Cardiovascular and metabolic response to adrenaline infusion in weight-losing patients with and without cancer

Summary. Fasting is generally accompanied by a decrease in energy metabolism and hormones. On the other hand, indirect evidence has suggested that the response to adrenergic agonists may be maintained or even increased in malnutrition. The present study evaluated whether weight-losing patients with and without cancer have increased plasma concentrations of catecholamines and different responses to intravenously infused adrenaline compared to weight-stable individuals. Eight malnourished cancer and 10 non-cancer patients (11% weight loss) were compared to seven well-nourished and weight-stable patients. Adrenaline was infused i.v. at a rate of 0·005 μg min^-1 kg^-1 body weight during 40 min followed by a 40 min rest period (without infusion) and then a final 40 min period with i.v. adrenaline infusion (0·02 μg min^-1 kg^-1 body weight). Plasma glycerol concentration at fast was higher in weight-losing patients compared to weight-stable individuals. Whole body oxygen uptake, carbon dioxide production, heart rate and plasma concentrations of free fatty acids (FFA) increased while the mean arterial pressure decreased significantly in response to adrenaline infusion at 0·02 μg kg^-1 min^-1 in both weight-losing and weight-stable patients. Adrenaline at 0·005 μg kg^-1 min^-1 increased plasma FFA levels by 19% (P<0·05) in weight-losing patients while no significant alteration was observed in well-nourished patients. Adrenaline infusion at 0·02 μg kg^-1 min^-1 decreased the mean arterial blood pressure and stimulated respiratory gas exchange and heart rate significantly more in weight-losing than in weight-stable patients. The slopes for oxygen uptake, carbon dioxide production, heart rate, plasma FFA and plasma glycerol vs. plasma adrenaline and noradrenaline were all significantly steeper (P<0·05–0·01) in malnourished patients than in well-nourished controls. The present study suggests an increased sensitivity to adrenaline in weight-losing patients compared to matched controls with normal nutritional state and stable weight.     

Endothelin‐1: increased plasma clearance,pulmonary affinity and renal vasoconstriction in young smokers

Pulmonary and renal haemodynamics and elimination of endothelin‐1 (ET‐1) were studied in six young smokers in response to 20 min intravenous infusion of ET‐1 (4 pmol kg^–1 min^–1) after smoking. At 20 min of ET‐1 infusion fractional ET‐1 extractions in the lungs and kidneys were 60 ± 2 and 60 ± 7%, respectively. Cardiac output and renal blood flow (RBF) fell by 18 ± 4% (P<0·05) and 34 ± 5% (P<0·01). Mean systemic arterial pressure increased (P<0·05) whereas pulmonary pressures were unchanged. Compared with previously published data in non‐smokers ( 38 , 39 ) basal arterial ET‐1 and ET‐1‐values during ET‐1 infusion were lower with a more rapid return to basal value. Smokers had higher pulmonary extraction of ET‐1 at the same pulmonary arterial concentration (P<0·05). RBF reduction was more pronounced (P<0·05). Systemic vascular resistance increased while pulmonary vascular resistance did not increase as in non‐smokers. Increased plasma clearance and more efficient pulmonary elimination of ET‐1 lowers the arterial level in young smokers. In addition ET‐1 evokes more pronounced renal vasoconstriction in these individuals.     

Intravenous adrenaline infusion causes vasoconstriction close to an intramuscular microdialysis catheter in humans

Aim: To test if a small muscle injury influences the vascular reactivity to adrenaline in human skeletal muscle. Methods: Blood flow was measured by ¹³³Xenon clearance in the gastrocnemius muscle of eight male subjects at basal and during i.v. infusion of adrenaline (0·1 nmol kg^?1 min^?1) or placebo. Measurements were done with (expts 2 and 3) or without (expt 1) the influence of a small muscle injury induced by inserting a microdialysis catheter. ¹³³Xenon was administered either (expt 1) conventionally into the muscle via a fine needle, or (expts 2 and 3) through a fine tube close to the inserted microdialysis catheter. Expt 3 (control expt) was identical to expt 2 except that placebo was infused instead of adrenaline. Mean ± SEM, n = 8. Results: The blood flow tended to increase during the adrenaline infusion in expt 1 (1·17 ± 0·10 to 1·39 ± 0·15, N.S.), whereas it decreased during the adrenaline infusion in expt 2, from 1·39 ± 0·14 to 1·03 ± 0·14 ml min^?1 100 g tissue^?1 (P<0·001). The blood flow change in response to adrenaline infusion was significantly different in expt 1 and expt 2 (P<0·05). Blood flow also decreased during the placebo infusion in expt 3 (1·15 ± 0·10 to 1·00 ± 0·09, P<0·01), but this decrease was significantly smaller than in response to the adrenaline infusion in expt 2, P<0·01. Conclusion: The present results are consistent with the hypothesis that the small muscle injury caused by the inserted microdialysis catheter influences the vascular reactivity to adrenaline in a vasoconstrictive direction.     

