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.     

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.     

Plasma lipid and lipoprotein profile in elderly male long-distance runners

Summary. The purpose of this study was to evaluate plasma lipid and lipoprotein profiles in 30 elderly male long-distance runners (aged 66 ± 5 years, body fat 12 ± 2%, mean ± SD) by comparing them with 30 middle-aged untrained men (43 ±8 years, 17 ±3%), 30 middle-aged endurance-trained men (45 ±8 years, 12 ± 2%) who were matched for training distance to the elderly runners, and 15 elderly sedentary persons (65 ± 4 years, 16 ± 4%). Both elderly and middle-aged runners averaged 43 km/week in the latest year. Maximal oxygen uptake in the elderly runners (48 ± 5 ml/kg/min) was 60% higher than in age-matched untrained men, but 15% lower than in middle-aged runners. Plasma high-density lipoprotein cholesterol (HDLC) was significantly higher in the elderly runners than in their age-matched counterparts (77 vs. 59 mg/dl), but not different from the middle-aged runners. The middle-aged runners had lower plasma low-density lipoprotein cholesterol (LDLC) concentrations than their untrained counterparts (114 vs. 129 mg/dl), whereas LDLC level in the elderly runners was almost identical to that of the age-matched untrained men (127 vs. 119 mg/dl). Total cholesterol concentration in the elderly runners (219 mg/dl) was 11% higher than in the age-matched untrained men, whereas there was no difference between the middle-aged trained and untrained men. The remarkable reduction of the LDLC/ HDLC ratio in the elderly runners, therefore, is attributable to the elevated HDLC rather than lowered LDLC compared with the age-matched sedentary men (1·7 vs. 2·2). The elderly runners had plasma triglyceride concentrations similar to those of the middle-aged runners, and lower than those of the sedentary men. These results suggest that regularly performed endurance exercise favourably modifies the lipid and lipoprotein profile, and may thus reduce the risk of developing coronary heart disease for elderly men.     

Plasma lipid and lipoprotein profile in elderly female runners

Plasma lipid and lipoprotein profiles were compared in elderly female runners (RU: n= 15, aged 66 ± 5 years, body fat 20 ± 4%, training distance 35 ± 15 km week¹, V?O_2max 36 ± 4 ml kg¹ min¹, mean ± SD) and age-matched untrained women (UT: n= 28, 66 ± 4 years, body fat 26 ± 6%, V?O_2max 26 ± 3 ml kg¹ min¹). There were insignificant differences in total cholesterol (RU: 5·04 ± 0·60 vs. UT: 5·48 ± 0·85 mmol 1¹), HDL-cholesterol (RU: 1·97 ± 0·41 vs. UT: 1·91 ± 0·36 mmol 1¹) and LDL-cholesterol (RU: 2·72 ± 0·59 vs. UT: 3·03 ± 0·80 mmol 1¹) between the two groups. Plasma triglyceride concentration of the runners was significantly lower than that of the untrained women (RU: 0·80 ± 0·27 vs UT: 1·14 ± 0·36 mmol 1¹, P < 0·01). No difference was observed in the LDL-cholesterol/HDL-cholesterol ratio between the two groups (RU: 1·45 ± 0·51 vs UT: 1·64 ± 0·53 units). These results suggest that regularly performed running of 35 km week¹ in elderly women does not further elevate their HDL-cholesterol level which is already high compared to the levels found in elderly men. However, elderly female runners appear to be protected against age-related increases in the levels of triglyceride and LDL-cholesterol.     

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.     

Effect of enteral versus parenteral feeding on hepatic blood flow and steady state propofol pharmacokinetics in ICU patients

