin and sympathetic nervous systems in normal man

To examine the effects of physiological insulin concentrations on the renin-angiotensin and sympathetic nervous systems, healthy volunteers were studied by the euglycaemic glucose clamp technique with sequential 60 min 0.5 and 1.0 mU kg-1 min-1 insulin infusions and, subsequently, by a control infusion simulating clamp conditions. Plasma renin activity increased from 0.8 +/- 0.1 ng ml-1 h-1 basally to 1.0 +/- 0.2 ng ml-1 h-1 during the 0.5 mU infusion to 1.4 +/- 0.1 ng ml-1 h-1 during the 1 mU infusion but did not change during control infusion (0.9 +/- 0.3 ng ml-1h-1 to 0.9 +/- 0.2 ng ml-1h-1 to 1.0 +/- 0.1 ng ml-1h-1) (P less than 0.001 insulin vs. control by ANOVAR). Plasma angiotensin II increased during insulin (21.2 +/- 1.8 to 25.2 +/- 2.3 to 29.3 +/- 2.4 pg ml-1) but not during control infusion (24.0 +/- 2.8 to 23.6 +/- 2.6 to 23.5 +/- 2.5 pg ml-1) (P less than 0.001 insulin vs. control). Serum aldosterone did not change significantly during either infusion (insulin: 239 +/- 89 pmol l-1 to 237 +/- 50 pmol l-1 to 231 +/- 97 pmol l-1, control: 222 +/- 79 to 237 +/- 50 to 213 +/- 97 pmol l-1). Plasma noradrenaline increased to a greater extent during insulin (1.03 +/- 0.2 to 1.14 +/- 0.8 to 1.27 +/- 0.17 nmol l-1) than control infusion (0.86 +/- 0.09 to 0.97 +/- 0.09 to 0.99 +/- 0.09 nmol 1-1 (P less than 0.01 insulin vs. control). Changes in mean systolic blood pressure during insulin infusion were significantly different from control (+ 3 vs. -4 mmHg, P less than 0.001). In conclusion acute hyperinsulinaemia within the physiological range increases circulating hormones of the renin-angiotensin and sympathetic nervous systems and also increases systolic blood pressure.     

Pressor effect of arginine vasopressin in progressive autonomic failure

The blood pressure (BP) and heart rate (HR) responses to 5 min incremental intravenous infusions of noradrenaline (NA) and arginine vasopressin (AVP) were investigated both in patients with progressive autonomic failure (PAF) and in normal volunteers. Stepwise infusion of NA at rates of 300-3000 pmol min-1 kg-1 produced a bradycardia and a dose related increase in BP in normal subjects. In subjects with PAF there was no significant HR response but the dose-BP response was shifted to the left with significant pressor responses at infusion rates of 60-300 pmol min-1 kg-1. Stepwise infusion of AVP at 0.2-5.0 pmol min-1 kg-1 caused transient bradycardia but no pressor response in seven normal volunteers. Further increases in AVP infusion in three other subjects achieved plasma AVP levels as high as 3000-4000 pmol/l, and still no significant pressor response was observed. Stepwise infusion of AVP at 0.05-2.0 pmol min-1 kg-1 in the eight subjects with PAF resulted in a pressor response without any change in HR. During this infusion plasma AVP increased from 0.8 +/- 0.2 (mean +/- SEM) to 30 +/- 2 pmol/l. A significant pressor response was already apparent at a plasma AVP level of 5.5 +/- 1.8 pmol/l.     

Hypertensive left ventricular hypertrophy is linked to an enhanced catecholamine response to submaximal exercise.

BACKGROUND: The serial plasma catecholamine response to exercise has not been studied fully in relation to left ventricular hypertrophy (LVH) in patients with hypertension (HT). This study determined whether plasma catecholamine responses to exercise are altered in essential HT in the presence or absence of LVH. MATERIALS AND METHODS: Plasma noradrenaline (NA) and plasma adrenaline (A) were measured at rest, during and after treadmill exercise in 59 hypertensive subjects and 22 age-matched control subjects. Patients were divided into LVH(-) (n = 20) and LVH(+) (n = 39) stratified by left ventricular mass index [LVMI: control subjects, LVH(-), LVH(+): 114 +/- 4, 105 +/- 3, 151 +/- 3 g m-2]. RESULTS: Exercise time (9.9 +/- 0.6, 7.6 +/- 0.7, 7.3 +/- 0.6 min) was shorter in patients with HT. Both systolic and diastolic blood pressures were higher in patients with HT, and no difference was observed between LVH(-) and LVH(+) patients. Resting plasma NA was not different (157 +/- 16, 173 +/- 17, 167 +/- 14 pg mL-1), but plasma NA at stage I (300 +/- 30, 342 +/- 40, 469 +/- 40 pg mL-1) was higher in LVH(+) patients than in LVH(-) patients or control subjects. Plasma A response to exercise was similar among the three groups. There was a positive correlation (r = 0.38, P < 0.001) between LVMI and Deltaplasma NA at stage I in all subjects. CONCLUSIONS: Patients with essential HT with LVH had augmented plasma NA response during submaximal exercise, whereas patients without LVH did not exhibit this augmentation. The positive correlation between LVMI and Deltaplasma NA suggested a possible association between the degree of cardiac hypertrophy and sympathetic activation during 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.     

Reassessment of the single intravenous injection method with inulin for measurement of the glomerular filtration rate in man.

