The effects of clonidine on arterial baroreflex sensitivity and cardiopulmonary baroreflex control of sympathetic nerve activity in patients with left ventricular dysfunction

Background: Clonidine is a potent sympatholytic drug with central neural effects. The aim of this study was to evaluate the effects of clonidine on arterial baroreflex sensitivity (BRS) and cardiopulmonary (CP) baroreflex control of muscle sympathetic nerve activity (MSNA) in patients with left ventricular (LV) dysfunction. Method: Twenty patients were randomly assigned to either clonidine or placebo groups (10 in each group). BRS (by phenylephrine method) and CP baroreflex (by lower body negative pressure) effects on sympathetic nerve activity (circulating norepinephrine and MSNA recordings) were measured before and after a 4‐week treatment period. Results: Clonidine lowered blood pressure and heart rate. Clonidine was accompanied not only by a decrease in plasma noradrenaline (from 444 ± 196 to 260 ± 144 pg ml^?1) but also by a reduction in directly measured MSNA (from 47 ± 16 to 36 ± 16 bursts min^?1). BRS increased significantly from 3·01 ± 1·19 to 6·86 ± 2·84 ms mmHg^?1 after clonidine. When expressed as per cent change in MSNA during CP baroreceptor stimulation, CP baroreflex control of MSNA was significantly increased from 9·26 ± 8·93% to 28·83 ± 11·96% after clonidine. However, there were no significant changes in the measured variables in the control group. Conclusion: Clonidine enhanced BRS and CP baroreflex control of MSNA while reducing baseline sympathetic activity in patients with LV dysfunction.     

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.     

肝硬化门脉高压患者门-腔分流状态对肝脏血流灌注的影响

目的应用肝脏CT血流灌注扫描和多层螺旋CT门静脉造影技术(CTPV),评价肝硬化患者门-腔静脉之间侧支循环的形成情况对肝脏血流灌注的影响。方法对我院101例肝硬化合并门静脉高压患者作CT血流灌注扫描和多层螺旋CT门静脉造影。计算肝血流灌注参数,分析不同类型门-腔静脉侧支循环类型的肝脏血流灌注血流参数改变。结果门静脉-上腔静脉分流组,肝血流量(HBF):(115.2±30.8)ml·100ml-1·min-1;肝动脉血流量(HAF):(29.8±21.1)ml·100ml-1·min-1;肝动脉指数(HPI):0.248±0.142;门静脉血流量(PVF):(85.3±23.6)ml·100ml-1·min-1。脾/胃-肾静脉分流组,HBF:(124.6±36.1)ml·100ml-1·min-1;HAF:46.6/29.1ml·100ml-1·min-1;HPI:0.365±0.175;PVF:(77.9±27.2)ml·100ml-1·min-1。门-腔静脉分流术后组,HBF:(101.9±36.5)ml·100ml-1·min-1;HAF:(46.0±21.4)ml·100ml-1·min-1;HPI:0.449±0.183;PVF:(55.8±22.5)ml·100ml-1·min-1。组间差异具有统计学意义,P<0.05。结论肝功能分级和分流方式两个变量对肝血流灌注有独立影响作用。     

Forearm metabolism during infusion of adrenaline: comparison of the dominant and non‐dominant arm

