Strong immunoreactivity of α1 co-localizes with β-amyloid protein and ubiquitin in vacuolated muscle fibers of inclusion-body myositis

Summary In 10 of 10 inclusion-body myositis (IBM) patients, including 1 hereditary case, vacuolated muscle fibers contained large or small cytoplasmic inclusions immunoreactive for (₁-ACT). All IBM muscle biopsies had characteristic cytoplasmic tubulo-filaments by electron microscopy. None of 17 control muscle biopsies contained the (₁-ACT) immunoreactive inclusions characteristic of IBM. In vacuolated muscle fibers, (₁-ACT) immunoreactive inclusions colocalized with -amyloid protein and ubiquitin immunoreactivities. Our study provides the first demonstration of (₁-ACT) accumulations in abnormal human muscle, and it suggest that, as in Alzheimer's disease and Down's syndrome, (₁-ACT) may be involved in the pathogenesis of IBM.Supported in part by the Norma Bard Research Fund. M.B. is a Research Postdoctoral Fellow     

αB-crystallin in oxidative muscle fibers and its accumulation in ragged-red fibers: a comparative immunohistochemical and histochemical study in human skeletal muscle

Summary The B-crystallin gene is abundantly experssed in the vertebrate lens and at lower levels in various non-lenticular tissues. Among the non-lenticular tissues, B-crystallin is present at high levels in the heart and skeletal muscle. Using a specific antibody against B-crystallin, the cellular localization of B-crystallin was studied in biopsies of human skeletal muscles. Expression of B-crystallin was observed in normal oxidative muscle fibers that show positive reactions for NADH-tetrazolium reductase and cytochrome c oxidase. In muscle diseases increased immunoreactivity for B-crystallin was found in ragged-red fibers, which stained darkly with histochemistry for succinate dehydrogenase. Since B-crystallin is related to small heat-shock proteins and can be induced by various stress conditions, the increased B-crystallin immunoreactivity of ragged-red fibers could result from profound oxidative stress produced by the abnormal mitochondrial metabolism.Supported by NIH grants NS 17125 and EYO9331 (J.E.G.)     

Comparison of integrin adhesion molecules expressed by primary brain lymphomas and nodal lymphomas

The expression of 17 adhesion molecules was immunohistochemically examined in 5 primary cerebral lymphomas (PCL) and in 5 histologically similar nodal lymphomas (NL) to evaluate their possible involvement in selective targeting of lymphoma cells to the brain. PCL and NL tumor cells showed very similar expression patterns: they were consistently positive for ₃, ₄ and ₁ integrin chains; negative for ₂, ₆, ₃ and ₄ integrin chains; and heterogeneous for ₅, _L, _M, _X, ₂ and ₇ integrin chains, as well as for intercellular adhesion molecule-1 (ICAM-1) and the selectin LECAM-1. Loosely infiltrating PCL showed lower levels of the _L2 integrin than compact cell clusters. Vessels stained for ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1). We conclude that the adhesion molecules implicated in the extravasation of non-neoplastic leukocytes (₄₁/VCAM-1 and _L2/ICAM-1) are also expressed by both PCL and NL. The adhesion molecules examined are apparently not selective mediators of lymphoma cell homing to the brain, but at least _L2 integrin might be related to the infiltration pattern of PCL within the brain parenchyma.Supported by the Sander Foundation     

Impairment of Gsα function in human brain cortex of Alzheimer’s disease: comparison with normal aging

