Postprandial impairment of resistance vessel function in insulin treated patients with diabetes mellitus type‐2

Reduced postischaemic reactive hyperaemia, is considered a marker of impaired resistance vessel function. Acute postprandial hyperlipidaemia has been shown to induce vascular dysfunction. In the present study, the impact of postprandial hyperglycaemia on resistance vessel reactivity was investigated in insulin treated type‐2 diabetic patients. The study was performed in 16 insulin treated type‐2 diabetics (eight male/eight female, age 47 ± 3 years, HbA1c 7·2 ± 0·2) and 16 controls. Reactive hyperaemia was measured in the forearm by venous occlusion plethysmography after 5 min of ischaemia in the fasting state and 90 min after a test meal. In diabetics, blood glucose increased from 8·7 ± 1·1 to 15·3 ± 1·0 mmol l^?1 (P<0·001) postprandially. This resulted in (i) a significant increase of resting blood flow (3·4 ± 0·3 to 4·8 ± 0·4 ml min^?1 100 ml^?1, P<0·01) and (ii) in a reduced peak reactive hyperaemia (52·3 ± 7·4 to 36·8 ± 4·3 ml min^?1 100 ml^?1, P<0·005). In controls, a similar effect of the meal on resting flow was observed but reactive hyperaemia was unaltered. In the absence of a test meal, basal flow as well as peak reactive hyperaemia remained unchanged in diabetic as well as in non‐diabetic subjects. Our data provide evidence that in the postprandial state resistance vessel reactivity becomes reduced in insulin treated type‐2 diabetic patients.     

Determinants of post-ischaemic reactive hyperaemia in patients with diabetes mellitus type II

Dysfunction of resistance arteries is thought to be an early reversible stage in the development of atherosclerosis. Dynamics of post-ischaemic reactive hyperaemia are believed to constitute a useful tool for monitoring resistance vessel function. Patient characteristics influencing reactive hyperaemia, however, need to be defined more precisely. Since reactive hyperaemia is a dynamic process, yielding submaximal peak values after 5 min of ischaemia, this period was chosen to investigate the determinants of reactive hyperaemia in 100 type II diabetic patients as well as in 61 control subjects. Reactive hyperaemia was measured by venous-occlusion plethysmography; clinical and laboratory data were acquired by routine methods. Statistical comparison was performed with SYSTAT 5·0 for Apple Macintosh. Overall, no significant differences between diabetic patients and controls were observed by group comparison. In control subjects, only gender showed an influence on peak reactive hyperaemia (females 40·5 ± 15·3; males 51·8 ± 17·7 ml min^–1 100 ml^–1, P<0·01). In diabetic patients, in addition to gender, actual blood glucose (r=0·377, P<0·05) and meal intake (non-fasting 42·8 ± 19·2; fasting 51·2 ± 19·5 ml min^–1 100 ml^–1, P<0·05) were found to influence reactive hyperaemia. Further investigation revealed a loss of the correlation between peak reactive hyperaemia and actual blood glucose observed in the fasting state (P<0·001) in non-fasting diabetic patients, indicating an influence of meal intake on resistance vessel reactivity. Our results suggest that, in diabetic subjects, in addition to gender actual blood glucose and the postprandial situation impacts on peak reactive hyperaemia.     

Effects of dipyridamole and theophylline on reactive hyperaemia in subcutaneous adipose tissue in humans