Interactions of stress hormones on lipid and carbohydrate metabolism in man with partial insulin deficiency

Abstract. The metabolic responses to 4-h infusions of adrenaline (3 μg kg^-1 h^-1) and cortisol (10 mg m^-2 h^-1 for 2 h followed by 5 mg m^-2 h^-1 for 2 h), separately and in combination, have been studied in six healthy subjects with concurrent somatostatin infusion (250 μg h^-1). A combined infusion of adrenaline, cortisol, glucagon (180 ng kg^-1 h^-1) and somatostatin has also been studied. Somatostatin plus adrenaline and somatostatin plus cortisol resulted in hyperglycaemia (at 240 min, somatostatin plus adrenaline 11·4 ± 0·4 mmol l^-1, P < 0·001; somatostatin plus cortisol 6·7 ± 0·3 mmol l^-1, P < 0·05; somatostatin alone 4·9 ± 0·4 mmol l^-1). No synergistic effect on blood glucose was seen with adrenaline and cortisol together. When glucagon was added, blood glucose rose more rapidly than without glucagon (9·3 ± 0·4 mmol l^-1v. 7·2 ± 0·5 mmol l^-1 at 45 min, P < 0·001), but plateau values were similar. Plasma NEFA levels were raised by somatostatin plus adrenaline (0·55 ± 0·04–1·82 ± 0·11 mmol l^-1 at 60 min). Somatostatin plus cortisol had no more effect on plasma NEFA than somatostatin alone. During the combined infusion of somatostatin plus adrenaline plus cortisol, a synergistic effect on plasma NEFA was observed (2·30 ± 0·11 mmol l^-1 at 60 min, P < 0·01 v. somatostatin plus adrenaline). This occurred despite a small escape of insulin secretion. The lipolytic actions of adrenaline are potentiated by elevated circulating cortisol levels in insulin-deficient man. Glucagon does not modify this response, but accelerates the development of hyperglycaemia.     

Renal and hormonal actions of atrial natriuretic peptide during angiotensin II or noradrenaline infusion in man

In order to study the renal and hormonal actions of atrial natriuretic peptide (ANP) during background infusions with angiotensin II (ANG II) or noradrenaline (NA), 69 healthy subjects were examined in three main groups receiving a 90-min infusion with either placebo, ANG II (1.5 ng kg^?1 min^?1), or NA (25 ng kg^?1 min^?1). Each of these three main groups were subdivided into two groups receiving an infusion with either placebo or ANP (10 ng kg^?1 min^?1) for the last 60 min of the background infusion. Lithium clearance was used to evaluate segmental tubular reabsorption. ANG II alone caused a decrease in glomerular filtration rate (GFR), renal plasma flow, urinary absolute and fractional excretion of sodium, both proximal and distal fractional tubular sodium reabsorption, and urinary flow. NA alone caused a decrease in renal plasma flow. ANP alone caused a decrease in renal plasma flow. Urinary absolute and fractional excretion of sodium were increased and the distal fractional tubular reabsorption of sodium decreased, whereas the proximal fractional tubular reabsorption was unchanged by ANP. ANG II + ANP: during a background ANG II infusion, ANP still increased fractional excretion of sodium. Proximal fractional reabsorption was decreased, whereas distal fractional reabsorption of sodium was unchanged by ANP during ANG II infusion. The ANP-induced decreases in proximal absolute (?147 vs. +714 μmol min^?1 1.73 m^?2P = 0.05) and fractional (?1.7% vs. +0.6%, P<0.01) tubular sodium reabsorption were more pronounced, and the decrease in distal fractional tubular reabsorption of sodium (?0.1% vs. ?1.4%, P<0.05) less pronounced compared with when ANP was given alone. NA + ANP: during a background NA infusion, ANP still increased urinary sodium excretion and decreased distal fractional reabsorption. None of the ANP-induced absolute changes seen during background infusion with NA were significantly different from the ANP-induced changes seen during placebo background infusion. It is concluded that the natriuretic action of low-dose ANP seems to be preserved during background infusions with ANG II and NA in man. Net sodium excretion during the combined infusion with ANG II and ANP seems to reflect the sum of the opposing influences of each peptide. Low-dose ANP had a very modest but significant inhibitory effect on proximal tubular sodium reabsorption prestimulated by ANG II infusion.     

