Sympathetic response to oral carbohydrate administration. Evidence from microelectrode nerve recordings.

Microneurography was used to measure sympathetic outflow in human muscle nerves (MSA) for up to 90 min after the ingestion of 100 g D-glucose, 75.8 g D-xylose, intravenous D-glucose (0.35 g/kg), and 300 ml water. 19 healthy subjects were examined using a microelectrode positioned in the right peroneal nerve. MSA increased from 21 +/- 0.9 bursts/min at rest to 36.9 +/- 4.3 bursts/min 30 min after ingestion of D-glucose and from 18.9 +/- 2.9 to 26.3 +/- 3.4 bursts/min 30 min after D-xylose. The increase in MSA was already significant by 15 min. MSA had not returned to the basal level after 90 min. Neither intravenous D-glucose nor water intake enhanced MSA. MSA increased in parallel with plasma norepinephrine, and a significant correlation (r = 0.55; P less than 0.001) was observed between the plasma insulin concentration and MSA after D-glucose ingestion. In three subjects the outflow of sympathetic nerve activity to the skin was examined after oral D-glucose and no change was observed, emphasizing the differentiated nature of the sympathetic nerve response to carbohydrate. Multiple factors such as insulin alone, hemodynamic adjustment to splanchnic vasodilation, and gastrointestinal distension are probably involved in the increased muscle nerve sympathetic outflow after carbohydrate ingestion.

Sympathetic outflow in human muscle nerves increases during hypoglycemia.

The normal response to insulin-induced hypoglycemia bears many characteristics of activation of the sympathetic nervous system. In this study, the impulse pattern of muscle nerve sympathetic activity (MSA) involved in cardiovascular homeostasis was identified by microneurography in the peroneal nerve of seven healthy and two adrenalectomized subjects. After recordings at rest and an intravenous injection of 0.15 IU insulin/kg body wt (0.10 IU insulin/kg body wt in adrenalectomized subjects), MSA was followed for 90 min. Nadir of hypoglycemia (2.0 +/- 0.1 mM) was reached at 30 min. All subjects, including the two adrenalectomized subjects, exhibited an increase of MSA, which peaked at the glucose nadir. The time course of MSA increase was a mirror image of the blood glucose curve. This directly measured increase of MSA may be part of the hemodynamic adjustment to the fall in plasma volume known to occur in hypoglycemia. Another possible cause is direct stimulation of central sympathetic motoneurons.

Brain energy metabolism and blood-brain barrier permeability in depressive patients: analyses of creatine, creatinine, urate, and albumin in CSF and blood.

A reliable method is described using high pressure liquid chromatography to measure creatine, creatinine, and urate in human cerebrospinal fluid (CSF) and blood; albumin was analyzed by routine methods. Creatine and creatinine serve as indices of one aspect of brain energy metabolism, the creatine-creatine phosphate (CrP) shuttle. CSF levels have been adjusted to a set blood level by analysis of covariance. The ratios between CSF and blood concentrations of urate and albumin are two sensitive indices of impaired blood-brain barrier (BBB) function. Analyses were performed on 41 male and 58 female inpatients with RDC major depressive disorders, with a mean age of about 40 years. The CSF creatinine and creatine levels were highly positively age-dependent; this factor as well as possible influences of body habits were removed by way of analysis of covariance from all measures in focus. We describe positive, highly significant correlations between creatinine and monoamine metabolites (HVA and 5HIAA) and purine metabolites (hypoxanthine and xanthine) in CSF, and a strong negative correlation between both BBB permeability measures and the noradrenalin CSF metabolite MHPG. CSF creatinine was negatively linked with suicidal ideation and increased appetite. The BBB tended to be the more permeable the less melancholic the depression. No measure appeared to be dependent on depressive state. Comparisons of depressive subgroups revealed a higher CSF creatinine concentration in sporadic unipolar patients according to Winokur. A particularly wide variance in the albumin ratio was found in pure unipolars. Pure unipolars with an impaired BBB had a more protracted onset, were more suicidal, had a higher erythrocyte sedimentation rate, and lower plasma cortisol levels than those without. Impaired BBB was further linked with a slower EEG rhythm and higher systolic blood pressure. Results suggest significant contributions of brain energy metabolism and deranged BBB permeability in accounting for some aspects of neuronal transmission and modulation as well as the symptomatology of depressive illness.

Depression and somatosensory evoked potentials: I. Correlations between SEP and monoamine and purine metabolites in CSF.