Summary. The importance of adenosine for reactive hyperaemia in subcutaneous adipose tissue was studied in healthy volunteers, using the adenosine uptake inhibitor dipyridamole (bolus 0·1 mg/kg i.v. followed by infusion of 0·7 μg/kg/min) and the adenosine receptor antagonist theophylline (4 or 6 mg/kg i.v.). Basal blood flow, total blood flow and hyperaemia (total minus basal flow) after a 20-min arterial occlusion were measured in the distal femoral region by the ¹³³Xe washout technique with and without drug treatment. Basal blood flow (mean±SEM) was 2·4 ± 0·3 ml/min/100 g, while total post-occlusive flow and total reactive hyperaemia were 97·3 ±8·4 and 61·8 ± 6·5 ml/100 g, respectively, without drug treatment. Basal blood flow was unaffected by dipyridamole but the total flow and hyperaemia were enhanced by 49 ± 24 and 60 ± 31%, respectively (P<·005 for both). This enhancement was due to increases in both amplitude and duration of the hyperaemia. Neither basal blood flow, total post-occlusive flow nor hyperaemia were significantly altered by theophylline. The amplitude of the enhanced hyperaemia during dipyridamole was not significantly counteracted by simultaneous theophylline treatment (6 mg/kg) but the duration of hyperaemia was reduced from 13 ± 1 to 8 ± 1 min (P<0·01). The results suggest that endogenous adenosine does not regulate basal blood flow or reactive hyperaemia of limited duration in human adipose tissue. However, reactive hyperaemia may be enhanced by pharmacological elevation of endogenous adenosine levels.     

Restoration of peak vascular conductance after simulated microgravity by maximal exercise

We sought to determine if (i) peak vascular conductance of the calf was reduced following prolonged exposure to simulated microgravity, and (ii) if maximal cycle ergometry performed at the end of microgravity exposure stimulated a restoration of peak calf vascular conductance. To do this, peak vascular conductance of the calf was recorded following ischaemic plantar flexion exercise to fatigue in seven men after 16 days of head-down tilt (HDT) under two conditions: (i) after one bout of maximal supine cycle ergometry completed 24 h prior to performance of ischaemic plantar flexion exercise, and (ii) in a control (no cycle ergometry) condition. Following HDT, peak vascular conductance was reduced in the control condition (0·38 ± 0·02 to 0·24 ± 0·02 ml 100 ml^?1 min^?1 mmHg^?1; P = 0·04), but was restored when subjects performed cycle ergometry (0·33 ± 0·05 to 0·28 ± 0·04 ml 100 ml^?1 min^?1 mmHg^?1; P = 0·46). After HDT, time to fatigue during ischaemic plantar flexion exercise was not different from pre-HDT 24 h after performance of exhaustive cycle ergometry (120 ± 24 vs. 122 ± 19 s), but was decreased in the control condition (116 ± 11 vs. 95 ± 8 s; P = 0·07). These data suggest that a single bout of maximal exercise can provide a stimulus to restore peak vascular conductance and maintain time to fatigue during performance of ischaemic plantar flexion exercise.     

Intensity of Nordic Walking in young females with different peak O2 consumption

The purpose of this cross‐sectional study was to determine the physiological reaction to the different intensity Nordic Walking exercise in young females with different aerobic capacity values. Twenty‐eight 19–24‐year‐old female university students participated in the study. Their peak O₂ consumption (VO₂ peak kg^?1) and individual ventilatory threshold (IVT) were measured using a continuous incremental protocol until volitional exhaustion on treadmill. The subjects were analysed as a whole group (n = 28) and were also divided into three groups based on the measured VO₂ peak kg^?1 (Difference between groups is 1 SD) as follows: 1. >46 ml min^?1 kg^?1 (n = 8), 2. 41–46 ml min^?1 kg^?1 (n = 12) and 3. <41 ml min^?1 kg^?1 (n = 8). The second test consisted of four times 1 km Nordic Walking with increasing speed on the 200 m indoor track, performed as a continuous study (Step 1 – slow walking, Step 2 – usual speed walking, Step 3 – faster speed walking and Step 4 – maximal speed walking). During the walking test expired gas was sampled breath‐by‐breath and heart rate (HR) was recorded continuously. Ratings of perceived exertion (RPE) were asked using the Borg RPE scale separately for every 1 km of the walking test. No significant differences emerged between groups in HR of IVT (172·4 ± 10·3–176·4 ± 4·9 beats min^?1) or maximal HR (190·1 ± 7·3–191·6 ± 7·8 beats min^?1) during the treadmill test. During maximal speed walking the speed (7·4 ± 0·4–7·5 ± 0·6 km h^?1) and O₂ consumption (30·4 ± 3·9–34·0 ± 4·5 ml min^?1 kg^?1) were relatively similar between groups (P > 0·05). However, during maximal speed walking, the O₂ consumption in the second and third groups was similar with the IVT (94·9 ± 17·5% and 99·4 ± 15·5%, respectively) but in the first group it was only 75·5 ± 8·0% from IVT. Mean HR during the maximal speed walking was in the first group 151·6 ± 12·5 beats min^?1, in the second (169·7 ± 10·3 beats min^?1) and the third (173·1 ± 15·8 beats min^?1) groups it was comparable with the calculated IVT level. The Borg RPE was very low in every group (11·9 ± 2·0–14·4 ± 2·3) and the relationship with VO₂and HR was not significant during maximal speed Nordic Walking. In summary, the present study indicated that walking is an acceptable exercise for young females independent of their initial VO₂ peak level. However, females with low initial VO₂ peak can be recommended to exercise with the subjective ‘faster speed walking’. In contrast, females with high initial VO₂ peak should exercise with maximal speed.     

