Biomedical subjects
Publications and source records attributed to L R Hegstrand.
Recurrent squamous cell cancer of the vulva metastasized via regional lymphatics. Hematogenous spread is late and unusual. A patient with metastatic disease presented with soft tissue mass in her thigh musculature. We believe this to be the first reported case of noncontiguous skeletal metastasis for this tumor.
The influence of nephrectomy on brain and peripheral tissue histamine and on brain norepinephrine, dopamine, serotonin, and 5-hydroxyindoleacetic acid was studied in germ-free and conventionally housed rats. The conventional controls had higher levels of histamine in the hypothalamus than the germ-free control animals, but no differences existed for histamine in whole brain minus the hypothalamus or in peripheral tissues. Nephrectomy increased brain histamine and 5-hydroxyindoleacetic acid levels in both germ-free and conventional rats, but had no effect on norepinephrine, dopamine or serotonin. In contrast, the histamine level in the heart of the nephrectomized germ-free animals was lower than that for germ-free controls. There were no changes in the heart or liver histamine levels of the conventional nephrectomized rats.
Brain histamine levels were determined in golden hamster hypothalamus and 'brain minus hypothalamus' on each of the 4 days of the estrous cycle and on selected days of pregnancy. The highest histamine content of the hypothalamus was observed on day 3 of the estrous cycle. The highest histamine content of the hypothalamus was observed on day 3 of the estrous cycle, which is the day prior to recurrence of heat on day 4. Day 4 terminates in ovulation. The histamine level in the remainder of the brain peaked on day 2. During gestation the histamine content of the 'brain minus hypothalamus' was greatest on day 5, while the maximum content of histamine in the hypothalamus was not reached until day 8. After the 8th day of pregnancy, there was an overall decline in brain histamine that continued until parturition. The hypothalamic histamine level in nonpregnant females was not different from that of males. However, in the remainder of the brain, histamine levels in females on days 1 and 2 of the estrous cycle were higher than in males.
A microassay procedure for mammalian histidine decarboxylase based on the conversion of L-[3H]histidine to [3H]histamine, which were separated by an alkaline butanol extraction followed by thin-layer chromatography, is described. This assay is direct and simple to perform, in addition to being very sensitive and reproducible. It is useful for tissues containing high levels of endogenous histamine, because only newly formed radiolabeled histamine is measured. This report includes information on histidine decarboxylase activity at various pH levels, in different buffers, and in the presence of selected histamine active drugs. In addition, it describes histidine decarboxylase activity in several fetal rat tissues.
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Histidine decarboxylase activity in hamster and rat brains were studied using a newly developed sensitive, direct radioenzymatic microassay. For our assay conditions, we determined a Km for L-histidine of 320 microM and a Vmax for histidine decarboxylase of 110 pmol histamine/hr/mg protein in rat hypothalamus. The regional distributions of both histidine decarboxylase and histamine levels were similar in the hamster and rat with the most activity in hypothalamus. Most of the histidine decarboxylase activity in rat hypothalamus was in the cytosol fraction. The developmental pattern of histidine decarboxylase in the fetal rat did not reveal a prenatal spike in activity. Histidine decarboxylase activity in rat brain reached adult levels by four weeks. Alpha-fluoromethylhistidine inhibited histidine decarboxylase activity almost totally in vitro at 10 microM and about 80% in vivo after six days of infusion (100 mg/kg/day) in all brain regions except the cerebellum. Likewise, histamine levels were depleted about 75% in all brain regions except the cerebellum.
A system for efficiently scraping thin-layer chromatography plates is described. A height-adjustable rack for holding the thin-layer chromatography plate is constructed of transparent acrylic plate. The base provides a surface on which to slide vial holders and also gives stability to the rack. The plate is scraped with a single-edge razor blade cut to an appropriate width and the scrapings fall into a polypropylene funnel which sits on a vial that is in either a test tube rack or a cassette from a scintillation counter. The plate-scraping system reduces scraping time by more than 60% and increases the accuracy of results.
Histidine transport and metabolism in rat brain synaptosomes were investigated to study the possible role of histidine uptake in the synthesis of the putative neurotransmitter histamine (HA). Histidine uptake was found to be regionally distributed and temperature sensitive, and was not totally independent of sodium or potassium ions. Transport was inhibited by metabolic inhibitors, as well as by promethazine and quinacrine. A number of other HA-related agents and several histidine metabolites had no effect. Kinetic analyses of histidine transport revealed the presence of both high- and low-affinity systems in cerebral cortex. Histidine uptake increased following preexposure of synaptosomes to depolarizing concentrations of potassium. This effect was dependent on the presence of calcium ions during the preincubation. No newly formed [3H]HA was detectable in rat brain synaptosomes following [3H]histidine transport. Lesions of the medial forebrain bundle did not alter histidine uptake in the hippocampus or cerebral cortex. Ontogenic studies indicated that the histidine uptake system developed rapidly and reached a peak during postnatal days 12-17. Overall, the present findings do not support a role for histidine transport in the regulation or maintenance of neurotransmitter pools of HA in rat brain.
