Acute myocardial infarction (AMI) is characterized by a rapid increase in circulating platelet size but the mechanism for this is unclear. Large platelets are hyperactive and associated with adverse clinical outcomes. We determined mean platelet volume (MPV) and platelet–monocyte conjugation (PMC) using blood samples from patients, and blood and the spleen from mice with AMI. We further measured changes in platelet size, PMC, cardiac and splenic contents of platelets and leucocyte infiltration into the mouse heart. In AMI patients, circulating MPV and PMC increased at 1–3 h post-MI and MPV returned to reference levels within 24 h after admission. In mice with MI, increases in platelet size and PMC became evident within 12 h and were sustained up to 72 h. Splenic platelets are bigger than circulating platelets in normal or infarct mice. At 24 h post-MI, splenic platelet storage was halved whereas cardiac platelets increased by 4-fold. Splenectomy attenuated all changes observed in the blood, reduced leucocyte and platelet accumulation in the infarct myocardium, limited infarct size and alleviated cardiac dilatation and dysfunction. AMI-induced elevated circulating levels of adenosine diphosphate and catecholamines in both human and the mouse, which may trigger splenic platelet release. Pharmacological inhibition of angiotensin-converting enzyme, β 1 -adrenergic receptor or platelet P2Y 12 receptor reduced platelet abundance in the murine infarct myocardium albeit having diverse effects on platelet size and PMC. In conclusion, AMI evokes release of splenic platelets, which contributes to the increase in platelet size and PMC and facilitates myocardial accumulation of platelets and leucocytes, thereby promoting post-infarct inflammation.

Potential mechanisms of cold-induced myocardial ischaemia are sympathetically mediated coronary vasoconstriction and/or catecholamine-induced increases in cardiac work. To examine these parameters, 11 human volunteers were each studied on one day with, and on another day without, β-adrenoceptor blockade. On each day, warm (37 °C) saline (control) and cold (4 °C) saline (hypothermia) were given intravenously. Myocardial perfusion was assessed by positron emission tomography using H 2 15 O, and coronary vascular resistance was calculated. Plasma catecholamines were measured to assess sympathoadrenal activation. The core temperature decreased by 1.0 ± 0.2 °C with the cold saline, and was unchanged with warm saline. Myocardial perfusion increased by 20% ( P = 0.01) and the rate–pressure product by 33% ( P = 0.0004) with cold saline compared with warm saline. β-Blockade eliminated these increases. Coronary vascular resistance was similar with warm and cold saline, and was unaffected by β-blockade. Plasma adrenaline increased by 120% and noradrenaline by 251% during cold saline, but were unchanged during warm saline. In conclusion, core hypothermia triggers β-adrenoceptor-mediated increased cardiac work, sympathoadrenal activation and increased myocardial perfusion. There is no evidence for hypothermia-induced coronary vasoconstriction.

Postoperative hypothermia increases the incidence of ischaemic cardiac events in patients at risk, but the underlying mechanism is unclear. One possibility is increased cardiac work related to the sympathoneural or adrenomedullary hormonal responses. In awake human volunteers, the present study assessed the effects of mild core hypothermia on these responses, and on the associated changes in indices of cardiac work. A total of 11healthy men were studied on two separate days. On one day, core temperature ( T c ) was decreased by the intravenous infusion of cold normal saline (4°C; 60ml/kg over 30min) through a central venous catheter. On the other day (normothermic control), warm normal saline (37°C; 60ml/kg over 30min) was given intravenously. Transthoracic echocardiograms, the sympathoneural response (noradrenaline) and the adrenomedullary response (adrenaline) were evaluated before, during and after the intravenous infusions. Echocardiography was used to measure left ventricular function and cardiac output. Compared with the normothermic control treatment, core cooling of 0.7°C was associated with increased plasma noradrenaline (220% increase; P = 0.001), whereas adrenaline, cardiac output, heart rate and the rate-pressure product were unchanged. After core cooling of 1.0°C, increases in noradrenaline (by 230%; P = 0.001), adrenaline (by 68%; P = 0.05), cardiac output (by 23%; P = 0.04), heart rate (by 16%; P = 0.04) and rate-pressure product (by 25%; P = 0.007) were all significant compared with the normothermic control treatment. In conclusion, there is a T c threshold, below which an adrenomedullary (adrenaline) response is triggered in addition to the sympathoneural (noradrenaline) response. This T c threshold (≈ 1°C below the normothermic baseline) is also associated with an increase in haemodynamic indices of cardiac work. Mild core hypothermia therefore constitutes a catecholamine-mediated cardiovascular ‘stress test’.

This study examined the effects of dopamine D 2 -receptor blockade on the early decrease in maximal heart rate at high altitude (4559m). We also attempted to clarify the time-dependent component of this reduction and the extent to which it is reversed by oxygen breathing. Twelve subjects performed two consecutive maximal exercise tests, without and with oxygen supplementation respectively, at sea level and after 1, 3 and 5 days at altitude. On each study day, domperidone (30mg; n = 6) or no medication ( n = 6) was given 1h before the first exercise session. Compared with sea level, hypoxia progressively decreased the maximal heart rate from day 1 and onwards; also, hypoxia by itself increased plasma noradrenaline levels after maximal exercise. Domperidone further increased maximal noradrenaline concentrations, but had no effect on maximal heart rate. On each study day at altitude, oxygen breathing completely reversed the decrease in maximal heart rate to values not different from those at sea level. In conclusion, dopamine D 2 -receptor blockade with domperidone demonstrates that hypoxic exercise in humans activates D 2 -receptors, resulting in a decrease in circulating levels of noradrenaline. However, dopamine D 2 -receptors are not involved in the hypoxia-induced decrease in the maximal heart rate. These data suggest that receptor uncoupling, and not down-regulation, of cardiac adrenoreceptors, is responsible for the early decrease in heart rate at maximal hypoxic exercise.

Experimental data indicate that adrenomedullin (AM) interacts at various levels with the renin–angiotensin–aldosterone system and the hypothalamic–pituitary–adrenal axis, but data from humans are scant. We examined the effects of intermediate-dose, short-term AM infusion on angiotensin II- and adrenocorticotrophic hormone (ACTH)-mediated hormone and haemodynamic responses in healthy subjects. Seven normal volunteers (age 18–25 years) completed a placebo-controlled crossover study. Each subject was studied on day 4 of two periods of a low-salt diet (40 mmol of sodium and 80 mmol of potassium daily), receiving incremental infusions of angiotensin II in the morning and ACTH in the afternoon of each study day, on a background infusion of AM (4 pmol·min -1 ƃkg -1 ) or vehicle (hemaccel). Achieved plasma AM levels (23±6 pmol/l) and peak angiotensin II levels (160 pmol/l) were similar on the two experimental days. While the pressor action of angiotensin II was attenuated by AM ( P < 0.01) and noradrenaline levels rose ( P < 0.05), the aldosterone response was unaltered. During ACTH infusion, AM increased heart rate ( P < 0.01), plasma adrenaline ( P < 0.01) and plasma noradrenaline ( P < 0.05), and augmented the cortisol response ( P < 0.01), but was without effect on aldosterone levels and blood pressure. We conclude that the threshold for the effects of AM on aldosterone secretion in humans is set higher than for other biological responses to this hormone, namely blood pressure, heart rate, sympathetic activity and cortisol secretion, under these experimental conditions.

We examined and compared findings from studies aimed at detecting and quantifying an effect of insulin per se on counter-regulatory responses to hypoglycaemia. The experimental protocols used in many of these studies were very different with regard to study design and patient population, resulting at times in inconsistencies and discrepancies. Taken together, the results from this extensive body of work clearly indicate that, at similar levels of hypoglycaemia, greater hyperinsulinaemia results in enhanced counter-regulatory responses. This enhancement includes higher circulating levels of counter-regulatory hormones (adrenaline, noradrenaline, cortisol and growth hormone, but not glucagon), more intense activation of hypoglycaemic symptoms (both neural-sympathetic and adrenal-sympathetic), and greater deterioration of neuropsychological skills. The insulin-induced enhancement of counter-regulatory responses is not influenced by gender, is present in several animal species, and applies to healthy subjects as well as to patients with Type I diabetes. The underlying mechanisms remain speculative, and possibly include a direct neuromodulatory effect and/or suppression of glucose utilization in various areas of the brain, which either independently or in a hierarchical fashion trigger the sequence of downstream counter-regulatory events.

Augmentation of circulating noradrenaline concentration stimulates ventilation during the initial stages of exercise and this is accompanied by an increased sensation of dyspnoea and exertion. This previous study [Clark, Galloway, MacFarlane, Henderson, Aitchison and McMurray (1997) Eur. Heart J. 18, 1829–1833] suggested a link between dyspnoea, which commonly limits exercise tolerance in heart failure patients, and high circulating noradrenaline concentration in these patients. The present study investigated this relationship further using sympathetic inhibition. Ten healthy normotensive males performed 10 min of submaximal cycling exercise at approx. 70% of maximal oxygen uptake per min ( Vċ O 2max ) on three occasions one week apart. The first of these sessions was a familiarization session and the other two were experimental study days. On each of the study days, subjects attended the laboratory in the morning after an overnight fast and, following a resting blood sample, were administered placebo or moxonidine (0.4 mg) in a double blind cross-over design. After a 90-min absorption period, subjects undertook the exercise task. Blood was drawn, expired gas was analysed breath by breath, blood pressure, heart rate and ratings of perceived dyspnoea and exertion were obtained. Moxonidine treatment significantly reduced plasma noradrenaline concentration ( P < 0.01), mean arterial pressure ( P < 0.01), and blood glycerol concentration ( P < 0.05), but no differences were observed in heart rate, the ventilatory response to exercise or subjective ratings of dyspnoea and exertion. This study indicates that reducing sympathetic activity does not affect ventilation, perceived dyspnoea or perceived exertion in normotensive males. Therefore it can be concluded that reducing sympathetic activity may not be an appropriate strategy to help reduce perceived dyspnoea.

