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.     

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.     

Effect of local warming on forearm reactive hyperaemia

Summary. Measurement of minimal vascular resistance has proved useful in quantifying structural changes in regional circulations. Accurate measurement of minimal vascular resistance requires full relaxation of all resistance vessels within the region under examination. The usual procedure in humans involves the measurement of maximal forearm blood-flow following 6–10 min of forearm ischaemia. We conducted this study to find whether forearm skin was fully vasodilated by this procedure. Peak forearm blood-flow was measured by plethysmography in six healthy subjects following 10 min of ischaemia while the arm was at a neutral temperature (33°C) and while the arm was locally warmed to 42°C. Peak reactive hyperaemia blood-flow was significantly elevated by local heating (P<0·001) to 79·6 ml100ml^-1min^-1 from a value of 50·2 ml100ml^-1min^-1 during normothermia. Peak reactive hyperaemia blood-flow in the contralateral unheated forearm showed no significant change between the two periods of ischaemia (P>0·05). These findings were confirmed in four subjects by laser Doppler velocimetry, which gives a linear index of skin blood-flow. In normothermic conditions, this index rose to 0·89 V following 10 min of ischaemia and to 1·26 V with local warming to 42°C (P<0·001). Ischaemia plus local warming did not cause a further significant rise in this index of skin blood-flow (1·35 V, P>0·05). These data suggest that 10 min of ischaemia during normothermia is insufficient to relax fully cutaneous resistance vessels and that maximal forearm blood-flow is underestimated by this procedure.     

Effects of a high‐fat meal on resistance vessel reactivity and on indicators of oxidative stress in healthy volunteers

High fat meals postprandially impair macrovascular endothelial function and a link to increased oxidative stress is suggested. Few information, on the other hand, exists on the effect of postprandial hyperlipidaemia on resistance vessel function. Under normal circumstances this vascular bed regulates tissue perfusion and, by controlling flow, impacts on macrovascular nitric oxide formation. The impact of a high fat meal (1200 kcal, 90 g fat, 46 g protein and 47 g carbohydrates) on postprandial resistance vessel reactivity and on indicators of oxidative stress was studied in 11 healthy subjects by venous‐occlusion plethysmography using another six subjects as time control group. Ingestion of the test meal resulted in a pronounced increase of serum triglycerides from 1·05 ± 0·61 mmol l^?1 in the fasting state to peak postprandial values of 1·94 ± 0·41 mmol l^?1 (P < 0·001) reached after 4 h and a return to baseline after 8 h. Fasting peak reactive hyperaemia (RH) was 19·6 ± 2·4 ml min^?1 (100 ml)^?1. Two hours after ingestion of the test meal peak RH was transiently reduced to 16·8 ± 2·2 ml min^?1 (100 ml)^?1 (P < 0·05). No alteration of resting forearm perfusion was observed. The time course of peak RH suggested a potential biphasic effect of the test meal with an early impairment and a late increase of RH. Ingestion of a lipid rich test meal did not exert any influence on either total plasma antioxidant capacity given in trolox equivalents (513 ± 26 μmol l^?1 at baseline) or on plasma peroxides measured as H₂O₂ equivalents (469 ± 117 μmol l^?1). Our results suggest that ingestion of a meal containing 90 g of fat results in a transient impairment of reactive hyperaemia in healthy subjects but these vascular alterations are not accompanied by signs of systemically increased oxidative stress.     

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.     

Role of alpha-adrenoceptor subtypes mediating sympathetic vasoconstriction in human digits

Abstract. The effects of intra-arterial administration of alpha-1 and alpha-2 adrenoceptor agonists and antagonists on human digital blood flow were studied before and during reflex sympathetic vasoconstriction in normal subjects. Total finger flow was measured by venous occlusion air plethysmography and capillary flow by the disappearance rate of a radioisotope from a local injection in a fingerpad. Intra-arterial phenylephrine (0·2–1·3 μg min^-1) and clonidine (0·12–0·48 μg min^-1) produced dose-related decreases in finger blood flow and increases in vascular resistance. Clonidine was the more potent vasoconstrictor. Prazosin (0·48 μg min^-1) effectively blocked the vasoconstrictor effect of phenylephrine but not clonidine, while yohimbine (30–70 μg min^-1) blocked the effect of clonidine but not phenylephrine. In a 20°C room, prazosin (0·4–13·2 μg min^-1) caused no significant changes in finger blood flow (7·7 ± 2·1 to 11·7 ± 3·3 ml min^-1) 100 ml^-1) or vascular resistance (30·9 ± 8·8 to 28·1 ± 8·7 mmHg ml^-1 min^-1 100 ml^-1). In the 20°C room, yohimbine (30–70 μg min^-1) produced a significant increase in finger blood flow (7·8 ± 2·8 to 23·4 ± 6·8 ml, P>0·01) and decrease in vascular resistance (20·5 ± 5·7 to 6·0 ± 2·2 units, P>0·01). No significant changes occurred in finger capillary flow with prazosin or yohimbine infusions. It is concluded that alpha-1 and alpha-2 adrenoceptors are present in human digital vasculature and that alpha-2 adrenoceptors are more important than alpha-1 adrenoceptors in sympathetic neural vasoconstriction. Since capillary blood flow was unaffected by yohimbine infusions during reflex sympathetic vasoconstriction, the alpha-2 adrenoceptors predominantly influence arteriovenous shunts in the finger.     

