Regional brain uptake of norepinephrine following mechanical or osmotic opening of the blood-brain barrier.
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Biomedical subjects
Publications and source records attributed to L Edvinsson.
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The vasomotor response of dopamine and dopaminergic agonists was studies on feline isolated middle cerebral arteries in vitro and pial arterioles in situ following microapplication. The action of various inhibitors was tested to define the receptors involved. The contractile response could be blocked by alpha-receptor as well as serotonin receptor antagonists. The mode of inhibition suggested that serotonin receptors rather than alpha-adrenoceptors mediated the dopamine-induced contraction. A dose-dependent dilation could be evoked by the dopaminergic agonists on actively contracting pial arteries in vitro and by apomorphine in situ. The relative potency for the agonists together with blocking experiments indicated that the vasodilation was mediated by specific dopamine receptors.
Histochemical studies have shown that the rabbit choroid plexus receives a well-developed adrenergic and cholinergic nerve supply. The adrenergic innervation, which originates almost entirely from the superior cervical sympathetic ganglia, begins to develop around birth and is fully established 3 weeks later. Electron microscopy has shown that the nerve terminals innervate both the plexus arterioles and its secretory epithelium. The sympathetic fibers have been shown to influence the plexus epithelium, as reflected by their effect on its carbonic anhydrase activity. They appear to have an inhibitory effect on the bulk CSF production, as revealed by electrical nerve stimulation and denervation experiments. The control seems to be exerted primarily on the plexus epithelium, although some of the effect may also be associated with alterations in choroid plexus blood flow.
Blood flow in the caudate nucleus was measured by the thermoclearance technique in non-anesthetized rabbits, accompanied by recording of electrocorticogram, systemic blood pressure, and Pao2 and Paco2 (mass spectrometry). Isoprenaline increased caudate nucleus blood flow and reduced systemic blood pressure. The beta2-receptor agonist, terbutaline, on the other hand, had only peripheral effects. The caudate nucleus flow response was selectively blocked by the beta1-receptor antagonist, practolol, whereas propranolol inhibited all effects of both agonists. Isoprenaline dilated isolated pieces of the tributary artery (middle cerebral) tested in cats, the effect being inhibited not only by propranolol but also by practolol. The results offer further evidence for the view that the beta-receptors in the cerebral vascular bed are of the beta1-type.
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Regional cerebral blood flow was measured by the 14C-ethanol technique in anesthetized rats before and after intraventricular injection of 6-hydroxydopamine. This treatment reduced the fluorescence of the central noradrenaline and dopamine nerve terminals, as well as of the perivascular nerve terminals in cerebral vessels. The administration of 6-hydroxydopamine had no significant effect on cerebral blood flow at normocapnia. The cerebrovascular reactivity to hypercapnia was significantly increased in the 6-hydroxydopamine treated animals. The results indicate an involvement of central catecholamine pathways in the cerebrovascular reactivity to hypercapnia.
The passage of noradrenaline from the cerebrovascular circulation into the brain (vessel walls and parenchyma) was studied quantitatively and regionally by a modification of Oldendorf's technique for determination of brain uptake index. Using 14C-ethanol as the highly diffusible internal standard, the index for noradrenaline varied between 2.7 and 4.5% in different regions, confirming the poor penetration of this neurotransmitter. The barrier was impaired transiently as evidenced by Evans blue extravasation, through osmotic opening by internal carotid injection of a hyperosmolar urea solution or mechanical disruption by a short-lasting elevation of the intracarotid hydrostatic pressure. This resulted in a 3-4-fold increase in the passage of noradrenaline from the circulation into the brain.
The ability of the blood-brain barrier to form dopamine from increasing doses of systemically administered L-DOPA has been studied in rats by a combination of chemical determination of dopamine, and histochemical and cytofluorometric measurements of L-DOPA and dopamine. The break-through of L-DOPA from the circulation into the brain parenchyma via the enzymatic blood-brain barrier was estimated by comparing the amount of newly formed dopamine in the caudate nucleus-putamen and in the cerebellum. The capillaries were found to efficiently trap L-DOPA in their walls, and an upper limit was reached (at an administered i.p. dose of 100 mg/kg of L-DOPA). It could be estimated that approximately 3% of the total dose of L-DOPA given was decarboxylated by the blood-brain barrier. The possible influence by the regional differences in perfusion of the two regions seen after administration of L-DOPA was ruled out in measurements of local cerebral blood flow using the 14C-ethanol technique.
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Brain mast cells were studied in mice, rats, rabbits, hamsters, guinea pigs, cats, cows, monkeys, and humans with use of a variety of techniques. They were localized by staining with Astrablau or by toluidine blue-induced metachromasia and characterized by their ultrastructural appearance and by the presence of histochemically demonstrable histamine (o-phthaldiadehyde fluorescence method). The identity of the fluorophore was secured by microspectrofluorometry. Mast cells in brain usually had a perivascular localization but were also found scattered in the parenchyma. The regional variations in the number of mast cells agreed with the histamine concentration as measured fluorometrically. The variation was in the order leptomeninges greater than hypothalamus greater than cerebral cortex = mesencephalon greater than cerebellum = brain stem. In addition to histamine, murine mast cells stored serotonin, whereas bovine mast cells contained dopamine, visualized histochemically by the formaldehyde technique.
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