Human skeletal muscle metabolism is often investigated by measurements of substrate fluxes across the forearm. To evaluate whether the two forearms give the same metabolic information, nine healthy subjects were studied in the fasted state and during infusion of adrenaline. Both arms were catheterized in a cubital vein in the retrograde direction. A femoral artery was catheterized for blood sampling, and a femoral vein for infusion of adrenaline. Forearm blood flow was measured by venous occlusion strain‐gauge plethysmography. Forearm subcutaneous adipose tissue blood flow was measured by the local ¹³³Xe washout method. Metabolic fluxes were calculated as the product of forearm blood flow and a‐v differences of metabolite concentrations. After baseline measurements, adrenaline was infused at a rate of 0·3 nmol kg^?1 min^?1. No difference in the metabolic information obtained in the fasting state could be demonstrated. During infusion of adrenaline, blood flow and lactate output increased significantly more in the non‐dominant arm (8·12 ± 1·24 versus 6·45 ± 1·19 ml 100 g^?1 min^?1) and (2·99 ± 0·60 versus 1·83 ± 0·43 μmol 100 g^?1 min^?1). Adrenaline induced a significant increase in oxygen uptake in the non‐dominant forearm (baseline period: 4·98 ± 0·72 μmol 100 g^?1 min^?1; adrenaline period: 6·63 ± 0·62 μmol 100 g^?1 min^?1) while there was no increase in the dominant forearm (baseline period: 5·69 ± 1·03 μmol 100 g^?1 min^?1; adrenaline period: 4·94 ± 0·84 μmol 100 g^?1 min^?1). It is concluded that the two forearms do not respond equally to adrenaline stimulation. Thus, when comparing results from different studies, it is necessary to know which arm was examined.     

Clonidine enhances the release of endogenous gamma-aminobutyric acid through alpha-2 and alpha-1 presynaptic adrenoceptors differentially located in rat cerebral cortex subregions

Clonidine (0.001-1 microM) increased the basal release of endogenous gamma-aminobutyric acid (GABA) in superfused synaptosomes from whole rat cerebral cortex. The effects of 0.1 to 1 microM clonidine were only in part sensitive to the alpha-2 adrenoceptor antagonist yohimbine; a complete antagonism by yohimbine could be seen only with 0.001 microM clonidine. The release of GABA induced by 0.1 to 1 microM clonidine was increasingly sensitive to the alpha-1 adrenoceptor antagonist prazosin. At all the concentrations tested clonidine was antagonized fully by a mixture yohimbine-prazosin (1 microM). The release of GABA was increased by phenylephrine in a concentration-dependent (0.01-1 microM) manner. At 1 microM phenylephrine was antagonized fully by 1 microM prazosin. When synaptosomes prepared from frontal, parietal, temporal and occipital cortex were exposed to clonidine (0.005 microM) or to phenylephrine (0.1 microM), the release of GABA was found to be region specific. Clonidine-induced GABA release could not be seen in temporal and occipital cortex but it was pronounced in parietal and frontal cortex. The effect of phenylephrine did not parallel that of clonidine: for instance, GABA release was most sensitive to phenylephrine in the occipital cortex where clonidine was ineffective. The opposite occurred in parietal cortex synaptosomes, where phenylephrine was much less effective than clonidine. In conclusion: 1) clonidine stimulates the release of GABA in rat cerebral cortex synaptosomes; 2) the effect is likely to occur by activation of alpha-1 and alpha-2 adrenoceptors possibly situated on GABAergic nerve endings; and 3) a differential distribution of alpha-1 and alpha-2 adrenoceptors regulating GABA release exists within the cortical subregions.     

A reproducible and stable model of acute ischaemic left ventricular failure in dogs

Summary. A model of acute ischaemic left ventricular (LV) failure is presented. In closed-chest anaesthetized dogs 50 μm plastic microspheres were injected repeatedly into the left main coronary artery over a period of about 40 min. The injections effected stepwise elevations of LV end-diastolic pressure (Lvedp ). Thus, Lvedp could be increased to a desired level, about 20 mmHg, in a very controlled manner. All dogs developed signs of markedly depressed LV performance. Haemodynamic conditions stabilized about 60 min after embolization, and then remained essentially stable for at least 75 min. Lvedp increased from 5·7 ± 0·6 before to 26·1 ± 0·8 mmHg (mean ± SEM) 60 min after embolization. The maximum LVdP/dt decreased from 2696 ± 169 to 1823 ± 98 mmHg·s^-1, cardiac output decreased from 2·81 ± 0·20 to 1·98 ± 0·14 1·min^-1 and mean aortic blood pressure decreased from 144±4 to 127±3 mmHg, while total peripheral resistance increased from 56±3 to 69±3 mmHg·l^-1·min. Myocardial blood flow decreased from 103±7 to 79 ±6 ml·min^-1·100 g^-1 and myocardial oxygen consumption decreased from 12·5±0·9 to 8·3·0·8 ml· min^-1·100 g^-1. Myocardial uptake of lactate and free fatty acids decreased markedly. Electrocardiography showed signs of acute ischaemia. There were no deaths due to ventricular fibrillation. Morphological studies showed multiple small infarcts throughout the entire LV. In conclusion, repeated coronary embolization with 50 μm plastic microspheres, guided by the rise of Lvedp represents a simple and reproducible method for induction of uniform and stable acute LV failure.     