Effects of atriopeptin III on renal function, regional blood flows and left ventricular function in conscious dogs in presence or absence of hypovolaemia

Abstract. The effects of atriopeptin III (AP III) on the left ventricular and renal functions were studied in thirteen chronically instrumented conscious dogs and compared to those of the solvent (saline). In the normovolaemic state, an AP III infusion (1 μg kg^-1 min^-1 i.v.) had no effects on heart rate, on mean arterial or left ventricular pressure, on (dP/dt) Max (2989±119 vs. 3007±155 mmHg s^-1; NS) or on the relaxation rate. The left ventricular endocardial and epicardial coronary blood flows (radioactive microspheres) and the renal flow in the outer cortex (707–683 ml (min^-1 100 g^-1); NS) or in the inner cortex (563–570; NS) were also insignificantly affected by AP III infusion. However, AP III increased urinary flow from 24±6 to 36±7 ml h^-1 (P<0·025) and the Na⁺ and Cl^- excretions by 92 and 98%, respectively, (P<0·025 and P<0·05 vs. saline group) without altering significantly K⁺, urea and creatinine eliminations. In the moderately hypovolaemic state (mean reduction in renal flow: outer cortex -15%; P<0·05, inner cortex -5%; NS), AP III infusion at two doses (1 and 3 μg kg^-1 min^-1) still had no effects on arterial pressure and on the indexes of left ventricular inotropic state and relaxation but in this setting, the diuretic effect of AP III became variable. Five dogs markedly increased their excretion of water, Na⁺ and Cl^- whereas no change was noted in the seven remaining dogs. Regional renal blood flows and urinary output before infusion were similar in the responders and non-responders but the mean arterial pressure (81±2 vs. 73±3 mmHg; P<0·01) was lower in the non-responders. It is concluded that AP III has no effect on left ventricular contractility or on the coronary vasculature; at small doses, its diuretic effects appear independent of a renal vasodilation and are rapidly blunted in the presence of hypotension.     

Vasoactive neuroendocrine responses associated with tolerance to lower body negative pressure in humans

The purpose of this investigation was to test the hypothesis that peripheral vasoconstriction and orthostatic tolerance are associated with increased circulating plasma concentrations of noradrenaline, vasopressin and renin–angiotensin. Sixteen men were categorized as having high (HT, n=9) or low (LT, n=7) tolerance to lower body negative pressure (LBNP) based on whether the endpoint of their pre‐syncopal‐limited LBNP (peak LBNP) exposure exceeded ?60 mmHg. The two groups were matched for age, height, weight, leg volume, blood volume and maximal oxygen uptake, as well as baseline blood volume and plasma concentrations of vasoactive hormones. Peak LBNP induced similar reductions in mean arterial pressure in both groups. The reduction in legarterial pulse volume (measured by impedance rheography), an index of peripheral vascular constriction, from baseline to peak LBNP was greater (P<0·05) in the HT group (?0·041 ± 0·005 ml 100 ml^?1) compared to the reduction in the LT group (?0·025 ± 0·003 ml 100 ml^?1). Greater peak LBNP in the HT group was associated with higher (P<0·05) average elevations in plasma concentrations of vasopressin (pVP, Δ=+7·2 ± 2·0 pg ml^?1) and plasma renin–angiotensin (PRA, Δ=+2·9 ± 1·3 ng Ang II ml^?1 h^?1) compared to average elevations of pVP (+2·2 ± 1·0 pg ml^?1) and PRA (+0·1 ± 0·1 ng Ang II ml^?1 h^?1) in the LT group. Plasma noradrenaline concentrations were increased (P<0·05) from baseline to peak LBNP in both HT and LT groups, with no statistically distinguishable difference between groups. These data suggest that the renin–angiotensin and vasopressin systems may contribute to sustaining arterial pressure and orthostatic tolerance by their vasoconstrictive actions.     

Atrial natriuretic peptide concentrations in umbilical cord plasma from pre-eclamptic women

Summary. Atrial natriuretic peptide (ANP) was measured in arterial and venous umbilical cord plasma at the time of delivery by cesarean section in pre-eclamptic (n= 7) and normal women (n= 6). In addition venous samples were obtained from pre-eclamptic (n= 7) and normal pregnant women (n= 7) near term. ANP plasma levels were higher in pregnant women with pre-eclampsia than in normal pregnant women (27·9±4·4 [mean±SEM] and 14·1 ±2·5 pmol 1^-1, respectively, P<0·05). Immediately after delivery plasma ANP in pre-eclamptic mothers was 66·7 ± 12·8 pmol 1^-1 compared to 13·9 ±2·2 pmol 1^-1 in normal mothers (P<0·01). However, in the pre-eclamptic group the levels of ANP in arterial and venous umbilical cord plasma (19·5 ±4·2 and 16·7±4·3 pmol 1^-1 respectively) were significantly (P<0·01) lower than ANP levels in arterial and venous cord plasma (39·6 ± 1·0 and 31·1±4·2 pmol 1^-1, respectively) from normal mothers. It is concluded that the increased ANP plasma level in pre-eclamptic women originates from a maternal source. In addition, since the ANP level is lower in cord plasma than in maternal plasma in pre-eclampsia, fetoplacental volume homeostasis may also be changed in pre-eclampsia.     