Early activation of the coagulation system during lower body negative pressure

We considered that a moderate reduction of the central blood volume (CBV) may activate the coagulation system. Lower body negative pressure (LBNP) is a non‐invasive means of reducing CBV and, thereby, simulates haemorrhage. We tested the hypothesis that coagulation markers would increase following moderate hypovolemia by exposing 10 healthy male volunteers to 10 min of 30 mmHg LBNP. Thoracic electrical impedance increased during LBNP (by 2·6 ± 0·7 Ω, mean ± SD; P < 0·001), signifying a reduced CBV. Heart rate was unchanged during LBNP, while mean arterial pressure decreased (84 ± 5 to 80 ± 6 mmHg; P < 0·001) along with stroke volume (114 ± 22 to 96 ± 19 ml min^?1; P < 0·001) and cardiac output (6·4 ± 2·0 to 5·5 ± 1·7 l min^?1; P < 0·01). Plasma thrombin–antithrombin III complexes increased (TAT, 5 ± 6 to 19 ± 20 μg l^?1; P < 0·05), indicating that LBNP activated the thrombin generating part of the coagulation system, while plasma D‐dimer was unchanged, signifying that the increased thrombin generation did not cause further intravascular clot formation. The plasma pancreatic polypeptide level decreased (13 ± 11 to 6 ± 8 pmol l^?1; P < 0·05), reflecting reduced vagal activity. In conclusion, thrombin generation was activated by a modest decrease in CBV by LBNP in healthy humans independent of the vagal activity.     

Postprandial chylomicron and plasma vitamin E responses in healthy older subjects compared with younger ones

The effect of ageing on vitamin E bioavailability in humans was assessed by comparing chylomicron and plasma α-tocopherol postprandial concentrations after a dose of vitamin E (432 or 937 IU as dl-α-tocopherol acetate), in eight young (20–30 years old) and eight healthy elderly men (64–72 years old). The fasting plasma α-tocopherol concentration was significantly higher in the elderly (33 ± 2 μmol L^?1) than in the young (22 ± 2 μmol L^?1). In both groups, the plasma and chylomicron α-tocopherol postprandial concentrations were significantly, approximately twofold, higher after the 937-IU meal than after the 432-IU meal. For both test meals, the chylomicron α-tocopherol areas under the curve were significantly lower in the elderly than in the young subjects: 98.9 ± 16.5 (young group) vs. 55.3 ± 7.8 (elderly group) μmol L^?1 h for the 937-IU test meal and 60.4 ± 14.1 (young group) vs. 26.0 ± 7.6 (elderly group) μmol L^?1 h for the 432-IU test meal, whereas the plasma α-tocopherol area under the curve was significantly higher in elderly than in young subjects: 337.56 ± 16.11 (937-IU test meal) vs. 159.81 ± 35.55 (432-IU test meal) μmol L^?1 h in the young group and 709.55 ± 69.33 (937-IU test meal) vs. 436.39 ± 41.08 (432-IU test meal) μmol L^?1 h in the elderly group. We concluded that (a) the amount of vitamin E appearing in plasma is proportional to the dose ingested (up to 937 IU); (b) the intestinal absorption of vitamin E is not increased, even possibly decreased, in the elderly; and (c) the amount of vitamin E transported by non-chylomicron lipoproteins is apparently higher in the elderly. This suggests that vitamin E postprandial transport is affected by ageing, mainly as the consequence of age-related modifications of lipoprotein metabolism.     

