Haemodynamic responses to static and dynamic handgrip before and after autonomic blockade

1. Six healthy men performed static and dynamic handgrip to local muscular fatigue in approximately 6 min under control conditions, i.e. without drugs and after combined parasympathetic and beta-adrenergic blockade with atropine and metoprolol. 2. From rest to exercise at fatigue, systolic, diastolic and mean arterial pressures increased by 32 +/- 4 and 39 +/- 3 mmHg, 24 +/- 3 and 26 +/- 4 mmHg, and 26 +/- 3 and 30 +/- 3 mmHg respectively for static and dynamic handgrip. There were no significant differences between the pressor responses for the two modes of contraction. Cardiac output increased significantly only during dynamic exercise. Total peripheral resistance increased by 2.3 +/- 1.0 units for static handgrip (P less than 0.05) and by 0.7 +/- 0.8 unit (P greater than 0.05) for dynamic handgrip. Autonomic blockade abolished the heart rate response to both static and dynamic handgrip. For both modes of contraction the systolic arterial pressure responses were 9-12 mmHg lower (P less than 0.05) after autonomic blockade, but the diastolic and mean pressure responses were not significantly affected. A significant increase in cardiac output persisted during dynamic exercise. The increase in peripheral resistance during static exercise tended to be greater after blockade. Plasma noradrenaline and adrenaline levels showed only minor elevations in response to static and dynamic handgrip and were not changed by autonomic blockade. 3. These data indicate that when performed to a common end-point with identical small muscle groups static and dynamic exercise produce an equally large pressor response, which is only slightly attenuated by autonomic blockade.     

Effects of euglycaemic and hypoglycaemic hyperinsulinaemia on sympathetic and parasympathetic regulation of haemodynamics in healthy subjects

The effects of hypoglycaemia during hyperinsulinaemia, occurring under various pathophysiological conditions, on the cardiovascular regulatory system and vasculature are largely unknown. The aim of the present study was to investigate regulatory and haemodynamic responses to acute hyperinsulinaemia and consequent hypoglycaemia in 18 healthy subjects. Blood sampling and 5 min ECG and blood pressure recordings were performed at baseline and during the euglycaemic and hypoglycaemic phases of a hyperinsulinaemic clamp. Heart rate variability (HRV) and blood pressure variability (BPV) were assessed by using power spectral analysis, and baroreflex sensitivity (BRS) was assessed using the cross-spectral method. Stroke volume was assessed from the non-invasive blood pressure signal by the arterial pulse contour method. Euglycaemic hyperinsulinaemia did not change plasma catecholamine concentrations, HRV, BPV, BRS, heart rate, blood pressure, stroke volume, cardiac output or peripheral resistance. However, hyperinsulinaemic hypoglycaemia resulted in an 11.7-fold increase in the plasma adrenaline concentration (from 0.19+/-0.03 to 1.68+/-0.32 nmol/l; P <0.001), and a modest 1.3-fold increase in the plasma noradrenaline concentration (from 1.74+/-0.22 to 2.02+/-0.19 nmol/l; P <0.05) compared with baseline. Furthermore, we observed significant decreases in diastolic blood pressure (from 68+/-3 to 60+/-3 mmHg; P <0.05) and peripheral resistance (from 24.1+/-1.2 to 18.5+/-1.1 mmHg.min(-1) x l(-1); P <0.01). Stroke volume and cardiac output increased markedly from the euglycaemic to the hypoglycaemic period only ( P <0.01 for both). Hypoglycaemia did not influence HRV, BPV or BRS. Our findings indicate that hyperinsulinaemic hypoglycaemia is characterized by a significant increase in the plasma adrenaline concentration and by decreases in peripheral resistance and blood pressure. Counter-regulation during hyperinsulinaemic hypoglycaemia involves selective adrenomedullary sympathetic activation, and does not influence cardiac parasympathetic regulation or baroreflex control of heart rate.     

Alpha-adrenoceptor blockade by phentolamine inhibits adrenaline-induced platelet activation in vivo without affecting resting measurements.