An 18oxygen inhalation method for determination of total body formation of nitric oxide in humans

The formation of nitric oxide (NO) and the subsequent conversion of the NO formed into nitrate require molecular oxygen. Based on this fact, we have recently developed a method using inhalation of the stable oxygen isotope, i.e. ¹⁸O₂, to determine total formation of NO in small laboratory animals. The method has now been further developed to be applicable also in humans. Five healthy awake male subjects inhaled a gas mixture of unlabelled and 18-labelled oxygen (approximate ratio 4:1) in nitrogen from a closed breathing system equipped with eliminators for carbon dioxide and water vapour. The ratio of unlabelled to 18-labelled oxygen, as well as the total oxygen concentration during the inhalation, were monitored. Venous blood samples were taken before and after the inhalation for analysis of unlabelled and ¹⁸O-labelled nitrate by gas chromatography/mass spectrometry. The procedure was repeated with the same protocol on a later occasion, during ongoing treatment with the NO synthesis inhibitor N^G-monomethyl- L -arginine ( L -NMMA). The average nitrate level in plasma in the absence of L -NMMA was 26 μmol l^–1. The rate of total synthesis of NO was estimated to be 0·38 ± 0·06 μmol kg^–1 h^–1, corresponding to a total body formation of 600–700 μmol/24 h in an adult male. Infusion of L -NMMA caused an increase in mean arterial blood pressure from 86 ± 4 to 99 ± 5 mmHg (P<0·05). The average plasma level of nitrate during infusion of L -NMMA was 24 μmol l^–1. NO formation during infusion of L -NMMA was 0·17 ± 0·03 μmol kg^–1 h^–1, i.e. significantly (P<0·05) lower than in the absence of L -NMMA. We suggest that the described method allows direct determination of total NO formation in man. The method may be useful in the study of various experimental and pathophysiological conditions affecting NO formation.     

Effect of non-hypotensive haemorrhage on plasma catecholamine levels and cardiovascular variability in man

Background: It is well known from animal research that non‐hypotensive haemorrhage produces sympathoexcitatory responses assessable by both the rise in plasma catecholamine levels and the shift of autonomic influences on the heart to more sympathetic and less parasympathetic control. Data in humans are restricted. Methods: Heart rate variability (HRV), systolic blood pressure (FINAPRES) variability (BPV), and catecholamine plasma levels were measured before and after haemorrhage in 30 healthy blood donors and compared with those from 10 control subjects without blood loss. Spectral power of HRV and BPV in very low (0·02–0·06 Hz), low (0·07–0·14 Hz), and high (0·15–0·40 Hz) frequency bands were calculated by Fourier analysis. Catecholamine plasma levels were assayed by dual column reverse‐phased high‐performance liquid chromatography (HPLC). Results: Haemorrhage of 5·6 ± 1·2 ml kg^?1 body weight increased plasma norepinephrine levels (215 ± 92 pg ml^?1 versus 254 ± 95 pg ml^?1; P = 0·002), increased BPV in the low frequency band (Mayer waves; 1·8 ± 1·0 ln [mmHg²] versus 2·0 ± 0·9 ln [mmHg²]; P = 0·021), and decreased the vagally transmitted high frequency HRV (6·9 ± 1·1 ln [MI²] versus 6·5±1·2 ln [MI²]; P<0·0001), but did not induce significant changes in heart rate (66 ± 11 bpm versus 67 ± 11 bpm; P = 0·79) and arterial blood pressure (mean values: 84 ± 13 mmHg versus 87 ± 13 mmHg; P = 0·12). Conclusions: As suggested by plasma norepinephrine levels, systolic BPV and HRV, non‐hypotensive haemorrhage produces sympathoexcitatory responses as well as vagal withdrawal of heart rate control in humans.     