Objective: The main objective of this study was to evaluate the effect of switching from parenteral to enteral feeding on liver blood flow and propofol steady-state blood concentrations in patients in the intensive care unit (ICU). Design and patients: Steady-state blood concentrations of propofol were measured in eight ICU patients before (on days D –3, D –2, and D –1) and after (on days D + 1, D + 2, and D + 3) switching from parenteral to enteral feeding (on day D0). All patients received a continuous intravenous infusion of propofol (4.5 mg · kg^–1· h^–1) from several days before the start of the study, continuing throughout the experimental period. Hepatic blood flow was estimated by measuring steady-state D-sorbitol hepatic clearance. Results: Hepatic blood flow was high and was not affected by switching from parenteral to enteral feeding: 33 ± 8 ml · min^–1· kg^–1 (mean ± SD) and 33 ± 10 ml · min^–1· kg^–1 on D-3 and D –1, respectively, as compared to 37 ± 11 ml · min^–1· kg^–1 and 34 ± 8 ml · min^–1· kg^–1 on days D + l and D + 3, respectively. Systemic clearance of propofol was much higher than liver blood flow with average values on the six observation days ranging from 74.0 to 81.2 ml · min^–1· kg^–1 and was not affected by switching from parenteral to enteral feeding. Conclusions: Liver blood flow and systemic clearance of propofol were not affected by switching from parenteral to enteral feeding in the eight ICU patients studied. Extrahepatic clearance accounted for at least two thirds of the overall systemic clearance of propofol. Received: 18 July 1997 Accepted: 1 April 1998     

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.     

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.     

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.     

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.     

Relation of running distance to plasma HDL-cholesterol level in middle-aged male runners

Summary. This study examined the relation of training distance to plasma high density lipoprotein cholesterol (HDLC) concentration in runners. Forty-eight male endurance runners, aged from 30 to 57 years, were classified into three groups according to training distance (Grade I: n= 12, 30 km/week; Grade II: n= 22, 60 km/week; Grade III: n= 14, 100 km/week in average running distance), with 12 non-lean and 12 lean subjects as age-matched untrained controls. There were no significant differences in plasma total cholesterol among the groups (194–208 mg/dl on average). HDLC level was significantly higher in the untrained, lean group than in the untrained, non-lean men (63 ± 13 vs. 46 ± 8 mg/dl, mean ± SD). HDLC levels in all the runner groups were significantly higher than in untrained, lean subjects, and no differences were observed among Grade I, II and III runner groups (76 ± 15, 76 ± 13, 77 ± 11 mg/dl, respectively). This study suggests that further increases in HDLC could not occur in response to further elevation of training distance in well-trained runners.     

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.     

Mannitol clearance for the determination of glomerular filtration rate–a validation against clearance of 51Cr‐EDTA

We studied the agreement between plasma clearance of mannitol and the reference method, plasma clearance of ⁵¹Cr‐EDTA in outpatients with normal to moderately impaired renal function. Forty‐one patients with a serum creatinine <200 μmol l^?1 entered the study. ⁵¹Cr‐EDTA clearance was measured with the standard bolus injection technique and glomerular filtration rate (GFR) was calculated by the single‐sample method described by Jacobsson. Mannitol, 0·25 g kg^?1 body weight (150 mg ml^?1), was infused for 4–14 min and blood samples taken at 1‐, 2‐, 3‐ and 4‐h (n = 24) or 2‐, 3‐, 3·5‐ and 4‐h after infusion (n = 17). Mannitol in serum was measured by an enzymatic method. Plasma clearance for mannitol and its apparent volume of distribution (Vd) were calculated according to Brøchner‐Mortensen. Mean plasma clearance (±SD) for ⁵¹Cr‐EDTA was 59·7 ± 18·8 ml min^?1. The mean plasma clearance for mannitol ranged between 57·0 ± 20·1 and 61·1 ± 16·7 ml min^?1 and Vd was 21·3 ± 6·2% per kg b.w. The between‐method bias ranged between ?0·23 and 2·73 ml min^?1, the percentage error between 26·7 and 39·5% and the limits of agreement between ?14·3/17·2 and ?25·3/19·9 ml min^?1. The best agreement was seen when three‐ or four‐sample measurements of plasma mannitol were obtained and when sampling started 60 min after injection. Furthermore, accuracy of plasma clearance determinations was 88–96% (P30) and 41–63% (P10) and was highest when three‐ or four‐sample measurements of plasma mannitol were obtained, including the first hour after the bolus dose. We conclude that there is a good agreement between plasma clearances of mannitol and ⁵¹Cr‐EDTA for the assessment of GFR.     