1. The effects of phentolamine (500 micrograms/min) on platelet aggregability in vivo at rest and during adrenaline infusion were assessed by ex vivo filtragometry and measurements of plasma beta-thromboglobulin levels in 10 healthy male subjects. Plasma levels of von Willebrand factor antigen and free fatty acids were also measured. 2. Adrenaline induced marked and expected increases in heart rate and systolic blood pressure and decreased diastolic blood pressure when venous plasma adrenaline levels were elevated from 0.12 +/- 0.02 to 2.9 +/- 0.3 nmol/l (P less than 0.01). 3. Adrenaline caused platelet activation in vivo. Ex vivo filtragometry readings were shortened by 58 +/- 9% (P less than 0.01), plasma beta-thromboglobulin levels increased by 99 +/- 44% (P less than 0.01) and platelet counts increased by 26 +/- 6% (P less than 0.01). Plasma levels of von Willebrand factor antigen and free fatty acids increased by 53 +/- 5% and 475 +/- 113% (both P less than 0.01), respectively. 4. Phentolamine enhanced the beta-adrenergic vasodilator responses to adrenaline, as both the decrease in diastolic blood pressure and the reflexogenic increase in heart rate were enhanced (both P less than 0.01). Marked elevations in plasma noradrenaline levels were found during infusions of phentolamine and adrenaline (P less than 0.001). 5. Phentolamine did not alter platelet indices at rest, but abolished adrenaline-induced platelet activation, as filtragometry readings, plasma beta-thromboglobulin levels and platelet counts remained at, or below, resting levels. Responses of plasma levels of von Willebrand factor antigen and free fatty acids to adrenaline were not influenced by phentolamine and did not seem to influence platelet responses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Defective glucose counterregulation after subcutaneous insulin in noninsulin-dependent diabetes mellitus. Paradoxical suppression of glucose utilization and lack of compensatory increase in glucose production, roles of insulin resistance, abnormal neuroendocrine responses, and islet paracrine interactions.

To characterize glucose counterregulatory mechanisms in patients with noninsulin-dependent diabetes mellitus (NIDDM) and to test the hypothesis that the increase in glucagon secretion during hypoglycemia occurs primarily via a paracrine islet A-B cell interaction, we examined the effects of a subcutaneously injected therapeutic dose of insulin (0.15 U/kg) on plasma glucose kinetics, rates of glucose production and utilization, and their relationships to changes in the circulating concentrations of neuroendocrine glucoregulatory factors (glucagon, epinephrine, norepinephrine, growth hormone, and cortisol), as well as to changes in endogenous insulin secretion in 13 nonobese NIDDM patients with no clinical evidence of autonomic neuropathy. Compared with 11 age-weight matched nondiabetic volunteers in whom euglycemia was restored primarily by a compensatory increase in glucose production, in the diabetics there was no compensatory increase in glucose production (basal 2.08 +/- 0.04----1.79 +/- 0.07 mg/kg per min at 21/2 h in diabetics vs. basal 2.06 +/- 0.04----2.32 +/- 0.11 mg/kg per min at 21/2 h in nondiabetics, P less than 0.01) despite the fact that plasma insulin concentrations were similar in both groups (peak values 22 +/- 2 vs. 23 +/- 2 microU/ml in diabetics and nondiabetics, respectively). This abnormality in glucose production was nearly completely compensated for by a paradoxical decrease in glucose utilization after injection of insulin (basal 2.11 +/- 0.03----1.86 +/- 0.06 mg/kg per min at 21/2 h in diabetics vs. basal 2.08 +/- 0.04----2.39 +/- 0.11 mg/kg per min at 21/2 h nondiabetics, P less than 0.01), which could not be accounted for by differences in plasma glucose concentrations; the net result was a modest prolongation of hypoglycemia. Plasma glucagon (area under the curve [AUC] above base line, 12 +/- 3 vs. 23 +/- 3 mg/ml X 12 h in nondiabetics, P less than 0.05), cortisol (AUC 2.2 +/- 0.5 vs. 4.0 +/- 0.7 mg/dl X 12 h in nondiabetics, P less than 0.05), and growth hormone (AUC 1.6 +/- 0.4 vs. 2.9 +/- 0.4 micrograms/ml X 12 h in nondiabetics, P less than 0.05) responses in the diabetics were decreased 50% while their plasma norepinephrine responses (AUC 49 +/- 12 vs. 21 +/- 5 ng/ml X 12 h in nondiabetics, P less than 0.05) were increased twofold (P less than 0.05) and their plasma epinephrine responses were similar to those of the nondiabetics (AUC 106 +/- 17 vs. 112 +/- 10 ng/ml X 12 h in nondiabetics). In both groups of subjects, increases in plasma glucagon were inversely correlated with plasma glucose concentrations (r = -0.80 in both groups, P less than 0.01) and suppression of endogenous insulin secretion (r = -0.57 in nondiabe     

Decreased exercise heart rate and blood pressure response in diabetic subjects with cardiac autonomic neuropathy