The pathophysiology of the insulin-like growth factor axis in fetal growth failure: a basis for programming by undernutrition?

Abstract. Recent evidence suggests that a number of adulthood conditions, including non-insulin dependent diabetes mellitus (NIDDM) and lipid and cardiovascular abnormalities are associated with intra-uterine growth retardation (IUGR). It is possible that this arises from programming of endocrine axes during development as a result of an adverse intra-uterine environment. Insulin-like growth factors (IGFs) are mitogenic polypeptides which stimulate cellular proliferation and differentiation and are important in human fetal development. The functions of IGFs are modulated by specific high affinity binding proteins (IGFBPs). IGFBP-1 is antagonistic to the insulin-like and growth promoting effects of IGF-I, and IGFBP-3 holds IGFs in the circulation by associating with IGFs and an acid labile subunit to form a ternary complex. Using specific radioimmunoassays and fetal serum obtained during diagnostic cordocentesis we have investigated the role of the IGF/IGFBP axis in human fetal development. In a study of 130 singleton pregnancies we have examined levels of immunoreactive IGFs and IGFBPs in normally grown fetuses (AGA), starved small fetuses affected by uteroplacental insufficiency (UPI), and non-starved small fetuses (SGA). IGF-1 was significantly lower in the UPI group (n= 14, 7·8±0·6 μg l^-1), than in either the SGA group (n= 22, 31·4±3·5 μg l^-1, P= 0·0001) or the AGA group (n= 94, 36·3±1·9 μg l^-1, P= 0·0001). IGFBP-3 showed similar changes (UPI: 682·6±50·0 μg l^-1; SGA: 831·9±55·5 μg l^-1; AGA: 847·7±19·8 μg l^-1). In contrast, IGFBP-1 levels were significantly higher in the UPI group (312·4±57·5 μg l^-1) than in either the SGA group (132·6±39·5 μg l^-1, P= 0·009) or the AGA group (116·9±25·4 μg l^-1, P= 0·003), and the normal inverse relationship between IGFBP-1 and insulin levels was lost in the UPI group. IGFBP-2 levels showed a similar pattern (UPI: 2510·3±178·0 μg l^-1; SGA: 878·5±80·3μg l^-1, P= 0·0001; AGA: 791·6±27·0 μg l^-1, P= 0·0001). Thus, there are clear differences between the two groups of SGA fetuses. It is possible that in utero‘programming’ of the IGF/IGFBP axis, as a result of fetal undernutrition, may be important in the pathogenesis of disease in adulthood.     