In 32 patients with major depressive disorders diagnosed according to Research Diagnostic Criteria (RDC), somatosensory evoked potentials elicited at four levels of tactile fingertip stimulation were recorded. Four peak-to-baseline amplitudes (P100, N140, P200, and P300) and two peak-to-trough amplitudes (P100-N140 and N140-P200) plus their amplitude/stimulus intensity slopes were selected for analysis. All 12 measures were adjusted to same sex, age, height, and weight. Values were linearly and curvilinearly correlated with adjusted levels of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5HIAA), 3-methoxy-4-hydroxyphenylglycol (MPHG), hypoxanthine, and xanthine in the cerebrospinal fluid (CSF), monoamine and purine metabolites, respectively. Significant negative linear correlations were found between the P300 amplitude and both HVA and hypoxanthine, and between the P200 slope and both 5HIAA and hypoxanthine. A significant positive correlation existed between the N140-P200 slope and 5HIAA. Curvilinear bivariate regressions demonstrated complex topologies of regression surfaces. Neither attention nor benzodiazepine medication were of significant importance in these relationships.

Continuous recording of muscle nerve sympathetic activity during percutaneous transluminal angioplasty in renovascular hypertension in man.

We have previously shown that during percutaneous transluminal renal angioplasty (PTRA) there is a transient increase in plasma renin activity (PRA) that is partly mediated by adrenergic beta-receptors. Despite a concomitant increase in plasma aldosterone, no increase in blood pressure occurred. The aim of this study was to record sympathetic outflow in man during PTRA as reflected by muscle nerve sympathetic activity and arterial plasma noradrenaline. Nine patients with hypertension and unilateral renal artery stenosis underwent PTRA by the Grüntzig technique and simultaneous microelectrode recording of muscle nerve sympathetic activity in the peroneal nerve. Blood pressure and heart rate were recorded and blood specimens were drawn for determination of noradrenaline and PRA. During total occlusion of the renal artery, muscle nerve sympathetic activity and the heart rate were unchanged. In the first 6 min after occlusion PRA increased transiently, but there was no significant change in muscle nerve sympathetic activity, arterial noradrenaline, heart rate or blood pressure. From 10 min after PTRA, muscle nerve sympathetic activity was significantly increased and after 40 min there was a significant increase in noradrenaline. The heart rate remained unchanged throughout the procedure, but the blood pressure decreased progressively and the diastolic blood pressure was significantly reduced at 40 min, indicating successful dilation. Despite activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system, two strong pressor systems, the only circulatory reaction was a decrease in diastolic blood pressure. These findings indicate simultaneous activation of a potent depressor mechanism during PTRA.

Cerebrospinal fluid calcium, parathyroid hormone, and monoamine and purine metabolites and the blood-brain barrier function in primary hyperparathyroidism.

Psychiatric disturbances are common in primary hyperparathyroidism (HPT), but their pathogenesis is essentially unknown. This study deals with cerebrospinal fluid (CSF) calcium homeostasis and its connection with parathyroid hormone (PTH), blood-brain barrier (BBB) function, and central monoamine and purine metabolites in patients with primary HPT. In 22 patients with primary HPT (serum calcium 2.85 +/- 0.21 mmol/l), the CSF concentrations of total and ionized calcium were higher (1.21 +/- 0.08 mmol/l, p less than 0.01, and 1.09 +/- 0.05 mmol/l, p less than 0.001, respectively) than in 11 normocalcemic reference subjects. The values correlated with serum calcium concentration (p less than 0.001) and CSF/serum albumin ratio, a measure of BBB permeability. The latter ratio was elevated in one-third of the patients with HPT, indicating BBB damage. CSF immunoreactive intact PTH was higher in the HPT patients than in the reference group (p less than 0.05), and serum and CSF PTH were positively correlated (p less than 0.05). The CSF levels of the monoamine metabolites 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) were lower, and the level of urate in CSF was higher, in the HPT patients than in the reference subjects, while there were no consistent differences in CSF hypoxanthine or xanthine. CSF 5HIAA correlated inversely with CSF ionized calcium (r = -0.42, p = 0.02). After parathyroid surgery, CSF calcium and urate decreased significantly and CSF monoamine metabolites increased slightly. The decrease in CSF ionized calcium correlated with the alleviation of psychiatric symptoms. The results indicate the importance of increased CSF calcium concentrations in patients with primary HPT and suggest a relation between central calcium regulation and central turnover of monoamines.

Splanchnic oxygen consumption in septic and hemorrhagic shock.