Abnormal hemodynamic responses to exercise have been observed in diabetic subjects, but the pathogenesis and significance remain uncertain. We used maximal treadmill exercise to study 32 subjects with long-term insulin-dependent diabetes without clinical evidence of cardiac disease. Two of the 32 had occult ischemic heart disease revealed by stress electrocardiography and myocardial-perfusion scintigraphy and were excluded from subsequent analysis. In the remaining 30 subjects, we compared the responses to exercise of the 17 subjects with cardiac autonomic neuropathy diagnosed by noninvasive maneuvers (group 1) with the 13 without (group 2). At rest, the pressure-rate product (PRP) was higher in group 1 (114.0 +/- 5.7 vs. 95.9 +/- 5.3, P less than .05). With maximal exercise the increase in heart rate (44.6 +/- 4.8 vs. 79.0 +/- 5.4 beats/min, P less than .001), systolic blood pressure (36.8 +/- 5.9 vs. 55.0 +/- 5.8 mmHg, P = .02), and the PRP (102.0 +/- 7.3 vs. 182.0 +/- 8.2, P less than .001) were all lower in group 1 than in group 2, despite similar total treadmill times (631 +/- 47 vs. 587 +/- 40 s, P greater than .1). At each stage of exercise, the increase in heart rate and systolic blood pressure was lower in group 1 patients. The severity of cardiac autonomic neuropathy correlated inversely with the maximal increase in heart rate (r = -.68, P less than .001) and the PRP (r = -.58, P less than .005). Age, duration of diabetes, and the presence and severity of microvascular disease did not correlate with any of the hemodynamic parameters.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of cardiac tamponade on atrial natriuretic peptide concentrations: influence of stretch and pressure

1. In order to study the role of atrial pressure and atrial stretch on the release of atrial natriuretic peptide we have measured plasma atrial natriuretic peptide concentration, urine output and haemodynamic variables in eight patients during and 30 min after the relief of cardiac tamponade. This condition is characterized by high atrial pressure with little or no atrial stretch. 2. Relief of tamponade was associated with a rise in urine output (53 +/- 27.9 to 101 +/- 24.5 ml/h, mean +/- SEM; P = 0.09), systolic blood pressure (95 +/- 9.6 to 126 +/- 7.0 mmHg, P less than 0.0001), and plasma atrial natriuretic peptide concentration (369.5 +/- 70.9 to 490.3 +/- 94.7 pg/ml, P less than 0.05) despite a large fall in right atrial pressure (18.6 +/- 1.6 to 9.5 +/- 1.3 mmHg, P less than 0.001). 3. These results suggest, therefore, that an increase in atrial stretch, rather than in atrial pressure, stimulates the release of atrial natriuretic peptide.     

Cardiac and whole-body [3H]noradrenaline kinetics during adrenaline infusion in man.

1. To investigate the possible role of adrenaline as a modulator of noradrenaline release from the sympathetic nervous system, the responses of cardiac and whole-body noradrenaline kinetics to intravenous infusions of adrenaline (30 ng min-1 kg-1) and matching saline placebo were determined at rest and during supine bicycle exercise in 16 patients undergoing cardiac catheterization, in whom beta-adrenoceptor antagonists had been discontinued for 72 h. 2. At rest and compared with placebo, infusion of adrenaline was associated with a small increase in arterial plasma noradrenaline from 211 +/- 29 pg/ml to 245 +/- 29 pg/ml (P less than 0.05). Increases in whole-body noradrenaline spillover to arterial plasma were larger (from 282 +/- 40 ng min-1 m-2 to 358 +/- 41 ng min-1 m-2, P less than 0.01) and there was a trend towards an increase in whole-body noradrenaline clearance. Cardiac noradrenaline clearance was modestly increased during adrenaline infusion, but cardiac noradrenaline spillover was not altered despite increases in heart rate and coronary sinus plasma flow. Adrenaline infusion was associated with symptomatic myocardial ischaemia in four of 14 patients with coronary heart disease. 3. Supine bicycle exercise was associated with significant increases in peripheral noradrenaline concentrations and in cardiac and whole-body noradrenaline spillover. The increases on exercise were not significantly different for these variables during saline and adrenaline infusions. 4. Infusion of adrenaline to produce 'physiological' increases in plasma adrenaline concentration was associated with an increase in total noradrenaline release, as assessed by whole-body noradrenaline spillover to plasma.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adrenaline secretion during exercise

By studying six normal subjects during graduated treadmill exercise, we have confirmed that there is very little rise in venous plasma adrenaline levels during mild or moderate exercise. During a second study, adrenaline was infused intravenously in six resting subjects at a rate of 0.025 micrograms min-1 kg-1. This elevated the basal plasma adrenaline level from 0.28 +/- 0.04 nmol/l to 0.92 +/- 0.16, 1.16 +/- 0.20 and 1.28 +/- 0.19 nmol/l at 3, 5 and 7 min after the start of the infusion. The same adrenaline infusion was repeated in the same subjects 7 min after they started moderate exercise at a constant rate on a static exercise bicycle. Just before the start of the infusion, 7 min after the onset of exercise, plasma adrenaline had risen to 0.36 +/- 0.07 nmol/l. This rose to 1.86 +/- 0.30, 1.98 +/- 0.26 and 2.19 +/- 0.29 nmol/l at 3, 5 and 7 min after the start of this second infusion. Five minutes after the end of the infusion, while the subjects were still exercising, the mean level was 0.56 +/- 0.04 nmol/l. The venous plasma level of adrenaline is the result of a balance between the secretion of adrenaline by the adrenal medulla and the clearance of adrenaline from plasma. Our results suggest that the lack of any significant rise in plasma adrenaline during moderate exercise does not result from an accelerated clearance of adrenaline by exercising tissue. The clearance rate of adrenaline from plasma is reduced during exercise. There is no significant increase in secretion by the adrenal medulla in response to the stimulus of mild or moderate exercise.     