Measurement of cardiac output with non-invasive Aesculon impedance versus thermodilution

Background: This study compared the non‐invasive thoracic electrical bioimpedance Aesculon^® technique (TEB_Aesculon) with thermodilution (TD) to evaluate whether TEB_Aesculon may offer a reliable means for estimating cardiac output (CO) in humans. Material and method: Cardiac output was measured with TD and TEB_Aesculon in 33 patients, with a mean age ± SEM of 59 ± 2·7 years, that underwent right heart catheterization for clinical investigation of pulmonary hypertension or severe heart failure. Four to five CO measurements were performed with each technique simultaneously in 33 patients at rest, 11 during exercise and seven during NO inhalation. Result: Cardiac output correlated poorly between TEB_Aesculon and TD at rest (r = 0·46, P<0·001), during exercise (r = 0·35, P<0·013) and NO inhalation (r = 0·41, P<0·017). CO was higher for TEB_Aesculon than TD with 0·86 ± 0·14 l min^?1 at rest (P<0·001) and 2·95 ± 0·69 l min^?1 during exercise (P<0·003), but similar during NO inhalation, with a tendency (P<0·079) to be 0·44 ± 0·19 l min^?1 higher for TEB_Aesculon than TD. CO increased from rest to exercise for TEB_Aesculon and TD with 6·11 ± 0·6 l min^?1 (P<0·001) and 3·91 ± 0·36 l min^?1 (P<0·001), respectively; an increase that was higher (P<0·002) for TEB_Aesculon than TD. During NO inhalation, compared to rest, CO decreased for TEB_Aesculon with 0·62 ± 0·11 l min^?1 (P<0·002), but not significantly for TD with 0·21 ± 0·12 l min^?1 (P<0·11). Bland–Altman analysis showed a poor agreement between TEB_Aesculon and TD. Conclusion: TEB_Aesculon overestimated CO compared to TD with ～17% at rest and ～34% during exercise, but the techniques showed similar results during NO inhalation. CO, furthermore, correlated poorly between TEB_Aesculon and TD. TEB_Aesculon may at present not replace TD for reliable CO measurements in humans.     

Effects of walking with blood flow restriction on limb venous compliance in elderly subjects

Venous compliance declines with age and improves with chronic endurance exercise. KAATSU, an exercise combined with blood flow restriction (BFR), is a unique training method for promoting muscle hypertrophy and strength gains by using low‐intensity resistance exercises or walking. This method also induces pooling of venous blood in the legs. Therefore, we hypothesized that slow walking with BFR may affect limb venous compliance and examined the influence of 6 weeks of walking with BFR on venous compliance in older women. Sixteen women aged 59–78 years were partially randomized into either a slow walking with BFR group (n = 9, BFR walk group) or a non‐exercising control group (n = 7, control group). The BFR walk group performed 20‐min treadmill slow walking (67 m min^?1), 5 days per week for 6 weeks. Before (pre) and after (post) those 6 weeks, venous properties were assessed using strain gauge venous occlusion plethysmography. After 6 weeks, leg venous compliance increased significantly in the BFR walk group (pre: 0·0518 ± 0·0084, post: 0·0619 ± 0·0150 ml 100 ml^?1 mmHg^?1, P<0·05), and maximal venous outflow (MVO) at 80 mmHg also increased significantly after the BFR walk group trained for 6 weeks (pre: 55·3 ± 15·6, post: 67·1 ± 18·9 ml 100 ml^?1 min^?1, P<0·01), but no significant differences were observed in venous compliance and MVO in the control group. In addition, there was no significant change in arm compliance in the BFR walk group. In conclusion, this study provides the first evidence that 6 weeks of walking exercise with BFR may improve limb venous compliance in untrained elder female subjects.     

Influence of combined intravenous and oral glucose administration on splanchnic glucose uptake in man