Summary. We examined the quantity and quality of G proteins in membrane preparations of post-mortem human brain, i.e. in parietal, temporal and occipital cortical regions, from normal subjects over age (17–89 years old) and with Alzheimers disease (AD) in comparison with aged-matched controls. In normal aging, the immunoreactivities determined of G_i, G_q and G were inversely correlated with age. The function of G proteins was examined by photoaffinity GTP analogue [azidoanilido GTP (AAGTP)] labelling. AAGTP labelling to G_s and G_i/o, and the ratio of G_s to G_i/o AAGTP labelling showed no age-dependent changes. In AD compared to age-matched controls, there were no significant differences in the levels of G_sH, G_sL, G_i, G_o, G_q and G subunits. Functional effects of G proteins, however, as measured by AAGTP labelling to G_s, but not to G_i/o, was significantly decreased in AD compared to controls in the parietal and temporal cortex, but not in the occipital cortex. These results suggest that the disturbances of post-receptor trans-membrane signalling in AD can be attributed to functional changes of G_s, and these are independent of alterations in the level for those proteins in normal aging.     

Activation of α2-adrenoreceptors enhances haloperidol-induced suppression of operant behavior

Summary Inhibition of catecholamine synthesis by-methyl paratyrosine (-MT) was previously shown to potentiate the behavioral suppression caused by dopamine-receptor antagonists. This effect of-MT is in all probability due to inhibition of the compensatory increase in dopamine turnover induced by the dopamine receptor antagonists. In the present study we investigated the effect of the ₂-adrenoreceptor agonist clonidine on the haloperidol-induced suppression of food-reinforced lever-pressing behavior (fixed ratio 401) in rats. Small behaviorally inactive doses of clonidine were found, in analogy with-MT, to enhance the haloperidol-induced suppression of the lever-pressing behavior. The haloperidol-induced increase in dopamine synthesis (measured as the accumulation of DOPA after inhibition of aromatic amino acid decarboxylare) was antagonized by clonidine in the striatum as well as in the dopamine rich limbic regions. Prazosin, a selective ₁-adrenoreceptor antagonist had no effect on the clonidine induced behavioral changes. Idazoxane, a selective ₂-adrenoreceptor antagonist, counteracted both the behavioral and biochemical effects of clonidine, indicating that these effects of clonidine are mediated via its action on ₂-adrenoreceptors. The present findings provide support for the notion that ₂-adrenoreceptors may participate in the regulation of nigro-striatal as well as meso-limbic dopaminergic activity. It is suggested that ₂-adrenoreceptor agents, especially in combination with classical antipsychotics, might be of therapeutic value in the treatment of disorders associated with abnormal dopaminergic activity.     

Chronic treatment with the potential antidepressant drug rolipram: the effect on the behavioural responses to adrenergic and dopaminergic receptor agonists with some biochemical correlates

Summary We studied the effect of acute and chronic treatment with rolipram, a potential antidepressant drug, on the behavioural responses induced by adrenergic and dopaminergic receptor agonists in mice and rats, and on (³H)prazosin and (³H)dihydroalprenolol binding to cortical membranes and whole brain noradrenaline and dopamine utilization in rats. Chronic, but not acute, administration of rolipram potentiated a behavioural response mediated through central ₁-adrenoceptors, attenuated an ₂-adrenoceptormediated response and inhibited a-adrenoceptor-mediated response. Neither treatment affected the behavioural responses to dopaminergic stimulants. Repeated treatment with rolipram decreased the density of cortical (³H)dihydroalprenolol, but not (³H)prazosin bindings sites, and reduced brain noradrenaline, but not dopamine utilization. These results suggest that chronic administration of rolipram induces the down-regulation of the central- and ₂-adrenoceptors and enhances the responsiveness of the central ₁-adrenoceptors with no apparent changes in the ₁-adrenoceptor density.     

Increasedα 2;-adrenoceptor density in the frontal cortex of depressed suicide victims

Summary The density of brain ₂-adrenoceptors, quantitated by means of the binding of the agonist [³H]clonidine, was studied in post-mortem cortical membranes of matched control subjects and depressed suicide victims. In the depressed suicide group, the specific high affinity binding of [³H]clonidine was found to be significantly increased (B_max, 72% greater; p<0.01) without significant changes in the K_D value for the radioligand. These preliminary results indicate that ₂-adrenoceptor density in the high affinity state _2H) is increased in the brain of depressed patients and add strong support to the hypothesis that endogenous depression is related to supersensitive ₂-adrenoceptors.     