Catecholamine Levels and Pacing Behavior of QT-Driven Pacemakers During Exercise

It is thought that increasing catecholamine levels in the heart are partly responsible for shortening of the repolarization time and so indirectly for the pacing behavior of the QT driven pacemaker. Adrenaline and noradrenaline (NA) plasma levels were determined at rest, during symptom-limited exercise, and during recovery more than 1 month after the implantation of a 919 or a Rhythmyx pacemaker (Vitatron, The Netherlands) in eight patients (age 54-85 yrs). Significant increases were detected in NA level (from 0.57 +/- 0.23 ng/mL to 2.15 +/- 0.76 ng/mL), but not in the circulating adrenaline level. The correlation coefficient of the mean pacing rate and the mean NA level during exercise and recovery was 0.963 (P less than 0.0001), the correlation coefficient with the mean oxygen consumption was 0.888 (P less than 0.01). No correlation with the adrenaline level was observed. The correlation coefficient of the changes of pacing rate and the changes of NA level during exercise and recovery was 0.882 (P less than 0.005). The pacing rate of the new generation of QT driven pacemakers is closely correlated with the noradrenaline spillover in the plasma, not with the adrenaline level. A short delay (less than 1 minute) is observed in the adaptation.     

The role of opioid peptides in the hormonal responses to acute exercise in man

Opioid involvement in the physiological and hormonal responses to acute exercise was investigated in six normal male subjects. Each was exercised to 40% (mild exercise) and 80% (severe exercise) of his previously determined maximal oxygen consumption on two occasions, with and without an infusion of high-dose naloxone. The exercise task was a bicycle ergometer; mild and severe exercise were performed for 20 min each, followed by a recovery period. Exercise produced the expected increases in heart rate, blood pressure, ventilation, tidal volume, respiratory rate, oxygen consumption and carbon dioxide production. After severe exercise, naloxone infusion increased ventilation from 94.8 +/- 4.9 litres/min to 105.7 +/- 5.0 litres/min (P less than 0.05), but had no effect on any of the other physiological variables. Exercise-induced changes in several hormones and metabolites were noted, including elevations in circulating lactate, growth hormone (GH), prolactin, cortisol, luteinizing hormone (LH), follicle stimulating hormone (FSH), adrenaline noradrenaline, plasma renin activity (PRA) and aldosterone. There was no change in plasma met-enkephalin. Naloxone infusion produced the expected increases in LH and cortisol, but also significantly enhanced the elevations in prolactin, adrenaline, noradrenaline, plasma renin activity and aldosterone (P less than 0.05). Psychological questionnaires revealed minor mood changes after exercise, but no evidence was found for the suggested 'high' or euphoria of exercise. Effort was perceived as greater during the naloxone infusion than the saline infusion in every subject.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of adrenaline infusion on fatty acid and glucose turnover in lean and obese human subjects in the post-absorptive and fed states.

