The glucocorticoid receptor in the adrenal gland is localized in the cytoplasm of adrenaline cells.
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Adrenal Glands↗
Biomedical subjects
M Goldstein
Publications and source records attributed to M Goldstein.
Effects of prolonged hyperinsulinemia on erythropoiesis in fetal sheep.
Offspring of diabetic mothers have an increased incidence of neonatal polycythemia, decreased oxygen tension in cord blood at delivery, and elevated plasma erythropoietin levels at birth. Experimental fetal hyperinsulinemia has been associated with reduced fetal oxygen content and increased erythropoietin concentration. To test the hypothesis that prolonged fetal hyperinsulinemia results in increased fetal erythropoiesis and red cell volume during gestation, we infused insulin or placebo for 11 +/- 0.2 (+/- SE) days into chronically catheterized fetal sheep, beginning at 124 days of gestation. Indices of fetal erythropoiesis, red cell and blood volume were measured before and during the infusions. Insulin infusion resulted in increased plasma insulin, decreased plasma glucose, and decreased oxygen saturation values. The nucleated red blood cell (RBC) and RBC counts were significantly higher in the insulin- compared with the placebo-treated fetal sheep after 6-8 and 9-12 days of infusion, respectively. Although erythropoietin concentration did not differ between the groups, red cell volume expressed as a change from the base-line value was significantly higher in the insulin-treated group. We conclude that prolonged fetal hyperinsulinemia augmented erythropoiesis and red cell volume during late gestation in fetal sheep.
Animals↗
Neuropeptide Y and galanin in norepinephrine release in hypothalamic slices.
Noradrenergic neurons in the locus ceruleus contain neuropeptide Y and galanin, which project to the hypothalamic region. We have investigated the regulatory mechanisms of these peptides on norepinephrine release in rat hypothalamic slices in vitro. Neuropeptide Y and galanin significantly inhibited the stimulation-evoked [3H]norepinephrine release in a dose-dependent manner (1 Hz: S2/S1 ratio (mean +/- SEM), control 0.947 +/- 0.040, n = 11, neuropeptide Y 1 x 10(-8) M 0.509 +/- 0.013, n = 8, p less than 0.01, neuropeptide Y 1 x 10(-7) M 0.283 +/- 0.021, n = 8, p less than 0.01; galanin 1 x 10(-7) M 0.448 +/- 0.026, n = 8, p less than 0.01, galanin 1 x 10(-6) M 0.261 +/- 0.023, n = 8, p less than 0.01). The inhibition of norepinephrine release by the alpha-2 agonist UK 14,304 was potentiated by neuropeptide Y and galanin. The blockade of the alpha 2-adrenergic receptors by RX 781094 diminished the inhibitory effects of neuropeptide Y and galanin on norepinephrine release. Pretreatment of hypothalamic slices with islet activating protein (a toxin that interferes with the coupling of inhibitory receptors to adenylate cyclase) attenuated the suppression of norepinephrine release by UK 14,304, neuropeptide Y, and galanin. These results support the idea that neuropeptide Y and galanin are involved in the regulation of central adrenergic transmission partially mediated by alpha 2-adrenergic receptors and islet-activating protein-sensitive guanosine triphosphate-binding proteins in rat hypothalamus.
Adenylate Cyclase Toxin↗
Hearing loss and adenoidal hypertrophy in an adolescent with nephropathic cystinosis.
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Adenoids↗
Neuropeptide Y, peptide YY, and sympathetic control of rectal tone and anal canal pressure in the cat.