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.     

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.     

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.     

Standardized submaximal exercise testing in never smokers: a normative study

In a population survey on the south‐western coast of Norway, 373 never smokers aged 18–73 years (230 women) without respiratory symptoms performed a standardized, progressive, incremental submaximal bicycle exercise test. All individuals were able to do an exercise involving oxygen uptake of 1·0 l min^–1, 80% of the subjects reached 1·5 l min^–1 and 50% of the subjects reached 2·0 l min^–1. The respiratory frequency (RF), ventilation (VE) and heart rate (HR) for a given oxygen uptake were all higher in women than in men. Significant predictors of failure to reach oxygen uptake of 1·5 and 2·0 l min^–1 were sex, age, body height and weight. Prediction equations are given for respiratory frequency, heart rate and ventilation for an oxygen uptake of 1·0 l min^–1 in women and 1·5 l min^–1 in men; and body height is a strong predictor for all dependent variables. A multiple linear regression analysis in women showed that age was a significant predictor of respiratory frequency (P<0·05), ventilation (P<0·001) and heart rate (P<0·001), while in men age was a significant predictor only of ventilation (P<0·001) during the bicycle exercise protocol.     

Persistence of counter-regulatory abnormalities in insulin-dependent diabetes mellitus after pancreas transplantation

Abstract Conventional insulin therapy does not correct the counter-regulatory abnormalities of insulin-dependent diabetes mellitus. Pancreas transplantation is an alternative therapy that restores the endogenous insulin secretion in diabetes. In this study, the effects of segmental pancreas transplantation on counter-regulation to mild hypoglycaemia were evaluated. Glucose kinetics and the counter-regulatory hormonal responses were assessed in eight insulin-dependent diabetics with end-stage renal failure who had received pancreas and kidney transplantation 1 year previously, seven diabetic uraemic subjects (candidates for combined transplantation), five patients with chronic uveitis on immunosuppressive therapy comparable to pancreas recipients and 10 normal subjects. Insulin (0·3 mU kg^-1 min^-1) was infused for 2h to induce mild hypoglycaemia (plasma glucose 3·2–3·5-mmol l^-1) and exogenous glucose was infused as required to prevent any glucose decrease below 3·1 mmol l^-1. After transplantation, two of eight recipients had hypoglycaemic episodes reported in their medical records. During the study, hepatic glucose production was rapidly suppressed in the controls and in the patients on immunsuppression (–80 ± 7 and –54 ± 7%, P < 0·001 vs. basal), and rebounded to the baseline values within 1 h (–3 ± 1 and –6 ± 2%, P= NS vs. basal). The transplant recipients had similar suppression in the first hour (–88 ± 8%, P < 0·001 vs. basal), but the suppression persisted in the second hour (–69 ± 11%, P < 0·001 vs. basal) indicating a lack of glucose counter-regulatory response. The uraemic-diabetics had reduced suppression of hepatic glucose production (–45 ± 14%, P < 0·001 vs. basal) with respect to the recipients (P < 0·001), but had the same lack of response in the second hour (suppression: –39 ± 12%, P < 0·001 vs. basal). In addition, the response of glucagon to hypoglycaemia was blunted in both the recipients and in the diabetic subjects. In conclusion, the alterations in glucose counter-regulation of insulin-dependent diabetes persists after segmental pancreas transplantation. Specifically, the increased sensitivity of hepatic glucose production to the action of insulin renders this defect more evident after transplantation.     