1. Energy expenditure, plasma glucose and palmitate kinetics and leg glycerol release were determined simultaneously both before and during adrenaline infusion in lean and obese human subjects. Seven lean subjects (mean 96.5% of ideal body weight) were studied in the post-absorptive state and also during mixed nutrient liquid feeding, eight obese subjects (mean 165% of ideal body weight) were studied in the post-absorptive state and six obese subjects (mean 174% of ideal body weight) were studied during feeding. 2. Resting energy expenditure was higher in the obese subjects, but the thermic response to adrenaline, both in absolute and percentage terms, was similar in lean and obese subjects. Plasma adrenaline concentrations attained (3 nmol/l) were comparable in all groups and the infusion had no differential effects on the plasma insulin concentration. Before adrenaline infusion the plasma glucose flux was higher in the obese than in the lean subjects in the fed state only (45.8 +/- 3.8 versus 36.6 +/- 1.0 mmol/h, P less than 0.05); it increased to the same extent in both groups with the adrenaline infusion. 3. Before the adrenaline infusion plasma palmitate flux was higher in the obese than in the lean subjects (by 51%, P less than 0.01, in the post-absorptive state and by 78%, P less than 0.05, in the fed state). However, there was no significant change during adrenaline infusion in the obese subjects (from 13.5 +/- 1.00 to 15.0 +/- 1.84 mmol/h, not significant, in the post-absorptive state and from 14.4 +/- 2.13 to 15.7 +/- 1.74 mmol/h, not significant, in the fed state), whereas there were increases in the lean subjects (from 8.93 +/- 1.10 to 11.2 +/- 1.19 mmol/h, P less than 0.05, in the post-absorptive state, and from 8.06 +/- 1.19 to 9.86 +/- 0.93 mmol/h, P less than 0.05, in the fed state). 4. Before adrenaline infusion the palmitate oxidation rate was also higher in the obese than in the lean subjects (1.86 +/- 0.14 versus 1.22 +/- 0.09 mmol/h, P less than 0.01, in the post-absorptive state and 1.73 +/- 0.25 versus 1.12 +/- 0.12 mmol/h, P less than 0.05, in the fed state). However, in response to adrenaline the fractional oxidation rate (% of flux) increased less in the obese than in the lean subjects, especially in the post-absorptive state (from 13.8 +/- 1.02 to 14.9 +/- 1.39%, not significant, versus from 13.7 +/- 0.98 to 19.3 +/- 1.92%, P less than 0.05). These effects were independent of feeding.(ABSTRACT TRUNCATED AT 400 WORDS)     

Exercise and posture-related changes of atrial natriuretic factor and cardiac function in diabetes

To study whether the release of atrial natriuretic factor (ANF) was altered in diabetic cardiac autonomic neuropathy (CAN), we determined plasma ANF concentrations during exercise and changes of posture in three groups of age- and sex-matched subjects (9 healthy subjects, 7 diabetic patients with CAN, and 7 diabetic patients without CAN). During exercise, plasma ANF concentrations rose threefold (P less than .001), and this increase was similar in the three groups. However, heart-rate response to exercise was impaired in the two groups of diabetic patients (P less than .004 vs. healthy subjects) but was more severely impaired in patients with CAN (P less than .03 vs. patients without CAN). In healthy subjects and patients without CAN, the increases of ANF during exercise correlated significantly with those of heart rate, systolic blood pressure, and rate-pressure product (P less than .01). In patients with CAN, the correlation was found exclusively with heart rate (P less than .01). An increase of ventricular ejection fraction occurred in all groups (P less than .001) but without showing statistical differences between groups. After 30 min of standing, a similar postural drop of plasma ANF concentrations (P less than .002) was observed in all subjects, reflecting preserved sympathetic control of vessels. In conclusion, exercise induces an increase of plasma ANF in diabetic patients with CAN. This increase, occurring similarly to healthy subjects, indicates that autonomic activation plays a minor role in ANF release during exercise. Impaired heart-rate response to exercise in patients without CAN suggests early damage of autonomic function, undetected by conventional rest tests.     

Effect of aminophylline on plasma and urinary catecholamine levels during heavy leg exercise in healthy young men

1. Methylxanthines have been shown to elevate the basal plasma level and/or urinary excretion of noradrenaline (NA) and adrenaline (ADR) in healthy subjects. The present study addressed the hypothesis that the methylxanthine aminophylline also augments plasma and urinary catecholamines during increased sympathoadrenal activity. 2. Eleven healthy young men performed a maximal 2 h bicycle exercise twice, after double-blind intravenous administration of placebo or aminophylline. Femoral venous plasma and urinary concentrations of NA and ADR were analysed in samples representing basal state, exercise and recovery, using liquid chromatography with electrochemical detection. 3. Leg exercise induced eight- and six-fold increases in the plasma concentrations of NA and ADR, respectively, and seven- and four-fold increases in the urinary concentrations of NA and ADR, respectively, indicating that sympathoadrenal activity was considerably elevated. 4. After aminophylline (mean plasma concentration 20-35 mumol/l), the plasma concentrations of NA (P less than 0.001) and ADR (P less than 0.05) were independently higher at rest, during exercise and during recovery, in comparison to after placebo; the mean exercise plasma level of NA was increased by the drug from 13 +/- 1 to 21 +/- 2 nmol/l and the corresponding level of ADR from 2.1 +/- 0.4 to 2.9 +/- 0.5 nmol/l. Also urinary NA (P less than 0.01) and ADR (P less than 0.05) were elevated by aminophylline; the exercise concentrations of NA in the urine were 75 +/- 8 and 97 +/- 10 mumol/mol of creatinine after placebo and aminophylline, respectively, and the corresponding levels of ADR were 12 +/- 3 and 16 +/- 3 mumol/mol of creatinine, respectively.     