Changes in circulating levels of catecholamines, cortisol, glucose, interleukin-6 and C-reactive protein and in the leucocyte count were investigated for 7 days after surgery in 158 patients undergoing hip or knee arthroplasty. We compared the responses to the two operations, and also examined the effects of pathology (osteoarthritis and rheumatoid arthritis) on the changes associated with knee arthroplasty. Exploratory factor analysis was applied to the data to identify the variables and sampling times that could be used in future to provide a concise description of the response. Patients undergoing knee arthroplasty showed significantly greater changes in noradrenaline, adrenaline and glucose levels, but not in cortisol levels, compared with those undergoing hip arthroplasty. Interleukin-6 and C-reactive protein concentrations were also significantly greater in knee patients than hip patients; however, when corrected for pathology, many of these differences were not significant. Minimal effects of pathology (chronic inflammation with rheumatoid arthritis) were found on the hormonal changes in knee patients. In particular, there was little evidence to support the inference from animal data that the hypothalamic–pituitary–adrenal axis is impaired. The expected increases in interleukin-6 and C-reactive protein concentrations were found in the rheumatoid arthritis patients. Exploratory factor analysis showed that the response could be separated into six components, accounting for 60% of the total variance, and identified the variables and sampling times indicative of each. In conclusion, there are differences in the hormonal, but not inflammatory, responses to hip and knee arthroplasty. Little evidence was found for an important effect of pathology on the changes associated with knee surgery. Factor analysis provided a useful summary of the data.

The aim of this investigation was to study the effects of isoglycaemic hyperinsulinaemia on the renal metabolism of electrolytes and water in subjects with a strong genetic predisposition to essential hypertension, compared with that in non-predisposed subjects. We studied 25 normotensive subjects aged 18–35 years whose parents both had essential hypertension, and 22 age- and sex-matched subjects whose parents were both normotensive. Diabetes or morbid obesity in any subject or parent excluded the family. The 24-h blood pressure was measured. The subjects received an isocaloric diet with a fixed content of sodium and potassium for 4 days before the study. An isoglycaemic, hyperinsulinaemic clamp with infusion of insulin (40 munits·min -1 ·m -2 ) was performed. We measured the renal clearance of diethylenetriaminepenta-acetic acid, sodium, potassium and lithium both under basal conditions and during hyperinsulinaemia. In response to hyperinsulinaemia, renal sodium clearance decreased to a significantly greater extent in the hypertension-prone subjects [0.57 (0.74, 0.36) ml·min -1 ·1.73 m 2 (median and quartiles)] than in the controls [0.34 (0.56, 0.18) ml·min -1 ·1.73 m 2 ] ( P = 0.04). Compared with the controls, the subjects predisposed to hypertension had a higher 24-h diastolic blood pressure [78 (70, 82) mmHg, compared with 73 (68, 77) mmHg], but a similar insulin sensitivity index {10 7 ×[313 (225, 427)] compared with 10 7 ×[354 (218, 435)] l 2 ·min -1 ·pmol -1 ·kg -1 }. Thus the sodium-retaining effect of insulin was more pronounced in subjects with a strong genetic predisposition to essential hypertension than in subjects with normotensive parents. This effect may contribute to the development of hypertension in subjects with a genetic predisposition to hypertension.

We re-examined, in the context of modern practice, plasma insulin and stress hormone concentrations in patients admitted to hospital with acute coronary syndromes. Venous blood sampling was carried out prior to anti-thrombotic therapy in 148 patients with myocardial infarction (MI); 76 patients with unstable angina (UA) pectoris were also studied, together with 27 patients with non-cardiac chest pain (NCP). There were significant progressive increases in the concentrations of catecholamines, cortisol, glucose and insulin from NCP to UA to MI patients. Hyperglycaemia (glucose > 8 mmol/l) was present in over 50% of MI patients. The plasma cortisol and insulin levels were both significantly positively correlated with the glucose concentration on admission. Only the cortisol concentration was correlated with peak cardiac enzyme levels. The glucose and insulin concentrations on admission in 141 MI and UA patients were related to insulin resistance, as judged from subsequent insulin and glucose concentrations measured while fasting and during a glucose tolerance test. The product of admission insulin×glucose (divided by 25; the admission insulin-resistance index, or AIRI) was significantly correlated with indices of insulin resistance, and was significantly higher (approximately double) in the MI group (7.81±0.76) and the UA group (6.88±1.19) than in the control NCP group (3.59±0.06; Kuskul–Wallis: P = 0.0001), implying that the insulin levels in the first two groups were approximately twice as high as is appropriate for the glucose levels. The ethnic origin of 20% of the patients was the Indian subcontinent; admission insulin and glucose levels in this subgroup were higher than in the non-Asians across all the groups with chest pain. Cortisol was the only stress hormone that was raised in proportion to the size of the infarct, and is a likely partial cause of the elevation in blood glucose. The high insulin levels were related to the prevalence of insulin resistance, and this was particularly important in the Asian subgroup presenting with MI and UA. Thus it appears feasible to identify acute coronary syndrome patients who are insulin-resistant at a time (on admission) when alternative early therapeutic strategies can be instituted.

1. The Na + ,K + -ATPase or Na + ,K + -pump, mediating the active transport of Na + and K + , which was first identified 40 years ago, is a central target for acute and long-term regulation, as well as for therapeutic intervention. Acute stimulation of the Na + ,K + -pump in skeletal muscle by insulin, catecholamines, β 2 -agonists or theophylline increases the intracellular uptake of K + and accounts for the hypokalaemia elicited by these agents. Conversely, digitalis intoxication elicits hyperkalaemia via acute inhibition of the Na + ,K + -pump. 2. Simple and accurate methods have been developed for the quantification of the total concentration of Na + ,K + -pumps in small (0.5–5 mg) fresh or frozen biopsies of human skeletal muscle, myocardium or other tissues. This has allowed the identification of several long-term regulatory changes in the concentration of this transport system in human tissues. In skeletal muscle, upregulation is induced by training, thyroid hormones or glucocorticoids. Downregulation is seen in hypothyroidism, cardiac insufficiency, myotonic dystrophy, McArdle disease, K + deficiency and after muscle inactivity. 3. Since the skeletal muscles contain one of the major pools of Na + ,K + -pumps, these changes are important for the ability to counterregulate the hyperkalaemia elicited by exercise or the ingestion of K + . Moreover, downregulation or inhibition of the Na + ,K + -pumps in skeletal muscle interferes with contractile performance. Since digitalis glycosides bind to the Na + ,K + -pump, the muscles constitute a large distribution volume for these agents and are therefore an important determinant for their plasma level. 4. In cardiac insufficiency, the decrease in the concentration of Na + ,K + -pumps in the myocardium is over a wide range correlated to the concomitant reduction in ejection fraction. The regulatory and pathophysiological changes in the activity and concentration of Na + ,K + -pumps are important for the contractile function of skeletal muscle and heart as well as for K + homoeostasis and the response to digitalization.

1. Hormones involved in cardiovascular regulation are influenced by drug treatment. It is therefore difficult to study endocrine mechanisms in heart failure as most patients are already on treatment by the time they reach hospital. 2. We studied nine hospital in-patients before and after treatment of acute New York Heart Association class IV heart failure. 3. Before treatment, plasma brain and atrial natriuretic peptides were markedly elevated (BNP 121 ± 26 pg/ml, ANP 163 ± 33 pg/ml; normal range: BNP 3.9 ± 0.3 pg/ml, ANP 8.6 ± 0.8 pg/ml) and correlated positively with serum creatinine and left ventricular end-diastolic diameter and negatively with ejection fraction. Eight patients improved and one died. 4. With improvement plasma ANP and BNP fell. Initial renin activity was within the normal range but increased on treatment. Plasma neuropeptide Y and adrenaline remained normal before and after treatment in the eight patients who improved. Initial plasma noradrenaline was in the normal range in four of these patients and just above normal in a further four. In the patient who died, initial plasma neuropeptide Y and catecholamines were very high. 5. Plasma BNP emerged as complementary to ANP as a dynamic index in severe heart failure; however, renal function is also an important determinant of plasma BNP and ANP. There is little evidence for activation of the circulating renin—angiotensin—aldosterone system or neuropeptide Y before treatment of acute heart failure.