Sympathetic mechanisms in the regulation of rectal tone and anal canal pressure have been investigated in the cat. Immunohistochemical studies demonstrated neuropeptide Y-like immunoreactivity in noradrenergic cell bodies of the inferior mesenteric ganglion, in nerve endings in the circular smooth-muscle layers of the rectum and internal anal sphincter, in the myenteric plexuses, and around blood vessels and anal glands. Peptide YY-like immunoreactivity was demonstrated exclusively in endocrine cells of the rectal mucosa. By radioimmunoassay the amount of neuropeptide Y in the inferior mesenteric ganglion was found to be 28.5 (17.8-66.6) pmol g-1, in the rectum 0.8 (0.7-1.6) pmol g-1, and in the anal canal region 0.8 (0.5-1.0) pmol g-1 of tissue. Neuropeptide Y (4-80 pmol kg-1 min-1 intravenously) and peptide YY (1-25 pmol kg-1 min-1 intravenously) increased rectal tone and anal canal pressure. The effects were not inhibited by guanethidine, phentolamine, or propranolol. Noradrenaline (100-1000 pmol kg-1 min-1 intravenously) increased rectal tone and anal canal pressure. These effects were blocked by phentolamine and propranolol. Electric stimulation of the lumbar colonic nerves and the hypogastric nerves (8 Hz) increased rectal tone and anal canal pressure. After propranolol and phentolamine the responses partly remained. On lumbar colonic nerve stimulation the remaining responses of the rectum and anal canal were 60% (40-68%) (p less than 0.05) and 20% (15-29%), respectively, whereas on hypogastric stimulation the remaining rectal and anal responses were 32% (20-42%) (p less than 0.05) and 31% (20-47%) (p less than 0.05). Further administration of guanethidine abolished the remaining responses of the rectum and anal canal. Since neuropeptide Y is present in sympathetic neurons and mimics non-adrenergic responses to nerve stimulation, this peptide is a transmitter candidate for the effects resistant to adrenergic blocking agents but sensitive to guanethidine. Peptide YY may also play a role in sphincter control, but it cannot be excluded that it activates mechanisms similar to those activated by neuropeptide Y.
Adrenergic Agonists↗
Absence of spare autoreceptors regulating dopamine agonist inhibition of tyrosine hydroxylation in slices of rat striatum.
Incubation of rat striatal slices with forskolin (0.05-10 microM) elicited a dose-dependent increase in the activity of tyrosine hydroxylase (TH) assayed in subsequently solubilized extracts of the enzyme. At low concentrations (33 microM) of the cofactor (6R)-5,6,7,8-tetrahydro-L-biopterin dihydrochloride TH activity was increased 2.5 to 3-fold. Kinetic analysis of TH activity as a function of (6R)-5,6,7,8-tetrahydro-L-biopterin dihydrochloride concentration indicated that the enzyme isolated from control slices was composed of multiple species with different Km's for cofactor. Treatment with forskolin (1.5-15 microM) converted the enzyme into a single species with a low Km (28 microM) for (6R)-5,6,7,8-tetrahydro-L-biopterin dihydrochloride. The dopamine (DA) agonist R-(-)-N-n-propylnorapomorphine (0.1 microM) reversed forskolin-induced activation of TH. Concentration-response curves were obtained for inhibition of forskolin-stimulated TH by R-(-)-N-n-propylnorapomorphine and the DA autoreceptor-selective agonists (+)- and (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine and 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl-1)-butyl]indole. R-(-)-N-n-propylnorapomorphine maximally inhibited forskolin-stimulated activity 85%, as indicated by ALLFIT computer analysis of concentration-response curves. (+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine and 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl-1)-butyl]indole produced a lower degree of maximal inhibition (54 and 63%, respectively), whereas (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine was inactive. The D2 DA receptor blocker sulpiride (1 microM) competitively antagonised the effects of all the agonists.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Absence of cardio-depressant effects of CGP 17582 B, a new beta-blocking agent, in patients after coronary surgery.
The hemodynamic effects of CGP 17582 B, a new cardio-selective beta-blocking agent with moderate intrinsic sympathomimetic activity and minimal effects on myocardial contractility, were studied in patients after cardiac surgery for coronary artery bypass graft. Each patient had been treated preoperatively with beta-blocking agents and had a cineangiographic left ventricular ejection fraction between 40 and 60%. Fourteen patients were randomized to receive either 10 mg of propranolol or 50 mg of CGP 17582 B orally. Both drugs resulted in a significant and a similar decrease in heart rate. However, this was associated with a significant decrease in stroke volume after propranolol but not after CGP 17582 B, so that cardiac output significantly decreased only after propranolol. Thermodilution right ventricular ejection fraction significantly decreased after propranolol but not after CGP 17582 B. Each drug was well tolerated during the 10 following days and the recovery was uneventful in each patient. These results indicate that CGP 17582 B is a promising beta-blocking agent susceptible to reduce heart rate without altering cardiovascular function after cardiac surgery.
Adrenergic beta-Antagonists↗
Dopaminergic mechanisms in self-inflicting biting behavior.