Turnover and splanchnic metabolism of free fatty acids and ketones in insulin-dependent diabetics at rest and in response to exercise

Nine insulin-dependent diabetics and six healthy controls were studied at rest, during, and after 60 min of bicycle exercise at a work load corresponding to 45% of their maximal oxygen intake. The catheter technique was employed to determine splanchnic and leg exchange of metabolites. FFA turnover and regional exchange was evaluated using [14C]oleate infusion. Basal glucose (13.8 +/- 1.1 mmol/l), ketone body (1.12 +/- 0.12 mmol/l), and FFA (967 +/- 110 mumol/l) concentrations were elevated in the diabetics in comparison with controls. In the resting state, splanchnic ketone acid production in the diabetics was 6-10-fold greater than in controls. Uptake of oleic acid by the splanchnic bed was increased 2-3-fold, and the proportion of splanchnic FFA uptake converted to ketones (61%) was threefold greater than in controls. In contrast, splanchnic fractional extraction of oleic acid was identical in diabetics and controls. A direct relationship was observed between splanchnic uptake and splanchnic inflow (plasma concentration X hepatic plasma flow) of oleic acid that could be described by the same regression line in the diabetic and control groups. During exercise, splanchnic ketone production rose in both groups. In the control group the increase in ketogenesis was associated with a rise in splanchnic inflow and in uptake of oleic acid, a rise in splanchnic fractional extraction of oleate, and an increase in the proportion of splanchnic FFA uptake converted to ketone acids from 20-40%. In the diabetic group, the increase in ketogenesis occurred in the absence of a rise in splanchnic inflow or uptake of oleic acid, but was associated with an increase in splanchnic fractional extraction of oleic acid and a marked increase in hepatic conversion of FFA to ketones, so that the entire uptake of FFA was accountable as ketone acid output. Splanchnic uptake of oleic acid correlated directly with splanchnic oleic acid inflow in both groups, but the slope of the regression line was steeper than in the resting state. Plasma glucagon levels were higher in the diabetic group at rest and during exercise, while plasma norepinephrine showed a twofold greater increment in response to exercise in the diabetic group (to 1,400-1,500 pg/ml). A net uptake of ketone acids by the leg was observed during exercise but could account for less than 5% of leg oxidative metabolism in the diabetics and less than 1% in controls. Despite the increase in ketogenesis during exercise, a rise in arterial ketone acid levels was not observed in the diabetics until postexercise recovery, during which sustained increments to values of 1.8-1.9 mmol/l and sustained increases in splanchnic ketone production were observed at 30-60 min. The largest increment in blood ketone acids and in splanchnic ketone production above values observed in controls thus occurred in the diabetics after 60 min of recovery from exercise. We concluded that: (a) In the resting state, increased ketogenesis in the diabetic is a consequence of augmented splanchnic inflow of FFA and increased intrahepatic conversion of FFA to ketones, but does not depend on augmented fractional extraction of circulating FFA by the splanchnic bed. (b) Exercise-induced increases in ketogenesis in normal subjects are due to augmented splanchnic inflow and fractional extraction of FFA as well as increased intrahepatic conversion of FFA to ketones. (c) When exercise and diabetes are combined, ketogenesis increases further despite the absence of a rise in splanchnic inflow of FFA. An increase in splanchnic fractional extraction of FFA and a marked increase intrahepatic conversion of FFA to ketones accounts for the exaggerated ketogenic response to exercise in the diabetic. (d) Elevated levels of plasma glucagon and/or norepinephrine may account for the increased hepatic ketogenic response to exercise in the diabetic. (e) Ketone utilization by muscle increases during exercise but constitutes a quantitatively minor oxidative fuel for muscle even in the diabetic. (f) The accelerated ketogenesis during exercise in the diabetic continues unabated during the recovery period, resulting in an exaggerated postexercise ketosis.     

Threshold for adrenomedullary activation and increased cardiac work during mild core hypothermia.

