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Dopamine beta-hydroxylase activity was higher in mesenteric vessels, adrenal glands, and serum of 3-week-old spontaneously hypertensive rats but lower in the locus coeruleus than it was in the control Wistar-Kyoto rats. The results support the concept that the nervous system is an important regulator of blood pressure.
The behavioral effects of low doses of the catecholamine (CA) synthesis inhibitor, alpha-methyl-p-tyrosine (alpha-MPT, 50 mg/kg i.p.), or the norepinephrine (NE) synthesis inhibitors (FLA-63, 15 mg/kg i.p., U-14624, 50 mg/kg i.p., or disulfiram 150 mg/kg i.p.) were studied in rats pretreated with reserpine (1 mg/kg i.p.) 24 h before. Rats were implanted either in the area ventralis tegmenti (AVT) or in the lateral hypothalamus (LH). The modifications of CA synthesis and endogenous CA levels were estimated in a parallel experiment. Reserpine treatment produced a slow decrease in self-stimulation (SS) rates during the first 12 h; SS rates were 85% of control values 24 h after reserpine treatment. Injection of alpha-MPT in reserpine-pretreated rats inhibited SS (85% decrease 3 h after administration either in AVT or LH rats), whereas dopamine beta-hydroxylase inhibition had no great effect on SS. The administration of very low doses of alpha-MPT (20 mg/kg i.p.) to rats treated with reserpine (24 h before) plus FLA-63 (1 h before) induced an important decrease in SS rates in AVT-implanted rats only. The major conclusion is that dopaminergic neurons seem to be involved in AVT and LH SS. The last experiment suggests the involvement of a balance between dopaminergic and noradrenergic neurons in AVT SS.
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1 The effects of chronic nicotine administration (1 or 10 mg/kg, s.c., twice daily) were studied in intact and denervated rat adrenal glands to determine the relative roles of central input and direct actions on catecholamines. 2 Catecholamine depletion was obtained in the intact glands from 1-7 days of treatment with 10 mg/kg, with recovery by 14 days of treatment; catecholamines were not decreased in denervated adrenal glands. 3 Catecholamine depletion was accompanied by a decline in functional storage vesicles (determined by [3H]-adrenaline uptake per gland) in the intact side, while no change was seen in the denervated side; the proportion of newly synthesized vesicles increased markedly during 1-7 days of treatment with 10 mg/kg in the intact side, while a much smaller increase of shorter duration was seen in the denervated adrenal gland. 4 Chronic nicotine administration at either dose level induced tyrosine hydroxylase in both intact and denervated glands, but the increase occurred more slowly in the denervated glands. 5 Dopamine beta-hydroxylase levels increased similarly in both sides during treatment with nicotine (10 mg/kg). 6 These studies suggest that although long-term adrenal denervation eliminates the catecholamine depletion caused by chronic administration of nicotine, the mechanisms for induction of catecholamine synthesizing enzymes are still capable of responding to the drug.
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A transplantable mouse testicular teratoma (OTT 6050) which displays a spectrum of neuroepithelial differentiation was evaluated biochemically for concentrations of cyclic AMP (cAMP), serotonin (5-HT), and enzymes involved in the metabolism of the biogenic amines and acetylcholine. These values were compared between teratomas with neuroepithelial differentiation as the major or minor component and brains of neonatal and adult mice of related strains. cAMP, 5-HT, tryptophan hydroxylase (TPH), aromatic amino acid decarboxylase (AADC) and monoamine oxidase (MAO) were present. In addition, enzymes of the adrenergic system, i.e. tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH), and of the cholinergic system, i.e. choline acetyltransferase and acetylcholinesterase, were studied. Biochemical differences in tumor groups probably reflected variations in the proportion of neuroepithelial components: trends suggested an increase of cAMP and an increased activity of TPH, AADC, TH and DBH in tumors with increased proportions of neuroepithelial cells. These findings indicate that the neuroepithelial component of the mouse teratoma may serve as a model for the study of neuronal differentiation in primitive neuroepithelial neoplasms.