Dopaminergic mechanisms involved in self-inflicting biting behavior (SBB) were investigated in two animal models: monkeys with unilateral ventromedial tegmental (VMT) lesions of the brainstem and rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopamine (DA) neurons. The administration of mixed D1/D2 DA agonists to some monkeys with unilateral VMT lesions of the brainstem elicits SBB of the forelimb digits contralateral to the lesion and spasticity of the contralateral hindlimb. This behavior is prevented by pretreatment with the selective D1 antagonist SCH 23390 and with the D1/D2 antagonist fluphenazine. The combined administration of the D1 DA agonist SKF 38393 with the D2 DA agonist quinpirole produces SBB at doses that were ineffective when these drugs were administered individually. The intrastriatal (middle ventrolateral area [MVL]) microinjection of the D1/D2 DA agonist apomorphine (Apo) to rats with unilateral 6-OHDA lesions elicits SBB. This behavior is not prevented by systemic administration of SCH 23390 and partially prevented by the selective D2 antagonist raclopride. However, the combined administration of SCH 23390 and raclopride completely prevents the Apo-induced SBB. Thus, the pharmacological characteristics of the DA agonist-induced SBB in monkeys with unilateral VMT lesions of the brainstem seem to differ from those induced by intrastriatal (MVL area) administration of DA agonists into rats with 6-OHDA lesions of the nigrostriatal DA neurons. The role of DA neuronal systems in the expression of SBB in Lesch-Nyhan syndrome and in some patients with mental retardation, as well as the link between hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency and abnormal dopaminergic function in Lesch-Nyhan syndrome, is discussed.
Animals↗
Evidence for functional contact between cografted locus coeruleus and spinal cord in oculo: electrophysiological studies.
The functional consequences of the locus coeruleus innervation of the spinal cord are not yet clearly understood. In a recent histological study it was shown that intraocular spinal cord grafts will become innervated by tyrosine hydroxylase-positive nerve fibers from a cografted locus coeruleus. In the present study we use this intraocular model of the descending coeruleo-spinal pathway to investigate functional contact between locus coeruleus and the spinal cord. We have pharmacologically characterized the receptor mediation of norepinephrine-induced, as well as locus coeruleus-mediated depressions of spinal cord neurons grafted in oculo. We found that electrical stimulation of the locus coeruleus part of the double grafts predominantly caused an inhibition of cografted spinal cord neurons. Norepinephrine-induced inhibition of the firing rate of single grafted spinal cord neurons was antagonized by phentolamine, an alpha-adrenergic antagonist, but was unaffected by timolol, a beta-adrenergic antagonist. Similarly, inhibition of the firing rate of grafted spinal cord neurons by stimulation of cografted locus coeruleus was antagonized by phentolamine but not by timolol. Interestingly, single spinal cord grafts were more sensitive to the depressant effects of perfused norepinephrine than was the spinal cord cografted with locus coeruleus. We conclude that spinal cord grafts can be functionally innervated by cografted locus coeruleus and that the noradrenergic inputs to spinal cord from cografted locus coeruleus are alpha-adrenergically mediated. Furthermore, the postsynaptic receptors in single spinal cord grafts appear to be supersensitive to norepinephrine application.
Action Potentials↗
Receptor reserve at striatal dopamine receptors modulating the release of [3H]dopamine.
Electrically stimulated release of [3H]dopamine [( 3H]DA) in slices of rat striatum was dose dependently inhibited by apomorphine (67% maximal inhibition) with an EC50 of 17 nM. DA receptor inactivation with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; 0.5 and 2 mg/kg) dose dependently shifted the ED50 for apomorphine to the right and reduced the maximal inhibition obtained. Analysis of the results yielded a hyperbolic plot of receptor occupancy vs. response, indicating that a large receptor reserve (50-60%) for apomorphine exists at the DA autoreceptor in rat striatum mediating inhibition of transmitter release.
Animals↗
Absence of receptor reserve at striatal dopamine receptors regulating cholinergic neuronal activity.
N-propylnorapomorphine (NPA) dose dependently increased rat striatal ACh levels (ED50 = 18 micrograms/kg). After irreversible dopamine (DA) receptor inactivation with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), neither the ED50 nor the slope of the dose-response curve for NPA was altered, whereas the maximal response was reduced to 56% of control. Analysis of the results yielded a linear relationship between receptor occupancy and response (i.e. no receptor reserve). In contrast, DA autoreceptors display a large receptor reserve for NPA. The results support the hypothesis that a differential receptor reserve at pre- vs. postsynaptic DA receptors in rat striatum accounts for the autoreceptor selectivity of DA agonists.
Acetylcholine↗
Chronic nicotine treatment counteracts the disappearance of tyrosine-hydroxylase-immunoreactive nerve cell bodies, dendrites and terminals in the mesostriatal dopamine system of the male rat after partial hemitransection.
