N. J. Christensen

Plasma Norepinephrine and Epinephrine in Untreated Diabetics, During Fasting and After Insulin Administration

Employing a precise and sensitive double-isotope derivative technic, plasma norepinephrine and epinephrine were measured in twenty-three normal subjects and fourteen diabetics during various metabolic conditions. Patients with poorly controlled diabetes showed a rise in norepinephrine, which correlated with the degree of metabolic derangement, during resting conditions. High epinephrine values were seen only in patients with moderate to severe ketoacidosis. During exercise, diabetic patients with ketosis demonstrated large increments in plasma catecholamines as compared to normals. During insulin treatment, when good control had been achieved, plasma catecholaniine levels were similar to those in normal subjects. During prolonged fasting, plasma norepinephrine rose from 0.18 to 0.40 ng. per milliliter in four normal nonobese subjects. No change was observed in plasma epinephrine. During insulin hypoglycemia, high plasma epinephrine levels were seen only in subjects in whom the blood glucose concentration declined to values below 20 mg. per 100 ml. Plasma norepinephrine rose as blood glucose concentrations decreased even in diabetics in whom values had not reached hypoglycemic levels. No correlation was observed between plasma epinephrine and increase in pulse rate during hypoglycemia.

Central role for sodium in the pathogenesis of blood pressure changes independent of angiotensin, aldosterone and catecholamines in type 1 (insulin-dependent) diabetes mellitus.

SummaryWe studied 73 Type 1 (insulin-dependent) diabetic patients, 18 to 50 years of age, with a diabetes duration of more than five years. Group 1: normal urinary albumin excretion below 30 mg per 24 h (n=19); group 2: microalbuminuria, 30–300 mg per 24 h (n=36); and group 3: diabetic nephropathy, above 300 mg per 24 h (n=18). Fifteen non-diabetic persons matched for sex and age served as control subjects. The sodium intake evaluated on the basis of 24-h urine sodium excretion was similar in patients and control subjects. Blood pressure in groups 1 and 2 and control subjects was below 160/95 mmHg. The blood pressure was increased in group 3 as compared with the other groups (systolic/diastolic 161±22/101±9 mmHg vs 131±13/84±10, mean±SD, p<0.0001). Exchangeable sodium was increased in patients (p<0.01) and correlated to the mean blood pressure (n=70, r=0.41, p<0.01). Extracellular volume was increased in patients (p<0.05), whereas plasma volume was normal. Supine serum angiotensin II was suppressed in the patients (p<0.001). A negative correlation was found between mean blood pressure and supine serum aldosterone (n=68, r=-0.24, p<0.05), and exchangeable sodium and aldosterone (n=66, r=-0.36, p<0.002) in all patients. The catecholamine levels were also suppressed or normal in the patients. These data suggest that sodium retention plays a major role and that the aldosterone, angiotensin II and catecholamine levels are suppressed during the blood pressure rise observed in the very early stages of diabetic renal disease.

Acute and adaptive responses in humans to exercise in a warm, humid environment

Abstract Acute and repeated exposure for 8–13 consecutive days to exercise in humid heat was studied. Twelve fit subjects exercised at 150 W [45% of maximum O2 uptake (V.O2,max)] in ambient conditions of 35°C and 87% relative humidity which resulted in exhaustion after 45 min. Average core temperature reached 39.9 ± 0.1°C, mean skin temperature (T–sk) was 37.9 ± 0.1°C and heart rate (HR) 152 ± 6 beats min–1 at this stage. No effect of the increasing core temperature was seen on cardiac output and leg blood flow (LBF) during acute heat stress. LBF was 5.2 ± 0.3 l min–1 at 10 min and 5.3 ± 0.4 l min–1 at exhaustion (n = 6). After acclimation the subjects reached exhaustion after 52 min with a core temperature of 39.9 ± 0.1°C, T–sk 37.7 ± 0.2°C, HR 146 ± 4 beats min–1. Acclimation induced physiological adaptations, as shown by an increased resting plasma volume (3918 ± 168 to 4256 ± 270 ml), the lower exercise heart rate at exhaustion, a 26% increase in sweating rate, lower sweat sodium concentration and a 6% reduction in exercise V.O2. Neither in acute exposure nor after acclimation did the rise of core temperature to near 40°C affect metabolism and substrate utilization. The physiological adaptations were similar to those induced by dry heat acclimation. However, in humid heat the effect of acclimation on performance was small due to physical limitations for evaporative heat loss.

Natural killer cell activity during cortisol and adrenaline infusion in healthy volunteers.