Prostaglandin F2α levels in human cerebrospinal fluid in normal and pathological conditions

Summary Prostaglandin F₂ concentrations in cerebrospinal fluid (CSF) from normal human subjects and patients with various pathological disorders of the central nervous system (CNS) were measured by radioimmunoassay. The mean PGF₂ level in 54 controls with no evidence of organic CNS disease was 67 pg/ml (range: 25–150 pg/ml). A significant increase of PGF₂ levels was demonstrated in most samples from patients with CNS diseases. Extremely high values were found in patients with stroke and subarachnoid hemorrhage when samples were collected shortly after the cerebral attack. With the regression of clinical symptoms and radiological findings a decrease of PGF₂ levels was demonstrated in this group of patients. In 32 patients with cerebral transient ischemic attacks a mean PGF₂ concentration of 170 pg/ml (range: 35–355 pg/ml) was found. Increased PGF₂ levels were found in patients with epilepsy when samples were collected within a few days after a convulsion. PGF₂ levels of four patients with slow progredient forms of multiple sclerosis without clinical symptoms at the time of sample collection were not different from normal controls while the mean PGF₂ level of all other patients with multiple sclerosis was 152 pg/ml (range: 55–325 pg/ml). Moreover, increased values could be demonstrated in patients with cerebral tumors and inflammatory processes.

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Zusammenfassung Mittels Radioimmunoassay wurden PGF₂-Konzentrationen im Liquor cerebrospinalis von normalen Personen und von Patienten mit verschiedenen Erkrankungen des ZNS gemessen. Der mittlere Prostaglandin-F₂-Spiegel von 54 Normalpersonen betrug 67 pg/ml (Bereich: 25–150 pg/ml). Bei den meisten Erkrankungen des ZNS unseres Patientengutes konnten deutliche Erhöhungen der PGF₂-Konzentration im Liquor cerebrospinalis festgestellt werden. Auffallend hohe Werte fanden wir bei Patienten mit ischämischen und hämorrhagischen Insulten als auch bei Subarachnoidalblutungen, wenn die Liquorabnahme innerhalb weniger Tage nach der Attacke erfolgte. Mit zunehmender Besserung des klinischen und röntgenologischen Befundes zeigte sich bei dieser Krankheitsgruppe eine rasche Normalisierung der PGF₂-Konzentration im Liquor. Bei 27 Patienten mit transitorisch-ischämischen zerebralen Attacken fanden wir einen mittleren PGF₂-Spiegel von 170 pg/ml (Bereich: 35–355 pg/ml). Bei Patienten mit Epilepsie zeigte sich ein deutlicher Anstieg der PGF₂-Konzentration in Zusammenhang mit Krampfanfällen mit Normalisierung der Werte nach längeren, anfallsfreien Phasen.Bei 4 Patienten mit einer milden Verlaufsform einer Multiplen Sklerose ohne besondere klinische Symptomatik zum Zeitpunkt der Liquorabnahme wurden normale PGF₂-Spiegel gefunden, während der mittlere Spiegel aller 10 Patienten mit Multipler Sklerose mit 152 pg/ml doch deutlich erhöht war. Hohe PGF₂-Konzentrationen fanden wir auch im Liquor von Patienten mit Tumoren des ZNS und Meningitis bzw. Meningoenzephalitis.