Male Sprague-Dawley rats were partially hemitransected at the mesodiencephalic junction and treated with nicotine (nicotine hydrogen (+)-tartrate) using Alzet minipumps implanted subcutaneously. Nicotine was delivered for 2 weeks in a dose of 0.125 mg/kg/h resulting in a serum nicotine level of 50.0 +/- 5.1 ng/ml. Three other groups of rats were analyzed: hemitransected rats receiving saline treatment and sham-operated animals receiving nicotine and saline, respectively. The effects of hemitransection and nicotine rostrally as well as caudally to the lesion were evaluated with image analysis of tyrosine hydroxylase (TH)-immunoreactive (IR) nerve cell body and dendrite profiles in the rostral and caudal substantia nigra and of TH-IR nerve terminal profiles in the striatum. Adjacent sections were taken to Nissl staining. [3H]Nicotine binding in the midbrain and forebrain was studied by means of receptor autoradiography on partially hemitransected rats receiving no treatment. Catecholamine (CA) levels in the frontal cortex were measured using high-performance liquid chromatography (HPLC). Striatal dopamine (DA) function was analyzed studying apomorphine-induced (1.0 mg/kg) ipsilateral rotational behavior. The spontaneous behavior of the rats was evaluated with a hole board. Furthermore, body temperature and body weight were measured. The results demonstrated a lesion-induced disappearance of TH-IR cell body and dendrite profiles in the substantia nigra and of TH-IR nerve terminal profiles in the striatum. Similar findings were seen after Nissl staining. A significant counteraction of this disappearance was found in the nicotine-treated animals. On the lesioned animals a marked reduction of [3H]nicotine binding in the striatum and the substantia nigra was found. In the functional experiments an enhancement of the apomorphine-induced ipsilateral rotational behavior was demonstrated. The degree of rotation was positively correlated with the serum nicotine level. The study on spontaneous activity in the hole board showed a slower restoration of total activity in the hemitransected nicotine-treated rats. All these results are compatible with the hypothesis that the protective action of nicotine on the mesostriatal DA system may be due to a desensitization of excitatory nicotine cholinoceptors located on the nigral DA nerve cells, leading to a reduction of firing rate and reduced energy demands. Such an action of nicotine could be of importance for a possible anti-parkinsonian effect.
Animals↗
A subpopulation of dopaminergic neurons in rat ventral mesencephalon contains both neurotensin and cholecystokinin.
The coexistence of the neuropeptides neurotensin and cholecystokinin and the catecholamine-synthesizing enzyme tyrosine hydroxylase within neurons of the ventral mesencephalon was analyzed using an immunofluorescence triple-labeling technique. Virtually all of the neurotensin-positive cell bodies in the ventral tegmental area, medial substantia nigra pars compacta, retrorubral field, and rostral and caudal linear raphe nuclei were found to contain both cholecystokinin and tyrosine hydroxylase immunoreactivities. The degree of colocalization was lower and more variable in other regions including the ventral and central periaqueductal grey matter and dorsal raphe nucleus. It appeared that immunoreactivities for these 3 neuroactive substances were not contained within the same axonal-like fibers and terminals in the ventral midbrain. These results demonstrate that a subpopulation of dopaminergic neurons, which presumably comprise part of the ascending mesotelencephalic system, contains the two peptides neurotensin and cholecystokinin. Thus, the data suggest a morphological basis for some of the reported functional interactions of these 3 putative neurotransmitters/neuromodulators within this system.
Animals↗
The dopaminergic innervation of monkey prefrontal cortex: a tyrosine hydroxylase immunohistochemical study.
The distribution of tyrosine hydroxylase (TH)-immunoreactive fibers was characterized immunohistochemically in the prefrontal cortical regions of both Old World cynomolgus monkeys (Macaca fascicularis) and New World squirrel monkeys (Saimiri sciureus). In both species, differences in the density and/or laminar distribution of TH-labeled fibers were detected both across and within almost every prefrontal cytoarchitectonic region. In cynomolgus monkeys, areas 9 and 24 had the greatest density of TH-labeled fibers, areas 11, 12, 13 and 25 were of intermediate density, and areas 10 and 46 had the lowest density of immunoreactive fibers. Differences in fiber density within many of these regions were also consistently observed. On a laminar basis, the distribution of labeled fibers in a given area of cynomolgus prefrontal cortex was systematically related to the overall fiber density of that area. For example, in the lightly innervated fundus of the principal sulcus (area 46), labeled fibers were primarily present in layer I and layers V-VI, whereas in area 9, the most densely innervated region, TH-labeled fibers were present in all cortical layers. Similar regional differences in the density and laminar distribution of TH-immunoreactive fibers were also present in squirrel monkey prefrontal cortex. In previous studies, we have analyzed the regional and laminar distributions of fibers immunoreactive for TH and dopamine-beta-hydroxylase (DBH), a specific marker for noradrenergic cortical fibers, in multiple areas of cortex from both normal and locus ceruleus-lesioned animals. These comparisons, which have been confirmed in the present report, indicate that anti-TH and anti-DBH label distinct populations of axons in monkey neocortex, which presumably are dopaminergic and noradrenergic, respectively. Thus, the distribution of TH immunoreactivity described in the present report suggests that dopaminergic fibers are distributed in a very heterogeneous fashion in monkey prefrontal cortex. The distinctive innervation patterns exhibited by these fibers reveal the regions and layers that may be the principle sites of action of dopamine in exerting its effects on prefrontal cortical function.