1. There is an increase in circulating levels of vasoconstrictive hormones and an alteration in baroreceptor responsiveness with aging. The role of changes in endothelium-dependent and -independent vasoconstrictive hormones in relation to age and gender, with simultaneous assessment of autonomic balance in response to head-up tilt, has been incompletely studied. 2. Sixteen young [25 ± 3 years (mean ± SEM)] and 16 older normal volunteers (68 ± 7 years) underwent a 30 min head-up tilt test at 60°. Haemodynamics were measured every 5 min and blood samples for neurohormone measurement were drawn at baseline, 5, 10, 15 and 30 min into the test. Heart rate variability was analysed in 5 min segments at the baseline, and during the test. The younger subjects exhibited a greater increase in heart rate and diastolic blood pressure, despite lower absolute levels of noradrenaline (norepinephrine) and endothelin-1. Analysis of heart rate variability yielded a decrease in both high- and low-frequency bands in the aged; power at low-frequency decreased only in the young subjects. The age-related differences in blood pressure and noradrenaline levels were markedly attenuated in the female subjects. In addition, endothelin-1 levels and power spectral measurements at low frequency were the lowest in younger females throughout the tilt. 3. Despite attenuated cardiovascular response to tilt, both systemic adrenergic ‘drive’ and endothelin-1 levels increase in parallel with aging. Thus, endothelium-dependent and -independent vasoconstrictive hormone levels increase with age in the resting state and in response to neurohumoral stimulation in humans.

1. Adrenomedullin, a recently discovered 52-amino-acid peptide hormone, circulates in plasma at low picomolar levels in man. Animal studies and studies in vitro indicate that it has diverse biological actions, including vasodilatation, natriuresis and diuresis, and positive inotropism as well as antiproliferative effects. We investigated the bioactivity of two doses of adrenomedullin in healthy human subjects. 2. Human adrenomedullin was given intravenously to eight male subjects at 2 and 8 ng min −1 kg −1 , and haemodynamic, hormonal, renal and biochemical responses were recorded in a placebo (vehicle)-controlled, randomized study. 3. Compared with vehicle, adrenomedullin reduced mean arterial pressure ( P = 0.05 for duration of infusion, mean difference at end of infusion 7.7 mmHg), systolic arterial pressure ( P = 0.04 for duration of infusion, mean difference at end of infusion 10.7 mmHg) and at the lower dose reduced diastolic arterial pressure ( P = 0.05 for lower dose, mean difference at end of infusion 6.3 mmHg) in the absence of compensatory responses in sympathetic activity or renin release. Urine volume and electrolyte excretion were unaffected. 4. The threshold for biological activity of adrenomedullin in man is lower for arterial pressure than for renal or hormonal responses, and is evident at plasma concentrations seen in disorders of the circulation. Adrenomedullin may be an important hormone under pathophysiological circumstances.

1. Adrenaline was infused at a rate of 25 ng min −1 kg −1 into seven healthy volunteers and its effects on adipose tissue were studied by microdialysis. 2. Adrenaline infusion led to a rapid rise in plasma adrenaline concentration from a basal value of 0.15 ± 0.03 nmol/l to a peak value of 1.82 ± 0.15 nmol/l within 30 min (analysis of variance: P < 0.001). Plasma noradrenaline levels increased from the basal value of 1.48 ± 0.21 nmol/l to 1.78 ± 0.20 nmol/l within 30 min of infusion (analysis of variance: P < 0.05). Once the infusion was stopped the plasma adrenaline and noradrenaline levels returned to basal values within 15 min. 3. The arterialized blood glycerol concentration increased from the basal value of 47 ± 6μmol/l to 101 ± 8 μmol/l (analysis of variance: P < 0.001), and the interstitial glycerol concentration increased from 181 ± 17 μmol/l to 350 ± 47μmol/l (analysis of variance: P < 0.001) within 30 min of adrenaline infusion. Thereafter the concentrations declined gradually towards basal values. When the infusion was discontinued the levels declined further, below the basal value. 4. Adrenaline infusion caused a significant increase in the plasma glucose and blood lactate concentration (analysis of variance: P < 0.001 and P < 0.001), but no such effect was observed in the interstitial concentrations. 5. The basal dialysate concentrations of adrenaline and noradrenaline were 43 ± 37 pmol/l and 1170 ± 430 pmol/l respectively. There were difficulties in estimating the absolute interstitial concentrations of adrenaline and noradrenaline which are discussed. The dialysate adrenaline concentration increased to a peak value of 112 ± 48 pmol/l (analysis of variance: P < 0.05) within 30 min. The dialysate noradrenaline concentration increased to a peak value of 2830 ± 1470 pmol/l, but the rise was not significant. 6. These results show that the interstitial concentrations of metabolites and hormones can be significantly different from those of blood and plasma and these differences reflect tissue specialization.

1. The regulation of lipolysis was studied in 14 upper-body obese women aged 26–55 years. Isolated subcutaneous adipocytes from the abdominal region were examined before and after an 8 to 12-week-long weight reduction programme, during which the mean body mass index (kg/m 2 ) of the group was reduced from 36.4 ± 0.9 to 30.3 ± 1.0. 2. Fat cell volume was reduced from 891 ± 39 to 655 ± 45 pl. The sensitivity to noradrenaline stimulation of lipolysis in vitro increased fivefold after weight reduction. A corresponding increase in sensitivity was found with the β 2 -selective adrenoceptor agonist terbutaline. However, the number of β 2 -adrenoceptor binding sites as assessed by radioligand binding with 125 I-labelled cyanopindolol was not changed. No changes were observed when dobutamine (a β 1 -selective adrenoceptor agonist) and clonidine (an α 2 -adrenoceptor agonist) were used. 3. The basal lipolysis rates decreased by about 50% after weight reduction and the maximum enzyme activity of hormone-sensitive lipase was also reduced by almost 50%. 4. Plasma concentrations of insulin, noradrenaline and total testosterone decreased and sex hormone-binding globulin increased after weight reduction. Calculated apparent free testosterone levels decreased by more than 40% after weight reduction. 5. In conclusion, weight reduction leads to increased efficiency of adipocyte lipolysis with decreased resting lipolysis rate but increased sensitivity to stimulation by catecholamines, which may be attributed to a decreased activity of hormone-sensitive lipase and an increased sensitivity of β 2 -adrenoceptors. Changes in circulating levels of catecholamines, insulin and testosterone may play a role in these modifications of adipocyte function. The increased lipolytic efficiency may be of importance for amelioration of the metabolic complications of obesity that are observed after weight reduction.

1. Insulin-induced hypoglycaemia is characterized by an autonomic disturbance which produces some of the symptoms of hypoglycaemia. How an additional autonomic stress like postural change may alter physiological responses and symptoms of hypoglycaemia is not known. In 10 healthy male subjects (mean age 24 years) we observed physiological and symptomatic responses to postural change during acute (20 min) and prolonged (60 min) hyperinsulinaemic (60 m-units min −1 m −2 ) hypoglycaemia (2.5 mmol/l) and euglycaemia (4.5 mmol/l), and placebo control (saline). 2. In all studies standing increased plasma catecholamines (adrenaline, P < 0.001; noradrenaline, P < 0.0001), blood pressure ( P < 0.0001) and heart rate ( P < 0.0001). Catecholamine responses to standing were augmented by acute hypoglycaemia (adrenaline, P < 0.005; noradrenaline, P < 0.01), but less so by prolonged hypoglycaemia (adrenaline, P < 0.05; noradrenaline, P < 0.05). Supine heart rate was higher before standing during prolonged hypoglycaemia ( P < 0.05), but did not increase as much on standing when compared with acute hypoglycaemia and prolonged euglycaemia. 3. During acute hypoglycaemia, autonomic symptoms increased on standing, but during prolonged hypoglycaemia, in the presence of generally higher symptom scores, standing had no effect. Autonomic symptoms, with the exception of hunger, tended to decrease with time ( P < 0.05) during prolonged hypoglycaemia. 4. To conclude, posture does modify the catecholamine and symptomatic responses to hypoglycaemia, but this effect is dependent on the duration of hypoglycaemia. Hypoglycaemia and hyperinsulinaemia had little or no effect on the cardiovascular responses to changing posture.

1. The influence of single-dose intravenous ouabain on haemodynamics, renal function and vasoactive hormones was investigated in healthy subjects. 2. After ouabain injection there was a significant reduction in minimum and average hourly heart rates. Diastolic blood pressure fell immediately after ouabain, without a significant change in systolic blood pressure. 3. There was no change in renal blood flow, glomerular filtration rate, hourly urine volume or sodium and potassium excretion. 4. Ouabain injection was associated with a fall in plasma angiotensin II levels and a rise in plasma adrenaline levels, but plasma noradrenaline levels were unchanged. Both plasma atrial and brain natriuretic peptide levels were increased after ouabain administration. 5. The present study demonstrates that ouabain has significant although minor, acute effects on plasma levels of vasoactive hormones. It fails, however, to confirm that ouabain is an acute pressor or natriuretic substance. If it has an important influence on electrolyte and haemodynamic homoeostasis, its actions are likely to be slowly developed.