     

Involvement of postsynaptic α1- and α2-adrenoceptors in the flexor reflex activity in the spinal Rats

Summary Clonidine (0.2 mg/kg i.v.) and St 587 (1 mg/kg i.v.), selective agonsists of ₂- and ₁-adrenoceptors, respectively, increased the flexor reflex amplitude in the spinal rat. Yohimbine and rauwolscine, ₂-adrenoceptor antagonists, inhibited dose-dependently the effect of clonidine but not of St 587. However, prazosin and clozapine, ₁-adrenoceptor antagonists, diminished the action of both agonists in a dose-dependent manner. After central chemosympathectomy caused by 6-OH-DA or DSP-4 the response to clonidine did not differ from that in the sham-operated animals. In 6-OH-DA treated rats yohimbine (1 mg/kg i.v.) antagonized the effect of clonidine to the same extent as it did in unlesioned animals. It is concluded that the results are functional evidence that ₁- and ₂-adrenoceptors are present in the rat spinal cord, and stimulation of each receptor increases flexor reflex activity.     

Occurrence of α-synuclein pathology in the cerebellum of Guamanian patients with parkinsonism-dementia complex

Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disease affecting the indigenous Chamorro population of Guam. Neuropathologically, PDC is characterized by neuronal loss in the substantia nigra pars compacta with severe widespread neurofibrillary tangles (NFTs) similar to those observed in Alzheimers disease (AD), and is thus considered a tauopathy. Following reports of -synuclein pathology in PDC patients of Guam, PDC has also been neuropathologically classified as a synucleinopathy. Recently, the presence of -synuclein-positive bodies has been reported in the cerebellum of some patients with Parkinsons disease (PD), diffuse Lewy body disease (DLBD), or multiple system atrophy (MSA). Using immunohistochemical techniques, we investigated the deposition of -synuclein in the cerebellum of Guamanian PDC patients. Numerous -synuclein-immunoreactive spherical structures were found in the molecular layer of the cerebellum of 63.6% of PDC patients. These structures were only seen in patients showing -synuclein pathology in the amygdala. The average density of -synuclein-immunoreactive structures in the cerebellum of Guamanian PDC patients was almost an order of magnitude higher than in non-Guamanian PD patients, and this -synuclein pathology was much more pronounced in the hemisphere than in the vermis. In addition, double immunohistochemistry revealed that cerebellar -synuclein is co-localized with the neuronal marker calbindin and with glial-fibrillary acidic protein, suggesting the involvement of Purkinje cells and Bergmann glia. These findings demonstrate that the -synuclein pathology in PDC of Guam affects not only the amygdala, but also the cerebellum, where it appears to involve both Purkinje cells and specialized astrocytes.     

Antipsychotic treatment withα-methyltyrosine in combination with thioridazine: Prolactin response and interaction with dopaminergic precursor pools

Summary The antipsychotic effect of-methyltyrosine (-MT) in combination with thioridazine was investigated by means of rating scales for social behaviour and mental symptoms The clinical effect was also evaluated in relation to the serum concentrations of-MT and thioridazine and to the increase in prolactin secretion in response to the interaction with hypothalamic dopaminergic mechanisms. The interactions between the serum levels of-MT and those of the transmitter precursors phenylalanine and tyrosine were analysed. The results confirmed the ability of-MT (2g/day) to potentiate the antipsychotic effect of thioridazine, whereby the dose of neuroleptic drug required to control psychotic symptoms may be markedly reduced. None of the four patients who completed the trial showed side effects that could be ascribed to-MT. The antipsychotic effect of thioridazine, alone or in combination with-MT, correlated well with the prolactin response in the individual patient. No important interference with serum phenylalanine or tyrosine levels was noted during treatment with-MT.     

αB-Crystallin is present in reactive glia in Creutzfeldt-Jakob disease

Summary -Crystallin is a major eye lens protein, composed of two types of subunits, A and B. The A subunit is restricted to the lens, but B-crystallin has recently also been detected in non-lenticular tissues, including the nervous system. With the use of a polyclonal antiserum directed against a synthetic C-terminal peptide of human B-crystallin, the presence of B-crystallin could be demonstrated immunohistochemically in astrocytes in the brains of patients with Creutzfeldt-Jakob disease (CJD). Most intensive localization was observed in the spongiotic tissue representing abundant progressively changed astrocytes in CJD. In agematched control brains weak positive reaction was located in individual oligodendroglia cells and subpial astrocytes. Prominent increase of B-crystallin in pathological glia in CJD may represent a response to stress.     