Interstitial lactate levels in human skin at rest and during an oral glucose load: a microdialysis study

In vitro data have suggested that the skin is a significant lactate source. The purpose of the present study was to measure lactate and glucose concentrations in intact human skin in vivo using the microdialysis technique. Microdialysis fibres of 216 μm were inserted intradermally and perfused at a rate of 3 μl min^–1. In the first experimental protocol, dialysis fibres were calibrated by the method of no net flux in eight subjects. Skin lactate concentrations of 2·48 ± 0·17 mmol l^–1 were significantly greater than lactate concentrations of 0·84 ± 0·15 mmol l^–1 in venous plasma (P<0·01). Glucose concentrations in skin and venous plasma were similar (5·49 ± 0·18 vs. 5·26 ± 0·24 mmol l^–1). In the second experimental protocol, changes in lactate and glucose levels were studied in 10 subjects after an oral glucose tolerance test (OGTT). After the OGTT, plasma glucose and lactate levels increased by 54% and 39% to peak levels at 30 and 60 min respectively. In comparison, skin glucose and lactate increased by 41% and 18% at 60 and 90 min. No changes in skin blood flow were observed during the OGTT. The data suggest that resting skin is a significant lactate source with no significant lactate production during OGTT. The cellular source of lactate in the skin remains undetermined to date.     

Relationship between hyperglycaemia and aerobic power in men with newly diagnosed type 2 (non insulin-dependent) diabetes

Summary. The aim of the study described here was to evaluate aerobic function during exercise and its determinants in middle-aged men with newly diagnosed Type 2 (non insulin-dependent) diabetes. Using breath-by-breath technique, we measured O₂ uptake at anaerobic (ventilatory) threshold and at peak exercise in a group of diabetic men (n= 19; fasting blood glucose 8.6 ± 0.7 mmol l^-1, mean ± SEM) without any disease or medication that could have had an influence on exercise performance, and compared the results to those observed in non-diabetic healthy control men (n= 18). There were no differences in physical activity or smoking habits between the groups. Oxygen uptake was lower in the diabetic men than in the control men both at anaerobic threshold (15.0 ± 0.8 vs. 18.8 ± 1.0 ml min^-1 kg^-1, P< 0.01) and at peak exercise (25.3 ± 1.5 vs. 31.1 ± 1.4 ml min^-1 kg^-1, P<0.01). In the diabetic men peak O₂ uptake showed an inverse linear correlation with age (r= -0.71, P≤0.001), fasting blood glucose (r= -0.49, P<0.05) and glucose response in an oral glucose tolerance test (r=-0.43, P<0.05). In addition, long-term smoking was associated with impaired peak O₂ uptake. In a stepwise multiple regression procedure 75% of the total variance of peak O₂ uptake in the diabetic men was explained by age, post-load blood glucose response and smoking history. Thus, in addition to ageing and smoking, hyperglycaemia is correlated with impaired aerobic power in men with newly diagnosed Type 2 diabetes.     

Differing responses of cortisol to oCRF during endonasal and oral treatment with DDAVP

Abstract. Arginine vasopressin (AVP) exerts a potentiating effect on the responses of cortisol and ACTH to ovine CRF (oCRF). A stimulation test using AVP plus oCRF to assess ACTH reserve has been proposed. In central diabetes insipidus, long-term substitution therapy is commonly undertaken with desmopressin (DDAVP), an analogue of the natural hormone which has a greater antidiuretic action but whose effects on the ACTH-cortisol axis are still controversial. The aim of our study was to evaluate the variations in the responses of ACTH and cortisol to oCRF in various phases of the treatment of central diabetes insipidus: no treatment, endonasal treatment with DDAVP solution and oral treatment with DDAVP in tablet form. Seven patients suffering from central diabetes insipidus underwent testing with oCRF during the various phases of treatment. In the absence of DDAVP treatment, normal responses were registered for cortisol (basal 164·1 ± 29·4 ng ml^?1, peak 396·1 ± 37·9 ng ml^?1; P < 0·05) and ACTH (basal 20·4 ± 3·9 pg ml^?1, peak 86·3 ± 20·9 pg ml^?1; P < 0·05) in all patients. During oral treatment with DDAVP, no variation in cortisol response to oCRF was seen. By contrast, when DDAVP was administered endonasally, a significant reduction in cortisol responsiveness to oCRF (secretory area: 2429 ± 548 ng ml^?1 120 min) was noted in comparison with that found during the other two tests (no treatment: 3070 ± 704 ng ml^?1 120 min; oral DDAVP: 3419 ± 650 ng ml^?1 120 min; P < 0·05) performed. There is no clear explanation for this phenomenon, but an interesting hypothesis is that DDAVP acts as a weak agonist which exerts only a slight stimulatory effect on the corticotropic hypophyseal cells but which is able to compete with the natural hormone for receptor binding.     