Large platelets continue to circulate in an activated state after myocardial infarction

Abstract This study was intended to investigate the actual platelet activation status after an acute coronary event. The activation status of circulating platelets was assayed directly by measuring the membrane activation markers CD62 and CD63 with the Düssel-dorf III flow cytometry test in 22 patients with the diagnosis of acute myocardial infarction during the 48-h observation period following the acute event. The number of activated, marker-positive sample platelets was significantly increased in the post-MI patients: CD62: 5·8%× 2·25^±1 vs. 3·5%× 2·32^±1, P≤ 0·05; CD63: 18·7%× 1·77^±1 vs. 4·6%× 2·16^±1, P≤ 0·00·1. The platelet volume and count were concomitantly increased (12·1 ± 2·4 fl/ 236 ± 90 times 10³μl^-1 compared to 8·3 ± 1·6 fl/187 ± 42 times 10³μl^-1) in the control group. Particularly large platelets were identified as being activated documented by the exponential increase in the difference in CD63-binding sites per sample platelet above the 90%-percentile and below the 10%-percentile of the volume distribution: Δ+ 1341 ± 903 (MI patients) vs. Δ+ 276 ± 126 (controls), P≤ 0·00·1. Significant creatine kinase elevation and decrease in platelet count was found in the non-survivor subset (n= 5). We conclude that predominantly large platelets continue to circulate in an activated state after MI. This study provides direct evidence that the assumption of an increased thrombotic potential becomes operative in vivo in MI patients. Besides CK elevation and decrease in platelet count this might possibly constitute a prognostic factor for the short-term outcome of the patients.     

Decreased leg glucose uptake during exercise contributes to the hyperglycaemic effect of octreotide

Aim: During prolonged infusion of somatostatin, there is an increase in arterial glucose concentration, and this increase persists even during prolonged exercise. The aim of the study was to measure glucose uptake in the leg muscles during infusion of the somatostatin analogue octreotide before and during leg exercise. Material and methods: Eight healthy male subjects were investigated twice in the fasting state: during 3 h infusion of octreotide [30 ng (kg min)^?1] or sodium chloride with exercise at 50% of maximal VO₂ in the last hour. Glucose uptake and oxygen uptake in the leg were measured using Fick’s principle by blood sampling from an artery and a femoral vein. Blood flow in the leg was measured using the indicator (indocyanine green) dilution technique. Results: After an initial decrease during rest, octreotide infusion resulted in a significant increase in arterial glucose concentrations compared to control conditions during exercise (mean ± SEM: 7·6 ± 0·6 versus 5·6 ± 0·1 mmol l^?1, P<0·01). During rest, octreotide did not change the leg glucose uptake (59 ± 10 versus 55 ± 11 μmol min^?1). In contrast, leg glucose uptake was significantly lower during exercise compared to control conditions (208 ± 79 versus 423 ± 87 μmol min^?1, P<0·05). During exercise, leg oxygen uptake was not different in the two experiments (20·4 ± 1·3 versus 19·5 ± 1·1 μmol min^?1). Conclusion: In conclusion, infusion of octreotide reduced leg glucose uptake during exercise, despite the same leg oxygen consumption and blood flow compared to control conditions. The hyperglycaemic effect of octreotide can partly be explained by the reduction in leg glucose uptake. Furthermore, the results suggest that a certain level of circulating insulin is necessary to obtain sufficient stimulation of glucose uptake in the exercising muscles.     

Effect of acute acidosis and alkalosis on leucine kinetics in man

Summary. The effects of acute pH changes on whole body leucine kinetics (1-¹³C-leucine infusion technique) were determined in normal subjects. Plasma insulin, glucagon, and growth hormone concentrations were kept constant by somatostatin and replacement infusions of the three hormones. When acidosis was produced by ingestion of NH4CI (4 mmol kg^-1 p. os; n = 8) arterialized pH decreased within 3 h from 7.39±0.01 to 7.31 ±0.01 (P<0.001) and leucine plasma appearance increased by 0.13 ±0.04 μmol kg^-1 min^-1 (P<0.02); in contrast, when alkalosis was produced by intravenous infusion of 4 mmol kg^-1 NaHCO₃ (n= 1, pH 7.47 ±0.01), leucine plasma appearance decreased by -0.09 ± 0.04 (xmol kg^-1 min^-1 (P<0.01 vs. acidosis). Whole body leucine flux also increased during acidosis compared to alkalosis (P<0.05), suggesting an increase in whole body protein breakdown during acidosis. Apparent leucine oxidation increased during acidosis compared to alkalosis (P=0.05). Net forearm leucine exchange remained unaffected by acute pH changes. Plasma FFA concentrations decreased during acidosis by -107 ±67 μmol l^-1 (P<0.05) and plasma glucose increased by 1.90±0.25 mmol l^-1 (P<0.02); in contrast, alkalosis resulted in an increase in plasma FFA by 83 ± 40 (μmol 1^-1 (P<0.02; P<0.01 vs. acidosis), suggesting an increase in lipolysis; plasma glucose decreased compared to acidosis (P<0.01). The data demonstrate that acute metabolic acidosis and alkalosis, as they occur in clinical conditions, influence protein breakdown, and in the opposite direction, lipolysis.     