Abstract. The effects of cortisol and adrenaline on natural killer (NK) cell activity and the distribution of circulating lymphocyte subpopulations were studied in twenty volunteers, using a continuous intravenous infusion pattern to simulate some of the hormonal changes induced by major surgery. The participants were allocated to receive either cortisol for 5 h, adrenaline for 1 h, cortisol for 5 h with simultaneous adrenaline during the last hour, or placebo for 5 h. Cortisol induced leucocytosis, neutrophilia, and lymphopenia with marked reduction in the number of T‐lymphocyte subsets (OKT3+, OKT4+, and OKT8+ cells). No changes were induced in the activity or number of NK (Leu 11+) cells. Adrenaline produced an instantaneous increase in NK‐cell activity accompanied by a selective increase in circulating NK cells. Significant leucocytosis, lymphocytosis and neutrophilia occurred. All measurements returned to preinfusion levels within 15 min after completing infusion. The effects of simultaneous infusion of cortisol and adrenaline were equal to the additive response to the hormones administered separately, except for the leucocytosis, which clearly exceeded this. In the placebo group all measurements remained unchanged. The results confirm the role of adrenaline as a potent stimulator/inducer of NK‐cell activity. Adrenaline may be responsible for the increase in NK‐cell activity during anaesthesia and major surgery.

Natural Killer Cell Activity and Lymphocyte Function During and After Coronary Artery Bypass Grafting in Relation to the Endocrine Stress Response

The effects of elective coronary artery bypass grafting (CABG) and the associated endocrine stress response on natural killer (NK) cell activity in peripheral blood, the distribution of lymphocyte sub-populations, and the phytohemagglutinin (PHA)-induced lymphocyte transformation were studied in 20 patients anesthetized with cither etomidate-high dose fentanyl (75–125 μg · kg-1) or midazo-lam-low dose fentanyl (<20 μ · kg-1). The endocrine response to surgery was measured as changes in scrum cortisol, plasma epinephrine, and norepinephrine. Compared with control values, a significant increase of NK cell activity was found in both groups prior to induction of anesthesia, followed by a decrease after induction until initiation of cardiopulmonary bypass (CPB) and a gradual increase to levels exceeding controls during CPB. Postoperatively, NK cell activity and the lymphocyte transformation to PHA stimulation were significantly depressed for at least 1–3 days. These changes were accompanied by severe lymphopenia affecting the T-lymphocytes (T3, T4, and T8) and the NK cells (Leu 11). Apart from a delayed cortisol increase in the etomidate group, the endocrine response showed a similar pattern in the two groups. Compared with control values, a significant decrease in the serum cortisol until CPB could be demonstrated, followed by a significant increase persisting for at least 6 days postoperatively. The plasma catecholamines showed a steep rise and, consequently, a significant increase during CPB, followed by a gradual return to control values in the postoperative period. The results indicate that, in patients undergoing CABG, immune surveillance is impaired prior to CPB and during the early postoperative period. The mechanisms underlying the fluctuations in NK cell activity and lymphocyte function arc complex, but the results suggest that the endocrine stress response may be of major importance.

The Relationship between Plasma Catecholamine Concentration and Pulse Rate during Exercise and Standing

Abstract. Plasma catecholamine concentrations (PCA) were measured during standing and exercise using a precise and sensitive double‐isotope derivative technique. By plotting the increase in PCA in the standing position on the y‐axis of a coordinate system against the increase in pulse rate, PCA was resolved into two components: one corresponding to the intercept of the y‐axis where rise in pulse rate equals zero (CAP) while the other (CAH) was calculated by multiplying the slope of the regression line by the mean increase in pulse rate.–The rise in PCA, mainly noradrenaline, was considerably less during light to moderate exercise than during standing. Thus there was no rise in PCA during exercise until the increase in pulse rate exceeded approximately 30 beats/min and there was no rise in the CAP component during exercise. When PCA began to rise during exercise the increase in PCA per increment in pulse rate was similar to that observed in the standing experiments. There was no difference between the increments in PCA observed during exercise in the supine and the sitting positions but resting PCA was doubled in the sitting position.–It is suggested that 1. the initial rise in pulse rate during exercise is due to withdrawal of parasympathetic activity on the heart 2. the increase adrenergic in vasoconstrictor activity is considerably less during moderate exercise than during standing 3. the increase in plasma noradrenaline during moderate exercise is of cardiac origin.