Hypoglycaemia leads to an increased QT interval in normal men

Hypoglycaemia is presumed to be the cause of death in about 3% of insulin-treated diabetic patients. Some of these patients suffer from hypoglycaemic brain damage, but the majority have no evident brain damage and are supposed to have died from other causes such as a cardiac arrhythmia. The putative mechanism is a hypoglycaemia-induced prolongation of the QT interval which increases the risk of malignant ventricular tachycardia. The aim of the present study was to examine the electrocardiogram during and after hypoglycaemia in healthy men. To that end, hypoglycaemia was induced by an intravenous infusion of insulin (2·5 mU kg^?1 min^?1) in 10 healthy men to reach a venous blood glucose level of 2·1 ± 0·3 mmol l^?1 for 65 ± 9 min. Before hypoglycaemia, after 20 and 50 min of hypoglycaemia and 20 and 45 min after normalization of the blood glucose, the QT interval was measured by a ruler and corrected for the heart rate. Results are given as mean ± SD and comparisons were made with an ANOVA , except for symptom scores and plasma adrenaline where non-parametric tests were used. When this indicated significance, further analysis was performed with a two-tailed t-test. During hypoglycaemia the corrected QT interval increased from 380 ± 20 ms^½ to 440 ± 30 ms^½ (P<0·001), and the amplitude of the T wave decreased (P = 0·002). The serum potassium level decreased from 4·3 ± 0·3 mmol l^?1 to 3·5 ± 0·2 mmol l^?1 (P<0·001) and the plasma adrenaline concentration increased from 0·20 ± 0·04 nmol l^?1 to 2·46 ± 2·58 nmol l^?1 (P<0·01). The results of this study confirm that a prolongation of the QT interval occurs during hypoglycaemia, but the significance of this finding still has to be proven.     

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.     

Osteocalcin metabolism in the pulmonary circulation

The aim of this study was to evaluate the role of the pulmonary vessel endothelium in the removal of circulating osteocalcin, by measuring the osteocalcin levels in serum from pulmonary and radial artery blood from 39 patients undergoing aorto‐coronary bypass. Because of the discrepancies between methods of measurement, two methods were used. Significant differences were observed in group A (n = 18), tested with heterologous radioimmunoassay (2·85 ± 0·67 μg l^?1 in the pulmonary versus 2·69 ± 0·67 μg l^?1 in the radial artery serum, P<0·001) and in group B (n = 21), tested with a two‐site immunoradiometric assay (5·22 ± 1·46 versus 4·93 ± 1·36 μg l^?1, P<0·01). The percentage differences were –5·54 ± 4·76% (P<0·001) in group A and –4·99 ± 8·13% (P<0·01) in group B; the comparison between the percentage differences was not significant. These different osteocalcin concentrations between the two vascular compartments were considered a marker of osteocalcin degradation. Therefore, the study seems to demonstrate that, as well as kidney, liver and bone, the lung is a relevant site of osteocalcin catabolism. The proteolytic activity of pulmonary vessel endothelium seems to involve about 5% of the circulating peptide.     

Glucose metabolism in chronic diabetic foot ulcers measured in vivo using microdialysis

Ten subjects with diabetes mellitus and unilateral chronic foot ulcer were investigated. Local tissue concentrations of glucose and lactate were measured using the microdialysis method at a distance of 0·5–1 cm from the edge of the ulcer and in normal skin in the contralateral foot. Subcutaneous blood flow in the area investigated was measured using the ¹³³Xe-washout technique. The interstitial glucose concentration in the ulcer was found to be lower than in intact skin (8·0 ± 1·0 mmol l^?1 vs. 8·5 ± 1·1 mmol l^?1) (P<0·02), and the interstitial lactate concentration was higher in the ulcer than in intact skin (3·2 ± 0·2 mmol l^?1 vs. 2·1 ± 0·3 mmol l^?1) (P<0·01). The subcutaneous blood flow was on average 40% higher in the ulcer than in the intact skin. The calculated local glucose uptake and lactate outputs were twofold higher in the ulcer than in the intact skin. However, the molar ratio between lactate output and glucose uptake was approximately two, both in the ulcer and in the intact skin, indicating that the glucose metabolism was qualitatively the same in the two regions.     