Histopathological effects of intracerebral injections of human recombinant tumor necrosis factor-α in the rat

Summary Human recombinant tumor necrosis factor- (rTNF-) was administered to normal Fischer 344 rats by stereotaxic intracerebral (IC) injection. Animals received a single injection of either 6×10⁴ UrTNF- or excipient in their right parietal lobe. Others received three consecutive daily injections of either 6×10⁴ U rTNF- or excipient to examine effects of higher accumulative doses. Histological examination of the brain revealed that both single and multiple IC injections of rTNF- triggered an immigration of circulating leukocytes into the site of TNF- injection. After one injection, this cell population was composed mainly of macrophages and neutrophils. Maximal leukocytic influx occurred by 48 h and was composed mostly of neutrophils which were limited to the injection site and perivascular space. Quantitation of the inflammatory reaction by measurement of tissue myeloperoxidase levels supported these histological observations. One day after multiple rTNF- injections, leukocytic adhesion to endothelium, vascular cuffing and leukocytic infiltration into the neuropil was observed at levels comparable to those seen 3 days following a single rTNF- injection. We conclude that while one or more IC injection(s) of 6×10⁴ U rTNF- was well tolerated in normal rats, at this dose the cytokine triggers a pronounced leukocytic infiltration at the site of injection. These results support a role for TNF- as a mediator in inflammatory responses within the central nervous system.Supported in part by a grant from the A. D. Williams Research Fund and by gifts from the Kellogg Foundation, the Lind Lawrence Fund, and the family and friends of Christine Armstrong, Jack Harvey, Christopher Wemple, and Pearl Ylonen.     

Effect of interferon-α on DOI-induced wet-dog shakes in rats

Summary Acute (1h) intraperitoneal (ip) treatment with interferon (IFN)--2a (300IU/g) significantly inhibited wet-dog shakes (WDS) induced by (±)-1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane (DOI; 0.5, 1.0mg/kg), which is mediated by serotonin (5-hydroxytryptamine; 5-HT)₂ receptor in rats. IFN- did not affect spontaneous locomotion. The inhibition of DOI (0.5mg/kg)-induced WDS by IFN- was dose (90–300 IU/g)- and time (1–6 h)-dependent, and was prevented by 30 min pretreatment with naltrexone (NLTX; 1.0mg/kg, ip), an opioid receptor antagonist. Acute (1h) intracerebroventricular (icv) treatment with IFN- (1,500IU/rat) also inhibited DOI (0.5mg/kg)-induced WDS, and the effect was blocked by NLTX (50g/rat, icv). These results suggest that IFN- may modulate 5-HT₂ receptor-mediated behavior through opioid receptors in the central nervous system.Abbreviations CNS central nervous system - DOI (±)-1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane - 5-HT 5-hydroxytryptamine (serotonin) - icv intracerebroventricular - IFN interferon - ip intraperitoneal - IU international unit - NLTX naltrexone - sc subcutaneous - WDS wet-dog shakes     

Effect ofd,l-α-aminoadipate on the mediobasal hypothalamus and endocrine function in the rat