Kinetics of 13CO2 elimination after ingestion of 13C bicarbonate: the effects of exercise and acid base balance

Abstract. In order to investigate the effects of muscular work and preceding exercise on the retention of exogenous labelled bicarbonate, we studied the effects of oral administration of [¹³C]bicarbonate (0·1 mg kg^-1) in five subjects at rest before exercise and during and after 1 h of treadmill walking at 73% VO_2max on three separate occasions. Elimination of CO₂ from labelled bicarbonate was 62·6±8·1% at rest, 103·6±11·3% during exercise (P<0·01) and 43·0±4·7% during recovery from exercise (P= 0·01). During exercise mean residence time (MRT) was shorter than at rest (35±7 min vs. 54±9min, P < 0·02) and CO₂ pool size was larger (998±160 ml CO₂kg^-1, vs. 194±28ml CO₂kg^-1, P < 0·001). Compared to values obtained at rest, during recovery from exercise, MRT and CO₂ pool size were reduced (34±5min, P < 0·05; 116±19 ml CO₂kg^-1, P < 0·02, respectively). In an additional five subjects acidosis and alkalosis were induced prior to administration of oral [¹³C]bicarbonate at rest. Elimination of bicarbonate was lower during acidosis (46·1±5·6%, P < 0·01) but was unaltered (50·9±5·6%, NS) during alkalosis, compared to the values obtained at resting pH. During acidosis MRT and CO₂ pool size decreased (37±3min, P<0·01 and 123±10ml CO₂kg^-1, P < 0·01, respectively) whereas in alkalosis MRT was unchanged (65±8 min NS) but CO₂ pool size was increased (230±23ml CO₂kg^-1, P < 0·05). The kinetics of elimination of ¹³CO₂ from administered bicarbonate after exercise are different to those at rest and resemble acidosis. The appropriate correction factor for sequestered ¹³C should be used in metabolic studies of the post-exercise state when using ¹³C tracers.     

Association between biosynthesis of nitric oxide and changes in immunological and vascular parameters in patients treated with interleukin-2

Abstract Hypotension is a dose-limiting side effect of interleukin-2 (IL-2) therapy. This may be due to increased biosynthesis of the potent vasodilator nitric oxide (NO) induced by cytokines such as tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), which are known to be generated during IL-2 therapy. We describe the relationship between NO biosynthesis and changes in immunological and vascular parameters during IL-2 therapy in 13 patients with metastatic cancer. Plasma concentrations of neopterin and nitrite plus nitrate (NO_x) were higher in cancer patients prior to treatment compared with normal subjects (neopterin; 10·8±1·4 vs. 2·0±0·4 ng ml^-1, P<0·001: NO_x; 45±6 vs. 28±2 μM, P<0·005). Pretreatment TNF-α and IFN-γ plasma concentrations were not significantly different in cancer patients from those in controls. During infusion of IL-2 (18 times 10⁶ international units m^-2 per day for 5 days) these parameters increased, reaching maximal concentrations at day 3 for IFN-γ and day 5 for TNF-α, neopterin and NO_x. The maximal induced NO_x correlated with maximal TNF-α (r = 0·60, P<0·04), IFN-γ (r = 0·63, P<0·02) and neopterin (r = 0·66, P<0·01). As plasma NO_x concentrations increased, systolic blood pressure fell, reaching a minimum at day 3 despite a continued rise in NO_x concentrations. These changes were accompanied by a continuous increase in pulse rate throughout the infusion period. These findings indicate that induction of NO biosynthesis contributes to hypotension induced during IL-2 therapy. Inhibitors of NO synthase may be useful in limiting toxicity, thus allowing administration of higher and possibly more efficacious doses of this cytokine in the treatment of cancer.     