Post-exercise cutaneous hyperaemia resulting from local exercise of an extremity

Large changes in skin blood flow occur after exercise. Most studies have concentrated on the systemic effects of vigorous exercise on skin blood flow. We were interested in the post-exercise response in the neighbourhood of focal exercise. We used a painless neuromuscular electronic stimulator to exercise the muscles of the forearm, producing flexion of the fingers. There was no change in blood pressure and only a small increase in heart rate during this exercise. We measured blood flow during a 5-min pre-exercise period and a 5-min post-exercise period at the forearm, at the dorsum of the index finger and on the pad of the index finger. We also measured values on the contralateral non-exercised extremity during exercise as well as during matched time periods in control experiments with no exercise. Exercise did elicit an increased blood flow in the post-exercise period at all three sites compared with the control experiments with no exercise and on the contralateral extremity. For example, the increase in blood flow at the finger dorsum was 2.1±0.1 ml (min 100 g)^?1 after exercise compared with ?0.08±0.09 ml min^?1 100 g^?1 during the control experiment and 0.1±0.1 ml (min 100 g)^?1 on the contralateral arm (all P<0.01). The local application of heat at the site of blood flow monitoring produced a substantial increase in the post-exercise response at the two finger locations [27.4±0.4 ml (min 100g)^?1 at the finger dorsum], but not at the arm. This is the first demonstration that highly focal exercise, unaccompanied by a systemic haemodynamic response, can elicit a post-exercise cutaneous hyperaemia. Local heating produced a large synergistic increase in the post-exercise hyperaemia at sites with arteriovenous microvascular perfusion but not at sites with primarily nutritive perfusion. These findings show that local vasoregulatory changes occur in response to exercise, even in the absence of whole-body haemodynamic and thermal change.     

Effects of different periods of hypoxic training on glucose metabolism and insulin sensitivity

This study examined the effects of different periods of hypoxic training on glucose metabolism. Sedentary subjects underwent hypoxic training (FiO₂ = 15·0%) for either 2 weeks (2‐week group; n = 11) or 4 weeks (4‐week group; n = 10). The 2‐week group conducted training sessions on 6 days week^?1 for 2 weeks, whereas the 4‐week group conducted training sessions on 3 days week^?1 for 4 weeks. Body fat mass or abdominal fat area did not change after training period in either group. VO_2max increased in both groups after training period (42 ± 2 versus 43 ± 2 ml min^?1 kg^?1 in 2‐week group, 41 ± 1 versus 42 ± 2 ml min^?1 kg^?1 in 4‐week group). Both groups showed a reduction in mean blood pressure after training period (92 ± 3 versus 90 ± 3 mmHg in 2‐week group, 91 ± 2 versus 87 ± 2 mmHg in 4‐week group, P≤0·05). No change was observed in blood glucose response after glucose ingestion after training period. However, area under the curve for serum insulin concentrations after glucose ingestion significantly decreased in only 4‐week group (6910 ± 763 versus 5812 ± 872 μIU ml^?1 120 min, P≤0·05). In conclusion, hypoxic training reduced blood pressure with independent on training duration. However, a longer period of hypoxic training led to greater improvements in insulin sensitivity compared with equivalent training over a shorter period, suggesting that hypoxic training programmes for more than 4 weeks might be more beneficial for improving insulin sensitivity.     

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.     

Simultaneous quantification of myocardial perfusion,oxidative metabolism,cardiac efficiency and pump function at rest and during supine bicycle exercise using 1‐11C‐acetate PET – a pilot study

Background: PET using 1‐¹¹C‐acetate (ACE‐PET) applied at rest is used for measuring absolute myocardial blood flow (MBF) and oxidative metabolic rate (k_mono). We evaluated the feasibility of quantitative ACE‐PET during exercise. Methods: Five endurance athletes underwent dynamic PET scanning at rest and during supine bicycle stress. Exercise was maintained at a workload of 120 Watt for 17 min. The rate‐pressure product (RPP) was recorded repeatedly. MBF, k_mono in left (LV) and right (RV) ventricular wall, cardiac output (CO), cardiac efficiency and a lung uptake value reflecting left heart diastolic pressures were calculated from the PET data using previously validated models. Results: MBF increased from 0·71 ± 0·17 to 2·48 ± 0·25 ml min^?1 per ml, LV‐k_mono from 0·050 ± 0·005 to 0·146 ± 0·021 min^?1, RV‐k_mono from 0·023 + 0·006 to 0·087 + 0·014 min^‐1, RPP from 4·7 ± 0·8 to 13·2 ± 1·4 mmHg × min^?1 × 10³ and Cardiac Output from 5·2 ± 1·1 to 12·3 ± 1·2 l min ^?1 (all P < 0·001). Cardiac efficiency was unchanged (P = 0·99). Lung uptake decreased from 1·1 ± 0·2 to 0·6 ± 0·1 ml g^?1 (P < 0·001). Discussion: A number of important parameters related to cardiac function can be quantified non‐invasively and simultaneously with a short scanning protocol during steady state supine bicycling. This might open up new opportunities for studies of the integrated cardiac physiology in health and early asymptomatic disease.     