Tyrosine hydroxylase and dopamine-beta-hydroxylase have been measured in 34 discrete areas and nuclei of the limbic system of the rat. Both enzymes showed an uneven distribution in this system. The ratio between tyrosine hydroxylase and dopamine-beta-hydroxylase activities showed a significant correlation when compared with the ratio of dopamine and norepinephrine concentrations for the areas studied. The results strongly suggest that dopaminergic terminals are present in discrete areas of the limbic cortex, and several septal and amygdaloid nuclei, and allow the precise localization of dopaminergic and noradrenergic areas in the limbic system.
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Sensitive radiometric assays for tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH), phenylethanolamine-N-methyl transferase (PNMT), and glutamic acid decarboxylase (GAD) have been combined with microdissection techniques for quantitative localization of these synthetic enzymes in rabbit spinal cord. TH was present uniformly in gray and white matter. DBH was higher in the lateral horns than in the other gray matter areas, and was not detectable in white matter. PNMT was detectable in gray but not white matter, and was considerably lower in activity than the other catecholamine synthetic enzymes. GAD was higher in the dorsal horns at the cervical and lumbar levels than in other gray matter areas and relatively low in white matter. GAD activity was considerably higher than the catecholamine synthetic enzyme activities. The quantitative localizations are consistent with the qualitative immunohistochemical enzymes maps and distributions of the related putative neurotransmitters.
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BACKGROUND: Dopamine β-hydroxylase (DBH) plays an indispensable role in catecholamine synthesis by converting dopamine into norepinephrine. Here, we characterized a DBH promoter polymorphism (C-2073T; rs1989787; minor allele frequency ~16%) that influences not only gene transcription but also enzyme secretion and blood pressure (BP) in vivo. METHODS: Plasma DBH activity was measured spectrophotometrically. DBH genetic effects on BP were tested in subjects with the most extreme BP values in a large primary care population. Functional effects of promoter variants were studied by site-directed mutagenesis in DBH promoter haplotype/luciferase reporter plasmids transfected into chromaffin cells. Sequence motifs were predicted from position weight matrices, and endogenous transcription factor binding was probed by Chromatin ImmunoPrecipitation (ChIP). RESULTS: The T-allele of common promoter variant C-2073T was contained in a promoter haplotype that associated with plasma DBH activity, a trait also predicted by that variant itself. Promoter haplotypes including C-2073T predicted BP in the population, and the effect was also referable to C-2073T itself. Computationally, C-2073 disrupted a predicted match for transcription factor c-FOS. Site-directed mutagenesis at C-2073T altered not only basal promoter activity, but also transactivation by c-FOS, as well as the chromaffin cell secretory stimuli nicotine or pituitary adenylate cyclase-activating polypeptide (PACAP). Endogenous c-FOS bound to the motif in chromatin. CONCLUSIONS: These results suggest that DBH promoter variant C-2073T is functional in vivo: this promoter variant seems to initiate a cascade of transcriptional and biochemical changes including augmented DBH secretion, eventuating in elevation of basal BP, and hence cardiovascular risk. The observations suggest new strategies for probing the pathophysiology, risk, and treatment of hypertension.
Norepinephrine and the enzymes involved in its synthesis and degradation were found to be associated with isolated brain microvessels. The significance of these results are discussed with respect to adrenergic innervation of the cerebral microvessels and thereby neural regulation of the cerebral microcirculation.
The bovine median eminence was dissected into eight different subdivisions: rostral, anterior internal, anterior external, middle external medial, middle external lateral, middle internal medial, middle internal lateral, and caudal. Thyrotropin-releasing hormone (TRH) was found in the highest concentrations in the middle external medial and lateral subdivisions; luteinizing hormone-releasing hormone (LHRH) was concentrated in the middle external lateral and anterior internal subdivisions. Among the various neurotransmitters and enzymes assayed, only dopamine and choline acetyltransferase were present in highest concentrations in the same subdivisions of the bovine median eminence found to be rich in TRH and LHRH. The distributions of norepinephrine, dopamine-beta-hydroxylase, serotonin, tryptophan hydroxylase, phenylethanolamine-N-methyltransferase, glutamic acid decarboxylase, and histamine appeared to correlate poorly with the major distributions of TRH and LHRH. These findings suggest that at the level of the median eminence, central neuroendocrine regulation of TRH and LHRH release may involve an interaction only with dopamine and acetylcholine.