1. This study was designed to determine whether a 1 h period of mild hypoglycaemia (33 or 3.7 mmol/l) affected the response to an episode of moderate hypoglycaemia (2.5 mmol/l) immediately afterwards. 2. Eleven non-obese healthy men (age 26 + 1 years, mean + SEM) underwent three separate 3 h hyperinsulinaemic glucose clamps in single-blind, random order. On all three occasions, blood glucose was 4.5 mmol/l for the first hour, and on a control visit was maintained at this level for the second hour. In the other two visits, blood glucose was lowered to 3.7 or 33 mmol/l during the second hour. In the third hour, blood glucose was lowered to 2.5 mmol/l on all three visits. 3. In the second hour, adrenaline rose significantly ( P <0.05, analysis of variance) with a blood glucose of 33 and 3.7 mmol/l, as did cortisol and heart rate at 33 mmol/l, but glucagon, prolactin, sweating rate, symptom score and blood pressure were the same during the second hour on all three visits. 4. In the final hour at 2.5 mmol/l, there were no differences in adrenaline, noradrenaline, glucagon, prolactin, cortisol, symptom score, heart rate, blood pressure or sweating rate. 5. Thus, the overall magnitude of hormonal responses to moderate hypoglycaemia (2.5 mmol/l) are not modified by exposure to mild hypoglycaemia (33 or 3.7 mmol/l) for 1 h immediately beforehand.

1. This study was designed to determine whether the duration and pattern of prior insulin exposure modulate the symptomatic and counterregulatory responses to hypoglycaemia. 2. Ten healthy non-obese subjects (five males/five females age 25 + 1 years, mean + SEM) were made hypoglycaemic in three ways: (i) a hyperinsulinaemic (60 m-units min −1 m −2 ; plasma insulin concentration 95 m-units/l) clamp, with 1 h of euglycaemia, blood glucose level 4.5 mmol/l, followed by 30 min of hypoglycaemia, at a stable glucose nadir of 2.0 mmol/l (i.e. euglycaemic then hypoglycaemic clamp: E+HC); (ii) an identical hypoglycaemic clamp without preceding hyperinsulinaemic euglycaemia (i.e. a hypoglycaemic clamp: HC); (iii) insulin infusion only, discontinued at a blood glucose level of 3.0 mmol/l (II). Blood glucose level reached the same nadir as on E+HC and HC, and did not fall further. At the glucose nadir, and 15 and 30 min after, the plasma insulin concentration was 23, 7 and 4 m-units/l, respectively, on the II visit. 3. At the glucose nadir, plasma glucagon level, plasma adrenaline level, sweating rate, heart rate, blood pressure, and overall and individual symptom scores (using visual analogue scales) were the same on E+HC, HC and II. 4. There were no significant differences in neurohormonal response between E+HC and HC, but more subjects felt hypoglycaemic on E+HC on arrival at the glucose nadir ( P <0.05). There was significantly more blurring of vision (1.3+0.5 versus 0.2+0.1 cm) and tingling (1.2+0.4 versus 0.2+0.1 cm) 30 min after arriving at the glucose nadir on E+HC than HC ( P <0.05, analysis of variance). 5. Significant differences were only found between E+HC or HC and the II visit 15 min after arriving at the glucose nadir, when the blood glucose level had risen significantly to 2.9 mmol/l, and 30 min after arrived at the glucose nadir, by which time the blood glucose level had recovered to 3.8 mmol/l. 6. A 1 h run-in period of euglycaemic hyperinsulinaemia does not affect the hormonal or physiological response to an identical degree of hypoglycaemia, but appears to cause increased symptoms of neuroglycopenia during subsequent stable hypoglycaemia. 7. A difference in plasma insulin level within the physiological range does not affect the magnitude of symptomatic, hormonal or physiological responses to the same degree of hypoglycaemia.

1. Eleven untreated men with mild to moderate primary hypertension and 10 normotensive control subjects were studied at rest and during a mental stress test (Stroop colour word conflict test), which has previously been used in studies of hypertensive patients with regard to non-invasive cardiovascular variables and venous plasma catecholamine concentrations. 2. Heart rate, central cardiovascular pressures, cardiac output (thermodilution) and forearm blood flow (strain gauge plethysmography) were determined. Systemic and forearm vascular resistances were calculated. Arterial and venous plasma adrenaline and noradrenaline concentrations were measured by h.p.l.c., and arterial noradrenaline spillover and noradrenaline overflow from the forearm were assessed by isotope methodology ([ 3 H]noradrenaline). Neuropeptide Y-like immunoreactivity was measured by radioimmunoassay. 3. In hypertensive patients heart rate, arterial blood pressure, cardiac output and forearm blood flow increased by 28%, 13%, 37% and 115%, respectively, and forearm and systemic vascular resistances decreased by 48% and 21%, respectively ( P <0.001 for all responses), during stress. These responses were not different from those of the control group. 4. Arterial noradrenaline spillover rose by 63% and noradrenaline overflow from the forearm rose by 150% in the hypertensive patients in response to mental stress ( P <0.001); no significant group differences could be demonstrated. However, the forearm noradrenaline overflow response to stress tended to be greater in the hypertensive group ( P = 0.11). Arterial adrenaline concentrations doubled in both groups ( P <0.001). 5. Arterial neuropeptide Y-like immunoreactivity increased slightly and similarly in the two groups (+7% in hypertensive patients and +9% in control subjects, P <0.05 for both) in response to mental stress. No net overflow of neuropeptide-Y-like immunoreactivity could be detected over the forearm. 6. It is concluded that the cardiovascular and sympatho-adrenal responses to mental stress evaluated in this study are similar in hypertensive patients and control subjects. Stress-induced vasodilatation occurs in the forearm despite signs of increased local sympathetic activity, indicating that powerful neurohormonal vasodilator mechanisms are activated by mental stress.

1. The renal effects of incremental doses of intravenously infused noradrenaline were evaluated in normal subjects during two different water loads, 5 ml/kg ( n = 6) and 20 ml/kg ( n = 9), producing conditions of euhydration and overhydration, respectively. 2. Noradrenaline infusion rates ranged from 0.015 to 0.075 μg min −1 kg −1 . In the euhydrated subjects, noradrenaline caused a dose-dependent fall in urinary sodium excretion and an increase in urinary flow rate. During overhydration similar doses of noradrenaline caused a fall in urinary sodium excretion but a decrease in urinary flow rate. 3. Although there was no detectable change in glomerular filtration rate, a dose-dependent fall in effective renal plasma flow was observed in both hydration states during noradrenaline infusion. 4. Noradrenaline infusion was associated with a dose-dependent increase in proximal tubular sodium reabsorption as assessed by the lithium clearance method. Fractional reabsorption of sodium by the distal nephron was, however, unchanged by noradrenaline in both hydration states. 5. Plasma vasopressin concentration was unchanged by noradrenaline in euhydrated subjects. The renin-angiotensin-aldosterone axis was stimulated by noradrenaline in both euhydrated and overhydrated subjects. 6. Thus we conclude that plasma circulating noradrenaline has a dose-dependent antinatriuretic effect in man. The antinatriuretic effect of noradrenaline is mediated mainly at the proximal tubule in man. We have also shown that during overhydration, noradrenaline decreased urinary flow rate. In contrast, in euhydrated subjects, noradrenaline increased urinary flow rate with no accompanying changes in plasma vasopressin concentration, which suggests a direct effect of noradrenaline on the renal tubular permeability to water.

1. Dihydroxyphenylalanine is the precursor of all endogenous catecholamines. In laboratory animals, renal uptake and decarboxylation of circulating dihydroxyphenylalanine accounts for most of dopamine in urine. Dopamine is natriuretic, and in rats, dietary salt loading increases renal dihydroxyphenylalanine uptake by increasing the rate of entry (spillover) of dihydroxyphenylalanine into arterial plasma. In experimental animals and in humans, dietary salt loading increases urinary excretion of dihydroxyphenylalanine and dopamine. The present study examined in humans the extent to which circulating dihydroxyphenylalanine is the source of urinary dopamine and of the dopamine metabolite dihydroxyphenylacetic acid, and whether, as in animals, dietary salt loading affects dihydroxyphenylalanine spillover. 2. L-Dihydroxyphenylalanine (0.33 μg min −1 kg −1 ) was infused intravenously for 300 min after 7 days of a low-salt (mean 41 mmol/day) or a high-salt (mean 341 mmol/day) diet in 12 healthy subjects. Concentrations of dihydroxyphenylalanine, dopamine and dihydroxyphenylacetic acid were measured in urine and in antecubital venous plasma. Infusion of L-dihydroxyphenylalanine produced a steady-state mean dihydroxyphenylalanine level about 10 times the endogenous level. About 30% of infused dihydroxyphenylalanine estimated to be delivered to the kidneys via the arterial plasma was excreted as dopamine, and about 30% was excreted as dihydroxyphenylacetic acid. 3. Dietary salt loading increased urinary excretion rates of dihydroxyphenylalanine [from 0.08 ± (SEM) 0.01 to 0.14 ± 0.03 nmol/min, t = 2.80, P <0.02] and dopamine (from 1.03 ± 0.19 to 1.30 ± 0.28 nmol/min, t = 2.35, P <0.05), whereas dihydroxyphenylalanine spillover appeared to be unchanged. 4. Renal uptake and decarboxylation of circulating dihydroxyphenylalanine accounted for virtually all the urinary excretion of endogenous dopamine, but for only a minor portion of the excreted endogenous dihydroxyphenylacetic acid. 5. We conclude that in humans: (1) circulating dihydroxyphenylalanine is the main source of urinary dopamine but only a minor source of urinary dihydroxyphenylacetic acid; and (2) increased spillover of endogenous dihydroxyphenylalanine does not account for the increased excretion of these compounds during salt loading.