Muscle blood flow response to mental stress and adrenaline infusion in man: microdialysis ethanol technique compared to 133Xe clearance and venous occlusion plethysmography

Background and aim: Adrenaline, administered locally by microdialysis in skeletal muscle, causes vasoconstriction around the microdialysis catheter. This is contrary to the vasodilation that normally occurs when adrenaline is infused intravenously or intra‐arterially. The hypothesis was tested that vasoconstriction, measured by microdialysis, would not occur with two interventions causing increased plasma levels of adrenaline, mental stress and intravenous adrenaline infusion (0·1 nmol kg^?1 min^?1). Methods: Twenty‐four men (27 ± 1·6 years) underwent these interventions. Blood flow was determined by the microdialysis ethanol technique and ¹³³Xe clearance (gastrocnemius muscle, medial head) and by venous occlusion plethysmography (calf). Results: The ethanol outflow/inflow ratio, which is inversely related to blood flow, decreased to 92·0 ± 3·4% of basal, P = 0·014 (mean ± SEM, n = 16) during the mental stress test, but increased to 108·3 ± 2·2% of basal, P = 0·001 (n = 16) during the adrenaline infusion. The latter increase was abolished when adrenaline was infused during α‐receptor blockade by phentolamine. On the contrary, by ¹³³Xe clearance and venous occlusion plethysmography, blood flow increased during both interventions; 2·0–1·7‐fold (mental stress) and 1·3–1·4‐fold (adrenaline infusion), respectively, P<0·05. Conclusion: Adrenaline causes vasoconstriction in skeletal muscle when blood flow is measured with the microdialysis ethanol technique, irrespective of the mode of administration. The discrepant blood flow result obtained with the microdialysis ethanol technique might, at least partly, be explained by differential diffusion properties of ethanol and ¹³³Xe. An additional or alternative explanation might be that an inserted microdialysis catheter shifts the balance of vasoconstrictor and vasodilator effects of adrenaline in skeletal muscle.     

Progressive central hypovolaemia in man—resulting in a vasovagal syncope?

Summary. Hypotensive functional haemorrhage induced by venous pooling of blood in the legs has been reported to be characterized by a vasovagal reaction. In the present study these observations were extended by determination of the hormonal profile developed during progressive central hypovolaemia and an emotionally induced vasovagal syncope. In six subjects venous pooling resulted in normotensive central hypovolaemia, in one subject hypotensive central hypovolaemia was induced, and one subject experienced an emotionally induced vasovagal syncope. During normotensive central hypovolaemia heart rate increased from 58 ± 4 to 76 ± 4 beats min^-1 (P<0·05) and cardiac output fell from 6·1 ± 0·4 to 4·1 ± 0·21 min^-1. Pulse pressure and central venous pressure decreased from 64 ± 4 to 53 ± 4 mmHg, and from 8 ± 2 to 3 ± 2 mmHg, respectively. Adrenalin and noradrenalin increased from 87 ± 10 to 120 ± 20 pg/ml and from 196 ± 33 to 370 ± 50 pg/ml, respectively. Angiotensin II increased from 13 ± 4 to 36 ± 6 pg/ml and aldosterone from 63 ± 9 to 180 ± 27 pg/ml. In hypotensive central hypovolaemia the decrease in mean arterial pressure was accompanied by a decrease in heart rate and increments in the plasma concentrations of pancreatic polypeptide, indicating increased vagal activity and β-endorphin, while plasma noradrenalin was unchanged. In emotionally induced syncope heart rate decreased to cardiac arrest for 13 s, associated with increments in the plasma concentrations of pancreatic polypeptide and β-endorphin. It is concluded (1) that normotensive functional haemorrhage in man is associated with increased sympathetic activity and (2) that the qualitatively similar observations obtained during an emotionally and a hypovolaemic-induced hypotensive episode indicate that the hypotensive functional haemorrhage is characterized by a vasovagal reaction.     

Splanchnic and renal vasoconstriction during neuropeptide Y infusion in healthy humans

Summary. To assess whether neuropeptide Y (NPY) causes vasoconstriction in human splanchnic and renal tissues, six healthy subjects were given NPY intravenously in the basal resting state for 15 min. The NPY dose of 10, 25, and 50 pmol kg^-1 min^-1 was increased every 5 min. The infusion was accompanied by elevated arterial plasma levels of NPY-like immunoreactivity (Li) which were 15, 40, and 85 times higher than the basal value. After the infusion plasma NPY-Li fell with two half-lives of 5 ±0.4 and 29± 1.7 min but was still 4 times the basal values 60 min after the infusion (P<0.01). A vasoconstrictor effect was seen at about 500 pM plasma NPY-Li. During the NPY infusion splanchnic and renal blood flows decreased by 26% and 29% respectively. The blood flows in these regions were still below the basal value 40 to 60 min after the NPY infusion. Plasma noradrenaline fell by 20% (P<0.02) and arterial glucose by 3% (P<0–005) during the NPY infusion. It is concluded that NPY causes a dose-dependent long-lasting vasoconstriction in human renal and splanchnic tissues. The results also suggest that elevated plasma NPY-levels may be associated with changes in the turnover of noradrenaline and glucose.     