Properties of N-acetylhistamine deacetylase in rat brain were studied, utilizing a sensitive coupled radioenzymatic assay. The Km for N-acetylhistamine for this deacetylase was 660 microM and its Vmax was 330 pmol/h/mg protein. N-Acetylhistamine deacetylase activity increased 80% in the presence of 1 mM Mn2+. The Km of Mn2+ was 40 microM. The enzyme is primarily a soluble enzyme with a relatively uniform regional distribution, unlike the distribution for histamine and histidine decarboxylase. Neonatal activity of this enzyme in rat brain is higher than in adult brain. alpha-Fluoromethylhistidine does not affect the activity of N-acetylhistamine, indicating that deacetylation probably does not play a regulatory role in the synthesis of brain histamine.
The histamine content of reproductive tissues and skeletal muscle was determined in the golden hamster during the estrous cycle, pregnancy, and pseudopregnancy. Histidine decarboxylase activity was measured in uterine implantation sites and intersites from Day 4 to Day 10 of pregnancy. Histidine decarboxylase was also measured in mesometria and placentas on selected days of gestation. During the estrous cycle, uterine and skeletal muscle histamine levels were highest on Day 2 and lowest on Day 4 of the cycle. The ovarian histamine content did not change significantly among the different stages of the cycle. While the histamine content of uterine implantation sites of attachment was high on Days 4 and measurable on Days 5 and 6 of pregnancy, the levels were below the limits of detection by Day 7. On the other hand, the highest levels of histamine were in the uterine interimplantation sites on Days 8 and 9. The ovarian levels of histamine were highest on Day 13 of pregnancy. Histamine in skeletal muscle did not change significantly during pregnancy. The histidine decarboxylase activity in the implantation sites began rising on Day 9 and increased dramatically on Day 10. Placental histidine decarboxylase activity was very high on Days 13 and 15. Overall, we observed changes in uterine and skeletal muscle histamine during the estrous cycle that may be explainable in light of previously reported changes in mast cell numbers and circulating estrogens. During pregnancy, histamine levels of implantation sites and implantation intersites varied, as did the histamine content of ovarian tissue. Histidine decarboxylase activity rises in the uterus and placental tissue after the formation of the placenta.
Pharmacological studies have demonstrated that shock-induced defensive fighting is modulated by manipulations of the serotonergic, noradrenergic and dopaminergic neurotransmitter systems. In the present study, regional changes in 5- hydroxytryptamine , norepinephrine, dopamine and their metabolites 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenylethylene glycol and 3,4-dihydroxyphenylacetic acid were measured following shock-induced fighting using high performance liquid chromatography coupled with electrochemical detection. Fighting produced reductions in the serotonergic, noradrenergic and dopaminergic systems and elevations in the noradrenergic and dopaminergic systems within the brain stem, hypothalamus, hippocampus, caudate and amygdala relative to shocked or non-shocked controls. These data demonstrate that the activities of these neurotransmitters are involved in defensive aggression in rats. The changes in catecholamines may indicate adaptive responses to stress, while the changes in serotonin may indicate a permissive function for serotonin depletion in defensive fighting.
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Adult male rats were treated chronically with haloperidol (1 mg/kg) daily or propranolol (10 mg/kg bid) and evaluated for changes in shock-induced fighting. Haloperidol suppressed fighting. Chronic propranolol facilitated fighting when rats were tested eight hours after injection. Acutely, either 5 or 10 mg/kg of d,1-propranolol suppressed shock-induced fighting. Chronic pindolol (10 mg/kg bid) and chronic 1-propranolol (5 mg/kg bid) administration increased fighting. Chronic d,1-propranolol, 1-propranolol or pindolol administration was associated with an increase in Bmax for beta-adrenergic receptors. No change in fighting or Bmax was observed with the chronic administration of d-propranolol (5 mg/kg bid) or metoprolol (10 mg/kg bid). This increase in shock-induced fighting appears to be a behavioral response developing as a consequence of increased beta-adrenergic receptors responding to endogenously released norepinephrine.
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Using a 15-s intershock interval, an increase in shock-induced fighting was observed following intraventricular 96 microgram 5,7-dihydroxytryptamine (5,7-DHT) and 90 microgram 6-hydroxydopa (6-OHdopa). The incidence of predatory mouse killing was enhanced by 5,7-DHT, but was not affected by 6-OHdopa. Pain sensitivity was increased by 6-OHdopa, but both neurotoxins produced hyperreactivity to footshock. Specific serotonin depletion was produced by 5,7-DHT and norepinephrine depletion by 6-OHdopa. The increase in shock-induced fighting could not be predicted on the basis of monoamine depletion alone, since a long intershock interval was necessary to observe this increase.
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Using two procedures known to enhance shock-induced defensive fighting (SIF) and mouse-killing--septal lesions and 5,7-DHT lesions--we determined if a 5% tryptophan-loaded diet could reverse the lesion effects. The results indicated that SIF, but not mouse-killing, could be maintained at normal levels following dietary tryptophan loading in both septally lesioned and 5,7-DHT lesioned rats. This behavioral reversal was independent of pain sensitivity, feeding, drinking and body weight levels. Regional brain analysis of monoamines and metabolites indicated that the lesions produced substantial depletions in 5-HT and 5-HIAA with minimal reduction or no change in catecholamines. Dietary tryptophan loading elevated 5-HT and 5-HIAA in unlesioned animals and partially restored 5-HT and 5-HIAA levels in lesioned animals. These patterns of depletion and repletion were confined to the hippocampus following septal lesions and distributed throughout the brain following 5,7-DHT lesions. The results are discussed in terms of a possible hippocampal mediation of the dietary tryptophan reversal in shock-induced defensive fighting following lesioning.