Postoperative hypothermia increases the incidence of ischaemic cardiac events in patients at risk, but the underlying mechanism is unclear. One possibility is increased cardiac work related to the sympathoneural or adrenomedullary hormonal responses. In awake human volunteers, the present study assessed the effects of mild core hypothermia on these responses, and on the associated changes in indices of cardiac work. A total of 11 healthy men were studied on two separate days. On one day, core temperature (T(c)) was decreased by the intravenous infusion of cold normal saline (4 degrees C; 60 ml/kg over 30 min) through a central venous catheter. On the other day (normothermic control), warm normal saline (37 degrees C; 60 ml/kg over 30 min) was given intravenously. Transthoracic echocardiograms, the sympathoneural response (noradrenaline) and the adrenomedullary response (adrenaline) were evaluated before, during and after the intravenous infusions. Echocardiography was used to measure left ventricular function and cardiac output. Compared with the normothermic control treatment, core cooling of 0.7 degrees C was associated with increased plasma noradrenaline (220% increase; P=0.001), whereas adrenaline, cardiac output, heart rate and the rate-pressure product were unchanged. After core cooling of 1.0 degrees C, increases in noradrenaline (by 230%; P=0.001), adrenaline (by 68%; P=0.05), cardiac output (by 23%; P=0.04), heart rate (by 16%; P=0.04) and rate-pressure product (by 25%; P=0.007) were all significant compared with the normothermic control treatment. In conclusion, there is a T(c) threshold, below which an adrenomedullary (adrenaline) response is triggered in addition to the sympathoneural (noradrenaline) response. This T(c) threshold (approximately 1 degrees C below the normothermic baseline) is also associated with an increase in haemodynamic indices of cardiac work. Mild core hypothermia therefore constitutes a catecholamine-mediated cardiovascular "stress test".     

Endobronchial adrenaline: should it be reconsidered? Dose response and haemodynamic effect in dogs

BACKGROUND: Tracheal drug administration is a route for drug delivery during cardiopulmonary resuscitation when intravenous access is not immediately available. However, tracheal adrenaline (epinephrine) injection has been recently shown to be associated with detrimental decrease in blood pressure. This was attributed to exaggerated early beta2 mediated effects unopposed by alpha-adrenergic vasoconstriction. We hypothesized that endobronchial adrenaline administration is associated with better drug absorption, which may abolish the deleterious drop of blood pressure associated with tracheal drug administration. OBJECTIVE: To determine haemodynamic variables after endobronchial adrenaline administration in a non-arrest canine model. DESIGN: Prospective, randomized, laboratory study. METHODS: Adrenaline (0.02, 0.05, 0.1 mg/kg) diluted with normal saline was injected into the bronchial tree of five anaesthetized dogs. Injection of 10-ml saline served as control. Heart rate, blood pressure and arterial blood gases were monitored for 60 min after drug instillation. The protocol was repeated after 1 week. RESULTS: Adrenaline at a dose of 0.02 mg/kg produced only a minor initial decrease in diastolic (from 90 +/- 5 to 78 +/- 3 mmHg, P=0.05), and mean blood pressure (from 107 +/- 4 to 100 +/- 3 mmHg, P=0.05), in all dogs. This effect lasted less then 30 s following the drug administration. In contrast, higher adrenaline doses (0.05 and 0.1 mg/kg) produced an immediate increase in diastolic (from 90 +/- 5 to 120 +/- 7 mmHg; and from 90 +/- 5 to 170 +/- 6 mmHg, respectively), and mean blood pressure (from 107 +/- 4 to 155 +/- 10 mmHg; and from 107 +/- 4 to 219 +/- 6 mmHg, respectively). All adrenaline doses resulted in an immediate increase in systolic blood pressure and pulse. Endobronchial administration of saline (control) affected none of the haemodynamic variables. CONCLUSIONS: In a non-arrest model, endobronchial adrenaline administration, as opposed to the effect of tracheal adrenaline, produced only a minor decrease in diastolic and mean blood pressure. We suggest that endobronchial adrenaline administration should be investigated further in a CPR low-flow model when maintaining adequate diastolic pressure may be crucial for survival.     

Effect of low dose adrenaline and noradrenaline infusions on airway calibre in asthmatic patients

Airway, cardiovascular and metabolic responses were measured in six asthmatic patients with stable asthma during separate adrenaline, noradrenaline and control infusions. Four incremental infusion rates (4, 10, 25 and 62.5 ng min-1 kg-1) produced circulating catecholamine concentrations within the physiological range. Specific airways conductance and maximal expiratory flow rates measured from complete and partial flow-volume curves increased significantly (P less than 0.05) during adrenaline infusion, in a dose-response manner. No changes in specific airways conductance or maximal expiratory flow rates were seen during the noradrenaline or control infusion. The highest adrenaline infusion rate caused a rise in systolic blood pressure (P less than 0.05) and plasma glucose (P less than 0.05) and a fall in plasma potassium (P less than 0.05). Noradrenaline infusion caused a slight increase in diastolic blood pressure (P less than 0.05) but no metabolic changes. No cardiovascular or metabolic changes occurred during the control infusion. Infused adrenaline, producing circulating concentrations within the physiological range, caused dose-related bronchodilatation in asthmatic patients. Circulating noradrenaline does not appear to have a role in the control of basal airway tone in asthmatic patients.     

Haemodynamics of orally-active converting enzyme inhibitor (SQ 14225) in hypertensive patients.