Summary. The influence of intravenous plus oral glucose administration on splanchnic glucose handling was examined in healthy young individuals by combining the hepatic vein catheterization technique with the double glucose tracer method. After 1 h of steady state hyperglycaemia (11·7 Itim ) induced by intravenous glucose alone (hyperglycaemic clamp technique), subjects ingested 89 ± 1 g of glucose, and the hyper-glycaemic plateau was maintained for the subsequent 4 h by adjusting the exogenous glucose infusion rate. Over the 4-h absorptive period, only 51 ± 4 g of oral glucose (i.e. 58 ±4% of the ingested load) appeared in the systemic circulation, while 193 ± 15 g (1·072±0·083 mol) of glucose had to be infused exogenously to sustain the hyperglycaemia. Endogenous glucose production was suppressed by over 60%. Net splanchnic glucose balance switched from a positive value (i.e. net uptake) of 506 ± 2–56 uniol min^-1kg^-1with intravenous glucose alone (0·60 min) to a negative one (i.e. net output) of 12·50 ± 2·44 u. mol min^-1kg^-1during 4 h (60–300 min) of intravenous+oral glucose. The mean rate of splanchnic glucose uptake was estimated to be 6·39 ±4·67 ixmol min^-1kg^-1with intravenous glucose alone, and 8·83 ±4·28 u. mol min^-1kg^-1with intravenous+oral glucose. In either case, the large majority (80–90%) of the glucose appearing in the systemic circulation was disposed of by extrasplanchnic tissues. These results indicate that pre-existing hyperglycaemia and/or hyperinsulinaemia inhibit gastrointestinal glucose absorption, and that oral glucose administration does not result in a major redistribution of intravenous glucose between splanchnic and extrasplanchnic tissues.     

Acute dexfenfluramine administration normalizes glucose tolerance in rats with insulin-deficient diabetes

Abstract. Dexfenfluramine has been shown to lower blood glucose concentrations independently of its effects in reducing food intake and body weight, in human and animal syndromes of non-insulin dependent diabetes. This study aimed to determine whether dexfenfluramine could also reduce glycaemia in rats with severe insulin-deficient diabetes induced by the β-cell toxin, streptozotocin (55 mg kg^-1). Three weeks after diabetes induction, nine groups (each n= 10) of diabetic and non-diabetic rats underwent oral glucose tolerance tests (1 g kg^-1, by gavage). These tests were preceded by 12–18 h of fasting to remove the confounding effects of hyperphagia in diabetic rats, and to stabilize glycaemia. Dexfenfluramine (1·0 mg kg^-1), given 2 h before the glucose challenge, significantly reduced basal glycaemia and decreased the post-challenge glycaemic rise (P<0·01 vs. untreated diabetics). Dexfenfluramine dosages of 2·5 and 5·0 mg kg^-1 both further flattened the post-challenge glycaemic profiles (both P<0·01 vs. untreated diabetics) and achieved levels that did not differ significantly from those in non-diabetics (both P> 0·05). Subsequently, the studies using dexfenfluramine dosages of 2·5 and 5·0 mg kg^-1 were repeated to determine whether the drug affected plasma insulin levels 2 h after dosing. In diabetic rats, plasma insulin concentrations were reduced to 10–20% of non-diabetic values, and were not significantly altered by dexfenfluramine. Acute dexfenfluramine administration therefore improves and (at dosages of 2·5 and 5·0 mg kg^-1) essentially normalizes glucose tolerance in rats with severe insulin-deficient diabetes. As circulating insulin concentrations were not increased, dexfenfluramine probably acts by enhancing and/or mimicking insulin action. The magnitude of this effect suggests that dexfenfluramine could find application as adjunctive treatment in the management of human insulin-dependent diabetic patients with insulin insensitivity, such as that associated with obesity.     

Enhancement of cyclosporin A induced hepato- and nephrotoxicity by glutathione depletion

Abstract The role of glutathione in cyclosporin A (cyclosporin) hepato- and nephrotoxicity has not been clarified yet. The hypothesis that a glutathione deficit enhances the hepato- and nephrotoxicity of cyclosporin was tested in an animal model. Glutathione depletion was achieved by administration of diethyl maleate (DEM). Adult Sprague Dawley rats were divided into four groups (A–D; n≥ 8) and treated for 8 d as follows: group A, glucose 5% (0·4 ml kg^-1, i.p.) + 3 h later olive oil (0·5 ml kg^-1, oral); group B, DEM (0·4 ml kg^-1, i.p.) + 3 h later olive oil (0·5 ml kg^-1, oral); group C, glucose 5% (0·4 ml kg^-1, i.p.) + 3 h later cyclosporin (50 mg kg^-1, oral); group D, DEM (0·4 ml kg^-1, i.p.) + 3 h later cyclosporin (50 mg kg^-1, oral). Cyclosporin alone increased bilirubin concentration from 1·0 ± 0·6 μmol l^-1 to 8·4 ± 1·9 μmol l^-1 (P < 0·05) without changing transaminases. In glutathione depleted rats cyclosporin caused a further elevation of serum bilirubin up to 23·4 ± 5·5 μmol l^-1. This was accompanied by a 50% increase of serum glutamic oxaloacetic transaminase (GOT). Cyclosporin alone significantly decreased creatinine clearance to 50% of controls (P < 0·05). Cyclosporin treatment following glutathione depletion resulted in a further decline of creatinine clearance to 22% of controls. DEM had no effect on kidney or liver function. In conclusion glutathione depletion increases the susceptibility to cyclosporin-induced liver and kidney injury. The results support the hypothesis that sufficient cellular glutathione concentrations may be important to prevent cyclosporin-induced hepato- and nephrotoxicity.     