Effects of intense exercise training on endothelium-dependent exercise-induced vasodilatation

To determine whether intense exercise training affects exercise-induced vasodilatation, six subjects underwent 4 weeks of handgrip training at 70% of maximal voluntary contraction. Exercise forearm vascular conductance (FVC) responses to an endothelium-dependent vasodilator (acetylcholine, ACH; 15, 30, 60 μg min^?1) and an endothelium-independent vasodilator (sodium nitroprusside, SNP; 1·6, 3·2, 6·4 μg min^?1) and FVC after 10 min of forearm ischaemia were determined before and after training. Training elicited significant (P<0·001) increases in grip strength (43·4 ± 2·3 vs. 64·1 ± 3·5 kg, before vs. after, mean ± SEM), forearm circumference (26·7 ± 0·4 vs. 27·9 ± 0·4 cm) and maximal FVC (0·4630 ± 0·0387 vs. 0.6258 ± 0·0389 units, P<0·05). Resting FVC did not change significantly with training (0·0723 ± 0·0162 vs. 0.0985 ± 0·0171 units, P>0·4), but exercise FVC increased (0·1330 ± 0·0190 vs. 0.2534 ± 0·0387 units, P<0·05). Before and after the training, ACH increased exercise FVC above the control (no drug) exercise FVC, whereas SNP did not. Training increased (P<0·05) the exercise FVC responses to ACH (0·3344 ± 0·1208 vs. 0.4303 ± 0·0858 units, before vs. after training, 60 μg min^?1) and SNP (0·2066 ± 0·0849 vs. 0.3172 ± 0·0628 units, 6·4 μg min^?1). However, these increases were due to the increase in control (no drug) exercise FVC, as the drug-associated increase in exercise FVC above control did not differ between trials (P>0·6). These results suggest that exercise FVC is increased by both exercise training and stimulating the release of endothelium-dependent vasodilators. However, training does not affect the vascular response to these vasodilators.     

Lower limb vascular conductance and resting popliteal blood flow during head‐up and head‐down postural challenges

This study hypothesized that central and local reflex mechanisms affecting vascular conductance (VC) through the popliteal artery compensated for the reduction in muscle perfusion pressure (MPP) to maintain popliteal blood flow (PBF) during head‐down tilt (35? HDT), but not in head‐up tilt (45? HUT). Resting measurements were made on 15 healthy men in prone position to facilitate the access to the popliteal artery, on two separate days in random order during horizontal (HOR), HDT or HUT. In each body position, the body was supported, and the ankles were maintained in relaxed state so that there was no muscle tension, as with normal standing. Popliteal blood flow velocity and popliteal arterial diameter were measured by ultrasound, and PBF was calculated. MPP was corrected to mid‐calf from measured finger cuff pressure, and VC was estimated by dividing PBF by MPP. The MPP in HDT (48 ± 2 mmHg) was ~100mmHg less than in HUT (145 ± 2 mmHg). PBF was similar between HOR (51 ± 18 ml min^?1) and HDT (47 ± 13 ml min^?1), but was lower in HUT (30 ± 9 ml min^?1). VC was different between HDT (1·0 ± 0·3 ml min^?1 mmHg^?1), HOR (0·6 ± 0·2 ml min^?1 mmHg^?1) and HUT (0·2 ± 0·1 ml min^?1 mmHg^?1). In conclusion, the interactions of central and local regulatory mechanisms resulted in a disproportionate reduction of VC during HUT lowering PBF even though MPP was higher, while in HDT, increased VC contributed to maintain PBF at the same level as the HOR control condition.     