Animals↗
Isolation and partial characterization of an ion channel protein from human sperm membranes.
Human sperm cells were fractionated and plasma membrane proteins were separated by molecular gel sieving chromatography (Sephacryl S-200 followed by HPLC). A pore-forming protein was extracted from sperm cell membranes. The partially purified protein migrated with Mr 100,000-110,000, as determined by molecular sieving gel chromatography, and with a Mr 90,000 when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions. The channel activity was also extracted with Triton X-114, suggesting a hydrophobic nature for this protein. This protein was incorporated into planar lipid bilayers, resulting in the formation of voltage-dependent ion channels. Single channel fluctuations of 130 pS/unit in 0.1 M NaCl were resolved; however, channels preferentially aggregated in triplets having an open state life-time that persisted for several seconds. The channels studied here were more selective for monovalent cations than anions, but also showed some permeability to anions and larger electrolytes, suggesting a large functional pore diameter. The role of this sperm channel in normal sperm physiology and/or fertilization is presently unclear.
Cell Membrane Permeability↗
Brainstem dopaminergic neurons project to monkey parietal cortex.
In this study, retrograde transport of Fast blue was combined with tyrosine hydroxylase immunohistochemistry to reveal the presence of projections from both dopaminergic and non-dopaminergic neurons of the substantia nigra-ventral tegmental area to the parietal cortex of cynomolgus monkeys (Macaca fascicularis). These findings confirm the results of previous studies demonstrating the existence of a dopaminergic innervation of monkey parietal cortex.
Amidines↗
Biochemical analysis of caudate nucleus biopsy samples from parkinsonian patients.
Biochemical analyses of caudate nucleus biopsy samples from patients with Parkinson's disease undergoing autologous adrenal transplantation were performed. Activity of the dopamine biosynthetic enzyme tyrosine hydroxylase, and concentrations of dopamine and its primary metabolite homovanillic acid were significantly greater than anticipated on the basis of previously published postmortem values. These data suggest that postmortem changes in various biochemical parameters of dopamine function are more rapid than has been generally appreciated. Further analysis of striatal biopsy samples may reveal predictive relationships between striatal indices of dopamine function and therapeutic response to adrenal transplantation.
Adult↗
Isolation and characterization of cDNA clones encoding epitopes shared with Alzheimer neurofibrillary tangles.
A pool of ten monoclonal antibodies to SDS-insoluble epitopes of Alzheimer neurofibrillary tangles (NFT) was used to screen an adult human brain cDNA expression library. Fourteen clones were isolated, two of which are described. The largest of the clones encodes 80 kD, or approximately 600 amino acids, of microtubule-associated protein 2 (MAP 2). The MAP 2 region encoded by the clone shares at least two epitopes with human tau, another microtubule-associated protein which cross-reacts with NFT. In rat brain mRNA, the MAP 2 cDNA hybridizes to a single transcript of 9.5 kb. In human neuroblastoma mRNA, the MAP 2 cDNA hybridizes, at high stringency, to two transcripts of 9.5 kb and 6 kb. The 6-kb transcript comigrates with the transcript for tau, as detected by a human tau cDNA. The properties of the MAP 2 cDNA suggest that, in humans, MAP 2 and tau have a common domain which may play a role in NFT formation. Another clone isolated with the anti-NFT antibodies shares epitopes, but not nucleic acid homology, with the MAP 2 cDNA. This clone detects a single abundant transcript of 1 kb present in RNA from human neuroblastoma and from several non-neuronal human cell lines. The properties of this cDNA suggest that it encodes a protein other than those previously reported to cross-react with NFT.
Adult↗