1. Twenty-two patients with renovascular hypertension and significant lateralization of renin secretion were investigated with respect to arterial and renal venous plasma noradrenaline and dopamine concentrations before and 30 min after two different blood pressure-lowering procedures (enalaprilat or dihydralazine intravenously). 2. In one group of patients ( n = 10) blood pressure reduction by 7.5 mg of dihydralazine caused stimulation of the renin-angiotensin system and increased heart rate ( P < 0.01) as well as arterial and renal venous plasma noradrenaline and dopamine concentrations ( P < 0.01 for both). The elevation of the plasma dopamine concentration was more pronounced than that of noradrenaline, yielding increased dopamine/noradrenaline ratios both peripherally ( P < 0.05) and in the renal veins ( P < 0.05). 3. In the second group of patients ( n = 12) a comparable reduction in blood pressure elicited by 1.25 mg of enalaprilat was not accompanied by alterations in heart rate or in noradrenaline or dopamine levels in arterial plasma or renal venous plasma from either kidney. 4. Thus, inhibition of angiotensin-converting enzyme does not elicit the expected sympathetic counter-regulatory response to blood pressure reduction; the mechanism(s) involved remains to be clarified.

1. Plasma concentrations of noradrenaline and adrenaline were measured in 11 anaesthetized patients during normocapnia, hypocapnia and hypercapnia. Hypocapnia was produced by deliberate hyperventilation and hypercapnia by adding carbon dioxide to the inspired gas mixture. 2. With a median (range) arterial partial pressure of carbon dioxide of 4.7 (4.2–5.2) kPa, the median (range) plasma concentration of noradrenaline was 0.41 (0.12–0.94) nmol/l and of adrenaline was 0.15 (0.05–0.31) nmol/l. 3. With an arterial partial pressure of carbon dioxide of 2.6 (2.2–3.3) kPa, there was no change in the plasma concentration of noradrenaline [0.37 (0.12–0.86) nmol/l] or that of adrenaline [0.16 (0.05–0.32) nmol/l]. 4. However, with an arterial partial pressure of carbon dioxide of 10.4 (7.6–13.2) kPa, there were significant increases in the plasma concentrations of both noradrenaline [1.13 (0.79–2.05) nmol/l, P < 0.01] and adrenaline [0.67 (0.20–2.92) nmol/l, P < 0.05]. 5. This is the first demonstration in man that respiratory acidosis causes an increase in plasma concentrations of catecholamines.

1. 11β-Hydroxysteroid dehydrogenase converts cortisol to inactive cortisone in man. In distal renal tubules, this inactivation protects mineralocorticoid receptors from cortisol. Congenital 11β-hydroxysteroid dehydrogenase deficiency and inhibition of 11β-hydroxysteroid dehydrogenase by liquorice or carbenoxolone result in cortisol-dependent hypokalaemia and hypertension. 2. 11β-Hydroxysteroid dehydrogenase is expressed in vascular smooth muscle. Both glucocorticoids and mineralocorticoids potentiate vascular responses to noradrenaline. 11β-Hydroxysteroid dehydrogenase activity may therefore influence vascular tone. 3. Experiments were performed in healthy subjects with and without 7 days of oral administration of 11β-hydroxysteroid dehydrogenase inhibitors (liquorice or carbenoxolone), and in a patient with congenital 11β-hydroxysteroid dehydrogenase deficiency. We measured the following parameters: dermal vasoconstriction after topical application of cortisol, forearm blood flow during brachial artery infusion of cortisol or noradrenaline, and blood pressure during systemic infusion of noradrenaline. 4. Cortisol-induced dermal vasoconstriction was increased by liquorice (23 ± 6 to 52 ± 7 units; P <0.04) and in congenital 11β-hydroxysteroid dehydrogenase deficiency (87 units). In congenital 11β-hydroxysteroid dehydrogenase deficiency intraarterial infusion of cortisol caused vasoconstriction (20% reduction in blood flow in the infused arm) and accentuated the response to application of lower-body negative pressure, which stimulates sympathetically mediated vasoconstriction (35% reduction). However, intra-arterial infusion of cortisol had no effect in healthy subjects either with or without administration of liquorice. 5. Carbenoxolone potentiated both noradrenaline-induced forearm vasoconstriction ( P <0.01) and pressor response ( P <0.001). 6. We conclude that 11β-hydroxysteroid dehydrogenase modulates the access of cortisol to vascular receptors and thereby influences vascular sensitivity to noradrenaline. Complementary to its role in kidney, 11β-hydroxysteroid dehydrogenase could influence blood pressure by this mechanism, which may underlie our observations of impairment of 11β-hydroxysteroid dehydrogenase and increased dermal vascular sensitivity to cortisol in patients with essential hypertension.

1. We investigated the effects of the chronic administration of a sympathomimetic agent on energy expenditure, protein metabolism and levels of thyroid hormones and catecholamines in 10 obese subjects after a 6-week very-low-calorie-diet programme (1965 kJ, 60 g of protein, 45 g of carbohydrates). l -(-)-Ephedrine hydrochloride (50 mg three times a day by mouth) or placebo were administered during 2-week periods (weeks 2-5 of the VLCD programme) in a randomized, double-blind, crossover design. Five subjects began with ephedrine and five with placebo. 2. The results were analysed separately in the two groups. No difference was found between them as regards weight loss during the very-low-calorie diet and drug treatments. Conversely, ephedrine therapy induced a significantly lower daily urinary excretion of nitrogen (and, consequently, a better nitrogen balance) with respect to placebo, independently of the drug sequence. Daily urinary levels of 3-methylhistidine during ephedrine and placebo treatments were similar. The fasting resting metabolic rate (oxygen consumption, ml STP/min) fell significantly during the very-low-calorie diet in both groups, but this effect was partially and significantly prevented by administration of ephedrine. Diet therapy significantly reduced 24 h urine levels of vanillylmandelic acid and homovanillic acid, which, however, increased to pretreatment values during ephedrine treatment. No significant effects were shown on 24 h urinary concentrations of adrenaline, noradrenaline and dopamine during the very-low-calorie diet and/or ephedrine treatment. There were also no effects on the serum levels of thyrotropin, thyroxine, free-tri-iodothyronine and free-thyroxine, but ephedrine significantly prevented a further fall in the serum tri-iodothyronine level and the serum triiodothyronine/thyroxine ratio during the very-low-calorie diet. 3. These findings demonstrate that in obese subjects following a very-low-calorie-diet programme, administration of chronic adrenoceptor agonists, such as ephedrine, partially prevented the fall in resting metabolic rate and significantly improved the nitrogen balance. These effects may be of importance in the treatment of patients in whom a reduced capacity for energy expenditure may be involved in their obese state.

1. To evaluate the short-term reproducibility of heart rate, oscillometrically determined blood pressure, ante-cubital venous plasma catecholamine concentrations and subjective responses to strictly standardized mental arithmetic, we performed two identical tests 1 h apart in 14 young, healthy and normotensive male subjects (age 22–35 years) 2. Heart rate and blood pressure responses to the two stress tests were highly correlated, when expressed both as correlations between levels attained during stress ( r s >0.80 throughout) and as absolute reactivity measures (all r s >0.75). Also, subjective stress responses were highly correlated, when considering both levels during stress and reactivity ( r = 0.97 and r = 0.85, respectively). Stress levels of catecholamines were correlated, but the change scores (reactivity) were unrelated. 3. The measurement error sd for heart rate was 2.6 and 3.0 beats/min for reactivity and stress levels, respectively. The corresponding sd for blood pressure ranged between 2.7 and 4.4 mmHg. Subjective stress experience showed an sd of a similar magnitude. The responses of plasma catecholamine concentrations were subject to considerable variability. 4. It is concluded that haemodynamic and subjective stress responses and stress levels during the mental arithmetic stress test show acceptable reproducibility and high test-retest correlations. However, stress-induced changes in venous plasma catecholamine concentrations show low reproducibility.

1. The haemodynamic effects of hormonal changes during the menstrual cycle were examined in 11 normotensive women (age 20–46 years). The subjects were studied on days 2–8 (follicular phase) and days 18–26 (luteal phase) in a randomized order. A standardized mental stress test and a 24 h recording of ambulatory blood pressure and heart rate were performed. 2. Pre-stress resting levels of heart rate and blood pressure were similar during the two phases of the menstrual cycle. 3. During mental stress, the heart rate response was significantly greater during the luteal phase than during the follicular phase (14.7 versus 9.7 beats/min; P < 0.05). 4. Blood pressure, plasma catecholamine concentrations and subjective stress experience increased significantly in response to stress, without any significant differences between the two phases. 5. During 24 h ambulatory monitoring, higher levels of systolic blood pressure and heart rate were observed in the luteal phase than in the follicular phase ( P < 0.005 and P < 0.0001, respectively). 6. These data indicate that cyclic variations in female sex hormones not only affect systolic blood pressure and heart rate, but also alter the haemodynamic responses to psychosocial stress.