Postprandial apolipoprotein B100 and B48 metabolism in familial combined hyperlipidaemia before and after reduction of fasting plasma triglycerides*

Abstract Hepatic VLDL overproduction in familial combined hyperlipidaemia (FCH) may delay the clearance of atherogenic apolipoprotein (apo) B containing particles. We investigated if normalization of fasting plasma triglycerides (TG) by hypolipidaemic treatment results in improved metabolism of apo B48 and apo B100 in six male subjects with FCH and compared them to six normolipidaemic controls. The FCH patients were studied before (TG, 5·2±1·2 mmoll^-1; mean ± SEM) and after therapy (TG, 2·1±0·3 mmoll^-1) with either simvastatin (n= 4) or combined therapy with gemfibrozil (n= 2). The post-prandial changes of apo B100 and apo B48 were studied after a single oral fat meal (24h; 50 gram fatm^-2). Changes in triglyceride rich particles (TRP; d < 1·006 gml^-1) and remnant fractions (REM; d: 1·006–1·019g ml^-1) of apo B were quantitated by scanning silverstained SDS-PAGE (4–15%). Apo B48 in fasting TRP in untreated and treated FCH was 15% and 14% of total apo B, and 6% in controls (P < 0·05). In controls, postprandial B48 increased maximally at 4h by 81% in TRP and by 137% in REM compared to baseline. In treated FCH, the post-prandial apo B48 pattern normalized in TRP compared to the untreated state. Postprandial apo B100 in controls decreased in TRP and REM by 33% and 18% (P < 0·05). In untreated and treated FCH, postprandial apo B100 remained unchanged vs. baseline in TRP and in REM suggesting hypersecretion of VLDL. The elimination of B100—assessed as area under the curve—in TRP (32·5±3·6 au.h; mean±SEM) and REM fractions (33·2±3·1 au.h), improved significantly after treatment (21·0±2·8 and 20·4±3·3 au.h, respectively). The apo B48 clearance in TRP fractions was improved after treatment (4·3±1·4 au.h vs. 2·9±1·2 au.h; P= 0·06), but not in REM fractions (2·8±1·0 au.h vs. 1·8±0·5 au.h; NS). In conclusion, in FCH subjects with apo B100 hypersecretion and increased fasting plasma apo B48 levels, reduction of fasting plasma TG improved, but did not normalize, TRP apo B48 and B100 metabolism. However, therapy normalized postprandial apo B100 remnant metabolism. Impaired postprandial apo B metabolism may be instrumental in the development of premature atherosclerosis in FCH subjects.     

Evaluation of gender differences in endothelium-independent dilation using peripheral arterial tonometry