Oxygen consumption (VO2) is dependent on oxygen delivery (DO2) in septic shock. Local hypoxia with later secondary organ failure may develop, however, despite an often hyperdynamic circulation. The splanchnic organs seem to be of vital importance in this context. In experiments performed in pigs we compared total body VO2 and DO2 with oxygen consumption and delivery in the gastrointestinal organs and the liver in two different shock states: (1) septic shock induced by peritonitis (n = 6) and (2) hemorrhagic shock (n = 6). Another group of six animals not in shock served as controls. Total, gastrointestinal, and liver DO2 decreased in a similar pattern in both septic and hemorrhagic shock. Gastrointestinal and liver VO2 increased in sepsis, whereas it was unchanged in hemorrhage. In the later phase of sepsis, liver VO2, but not gastrointestinal VO2, again decreased, because liver oxygen extraction was almost total and liver DO2 decreased further. The development of flow-dependent liver hypoxia was reflected in a decrease in liver lactate turnover (increased liver lactate release) during late sepsis. Early hypoxia in the splanchnic region is suggested as a plausible mechanism behind the development of secondary organ failure, especially in sepsis.

A systematic study of nucleotide analysis of human erythrocytes using an anionic exchanger and HPLC.

A two-step procedure for rapid HPLC analysis of nucleotides from human erythrocytes is described. A strong anion exchanger Partisil-10 is used as column material. Elution of monophosphates requires about 12 min and the elution of di- and triphosphates 21 min. The elutions are performed separately and with different injections as such a procedure will save time otherwise used to re-condition the columns. In addition to the three adenylates other nucleotides such as GTP, GDP, IMP and NAD can be recorded as isolated, well-defined peaks, which can be subject to quantitative analysis. The mean value of ATP concentration for 12 healthy individuals was 1.55 +/- 0.05 mmol/l, about 25% higher than generally reported in the literature. Accurate estimates of ADP and AMP concentrations allowed calculation of mean values for the physiologically interesting ratios: adenylate energy charge (0.945 +/- 0.002) and equilibrium constant for adenylate kinase (1.205 +/- 0.053). GDP and GTP are present in concentrations that are about 4% of those for corresponding adenylates. The analysis of nucleotides in human erythrocytes is a useful way of studying erythrocyte preservation and investigating patients with hemolytic disorders.

Purine metabolism in normal and ITP-pyrophosphohydrolase-deficient human erythrocytes.

Fresh and stored erythrocytes from normal and ITP-pyrophosphohydrolase (ITP-ase, EC 3.6.1.19) deficient individuals were incubated with hypoxanthine, guanine, allopurinol, and inosine. Differences in the purine metabolism between the normal and the ITP-ase deficient erythrocytes were observed only in the IMP-ITP cycle. Hypoxanthine, guanine and allopurinol were converted to nucleotides at the same rate. Hypoxanthine (2.5 mumol/l) inhibited the salvage of allopurinol (40 mumol/l). A slow decrease (0.7%/day) in salvage rate was observed in both types of cells upon storage at +4 degrees C. Erythrocyte ITP-ase activity was measured in a reference sample group of 48 healthy volunteers. Two distinct groups were found with mean activities equal to 48.3 +/- 13.1 nkat/g Hb (means +/- SD, n = 38) and 11.4 +/- 4.3 nkat/g Hb (n = 10). In two previously selected subjects, the ITP-ase activity was 0.2 and 2.4 nkat/g Hb. A hypothetical genetic mechanism is discussed. The maximal energy turnover in the IMP-ITP cycle during hypoxanthine incubation was found to be less than 10% of the basal erythrocyte energy turnover.

Brain purinergic activity linked with depressive symptomatology: hypoxanthine and xanthine in CSF of patients with major depressive disorders.

The purine metabolites hypoxanthine and xanthine were analyzed in cerebrospinal fluid (CSF) of 70 patients with major depressive disorders (diagnosed according to Research Diagnostic Criteria) and, for reference, in 26 nonpsychiatric individuals. In the patient group, levels adjusted by analysis of covariance to same sex, age, height, and weight were univariately and multivariately correlated with both depressive subdiagnoses and individual depressive symptoms. Results indicate that raw CSF levels in depressed patients are significantly correlated with the four variables used in adjustment (for hypoxanthine mainly negatively with height; for xanthine mainly positively with age). Hypoxanthine and xanthine both appear to be linked with the expression of depressive symptomatology: lower levels of hypoxanthine are associated with anger and suicidal tendencies, and higher levels are related to memory disturbance; lower xanthine levels characterize patients with subjective feelings of depression, and in patients with higher levels appetite is poor.

Substance rates of different steps of purine metabolism in normal and preserved red blood cells (RBC) studied in experiments simulating in vivo conditions.

A dialysis incubation system simulating the conditions in the circulation can be used: To draw conclusions about the RBC in transporting purines between organs. To improve solutions for "rejuvenating" stored RBC. To design better systems for quality control of stored RBC.