Pre- and postsynaptic alpha adrenoceptor selectivity studies with yohimbine and its two diastereoisomers rauwolscine and corynanthine in the anesthetized dog

The selectivity of yohimbine and its two diastereoisomers rauwolscine and corynanthine for pre- and postsynaptic alpha adrenoceptors has been investigated in the anesthetized dog. Antagonism of the inhibitory effect of clonidine on the tachycardia produced by electrical stimulation of the ansa subclavia was used as a measure of presynaptic alpha-2 adrenoceptor blockade. Inhibition of the diastolic pressor response to phenylephrine in ganglion and beta blocked dogs was used as a measure of postsynaptic alpha-1 adrenoceptor blockade. All three of the isomers reduced, and at higher doses reversed, the inhibitory effect of clonidine Yohimbine and rauwolscine were equipotent in this respect and were approximately 100-fold more potent than corynanthine. However, all the isomers were equipotent as antagonists of the diastolic pressure response to phenylephrine. Yohimbine and rauwolscine were approximately 30 times more potent as alpha-2 adrenoceptor than alpha-1 adrenoceptor antagonists, whereas corynanthine was 10-fold more potent at alpha-1 adrenoceptors than at alpha-2 adrenoceptors. These results are in broad agreement with those previously reported from in vitro experiments showing yohimbine and rauwolscine to be preferential alpha-2 adrenoceptor antagonists and corynanthine to be a preferential alpha-1 adrenoceptor antagonist. It is concluded that the high affinity of the antagonists yohimbine and rauwolscine for alpha-2 adrenoceptors is responsible for their selectivity because at the level of blockade of postsynaptic alpha-1 adrenoceptors both isomers were equipotent with corynanthine.     

Postjunctional alpha-1 and alpha-2 adrenoceptors in human skin arteries. An in vitro study

Experiments were performed to characterize the postjunctional alpha adrenoceptors that mediate adrenergic constriction in human skin arteries. Abdominal s.c. arteries were obtained from patients who died 3 to 12 hr before, and vascular segments 2 mm in length and 600 to 1050 microns in external diameter were prepared for isometric tension recording. On application of norepinephrine, phenylephrine (alpha-1 adrenergic agonist) or clonidine (alpha-2 adrenergic agonist) the arteries contracted in a dose-dependent manner and, in terms of the mean EC50 values, the order of potencies was clonidine greater than norepinephrine greater than phenylephrine. With regard to their ability to induce maximal contraction, the order was norepinephrine = phenylephrine greater than clonidine. In the presence of phentolamine (nonspecific alpha adrenergic antagonist) or yohimbine (selective alpha-2 adrenergic antagonist) the control curve for norepinephrine was displaced to the right in a parallel way. Prazosin (selective alpha-1 adrenergic antagonist) depressed both the slope and maximal response of the control curve for norepinephrine but the shift was not significant. Prazosin and yohimbine produced a parallel rightward shift in the control curve for phenylephrine and clonidine, respectively. These results suggest that skin arteries of humans have a mixed population of postjunctional alpha-1 and alpha-2 adrenoceptors and that alpha-2 adrenoceptors are more prominent. They also suggest that the alpha-2 adrenergic component of the response to norepinephrine is a low-maximum effect compared to the alpha-1 adrenergic component. This could be of significance in regulating skin blood flow and thermoregulatory function.     