Background: A change in peripheral arterial tonometry (PAT) in response to reactive hyperaemia is often used to provide a non‐invasive measure of endothelium‐dependent dilation (EDD). Reactive hyperaemia does not allow one to quantify endothelium‐independent dilation (EID), which is part of overall vascular function. Although most research examining vascular function and cardiovascular disease has focused on EDD, there is evidence that cardiovascular risk factors may impair EID. Purpose: To examine the microvascular vasodilation response to nitroglycerin (NTG) in healthy adults using PAT. Methods: Microvascular responses to reactive hyperaemia and NTG were evaluated in 86 (41 female and 45 male) healthy subjects (age 37 ± 5 years). Beat‐to‐beat plethysmographic measurements of finger arterial pulse waves were recorded for 5 min following reactive hyperaemia. After a 10‐min rest period, sublingual NTG (0·4 mg) was administered and PAT signal changes were measured for 10 min. Peak reactive hyperaemic index (RHI) and peak NTG‐mediated index (NMI) were determined in all subjects. Results: There were no significant gender differences in peak RHI (females: 2·07 ± 0·56 versus males: 1·91 ± 0·58, P = 0·20). Mean peak NMI for all subjects was 2·78 (±1·49). Peak NMI was significantly greater in females than in males (3·11 ± 1·59 versus 2·50 ± 1·34, P = 0·05). Time to peak NMI was not significantly different between genders (7 min, 28 s [±1 min, 47 s], versus 7 min, 14 s [±1 min, 49 s], P = 0·58). Conclusion: In this population of healthy adults, peak NMI was significantly greater in females than in males. These findings suggest that gender differences exist in the microvascular vasodilation responses to NTG using PAT.     

The influence of a fast ramp rate on peak cardiopulmonary parameters during arm crank ergometry

The influence of a very fast ramp rate on cardiopulmonary variables at ventilatory threshold and peak exercise during a maximal arm crank exercise test has not been extensively studied. Considering that short arm crank tests could be sufficient to achieve maximal oxygen consumption (VO₂), it would be of practical interest to explore this possibility. Thus, this study aimed to analyse the influence of a fast ramp rate (20 W min^?1) on the cardiopulmonary responses of healthy individuals during a maximal arm crank ergometry test. Seventeen healthy individuals performed maximal cardiopulmonary exercise tests (Ultima CardiO2; Medical Graphics Corporation, St Louis, USA) in arm ergometer (Angio, LODE, Groningen, The Netherlands) following two protocols in random order: fast protocol (increment: 2 w/6 s) and slow protocol (increment: 1 w/6 s). The fast protocol was repeated 60–90 days after the 1st test to evaluate protocol reproducibility. Both protocols elicited the same peak VO₂ (fast: 23·51 ± 6·00 versus slow: 23·28 ± 7·77 ml kg^?1 min^?1; P = 0·12) but peak power load in the fast ramp protocol was higher than the one in the slow ramp protocol (119 ± 43 versus. 102 ± 39 W, P < 0·001). There was no other difference in ventilatory threshold and peak exercise variables when 1st and 2nd fast protocols were compared. Fast protocol seems to be useful when healthy young individuals perform arm cardiopulmonary exercise test. The usefulness of this protocol in other populations remains to be evaluated.     

Standardized intermittent static exercise increases peritendinous blood flow in human leg

Alteration in tendinous and peritendinous blood flow during and after exercise is suggested to contribute to the development of Achilles tendon injury and inflammation. In the present study a method for evaluating the influence of standardized workload on peritendinous flow is presented. The radioactive isotope xenon-133 was injected just ventrally to the Achilles tendon 5 cm proximal to the tendon's insertion on the calcaneus. The disappearance of ¹³³Xe was used to determine blood flow during intermittent static exercise of the calf muscle (1·5 s exercise/1·5 s rest) for 30 min at a workload equivalent to individual body weight (1 BW) in six healthy volunteers around both Achilles tendons (n = 12). During intermittent static exercise, blood flow was increased from 1·8 ± 0·3 ml 100 g tissue^?1 min^?1 (mean value and SEM) (rest) to 6·1 ± 1·3 ml 100 g tissue^?1 min^?1 (exercise) (P<0·05). The exercise induced an average increase in blood flow (3·4-fold) equivalent to results previously obtained during regular dynamic heel raises (P>0·05). It is concluded that the method is well suited to study the influence of standardized workload on the physiology and pathophysiology of the tissue around the Achilles tendon in humans.