Intravenous Insulin Causing Loss of Intravascular Water and Albumin and Increased Adrenergic Nervous Activity in Diabetics

Blood pressure, heart rate, plasma norepinephrine, forearm blood flow, plasma volume, plasma albumin, blood glucose, and plasma epinephrine were measured in six diabetic patients without neuropathy in the supine position and during feet-down tilting for seven minutes. The experiments were repeated after intravenous (i.v.) injection of 6 to 8 U. of insulin. The mean blood glucose concentration averaged 205 ± 14 (S. E. M.) mg./100 ml. in the control experiment and had decreased by 97 ± 17 mg./100 ml. 45 minutes after the injection of insulin. None of the patients had hypoglycemia, and plasma epinephrine did not increase. There was no change in arterial blood pressure after insulin was given either in the supine position or after tilting. The heart rate averaged 64 ± 5 beats per minute in the control experiment and had increased by 7 ± 2 beats per minute 40 minutes after the injection of insulin (2p = 0.035). The rise in heart rate In response to tilting was statistically significantly greater after administration of insulin (2p = 0.0064). Plasma norepinephrine averaged 0.17 ± 0.03 ng./ml. in the control experiment and had increased by 70 ± 24 per cent 45 minutes after the i.v. injection of insulin (2p = 0.045). The rise in plasma norepinephrine in response to tilting was statistically significantly greater after the injection of insulin (2p = 0.017). Forearm blood flow decreased from 2.13 ± 0.29 ml./l00 ml. per minute in the control experiment to 1.63 ± 0.32 ml./100 ml. per minute 40 minutes after the injection of insulin (2p = 0.011). Plasma volume averaged 3,061 ± 67 ml. before injection of insulin and had decreased by 265 ± 59 ml. 45 minutes after insulin was given (2p = 0.011). The intravascular mass of albumin averaged 118 ± 3 gm. and 109 ± 3 gm. before and 45 minutes after the administration of insulin, respectively (2p = 0.017). There was a dose correlation between the relative increase in plasma norepinephrine in the supine position and the relative decrease in plasma volume after the injection of insulin (r = −0.95, 2p = 0.013). It is concluded that i.v. injection of insulin results in an increased adrenergic nervous activity that is due to a decrease in plasma volume. The effect of insulin is accompanied by a significant reduction in the intravascular pool of albumin. These observations may explain the fact that patients with abnormal cardiovascular reflexes are unable to maintain arterial blood pressure, especially in the upright position, after the i. v. injection of insulin. The observed decrease in plasma volume after the administration of insulin was much larger than could be expected from the decrease in blood glucose concentration and the ensuing decrease in plasma osmolality. It is suggested that insulin either directly or secondarily to its metabolic effects may alter the function or the volume of the endothelial cells and thereby increase the transfer of fluid and albumin out of the vascular system.

Cardiovascular and adrenergic effects of cigarette smoking during immediate non-selective and selective beta adrenoceptor blockade in humans.

Abstract. The cardiovascular and adrenergic responses to cigarette smoking during acute selective and non‐selective beta adrenoceptor blockade were studied in seven young healthy volunteers in a double blind cross‐over fashion. Heart rate, arterial blood pressure, forearm blood flow and plasma levels of adrenaline and noradrenaline were determined before and during the terminal 5 min period of 15 min smoking test.

Catecholamines and Exercise

NOREPINEPHRINE Rise in plasma norepinephrine is correlated with an increase in heart rate, provided that the latter is mediated by the sympathetic nervous system. This is the case during exercise, with the exception of the initial rise in heart rate, which is due to withdrawal of vagal tone. Correspondingly, there is no rise in plasma norepinephrine during light work. The increase in heart rate that occurs when one stands up is mediated by sympathetic nerves, and plasma norepinephrine increases. Figure 1 shows the relationship between rise in heart rate and rise in plasma norepinephrine upon standing and during exercise. When one stands up, a part of the increase in plasma norepinephrine is independent of any change in heart rate, but there is a further rise in norepinephrine that is correlated to the rise in heart rate. During exercise there is no rise in plasma norepinephrine provided the increase in heart rate at steady state is less than approximately 25 beats/min. During an exercise requiring higher increases in heart rate, these increases are paralleled by increases in plasma norepinephrine. The greater rise in plasma norepinephrine when standing as compared with the rise in norepinephrine during exercise (with a comparable increase in heart rate) is explained, in part, by the different autonomic nervous mechanisms in-

Catecholamines and Diabetes Mellitus

The sympathetic nervous system is of major importance in the regulation of several physiological functions, such as cardiovascular and metabolic homeostasis. The last decade has seen an increasing interest in catecholamines as transmitters in the central nervous system and as regulators of endocrine secretion. There have been considerable advances in the understanding of the biochemistry of catecholamines [7, 56]. The potential role of catecholamines in a number of human diseases has however, until recent years been studied to a limited extent due to lack of methods for measurement of sympathetic nervous activity (SNA). Much work has been done to develop a radioimmunoassay for determining the enzyme dopamine-beta-hydroxylase in serum, which unfortunately has turned out to be a poor index of SNA [90]. The development of enzymatic isotope-derivative techniques [53, 54] enabled reliable measurements of plasma noradrenaline (NA) and adrenaline (A). Studies in man have shown that plasma NA is an index of SNA [34, 41]. The present survey deals mostly with the function of the sympathetic nervous system in various clinical situations occurring in diabetic patients, particularly