Effect of bicycle exercise on insulin absorption and subcutaneous blood flow in the normal subject

Summary. Elimination of 8 units ¹²⁵I-insulin and ^99mTc-pertechnetate from a subcutaneous depot on the thigh or the abdomen was studied at rest and during intense bicycle exercise in healthy postabsorptive volunteers. Disappearance rates of the tracers as well as plasma insulin and glucose concentrations were determined before, during and after the 20 min exercise period, and compared to corresponding values obtained during a non-exercise, control study on another day. Leg exercise caused a two-fold increase in the rate of ¹²⁵I-insulin disappearance from a leg depot (first-order rate constants rose from 0·68 ± 0·15 to 1·12 ± 0·12%·min^-1, P <0·05), but had no significant effect on the rate of disappearance from an abdominal depot (rate constants were 0·75 ±0·17 and 0·87±0·18%·min^-1 at rest and during exercise, respectively). ^99mTc-pertechnetate clearance from leg or abdomen showed no significant change during exercise, indicating that subcutaneous blood flow was unaltered. Leg, but not abdominal, injection of insulin was associated with a greater rise in plasma insulin during exercise than at rest. The average difference between exercise and control insulin area-under-curve in the leg group (1426 ± 594%·min) was significantly greater (P <0·05) than that from the abdominal group (298 ±251%· min). When the data from the two study groups were pooled, a direct relationship was found to exist between the change in ¹²⁵I-insulin disappearance rate and the change in plasma insulin concentration (r=0·61, P <0·02). Plasma glucose levels fell throughout the observation period both during the exercise and the control study, following leg as well as abdominal injection. The glucose decremental area was greater during exercise than at rest both following leg (P <0·05) and abdominal injection (P <0·01). The exercise-induced mean reduction in plasma glucose was 60% lower following abdominal injection, but this difference was not significant.     

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.     

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.     

Sustained hyperaemia stimulus is necessary to induce flow-mediated dilation of the human brachial artery

We studied the relative importance of the magnitude and duration of the shear stimulus to induce flow‐mediated dilation (FMD) in the brachial artery of 10 healthy men by ultrasound imaging. The shear stress stimulus was induced by different durations of reactive hyperaemia following 15‐min forearm occlusion. The control condition of continuous postocclusion hyperaemia was compared to 20, 40 and 60 s of reactive hyperaemia followed by reapplication of circulatory arrest for 2 min and a second cuff release. In response to the first cuff release, peak shear rate was not different between conditions; total shear during the first minute was reduced in the 40 s and further reduced in the 20 s conditions. FMD in control (10·0 ± 3·0%), 60 s (10·5 ± 3·2%) and 40 s (7·8 ± 3·6%) were greater than the 20‐s condition (2·9 ± 2·8%). At second cuff release, peak shear of the 20‐s condition was slightly reduced from the first release, but 40 and 60‐s conditions were progressively reduced. Total shear to peak dilation was reduced after the second cuff release for the 20 and 40‐s conditions and further after the 60‐s condition. FMD was maintained in the 20‐s condition (8·3 ± 3·7%) but reduced in the 40‐s (3·7 ± 1·7%) and 60‐s conditions (1·5 ± 2·6%). FMD was not related to peak shear rate after the first occlusion (r = 0·003) but was after the second cuff release (r = 0·32, P = 0·004). The FMD response was correlated with the total shear to time of peak diameter after the first (r = 0·35, P<0·001) and the second (r = 0·25, P = 0·009) cuff release.     

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.     

Changes in transfer factor of the lung in response to bronchodilatation

Measurement of the transfer factor for carbon monoxide (T_LCO) is a widely used clinical lung function test. Although it is frequently applied in patients with bronchial obstruction, there is little information on the effects of bronchodilatation on the test. We therefore measured T_LCO in 40 patients before and after inhalation of terbutaline. T_LCO was measured with the single‐breath technique in 20 patients and with the intra‐breath technique in 20 patients. T_LCO was also measured in 20 healthy subjects with the single‐breath technique. Forced expiratory volume (FEV₁) increased from 2·9 ± 1·1 to 3·2 ± 1·2 l in patients with bronchial obstruction in response to terbutaline inhalation. T_LCO increased from 8·2 ± 2·6 to 8·6 ± 2·7 mmol min^–1 kPa^–1 (P< 0·001) and alveolar volume (V_A) from 5·74 ± 1·21 to 5·90 ± 1·21 l (P<0·001). There was no difference between the single‐breath and the intra‐breath techniques. There was little change in FEV₁ in the healthy subjects in response to terbutaline. T_LCO increased from 10·2 ± 2·1 to 10·5 ± 2·2 mmol min^–1 kPa^–1 (P< 0·01), but there was no change in V_A. The increase in T_LCO in patients may partly be explained by improved distribution of the inhaled gas. In healthy subjects, terbutaline may increase pulmonary capillary volume. We conclude that bronchodilatation results in a small increase in T_LCO in patients with light to moderate bronchoconstriction as well as in healthy subjects. The effect is small and should in most cases be simple to account for in the interpretation of pulmonary function tests, provided the patient’s treatment is known.