Influence of portacaval shunt on bile formation in the rat

Abstract. Bile flow and bile acid secretion were measured in rats 21 to 28 days after a portacaval shunt and in sham-operated and normal animals. The following results were obtained. (1) Bile flow was significantly lower (6.65 ± SEM 0.36 μl-min^?1 · 100 g^?1) in the shunted rats than in the sham-operated animals (8.21 ± SEM 0.21 μl · min^?1 · 100 g^?1; P < 0.01). (2) Bile acid excretion was not significantly different in the shunted rats (0.27 ± SEM 0.03 μmol · min^?1 · 100 g^?1) and the sham-operated rats (0.26 ± SEM 0.02 μmol · min^?1 · 100 g^?1; NS). (3) During bile acid infusions, there was a linear relationship between bile flow and bile acid excretion in both groups of animals. The slope of the relationship was similar, suggesting that the osmotic activity of the bile acids was not modified in the shunted animals, and the bile acid-independent flow, estimated by the extrapolation of this relationship to a zero bile acid excretion, was significantly lower in the rats with a portacaval shunt (5.20 ± SEM 0.40 μl · min^?1 · 100 g^?1) than in the sham-operated animals (6.50 ± SEM 0.30 μl · min^?1 · 100 g^?1; P < 0.02). (4) The liver weight was significantly lower in the rats with a portacaval shunt than in the sham-operated animals and there was a parallel decrease of liver weight (-17%) and of the bile acid-independent flow (-22%). No difference was found between the sham-operated rats and the normal rats. It is concluded that portacaval shunt in the rat results in a decreased bile flow, due to a decrease in the bile acid-independent flow. Since bile acid secretion rate remained unchanged, it is suggested that the secretion of bile acids on the one hand and the bile acid-independent flow on the other are regulated by separate mechanisms.     

Strain gauge plethysmography and Doppler ultrasound in the measurement of limb blood flow

Abstract The maintenance of adequate oxygen delivery (DO₂) and tissue uptake (VO₂) has become central dogma in the management of the critically ill. However, these parameters are derived using gas tensions measured in mixed venous blood and may not reflect changes in regional blood flow. Therefore, it has become necessary to provide estimates of blood flow to specific organs and to evaluate the most adequate techniques available. In order to define the best means of assessing blood flow to the lower limb noninvasively in normal subjects, measurements of superficial femoral arterial blood flow using Doppler ultrasound (DU) and strain gauge plethysmography (SGP) were compared in 10 normal volunteers at rest and during exercise. To evaluate the effect of strain gauge positioning, results of measurements made under four different combinations of cuff/strain gauge placement were compared in 15 other volunteers. The correlation of the limb blood flow obtained using the two methods at rest and exercise was 0·57 and 0·62 and the limits of agreement (d±2SD) were 0·40±2·49 and -0·86±5·22 ml 100 ml^-1 tissue min^-1 at rest and on exercise, respectively. Results obtained using SGP were more reproducible (Coef. repeat. 0·45 vs. 0·94 ml 100 ml^-1 tissue min^-1, for SGP and DU, respectively). The various combinations of cuff/strain gauge positioning showed a tendency to over-read when the latter was placed on the thigh, but were not significantly different (P<0·05). Measurements of limb blood flow obtained using DU and SGP correlate poorly over a wide range of blood flow and do not agree, the results from the latter being more reproducible. Although the same position of cuff and strain gauge should be maintained throughout an experiment, varying the positions studied yields comparable results.     

Increased serum angiotensin converting enzyme activity in type T insulin—dependent diabetes mellitus: its relation to metabolic control and diabetic complications

Abstract. Serum angiotensin-converting enzyme (ACE) was measured in 150 insulin-dependent diabetes mellitus (IDDM) patients and 72 healthy subjects by radioassay, using [³H]-hippuryl-glycyl-glycine as a substrate. Mean (SD) serum ACE activity in diabetic patients was 120 ± 33 nmol ml^?1 min^?1 (range 46–215) and was significantly increased by 56% compared to control values (77 ± 23 nmol ml^?1 min^?1, range 46–125, P < 0·001). ACE activity > 125 nmol ml^?1 min^?1 was observed in 60 of 150 IDDM patients. 96 IDDM patients were normoalbuminuric (< 22 mg 24 h^?1) and 49 patients were micro- or macroalbuminuric (range 22–6010 mg 24 h^?1). Micro- and macroalbuminuric IDDM patients were found to have significantly greater ACE activity values than normoalbuminuric patients (128 ± 36 vs. 115 ± 30 nmol ml^?1 min^?1, P = 0·025). Metabolically well-controlled IDDM patients (glycosylated haemoglobin ≤ 8%) had lower ACE activity values than the patients with glycosylated haemoglobin greater than 8% (109 ± 20 vs. 127 ± 32 nmol ml^?1 min^?1, P < 0·02). A significant correlation between degree of metabolic control and ACE activity was found (r = 0.435, P < 0·001) so that an increase in one glycosylated quartile unit is accompanied by an increase in ACE activity of 10·5 nmol ml^?1 min^?1. Thus ACE activity in the serum of IDDM patients was increased by 56% in 40% of the patients. It was increased in IDDM patients without complications and in patients with retinopathy or nephropathy. In diabetic patients with nephropathy, ACE activity was greater than in diabetic patients without nephropathy. ACE activity was positively correlated with metabolic control. The role of increased ACE activity in the development of diabetic nephropathy remains to be established.     