Purine metabolites in the CSF in presenile and senile dementia of Alzheimer type, and in multi infarct dementia.

Concentrations of hypoxanthine, xanthine, uric acid and creatinine were measured in CSF of patients suffering form presenile and senile dementia of Alzheimer type (PDAT, SDAT) and multi infarct dementia (MID) and in a reference group of young neurotic patients. There was no difference in hypoxanthine concentration, but there was a marked elevation of xanthine concentration in each dementia group, independent of the type of dementia. There was a significant elevation of uric acid in SDAT and MID but not in PDAT. The concentration of uric acid was higher in MID than in SDAT. There was a higher level of creatinine in the dementia groups, but no difference was seen among the dementia groups. These results are discussed in order to better interpret the etiology and the differentiated diagnosis of the types of dementia.

Amino acid concentrations in cerebrospinal fluid in presenile and senile dementia of Alzheimer type and multi-infarct dementia.

Free amino acid levels were measured in cerebrospinal fluid (CSF) from demented patients (D, n = 30) suffering from presenile and senile dementia of Alzheimer type (PDAT, n = 7; SDAT, n = 9), multi-infarct dementia (MID, n = 14) and a reference sample group consisting of young neurotic patients (R, n = 16). Comparing the amino acid levels in the dementia subgroups, significantly higher alanine, methionine, phenylalanine and tyrosine levels were found both in MID and SDAT vs. PDAT. No difference was seen between SDAT and MID. Compared to the reference sample group, higher glycine levels were found in each dementia subgroup; higher alanine, methionine and ornithine levels in MID, and SDAT; and higher phenylalanine levels in MID. In PDAT the level of tyrosine was lower. Coefficients of correlation were calculated between amino acid levels and age, and the findings in the reference sample groups were divergent from those observed in dementia. The differences observed are discussed in terms of amino acid, carbohydrate and neurotransmitter metabolism.

Hypoxanthine, xanthine, urate and creatinine concentration gradients in cerebrospinal fluid.

The purine metabolites hypoxanthine, xanthine and urate as well as creatinine were measured in cerebrospinal fluid (CSF) from two groups of patients and a reference sample group. In one of the patient groups lumbar CSF was collected in 2 ml portions until a total volume of 14 ml was withdrawn. Every second portion was analysed for its content of the metabolites in focus. In the other patient group both cisternal CSF and a fixed volume (20 ml) of lumbar CSF were obtained and analysed. An increase in concentration of hypoxanthine, xanthine and creatinine and a decrease in urate concentration was found in the successive CSF specimens. The mean individual increase in hypoxanthine concentration between the first and the last 2 ml portion was as high as 39.6%, while it was lower for xanthine, 21.5%, and creatinine, 6.7%. The decrease in urate concentration was 17.2%. The results from the other patient group were in good agreement with these findings. The concentrations in the cisternal CSF was 162% of that in lumbar CSF for hypoxanthine, 155% for xanthine, 123% for creatinine and 80% for urate. Mechanisms behind inter- and intraindividual differences in gradients are discussed.

Changes in inspiratory activity after injection of adenosine and hypoxanthine in cats.

The effects of intra-arterial and intravenous injections of adenosine and hypoxanthine were investigated with special reference to respiratory variables in anesthetized young cats. Studies were made of the effects on inspiratory activity (phrenic nerve activity), heart rate, blood pressure and central venous pressure. To assess the risk of accumulation of adenosine degeneration products after several injections measurements were also made of hypoxanthine, xanthine and urate in plasma at intervals after the injections. It was found that intra-arterial and intravenous injections of adenosine increased central inspiratory activity during the first few breaths after the injection. The blood pressure and heart rate decreased slightly and central venous pressure increased slightly after the injection. Degradation of adenosine and its metabolites takes place rapidly and it is therefore unlikely that metabolites influence the results. It is concluded that adenosine causes brief stimulation of inspiratory activity.

Serological studies of an SLE-associated antigen-antibody system discovered as a precipitation reaction in agarose gel: the HAKATA antigen-antibody system.

Current population studies indicate that the HAKATA antigen is one of the normal plasma proteins not yet completely characterized. The frequency of Japanese donor, patients and Swedish patients was 100%, 99.99% and 99.98%, respectively. Anti-HAKATA antibody production was found in three patients, all with systemic lupus erythematosus (SLE). Transient HAKATA antigen deficiency was found in 13 patients and appeared to be strongly associated with SLE (11 out of 13). None of the 14 SLE patients had a history of transfusion. It is therefore concluded that anti-HAKATA antibody is produced as one of the autoantibodies in SLE.