1. A fall in intraocular pressure is induced by acute hypoglycaemia in humans. The role of the autonomic nervous system in mediating this response was investigated in 24 normal volunteers in whom hypoglycaemia was induced with intravenous soluble insulin, under four experimental conditions: (1) control ( n = 6), (2) nonselective α-adrenoceptor blockade (phentolamine) ( n = 6), (3) non-selective β-adrenoceptor blockade (propranolol) ( n = 6) and (4) cholinergic blockade (atropine) ( n = 6). Intraocular pressure was measured by using an applanation tonometer. In 12 subjects intraocular pressure was measured during each type of pharmacological blockade of similar duration without induction of hypoglycaemia, to assess the effects of individual antagonists. 2. In the control study intraocular pressure fell during hypoglycaemia from 15 ± 1.0 to 10 ± 1.3 mmHg ( P <0.01) 10 min after the autonomic reaction. β-Adrenoceptor blockade caused a reduction in intraocular pressure from 15 ± 1.1 to 9 ± 1.0 mmHg ( P <0.001) before the administration of insulin, and when hypoglycaemia was induced intraocular pressure decreased further to 7 ± 1.0 mmHg ( P <0.05, compared with immediately before insulin). A decrease in intraocular pressure of similar magnitude was observed with propranolol alone (16 ± 1.0 to 10 ± 1.0 mmHg, P <0.05). 3. Cholinergic blockade had no immediate effect on intraocular pressure, and the reduction in intraocular pressure during hypoglycaemia was of similar magnitude to that observed during the control study. α-Adrenoceptor blockade did not affect basal intraocular pressure, but the small reduction induced by hypoglycaemia (from 14 ± 1.4 to 12 ± 1.1 mmHg; P = not significant) was less than the decrement observed in the control experiment. The administration of atropine or phentolamine in the absence of hypoglycaemia had no significant effect on intraocular pressure. 4. In humans the reduction of intraocular pressure induced by acute hypoglycaemia appears to be mediated principally via an α-adrenoceptor-mediated mechanism.

1. Renal and cardiovascular effects of three dosages of insulin [50 (Ins I), 300 (Ins II) and 500 (Ins III) m-units h −1 kg −1 ] were investigated in healthy males by using a euglycaemic clamp technique. On separate days, control experiments were carried out to correct for any circadian variation in the variables studied. 2. All three insulin dosages resulted in a marked decline in fractional sodium excretion (actual experiments: basal, 0.95 ± 0.15%, Ins I, 0.79 ± 0.10%, Ins II, 0.80 ± 0.12%, Ins III, 0.84 ± 0.08%; control experiments: basal, 0.96 ± 0.10%, Ins I, 1.20 ± 0.12%, Ins II, 1.53 ± 0.15%, Ins III, 1.43 ± 0.10%; means ± sem, P < 0.005, analysis of variance). With the highest insulin dosage, the reduction in fractional sodium excretion tended to be less striking. This coincided with a rise in heart rate, pulse pressure and pulse rate-systolic blood pressure product (double product). Although blood pressure itself did not change, systolic blood pressure also tended to increase (actual experiments: basal, 133 ± 5 mmHg, Ins I, 132 ± 5 mmHg, Ins II, 139 ± 5 mmHg, Ins III, 143 ± 4 mmHg; control experiments: basal, 128 ± 3 mmHg, Ins I, 129 ± 3 mmHg, Ins II, 130 ± 3 mmHg, Ins III, 133 ± 3 mmHg; means ± sem, P = 0.09, analysis of variance). There was a positive correlation between the change in fractional sodium excretion and the change in systolic blood pressure over control values ( r = 0.696, P < 0.028). At a rise in systolic blood pressure of 18 mmHg, the sodium-retaining effect of insulin appeared to be offset. A shift of the pressure-natriuresis relation to the right is suggested. 3. Plasma catecholamines did not change. Plasma renin activity increased from 1.11 ± 0.17 (basal) to 2.13 ± 0.31 (Ins III) pmol of angiotensin I h −1 ml −1 ; on the control day, a decline from 1.28 ± 0.24 (basal) to 0.81 ± 0.13 (Ins III) pmol of angiotensin I h −1 ml −1 was noted ( P < 0.001). Despite this rise no concomitant rise in plasma aldosterone occurred. 4. Chronic hyperinsulinaemia may lead to blood pressure elevation in the long-term if it is postulated that resistance to the glucose-lowering effect of insulin is absent for the effects of insulin on the kidney and the cardiovascular system.

1. Measurement of blood pressure and heart rate over a 24 h period was peformed in 10 quadriplegic spinal cord injury patients and 10 immobilized, neurologically intact orthopaedic subjects by using the Spacelabs 90207 automated ambulatory monitoring system. 2. Systolic and diastolic blood pressure fell significantly at night in orthopaedic subjects but not in quadriplegic patients, and night-time blood pressures were similar in both groups. 3. Cumulative summation of differences from a reference value (cusum analysis) confirmed a markedly diminished diurnal blood pressure variation in the quadriplegic patients. 4. These findings could not be accounted for on the basis of blood pressure variations during chronic postural change. 5. Heart rate fell significantly at night in both groups. 6. The findings suggest that the increase in blood pressure during waking hours in neurologically intact subjects is a consequence of a diurnal variation in sympathetic activity (absent in quadriplegic patients with sympathetic decentralization) which is independent of changes in physical activity.

1. Dopamine in 5% (w/v) d-glucose was infused into five healthy male volunteers at doses of 2, 5 and 10 μg 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 < 0.001, analysis of variance) specifically at a rate of 10 μg min −1 kg −1 ( P < 0.05) when it was 14% higher, but not at a rate 2 of or 5 μg 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 μg of dopamine min −1 kg −1 , respectively ( P < 0.01). At 10 μg 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 < 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 < 0.01), but only transiently, during dopamine infusion at a rate of 2 μg 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 μg min −1 kg −1 . It increases energy expenditure and circulating free fatty acid and glycerol levels at an infusion rate of 10 μg min −1 kg −1 , presumably due to stimulation of lipolysis.

1. The responses of blood pressure, heart rate, autonomic function and plasma insulin to a high carbohydrate and a high fat meal of equivalent energy value were studied in nine young volunteers. 2. Neither meal produced a significant change in supine or erect blood pressure. The high carbohydrate meal, however, resulted in an overall rise in both supine (6 beats/min) and erect (6 beats/min; P < 0.05) heart rate, no such changes being seen after the high fat meal. 3. Plasma noradrenaline levels increased by a maximum of 126% at 90 min (0.98 to 2.22 nmol/l) after the high carbohydrate meal but were virtually unchanged after the high fat meal ( P < 0.01). Parasympathetic function showed no between-meal differences. Plasma insulin and glucose levels were significantly higher after the high carbohydrate meal than after the high fat meal. No postprandial difference in packed cell volume was found between meal types. 4. We conclude that, in young subjects, the postprandial blood pressure after a high carbohydrate meal is maintained by an increase in heart rate associated with increased sympathetic nervous system activity. These changes are at variance with the blood pressure and heart rate responses seen in the elderly after a high carbohydrate meal. A high fat meal has no significant cardiovascular or neuroendocrine effects in the young or old. The nutrient composition of meals has to be taken into account when studying the postprandial cardiovascular and neuroendocrine responses in the young.

1. Long-term oxygen therapy in appropriate patients prolongs survival and corrects neuropsychological function. Some tests of mental function paradoxically improve during short periods of oxygen withdrawal in patients on long-term oxygen therapy, although the mechanism of this response is unknown. 2. To evaluate the effects of transient hypoxaemia on plasma adrenaline and noradrenaline levels, we studied eight oxygen-dependent patients who underwent either a 4 h period of oxygen withdrawal or their routine therapy, in a randomized, blinded fashion, on 2 separate days. 3. Plasma noradrenaline did not differ at baseline between study days. During normoxic conditions, plasma noradrenaline levels did not increase significantly with time. By contrast, under hypoxic conditions, plasma levels of noradrenaline rose significantly from 0 to 4 h ( P < 0.05). The magnitude of the noradrenaline response was correlated with baseline noradrenaline such that subjects with the highest resting levels had the largest increase during hypoxia ( r = 0.95, P < 0.001). 4. Plasma adrenaline did not differ at baseline between study days and there were no significant effects of hypoxia on plasma adrenaline levels. 5. We conclude that the sympathetic nervous system, but not the adrenal medulla, is stimulated in chronically oxygen-dependent subjects made acutely hypoxaemic. The magnitude of this stimulation appears to be related to the state of sympathetic nervous system activity at baseline. Improvement in some tests of mental function during transient periods of oxygen withdrawal may be due to non-specific arousal caused by a catecholamine surge.