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.     

Autonomic nervous function at rest in aerobically trained and untrained oldermen

Therelationship between aerobictraining, vagal influence on the heart and ageing was examined by assessing aerobic fitness andresting heart rate variability in trained and untrained older men. Subjects were 11 trained cyclistsand runners (mean age=6±61·6 years) and 11 untrained, age-matchedmen (mean age=66±1·2 years). Heart rate variability testing involvedsubjects lying supine for 25 min during which subjects’ breathing was paced andmonitored (7·5 breaths min^?1). Heart rate variability was assessedthrough time series analysis (HRV_ts) of the interbeat interval. Results indicated thattrained older men (3·55±0·21 l min^?1) hadsignificantly (P<0·05) greater VO _2maxthan that of control subjects (2·35±0·15 l min^?1).Also, trained older men (52±1·8 beats min^?1) hadsignificantly (P<0·05) lower supine resting heart rate than that of controlsubjects (65±4·2 beats min^?1). HRV_ts at highfrequencies was greater for trained men (5·98±0·22) than for untrainedmen (5·23±0·32). These data suggest that regular aerobic exercise inolder men is associated with greater levels of HRV_ts at rest.     

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.     

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.     

The forearm and leg perfusion techniques in man do not give the same metabolic information

Summary. The present study evaluates whether forearm and leg perfusion techniques give the same metabolic information. Seven patients hospitalized for operation of uncomplicated disease were investigated pre-operatively in the fasted state, while seven other patients who were on intravenous nutrition were studied in the fed state. Blood flow and the extremity exchange of glucose, lactate, glycerol, free fatty acids and amino acids were measured simultaneously across the forearm and the leg in all individuals. In the fasted state the arteriovenous difference (a-v) of glucose uptake was statistically significant across the forearm while it was statistically insignificant across the. leg (0·27 ± 0·06 vs. -0·04±0·13 mmol l¹). The a-v differences of glycerol (0·025 ± 0·028 vs. -0·043 ± 0·013 mmol l¹) and free fatty acids (0·10 ± 0·03 vs. -0·10 ± 0·04 mmol l¹) were positive across the forearm while they were negative across the leg (P < 0·01). In the fasted state the a-v difference of oxygen uptake (3·93 ± 0·67 vs. 3·21 ± 0·44 mmol l¹) and blood flow (4·1 ± 1·0 vs. 4·0 ± 0·7 ml min¹ 100 g¹) did not differ between the arm and the leg, but the a-v difference in carbon dioxide production was significantly higher (P<0.05) across the forearm (2·43 ± 0·37 vs. 1·29 ± 0·29 mmol l¹) compared to the leg. In the fed state all the above-mentioned differences between forearm and leg became statistically insignificant. In the fed state the a-v difference of the sum of all amino acids was not significantly different from zero balance across the forearm (-146 ± 103 mmol l¹) while there was a significant release from the leg (-175 ± 6 mmol l¹, P<0.05). In the fed state the flux of the sum of all amino acids became significantly positive across the arm while it was not significantly different from zero balance across the leg. In the fed state, forearm blood flow was significantly higher than leg blood flow (6·2 ± 0·5 vs. 4·0 ± 0·2 ml min¹ 100 g¹, P<0.001). The results in the present study demonstrate that the metabolic balance across regions of peripheral tissues may simultaneously differ considerably, i.e. being positive across the forearm and negative across the leg. This fact may imply that some previous claims may need reconsideration about ‘peripheral tissue metabolism’ associated with a certain clinical condition.     