Summary Using the glutamate analog,d,l--aminoadipic acid (d,l-AA), experiments were conducted to examine the nature, extent, and specificity of its toxicity in the mediobasal hypothalamus and to determine its effect on endocrine homeostasis. Neonatal rats received daily injections ofd,l-AA (4 g/kg BW) on postnatal days 5–10 and were killed at various post-treatment intervals. Sex-matched littermates were given equimolar amounts of NaCl and served as controls. Treated rats killed 18 days post injection weighed slightly less than controls and had reduced testicular, ovarian, and uterine weights, but the differences were not statistically significant. Ind,l-AA treated rats serum and pituitary levels of TSH and PRL were comparable to control values. Pituitary content of LH ('s and 's) and FSH ('s), however, was lower (P<0.05) ind,l-AA treated rats than in controls, but serum levels were not significantly different. Distinct cytopathologic changes were evident in the arcuate nucleus and median eminence ofd,l-AA-treated rats killed at 2 and 6 h post injection only. By 12 h evidence of acute damage had largely disappeared. Both glial and ependymal cells underwent edematous swelling and necrosis, but neurons were largely unaffected. Evidence of reactive changes, such as gliosis, infiltration of microglia, and removal of debris, however, were not very conspicious. A random sample of mediobasal hypothalami of rats killed 18 days post injection failed to show any detectable lesion or residual effects of earlier pathology. Age at the time of exposure to the gliotoxin was found to be an important variable affecting both extent and duration of injury. The most deleterious effects were observed when the gliotoxin was administered in the form of a single injection on postnatal day 5 only. The results suggest that normal neuronal activity and endocrine homeostasis, specifically gonadotropin, may be irreversibly altered as a consequence of transient disruption of the glial compartment.Supported by grants from the Medical Research Council of Canada, the St. Boniface General Hospital, and Mrs. James A. Richardson Research Foundations     

Effect of repeated treatment with antidepressant drugs and electroconvulsive shock (ECS) on [3H] prazosin binding to different rat brain structures

Summary The influence of acute and repeated treatment with imipramine, amitriptyline, mianserin, citalopram and ECS on ₁-adrenoceptors in different structures of the rat brain (cerebral cortex, hippocampus and thalamus) was measured using [³H] prazosin as a ligand. Repeated, but not acute, treatment with all the above antidepressant drugs and ECS induced an increase in the density of ₁-adrenoceptors in the cerebral cortex. On the other hand, no changes were found in the hippocampus and thalamus, with an exception of the increased number of [³H] prazosin binding sites in the thalamus after imipramine. The results suggest that the up-regulation of ₁-adrenoceptors following repeated antidepressant treatment is not a general phenomenon within the central nervous system.This research was supported by the grant CPBP 06. 02. I. 1 of the Polish Academy of Sciences.     

Lectin histochemistry of scrapie amyloid plaques

Summary Peroxidase-labeled lectins were used for detection of specific monosaccharide residues in amyloid plaques in brains of scrapie-infected mice. The lectins tested recognize the following residues: -d-galactosyl (Ricinus communis agglutinin 120, RCA-1), -d-galactosyl and -d-galactopyranoside (Bandeirea simplicifolia aggl., BSA), -d-mannosyl and -d-glucosyl (Concanavalin A, Con A), N-acetylglucosaminyl and sialyl (Wheat germ aggl., WGA), sialoglycoconjugates (Limulus polyphemus aggl., LPA), -l-fucosyl (Ulex europeus aggl., UEA-1 and Tetragonolobus aggl., TPA), N-acetyl-d-galactosaminyl (Helix pomatia aggl., HPA). The most intense staining reaction in amyloid plaques was observed with BSA and WGA; it was less intense with RCA-1, Con A, and HPA. This indicates that the plaque material contains glycoproteins with abundance of accessible residues of - and -galactose, N-acetyl-d-glucosamine and N-actyl-d-galactosamine, and some types of sialoglycoconjugates recognized by WGA. Such residues, like -l-flucosyl recognized by UEA-1 and TPA, were almost undectectable in the examined plaques.There were also some differences in the staining intensity between small and large plaques (WGA and HPA) and between central and peripheral areas of the plaques.In the wall of micro-blood vessels relatively strong staining reaction was observed with RCA and BSA and less intense with WGA and Con A.Support in part by grant no. 5PO1 AG 04220-03 from the National Institute of Aging, NIH     

Effects of interferon-γ, interleukin-1β, and tumor necrosis factor-α on the serotonin metabolism in the nucleus raphe dorsalis of the rat