1. Haemodynamic and metabolic effects of intravenous infusion of adenosine, an endogenous vasodilator, were studied in healthy humans. 2. Catheters were inserted into pulmonary and brachial arteries and into the hepatic and subclavian veins. Cardiac output was determined according to the Fick principle, and splanchnic blood flow was measured by using extraction of Indocyanine Green. Skin blood flow was estimated by a laser Doppler technique, calf blood flow by venous occlusion plethysmography and skeletal muscle and adipose tissue blood flow by a local isotope clearance technique. 3. Adenosine (infused in steps from 40 to 80 μg min −-1 kg −-1 into a central vein) elicited a gradual reduction in the peripheral vascular resistance to less than 50% of the basal level. There was a slight increase in the systemic blood pressure, but the pulmonary arterial and the ventricular filling pressures were unchanged. Cardiac output was doubled, accomplished by a combination of a positive chronotropic effect and an increase in stroke volume, which may be secondary to diminished peripheral resistance. 4. Skin blood flow increased by 100% at 50 μg of adenosine min −-1 kg −-1 , whereas splanchnic blood flow rose significantly at 60 μg of adenosine min −-1 kg −-1 . Blood flow in the calf, gastrocnemius muscle and adipose tissue did not change significantly. 5. Arterial concentrations of noradrenaline and adrenaline increased by 62 and 43%, respectively, during infusion of adenosine. Arterial levels of glycerol were depressed by more than 50%, but those of glucose and pyruvate were unchanged. 6. In conclusion, exogenous adenosine caused a marked systemic vasodilatation, with different responsiveness in the investigated vascular beds. The vasodilatation occurred in the presence of an increase in generalized sympathetic activity. Adipose tissue blood flow was unaltered despite a considerable reduction in fat mobilization.

1. To examine the metabolic effects of increases in circulating endogenous plasma catecholamines, we measured plasma glucose, potassium and magnesium in 14 patients undergoing elective coronary artery bypass grafting. The patients were randomized into two groups and received either sodium nitroprusside (a direct-acting vasodilator) or trimetaphan camsylate (a ganglion-blocking agent) for routine control of blood pressure during the operation. 2. There were significant differences between the two groups in the levels of all three metabolic variables studied. Plasma glucose levels rose in both groups, but were significantly higher in the sodium nitroprusside group [peak levels 9.14 ( sem 0.72)mmol/l compared with 6.71 (0.88) mmol/l, P < 0.001, analysis of variance]. The cardioplegia solution caused a large increase in plasma magnesium in both groups but in the sodium nitroprusside group the level rose higher [to 1.59 (0.12)mmol/l compared with 1.34 (0.06)mmol/l] and fell faster ( P < 0.05, analysis of variance). In the group receiving sodium nitroprusside, plasma potassium fell, by a mean of 0.34 mmol/l, as plasma catecholamine levels rose; no such fall was seen in the group receiving trimetaphan camsylate ( P < 0.05, analysis of variance). 3. It is concluded that the sympathoadrenal system is important in causing metabolic changes during cardiopulmonary bypass and may be relevant in other conditions such as acute myocardial infarction.

1. Peripheral adrenergic responses were studied in eight obese women before and after 15 days of caloric restriction (2500 kJ/day) and in eight sex- and age-matched lean controls. 2. β-Adrenergic sensitivity (defined as the dose of isoprenaline required to increase resting heart rate by 25 beats/min) was evaluated before and after the diet. Density and affinity (determined as the apparent dissociation constant) of platelet α 2 -adrenergic receptors, and plasma adrenaline and noradrenaline levels, were measured after overnight bed-rest and after 9 min of standardized exercise performed before and after the low caloric diet. 3. Before the diet basal antecubital venous plasma noradrenaline concentrations were lower in obese women when compared with lean women (0.94 ± 0.06 vs 1.27 ± 0.17 nmol/l, P < 0.02). Isoprenaline sensitivity did not differ between lean and obese women. 4. At rest, platelet α 2 -adrenoceptor density was lower in overweight than in lean women (129 ± 21 vs 168 ± 16 fmol/mg of protein, P < 0.02). Exercise significantly increased platelet α 2 -adrenoceptor density and decreased affinity in lean women. This decrease correlated with the rise in plasma noradrenaline. 5. In obese women exercise did not modify platelet α 2 -adrenoceptor density or affinity, despite a significant increase in plasma catecholamines. However, the increase in plasma noradrenaline during exercise was lower in obese women. 6. The low caloric diet produced a β-adrenergic supersensitivity. 7. We conclude that (a) obesity does not alter β-adrenergic sensitivity; (b) 15 days of caloric restriction produces a β-adrenergic supersensitive state; (c) obese women show an inability to desensitize platelet α 2 -adrenoceptors in response to exercise.

1. The effects of four meals of similar energy, but different nutritional, composition on postprandial blood pressure, heart rate, autonomic function, catecholamines, insulin and packed cell volume levels were studied in seven fit elderly subjects. 2. The high carbohydrate and high protein meals led to a significant overall fall in supine systolic and diastolic blood pressure compared either with no change or a rise after the normal (i.e. mixed) and high fat meals. Similar between-meal differences were seen with erect diastolic but not erect systolic blood pressure. No significant postural blood pressure fall occurred after any of the meals. Supine heart rate was unaffected by meal type or by time, and although erect heart rate showed a small increase during the study there was no between-meal difference. 3. Parasympathetic function was unaffected by meal type. Plasma noradrenaline rose after the high carbohydrate and mixed meals only, remaining elevated for 120 min after meal consumption. This increase was not related to the changes in blood pressure or plasma insulin levels. 4. Plasma insulin and glucose rose after the high carbohydrate and mixed meals, but were unchanged after the high protein and high fat meals. Packed cell volume showed a small decrease towards the end of the study, although there was no between-meal variation. 5. The differences in the cardiovascular changes after the different meals could not be ascribed to alterations in autonomic function, insulin release or fall in plasma volume. We propose that the postprandial changes in blood pressure are due to the nutrient composition of the meal rather than the actual energy load.

1. Although the opiate antagonist naloxone has been shown to affect sympathoadrenomedullary function in some studies, this has not been a uniform finding in all investigations, using different doses of naloxone. We have therefore investigated the actions of saline placebo and increasing bolus doses of intravenous naloxone (25, 100 and 250 μg/kg) on the plasma noradrenaline, adrenaline, adrenocorticotrophin (ACTH) and cortisol responses to a cold-pressor test in six males and two females in a double-blind randomized study. 2. Basal levels of adrenaline did not differ on any of the study occasions: the cold-pressor stimulus produced a significant rise in mean plasma adrenaline to a peak of 0.16 nmol/l, with a peak incremental rise of 0.08 nmol/l. In the presence of the two higher doses of naloxone, the incremental rise in the mean adrenaline level was significantly enhanced, reaching 0.30 nmol/l at 100 μg of naloxone/kg and 0.29 nmol/l at 250 μg of naloxone/kg, with no significant enhancement observed at the lowest dose of naloxone. The rise in plasma noradrenaline, systolic and diastolic blood pressure and pulse rate during the cold-pressor test was not consistently altered by any dose of naloxone, but there was a significant trend for the degree of discomfort to increase with the dose of naloxone. 3. Neither plasma ACTH nor serum cortisol rose in response to the cold-pressor stimulus. Analysis of variance demonstrated a significant naloxone-treatment effect for both ACTH and cortisol, with the 100 μg/kg and 250 μg/kg doses of naloxone leading to a significant rise in mean plasma ACTH not seen at the lowest dose of 25 μg/kg. 4. In a separate study of the effect of naloxone on the clearance of plasma adrenaline, adrenaline was infused on two occasions into eight normal male subjects to a maximum dose of 5 μg/min for 15 min, and blood was sampled at regular intervals during and after termination of the infusion, preceded by 8 mg of naloxone or placebo. After termination of the adrenaline infusion, there was a rapid fall in plasma adrenaline (Λ = −1.9 ± 0.3 min), which was not altered by naloxone (Λ = −1.8 ± 0.3 min). 5. We conclude that the potentiation of the adrenaline response to a cold-pressor test by naloxone is mediated by increased secretion of adrenaline and not by a reduction in its clearance rate, and that this response is of low naloxone sensitivity.

1. Urinary excretion of dopamine (DA) increases during dietary salt loading. The majority of urinary DA is derived from circulating dihydroxyphenylalanine (dopa). Whether the increase in urinary DA excretion during salt loading results from increased efficiency of uptake of dopa by proximal tubular cells of the kidney, facilitation of intracellular conversion of dopa to DA, or increased delivery of dopa to tubular uptake sites, has been unknown. 2. In 10 inpatient normal volunteers on a constant diet, daily excretion of dopa and DA was assessed during normal sodium intake (109 mmol/day) for 1 week, low sodium intake (9 mmol/day) for 1 week and high sodium intake (249 mmol/day) for 1 week. 3. Urinary DA excretion exceeded urinary dopa excretion by about tenfold, and the excretion of both DA and dopa increased by about twofold between the low and high salt diets, with similar proportionate changes. Plasma dopa was unchanged by dietary salt manipulation. 4. The results indicate that increases in urinary DA excretion during dietary salt loading can be accounted for by increased delivery of dopa to sites of uptake by proximal tubular cells. Since dopa is released into the bloodstream by sympathetic nerve endings and by the brain, and since interference with decarboxylation of dopa attenuates natriuretic responses, dopa may function indirectly as a neurohormone involved in homoeostatic regulation of sodium balance.