Perfusion heterogeneity does not explain excess muscle oxygen uptake during variable intensity exercise

The association between muscle oxygen uptake (VO₂) and perfusion or perfusion heterogeneity (relative dispersion, RD) was studied in eight healthy male subjects during intermittent isometric (1 s on, 2 s off) one‐legged knee‐extension exercise at variable intensities using positron emission tomography and a‐v blood sampling. Resistance during the first 6 min of exercise was 50% of maximal isometric voluntary contraction force (MVC) (HI‐1), followed by 6 min at 10% MVC (LOW) and finishing with 6 min at 50% MVC (HI‐2). Muscle perfusion and O₂ delivery during HI‐1 (26 ± 5 and 5·4 ± 1·0 ml 100 g^?1 min^?1) and HI‐2 (28 ± 4 and 5·8 ± 0·7 ml 100 g^?1 min^?1) were similar, but both were higher (P<0·01) than during LOW (15 ± 3 and 3·0 ± 0·6 ml 100 g^?1 min^?1). Muscle VO₂ was also higher during both HI workloads (HI‐1 3·3 ± 0·4 and HI‐2 4·1 ± 0·6 ml 100 g^?1 min^?1) than LOW (1·4 ± 0·4 ml 100 g^?1 min^?1; P<0·01) and 25% higher during HI‐2 than HI‐1 (P<0·05). O₂ extraction was higher during HI workloads (HI‐1 62 ± 7 and HI‐2 70 ± 7%) than LOW (45 ± 8%; P<0·01). O₂ extraction tended to be higher (P = 0·08) during HI‐2 when compared to HI‐1. Perfusion was less heterogeneous (P<0·05) during HI workloads when compared to LOW with no difference between HI workloads. Thus, during one‐legged knee‐extension exercise at variable intensities, skeletal muscle perfusion and O₂ delivery are unchanged between high‐intensity workloads, whereas muscle VO₂ is increased during the second high‐intensity workload. Perfusion heterogeneity cannot explain this discrepancy between O₂ delivery and uptake. We propose that the excess muscle VO₂ during the second high‐intensity workload is derived from working muscle cells.     

Inert gas rebreathing: the effect of haemoglobin based pulmonary shunt flow correction on the accuracy of cardiac output measurements in clinical practice

Background: Cardiac output (CO) is an important cardiac parameter, however its determination is difficult in clinical routine. Non‐invasive inert gas rebreathing (IGR) measurements yielded promising results in recent studies. It directly measures pulmonary blood flow (PBF) which equals CO in absence of significant pulmonary shunt flow (Q_S). A reliable shunt correction requiring the haemoglobin concentration (c_Hb) as only value to be entered manually has been implemented. Therefore, the aim of the study was to evaluate the effect of various approaches to Q_S correction on the accuracy of IGR. Methods: Cardiac output determined by cardiac magnetic resonance imaging (CMR) served as reference values. The data was analysed in four groups: PBF without correcting for Q_S (group A), shunt correction using the patients’ individual c_Hb values (group B), a fixed standard c_Hb of 14·0 g dl^?1 (group C) and a gender‐adapted standard c_Hb for male (15·0 g dl^?1) and female (13·5 g dl^?1) probands each (group D). Results: 147 patients were analysed. Mean CO_CMR was 5·2 ± 1·4 l min^?1, mean CO_IGR was 4·8 ± 1·3 l min^?1 in group A, 5·1 ± 1·3 in group B, 5·1 ± 1·3 l min^?1 in group C and 5·1 ± 1·4 l min^?1 in group D. The accuracy in group A (mean bias 0·5 ± 1·1 l min^?1) was significantly lower as compared to groups B, C and D (0·1 ± 1·1 l min^?1; P<0·01). Conclusion: IGR allows a reliable non‐invasive determination of CO. Since PBF significantly increased the measurement bias, shunt correction should always be applied. A fixed c_Hb of 14·0 g dl^?1 can be used for both genders if the exact c_Hb value is not known. Nevertheless, the individual value should be used if any possible.