Summary The effects of the cytokines interferon (IFN)-, interleukin (IL)-1, and tumor necrosis factor (TNF)- on the serotoninergic transmission in the nucleus raphe dorsalis (NRD) were studied after peripheral and central application. The studies were performed in the freely moving rat using differential pulse voltammetry with multicarbon fibre electrodes to study the extracellular levels of the serotonin (5-HT) metabolite 5-hydroxyindoleacetic acid (5-HIAA). The extracellular 5-HIAA levels were not changed in the NRD after peripheral application of rat recombinant IFN-, but elevated by the cytokines IL-1 and TNF-. After intracerebroventricular (i.c.v.) application the cytokines IFN-, IL-1 and TNF- stimulated the serotoninergic transmission in the NRD. Our data suggest that the effect of peripherally elevated cytokine concentrations on the serotonin metabolism in the NRD of the rat is cytokine-dependent. In this respect the T-cell and NK-cell cytokine IFN- acts clearly different when compared to the mainly macrophage-derived cytokines IL-1 and TNF-, and plays a different role in the communication between immune and central nervous system.     

Heart rate variability in a case of pheochromocytoma

Indices of heart rate variability (HRV) reflect cardiac autonomic tone and may be markedly affected by pheochromocytoma. The effect of pheochromocytoma on HRV was determined by Holter monitoring before diagnosis, under pre-operative -blockade and 5 and 19 months after surgery in a 40 year-old female. Mean heart rates, although higher under -blockade, were unchanged by surgery but indices of HRV reflecting both short term (vagally mediated) and longer term (mediated by vagal, sympathetic and other influences) rhythms were diminished under -blockade and post-surgery. High frequency power (0.15–0.40 Hz), an index of vagal tone, declined from 512 ms² pre-diagnosis to 220 ms² under -blockade to just over 100 ms² post-surgery. Low frequency power (0.04–0.15 Hz), a measure reflecting both vagal and sympathetic tone, declined from 409 ms² pre-diagnosis to 186 ms² under -blockade and was just over 200 ms² post-surgery. SDNN, the standard deviation of normal-to-normal interbeat intervals over 24 hours, declined from 118 ms pre-diagnosis to just over 70 ms both under -blockade and post-surgery. The ratio of low frequency to high frequency power (LF/HF ratio) increased to 0.84 under -blockade, and doubled after surgery (0.79; before, 2.05; after). These changes in HRV may provide insights into the effects of endogenous catecholamines and intrinsic counter-regulatory autonomic mechanisms on HRV.     

Dose-dependent pharmacokinetics of α-methyl-p-tyrosine (α-MT) and comparison of catecholamine turnover rates after two doses of α-MT

Summary Groups of rats were injected i.p. with 0.407 or 1.02 mmoles/kg of D, L--methyl-p-tyrosine methylester HCl (-MT). The time-courses for-MT in plasma and brain were followed together with the endogenous brain dopamine (DA) and noradrenaline (NA) contents.The elimination of-MT from plasma and brain was markedly delayed after the high-MT dose compared with the low dose. At 40 hours after the injection of 1.02 mmoles/kg of-MT both plasma and brain levels were high, whereas no-MT could be detected in plasma or brain at 16 hours after the lower dose.The brain catecholamines were decreased to very low values after the higher-MT dose (DA 14% and NA 10% of controls at 8 and 24 hours respectively). There was no complete recuperation at 40 hours of any of the amines. After the lower-MT dose, the DA concentration was back to control levels at 16 hours and NA at 12 hours. Between 16–40 hours after the high-MT dose a majority of the rats showed prominent signs of sedation, weight loss and dehydration. No such signs were observed in rats receiving 0.407 mmoles/kg. During the first hour after the-MT injection the declines of DA and NA respectively were almost identical for both-MT doses. When the whole time-course (0–8 hours) after the high dose was considered, biphasic declines were obtained for both DA and NA, suggesting at least two different catecholamine pools. However, due to toxic effects after the high-MT dose, turnover data have to be interpreted with caution.