1. Factors influencing the total body and renal clearances of inulin were investigated in a total of 37 healthy adult volunteers and 10 patients with stable chronic renal failure after the single intravenous injection of a dose of 70 mg/kg given over 5 min. 2. The elimination of inulin was highly concentration-dependent, and in healthy volunteers the renal clearance fell from 103.7 +/- 14.4 ml min-1 1.73 m-2 during the first hour after administration to 49.1 +/- 20.9 ml min-1 1.73 m-2 over the period 6-8 h. In the patients with renal failure the renal clearance fell correspondingly from 39.7 +/- 16.5 to 26.6 +/- 8.6 ml min-1 1.73 m-2. There were no changes in the simultaneously measured clearances of creatinine. 3. The values obtained for the total body clearance of inulin after a single injection depend critically on dose, the number and timing of blood samples, the choice of pharmacokinetic model, the number of data points chosen for estimation of the slope of the terminal elimination phase for analysis by the methods of residuals, and the weighting used for curve fitting by non-linear regression analysis. 4. With standardized conditions of sampling from 0 to 2 h and weighted non-linear regression analysis of the plasma concentration-time data, the total body and renal clearances of inulin were almost identical in subjects with normal renal function at 105.2 +/- 10.2 and 102.9 +/- 13.0 ml min-1 1.73 m-2. In the patients with chronic renal failure sampling was continued for 3 h and the corresponding clearances were 40.4 +/- 15.3 and 38.9 +/- 15.7 ml min-1 1.73 m-2. 5. The 0-2 h total body and renal clearances of inulin were measured by the single injection method and the renal clearance was measured by the standard constant infusion method on different occasions in 10 healthy volunteers. The respective clearances were similar at 101.4 +/- 6.6, 94.9 +/- 11.9 and 88.4 +/- 12.1 ml min-1 1.73 m-2. 6. The reproducibility of the single injection and constant infusion methods was compared by measuring the inulin clearance with both techniques on three occasions in separate groups of eight and nine healthy volunteers. The mean coefficient of variation for the total body clearance with the single injection method was only 3.9% compared with 9.5% for the renal clearance determined the same way and 12.0% for the renal clearance during constant infusion.(ABSTRACT TRUNCATED AT 400 WORDS)     

Abnormal plasma noradrenaline response and exercise induced albuminuria in type 1 (insulin-dependent) diabetes mellitus.

Submaximal exercise provokes an abnormal elevation in albuminuria in type 1 (insulin-dependent) diabetes mellitus. Plasma catecholamines might be involved in this phenomenon by a renal vasoconstrictive effect. Twelve healthy subjects (Controls: albuminuria < 10 micrograms min-1), 13 normoalbuminuric type 1 diabetic patients (DNormo: albuminuria < 10 micrograms min-1) and 13 microalbuminuric type 1 diabetic patients (DMicro: albuminuria 10-200 micrograms min-1) performed a fixed bicycle workload (600 kpm for 20 min+urine collection 40 min post exercise). None of the patients suffered from autonomic neuropathy or hypertension. Fractional albumin clearance (FalbCl) rose in DNormo (p = 0.02) and DMicro (p = 0.01) but not in the Controls (p = 0.40). Basal plasma adrenaline and noradrenaline were not different in the three groups. The increments in noradrenaline were more pronounced in DNormo and DMicro than in Control (Controls < DNormo, p < 0.05; Controls < DMicro, p < 0.01). The changes in FalbCl were significantly correlated with the changes in noradrenaline (all subjects r = 0.65, p < 0.001). The increments in adrenaline were not different in the diabetic groups compared to the controls, and were not related to the changes in FalbCl. Multiple regression analysis showed that changes in plasma noradrenaline (p < 0.002) and in mean arterial pressure (p < 0.005) independently contributed to the changes in FalbCl (multiple r = 0.73). It is concluded that the exercise-induced plasma noradrenaline response is increased in normo- and microalbuminuric type-1 diabetic patients. Noradrenaline appears to contribute in the exercise-induced changes in renal protein handling, possibly by its effect on renal haemodynamics.     

Altered platelet function during mental stress and adrenaline infusion in humans: evidence for an increased aggregability in vivo as measured by filtragometry

1.The effects of mental stress induced by a colour word conflict test (CWT; n = 9) or 3 h infusions of placebo or adrenaline (0.4 nmol min-1 kg-1; n = 9) on platelet function in vivo were studied in 16 healthy male volunteers. 2. Platelet function was assessed by a filtragometry technique, which reflects aggregability in vivo, and by measurements of the plasma levels of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4). 3. Adrenaline and CWT induced marked cardiovascular responses as expected. Venous plasma adrenaline increased from 0.1-0.2 nmol/l at rest to 4.87 +/- 0.42 nmol/l during adrenaline infusion and to 0.46 +/- 0.10 nmol/l during CWT. 4. Filtragometry measurements were reproducible within individuals with coefficients of variation of 7.9% during placebo infusion and 5.4% for resting measurements between days. 5. Platelet aggregability, as measured by filtragometry, was similarly increased during both adrenaline infusion (P less than 0.05) and CWT (P less than 0.01). 6. The coefficients of variation for beta-TG and PF4 levels were 17.3% for log beta-TG and 27.9% for log PF4 between days, but could not be calculated for within-day variability. Both beta-TG (P less than 0.05) and PF4 (P less than 0.01) levels decreased time-dependently during placebo infusion, indicating that long resting periods (hours) are needed to attain basal levels. Artefactual results could not be identified by evaluating beta TG/PF4 ratios. 7. beta-TG and PF4 levels did not decrease time-dependently during adrenaline infusion. There were no significant changes of beta-TG or PF4 during CWT.(ABSTRACT TRUNCATED AT 250 WORDS)