Cardiac sympathetic activity is associated with inflammation and neurohumoral activation in patients with idiopathic dilated cardiomyopathy

Background: Idiopathic dilated cardiomyopathy (IDC) is characterized by sympathetic nervous overactivity, inflammation and neurohumoral activation; however, their interrelationships are poorly understood. Methods and results: We studied 99 patients with IDC (age 54 ± 1 years, left ventricular ejection fraction (EF) 40 ± 1%, maximum oxygen uptake (VO₂max) 20 ± 1 ml kg^?1 min^?2, mean ± SEM) by using ¹²³I‐metaiodobenzylguanidine (MIBG) imaging. MIBG washout and MIBG heart/mediastinum (H/M)‐ratio at 4 h postinjection were calculated. In addition, the plasma levels of interleukin (IL)‐6 and N‐terminal B‐type natriuretic peptide (NT‐proBNP) were measured. MIBG washout and MIBG H/M ratio had a significant correlation with IL‐6 (r = 0·42, P<0·001 and r = ?0·31, P<0·01) and NT‐proBNP (r = 0·48, P<0·001 and r = ?0·40, P<0·001). During a median follow‐up of 4·1 years, 20 patients (20%) had an adverse cardiac event (death, heart transplantation or application of biventricular pacemaker or implantable cardioverter–defibrillator). In these patients, MIBG washout was higher (53 ± 4 versus 40 ± 2%, P = 0·01) and H/M ratio lower (1·38 ± 0·04 versus 1·51 ± 0·02, P = 0·01) than in patients without an event. Conclusions: In dilated cardiomyopathy, myocardial sympathetic innervation and activity are related to inflammation and neurohumoral activation. These relationships are at least partly independent of left ventricular function and exercise capacity.     

Dose-dependent effects of almitrine on hemodynamics and gas exchange in an animal model of acute lung injury

Objective: To determine the dose-response relationship of almitrine (Alm) on pulmonary gas exchange and hemodynamics in an animal model of acute lung injury (ALI).¶Design: Prospective, randomized, controlled study.¶Methods: Twenty anesthetized, tracheotomized and mechanically ventilated (FIO₂ 1.0) pigs underwent induction of ALI by repeated saline washout of surfactant. Animals were randomly assigned to either receive cumulating doses of Alm intravenously (0.5, 1.0, 2.0, 4.0, 8.0 and 16.0 μg · kg^–1· min^–1) for 30 min each (treatment; n = 10) or to receive the solvent malic acid (controls; n = 10).¶Measurements and results: Measurements of pulmonary gas exchange and hemodynamics were performed at the end of each infusion period. Alm < 4.0 μg · kg^–1· min^–1 improved arterial oxygen pressure (PaO₂) (105 ± 9 mmHg for Alm 1.0 vs 59 ± 5 mmHg) and decreased intrapulmonary shunt (Q_s/Q_t) (32 ± 4 % for Alm 1.0 vs 46 ± 4 %) (P < 0.05). Alm ≥ 8.0 μg · kg^–1· min^–1 did not improve pulmonary gas exchange compared to controls. When compared to low doses of Alm < 4.0 μg · kg^–1· min^–1, high doses ≥ 8.0 μg · kg¹· min^–1 decreased PaO₂ (58 ± 11 mmHg for Alm 16.0) and increased Q_s/Q_t (67 ± 10 % for Alm 16.0) (P < 0.05).¶Conclusions: In experimental ALI, effects of almitrine on oxygenation are dose-dependent. Almitrine is most effective when used at low doses known to mimic hypoxic pulmonary vasoconstriction.