Plasma lipid and lipoprotein profiles in pre- and post-menopausal middle-aged runners

Summary. Plasma lipid and lipoprotein profiles were compared in middle-aged trained and untrained women before and after menopause. Subjects were assigned to one of four groups: (1) pre-menopausal trained (Pre-T: n= 17, aged 42 ±5 years, body fat 19±5%, training distance 53 ±20 km week^-1, V?o_2max 49 ±4 ml kg^-1 min^-1, mean±SD); (2) pre-menopausal untrained (Pre-UT: n= 26, 42 ±5 years, 24 ±7%, 34 ±6 ml kg^-1 min^-1); (3) post-menopausal trained (Post-T: n= 16, 54 ±3 years, 20 ±4%, 43 ±19 km week^-1, 41 ±5 ml kg^-1 min^-1); and (4) post-menopausal untrained (Post-UT: n= 15, 55 ±3 years, 25 ±6%, 31 ±3 ml kg^-1 min^-1). There were no significant differences in total cholesterol (range 173–194 mg dl^-1), triglyceride (56–72 mg dl^-1), and HDL-cholesterol (HDLC: 76–85 mg dl^-1) among the four groups. LDL-cholesterol (LDLC) in the post-menopausal women (Post-T: 96 ±32 mg dl^-1; Post-UT: 104 ±23 mg dl^-1) tended to be higher than in the premenopausal women (Pre-T: 86 ± 25 mg dl^-1, Pre-UT: 81 ± 23 mg dl^-1). LDLC/HDLC ratio in Post-UT (1·42 ±0·38 unit) was higher than in the pre-menopausal women (Pre-T: 1·03±0·31 unit, P<0·01; Pre-UT: 1·10±0·38 unit, P<0·05), whereas the ratio in Post-T (1·20 ±0·38 unit) was not different from those of the pre-menopausal groups. These results suggest that endurance running protects against the increase in LDLC/HDLC ratio that frequently occurs after menopause.     

Systemic interleukin-1 α and interleukin-2 secretion in response to acute stress and to corticotropin-releasing hormone in humans*

Abstract Acute stress results in activation of the hypothalamic-pituitary-adrenal (HPA) axis. ACTH and cortisol secretion is stimulated by corticotropin-releasing hormone (CRH). It has also been shown that activation of the HPA axis during stress is accompanied by changes in the immune response. However, little is known about the influence of acute stress on the release of cytokines such as inteleukin-1 (IL-1) or interleukin-2 (IL-2). In this study, we determined serum IL-1 α and IL-2 levels in 19 patients undergoing the acute stress of angioplasty for coronary artery disease. A second protocol was devised to determine serum IL-1 α and IL-2 concentrations as well as lymphocyte subpopulations in 10 normal volunteers receiving 1 μ kg^-1 human CRH intravenously. Finally, IL-1 α concentrations were measured in CRH-incubated mononuclear cell (MNC) and monocyte cultures. In response to the stress of angioplasty, ACTH and cortisol as well as IL-1 α and IL-2 concentrations were clearly above baseline levels (IL-1 α, mean ± SEM, baseline: 1·39 ± 0·34 ng ml^-1, after angioplasty: 2·64 ± 0·73 ng ml^-1, P < 0·05; IL-2, baseline: 1·2 ± 0·13 ng ml^-1, after angioplasty: 2·8 ± 1·14 ng ml, P < 0·05). A similar pattern was obtained in normal subjects in response to CRH (IL-1 α, baseline: 0·8 ± 0·2 ng ml^-1, after angioplasty: 3·7 ± 1·4 ng ml^-1, P < 0·05; IL-2, baseline: 1·9 ± 0·4 ng ml^-1, after angioplasty: 5·4 ± 2·2 ng ml^-1, P < 0·02). The percentage of IL-2 receptor-positive lymphocytes rose from 3·9 ± 1·2% to 6·2 ± 1·6% (P < 0·05), the relative number of CD-3 lymphocytes rose from 74·5 ± 1·6% to 78·3 ± 2·0% (P < 0·05). No significant changes were observed in the number of CD-4, CD-8, natural killer and B cells. In vitro, IL-1 α concentrations in cultures containing CRH were not significantly different from control cultures. Our data demonstrate significant activation of the HPA axis and secretion of IL-1 α and IL-2 in response to both angioplasty and CRH. Furthermore, CRH administration resulted in activation of the cellular immune system (indicated by an increase in IL-2 receptor positive lymphocytes). Our in vitro data suggest that CRH may not directly act on blood mononuclear cells to induce IL-1 α release or, alternatively, sources other than blood mononuclear cells may account for the elevated IL-1 α levels observed in vivo. We conclude that CRH may play a major role in neuroendocrine-immune interactions during acute stress.