1. The haemodynamic effects of oral converting enzyme inhibitor (SQ 14225) were assessed in eight patients with severe essential or renovascular hypertension. 2. Mean arterial pressure fell (149 +/- 5 to 127 +/- 8 mmHg, P less than 0.02), because of a fall in total peripheral resistance (6.9 +/- 0.53 to 5.7 +/- 0.40 kPa 1(-1)s m2) without a significant change in cardiac index. Two of the eight patients were non-responders without pressure reduction or a haemodynamic change. Sodium restriction (10 mmol/day) while the same dose of SQ 14225 was continued further lowered arterial pressure (137 +/- 8 to 111 +/- 12 mmHg, P less than 0.05) through further resistance reduction (6.5 +/- 0.53 to 5.2 +/- 0.40 kPa 1(-1)s m2, P less than 0.05). 3. Haemodynamic responses to head-up tilt (increased heart rate and resistance, decreased cardiac index) were unaffected by SQ 14225 regardless of sodium intake. 4. The pattern of reduction in peripheral resistance, with unchanged cardiac index, was similar to that produced by vasodilators acting at both arteriolar and venular levels.     

Hemodynamics in diabetic orthostatic hypotension.

Hemodynamic variables (blood pressure, cardiac output, heart rate, plasma volume, splanchnic blood flow, and peripheral subcutaneous blood flow) and plasma concentrations of norepinephrine, epinephrine, and renin were measured in the supine position and after 30 min of quiet standing. This was done in normal subjects (n = 7) and in juvenile-onset diabetic patients without neuropathy (n = 8), with slight neuropathy (decreased beat-to-beat variation in heart rate during hyperventilation) (n = 8), and with severe neuropathy including orthostatic hypotension (n = 7). Blood pressure decreased precipitously in the standing position in the diabetics with orthostatic hypotension, whereas moderate decreases were found in the other three groups. Upon standing, heart rate rose and cardiac output and plasma volume decreased similarly in the four groups. The increases in total peripheral resistance, splanchnic vascular resistance and subcutaneous vascular resistance were all significantly lower (P less than 0.025) in the patients with orthostatic hypotension compared with the other three groups. The increase in plasma norepinephrine concentrations in the patients with orthostatic hypotension was significantly lower (P less than 0.025) than in the patients without neuropathy, whereas plasma renin responses to standing were similar in the four groups. We conclude that in diabetic hypoadrenergic orthostatic hypotension the basic pathophysiological defect is lack of ability to increase vascular resistance, probably due to impaired sympathetic activity in the autonomic nerves innervating resistance vessels; cardiac output and plasma volume responses to standing are similar to those found in normal subjects and in diabetics without neuropathy.     

Effect of insulin-glucose infusions on plasma glucagon levels in fasting diabetics and nondiabetics.

The effect of the intravenous infusion of insulin plus glucose on plasma glucagon levels was studied in hyperglycemic fasting adult-type and juvenile-type diabetics and compared with fasting nondiabetics. Adult-type diabetics were given insulin for 2 h at a rate of 0.03 U/kg-min, raising their mean insulin to between 25 and 36 muU/ml; glucagon declined from a base-line value of 71+/-2 (SEM) to 56+/-1 pg/ml at 120 min (P less than 0.001). In juvenile-type diabetics given the same insulin-glucose infusion, glucagon declined from a base-line level of 74+/-8 to 55+/-5 pg/ml at 120 min (P less than 0.05). The absolute glucagon values in the diabetic groups did not differ significantly at any point from the mean glucagon levels in nondiabetics given insulin at the same rate plus enough glucose to maintain normoglycemia. When glucagon was expressed as percent of baseline, however, the normoglycemic nondiabetics exhibited significantly lower values than adult-type diabetics at 90 and 120 min and juvenile-type diabetics at 60 min. In nondiabetics given insulin plus glucose at a rate that caused hyperglycemia averaging between 134 and 160 mg/dl, glucagon fell to 41+/-7 pg/ml at 120 min, significantly below the adult diabetics at 90 and 120 min (P less than 0.01 and less than 0.05) and the juvenile group at 60 min (P less than 0.01). The mean minimal level of 39+/-2 pg/ml was significantly below the adult (P less than 0.001) and juvenile groups (P less than 0.05). When insulin was infused in the diabetic groups at a rate of 0.4 U/kg-min together with glucose, raising mean plasma insulin to between 300 and 600 muU/ml, differences from the hyperglycemic nondiabetics were no longer statistically significant. It is concluded that, contrary to the previously reported lack of insulin effect in diabetics during carbohydrate meals, intravenous administration for 2 h of physiologic amounts of insulin plus glucose is accompanied in unfed diabetics by a substantial decline in plasma glucagon. These levels are significantly above hyperglycemic nondiabetics at certain points but differ from normoglycemic nondiabetics only when expressed as percent of the baseline. At a supraphysiologic rate of insulin infusion in diabetics, these differences disappear.