1. In conscious rabbits, intravenous morphine caused hypertension, bradycardia, hyperglycaemia and increased plasma adrenaline and noradrenaline. These effects were prevented by ganglionic blockade with pentolinium. 2. The cardiovascular responses to morphine were not altered by pretreatment with a vasopressin V 1 -receptor antagonist. 3. After bilateral adrenalectomy morphine caused a similar rise in noradrenaline but no increase in adrenaline. The rise in blood pressure was attenuated and the hyperglycaemia was abolished. 4. Adrenaline infused intravenously to mimic the levels that occurred after morphine caused a similar degree of hyperglycaemia but only a small increase in blood pressure. 5. Pretreatment with intracerebroventricular naloxone prevented the morphine-induced hypertension, hyperglycaemia, increase in plasma catecholamines, respiratory depression and sedation. 6. These results demonstrate that, in conscious rabbits, intravenous morphine causes hypertension by increasing sympathetic vasoconstrictor nerve activity and elevating plasma adrenaline levels; the latter alone produces the hyperglycaemia. Vasopressin release is not involved in the hypertensive response to morphine. The effects of morphine appear to result from stimulation of central opiate receptors leading to enhanced sympathoadrenal outflow.

1. Antecubital venous plasma glucose and insulin concentrations after ingestion of 75 g of glucose were higher in six normal subjects when studied at an ambient temperature of 33°C than at an ambient temperature of 23°C; the mean area under the glucose-time curve increased from 833 at 23°C to 990 mmol min 1 −1 at 33°C, that for insulin from 5300 to 7900 m-units min 1 −1 . 2. Core temperature was elevated by 0.5°C at 33°C ambient, although there was no marked stress response as judged by plasma levels of catecholamines, cortisol and growth hormone; at 2 h after glucose ingestion, mean noradrenaline levels were lower at 33°C than at 23°C (1.1 at 33°C vs 1.8 nmol/l at 23°C), adrenaline slightly higher (0.18 at 33°C vs 0.09 nmol/l at 23°C), cortisol and growth hormone unchanged. 3. Forearm blood flow was markedly elevated at 33°C ambient (mean total flow 9.1 at 33°C vs 1.8 ml min −1 100 ml −1 at 23°C), as were antecubital venous partial pressure of oxygen (mean 10.1 at 33°C vs 5.6 kPa at 23°C) and oxygen saturation (mean 92% at 33°C vs 70% at 23°C). There was a positive correlation between oxygen saturation and area under the glucose tolerance curve. 4. In separate experiments, arterialized glucose concentrations were measured after glucose ingestion at 23°C ambient. Antecubital venous glucose concentrations at 33°C ambient were intermediate between venous and arterialized concentrations at 23°C ambient. 5. It is concluded that the apparent impairment of glucose tolerance at elevated ambient temperature is caused at least in part by increased arterialization of the antecubital venous blood. This potential variable must be considered in research or diagnostic procedures based on the use of venous blood.

1. We estimated the extent to which circulating dopa (3,4-dihydroxyphenylalanine) is the source of urinary dopamine (DA; 3,4-dihydroxyphenethylamine). Tritiated dopa ([ 3 H]dopa) was infused for 90 min into the left renal artery of seven anaesthetized foxhounds, and levels of labelled and unlabelled dopa and DA were measured in the ureteral urine and in the femoral arterial and left renal venous plasma. 2. Only a small percentage of [ 3 H]dopa delivered to the kidneys was excreted as [ 3 H]DA (0.59% from the left kidney, 0.68% from the right); however, the arterial concentration of endogenous dopa (1220 pg/ml) and the renal plasma flows (144 and 141 ml/min by p -aminohippurate clearances) were such that all of the urinary excretion of endogenous DA (about 1 ng/min from each kidney) could be accounted for by uptake and decarboxylation of circulating endogenous dopa. 3. Plasma dopa is the main source of urinary DA.

1. In conscious rabbits, intravenous morphine (3 mg/kg) caused hypertension, bradycardia, hyperglycaemia and sedation. These changes were accompanied by large increases in plasma adrenaline and smaller increases in plasma noradrenaline. 2. These effects of morphine were prevented by intravenous naloxone, demonstrating their dependence on stimulation of opiate receptors. 3. Pretreatment with the antihistamines cimetidine and chlorpheniramine enhanced the morphine-induced rise in blood pressure, excluding a role for histamine release in the hypertensive action of morphine. 4. The centrally acting α 2 -adrenergic agonist clonidine prevented the morphine-induced hypertension and rise in plasma catecholamines, suggesting that these effects are exerted via central pathways. Clonidine alone reduced blood pressure and heart rate and produced hyperglycaemia. 5. α-Adrenergic blockade with phenoxybenzamine reduced the increase in blood pressure after morphine, although the increase in plasma catecholamines was augmented. 6. Pentobarbitone anaesthesia prevented the morphine-induced cardiovascular changes, the increase in plasma catecholamines and the hyperglycaemia. 7. These findings indicate, that in conscious rabbits, morphine induces hypertension by stimulation of opiate receptors leading to increased sympatho-adrenal activity. The hyperglycaemia appears to be in response to secretion of adrenaline. These effects probably result from a central action of morphine.

1. From a screened cohort of 644 67-year-old men, drawn from the population of Gothenburg, 42 men with presumed cardiac dyspnoea were selected and compared with 45 random controls. 2. Cardiac function was evaluated by echocardiography and other non-invasive methods, and the potential of peripheral venous concentrations of immunoreactive atrial natriuretic peptide (IrANP), noradrenaline and adrenaline in revealing cardiac dysfunction was investigated. 3. Concentrations of venous IrANP and noradrenaline were both significantly, but weakly, related to the degree of dyspnoea and to pulmonary congestion. 4. IrANP, but not catecholamines, was also related to other indices of heart failure. The correlations were, however, due solely to increased immunoreactivity in men with severe dyspnoea; in most subjects with mild to moderate dyspnoea the level of IrANP was similar to that of the controls. 5. It is concluded that, in a population sample, the peripheral venous level of IrANP is more closely related to cardiac function than are catecholamines. Yet, the level of IrANP is not a very sensitive marker of cardiac dysfunction, suggesting that stimulation of α-human atrial natriuretic peptide release is a late phenomenon in the development of cardiac failure.

1. The effects of intravenous bolus doses of human calcitonin-gene-related peptide (hCGRP) were studied in ten healthy male volunteers. 2.5, 10 and 25 μg of hCGRP and placebo were administered to each subject in a randomized double-blind study. 2. hCGRP had no effect on systolic or diastolic blood pressure in the supine or standing position. 3. hCGRP increased supine and standing heart rate. Both the extent and duration of the tachycardia were dose related. 4. Plasma noradrenaline levels were transiently increased after 10 and 25 μg of hCGRP. 5. All subjects displayed marked facial flushing after the two higher doses of hCGRP. 6. We conclude that systemic administration of hCGRP produces tachycardia and stimulation of the sympathetic nervous system in the absence of any change in blood pressure.

1. We have studied endocrine function in nine healthy young men 16 weeks before and immediately after Final degree examinations. Factors other than psychological stress which might have affected hormone levels were excluded. 2. The presence of psychological stress at the time of examinations was confirmed by finding increased values for two self-rating anxiety scales. 3. Urine metadrenaline excretion was increased in all subjects at the time of examination. Serum and early morning urine Cortisol as well as pituitary–testicular and pituitary–thyroid function and prolactin levels were unaffected by examination stress. 4. This study questions the popular belief that psychological stress stimulates prolactin secretion and suppresses pituitary–testicular function.

1. Acute ethanol consumption in human volunteers did not appear to alter active cation fluxes by Na + ,K + -ATPase, or intracellular electrolyte concentrations, in peripheral leucocytes or erythrocytes. 2. Urinary electrolyte excretion was decreased after ethanol consumption, compared with controls. 3. Neither plasma glucose nor serum insulin was altered by ethanol. 4. After ethanol consumption there was an elevation of endogenous plasma adrenaline levels. This was accompanied by a leucocytosis, which could be attributed to a raised neutrophil count. 5. The raised adrenaline levels were not associated with hypokalaemia. 6. It is possible that in vivo ethanol may prevent adrenaline-induced hypokalaemia by fluidizing the membrane and/or decreasing the affinity of β-receptors for adrenaline.

1. The effects of hypothyroidism in utero , and continuing into postnatal life, on the central turnover of catecholamines, noradrenaline and dopamine were studied in rats. 2. Rats were rendered hypothyroid in utero by treating pregnant females with methimazole in the drinking water. In two groups goitrpgen treatment continued for 3 or 10 weeks postnatally. 3. Methimazole treatment in utero did not produce significant changes in noradrenaline, dopamine or tyrosine content in either the hypothalamus or striatum. 4. Three weeks' postnatal treatment reduced tyrosine specific radioactivity in the anterior hypothalamus and dopamine specific radioactivity in the striatum. Ten weeks' treatment increased dopamine content and reduced noradrenaline synthesis in the mediobasal hypothalamus and a reduction in tyrosine content in the anterior hypothalamus. 5. These data suggest that hypothyroidism restricted to intrauterine life does not produce permanent changes in adult catecholamine neuronal function. Long term hypothyroidism produced localized changes, suggesting a specific rather than general effect.