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Biomedical subjects

J E Hardebo

Publications and source records attributed to J E Hardebo.

At least 109 records · Page 6Linked to original sources
PubMed1979

Histofluorescence study on monoamine entry into the brain before and after opening of the blood-brain barrier by various mechanisms.

The relationship between exogenous, circulating monoamines to the wall of cerebral microvessels, and the entrance of these amines into the cerebral parenchyma was studied by the formaldehyde histofluorescence technique in rats. No monoamine fluorescence could be detected in the wall tissue of the microvessels (pericytes and andothelial cells) unless either MAO or COMT were inhibited; these are integral to the blood-brain barrier mechanisms to monoamines. After transient opening of the morphologic blood-brain barrier by either a hypertonic of hypertensive insult, the amine fluorescence in the walls of the microvessels was intensified compared to that which was noted after monoamine oxidase inhibition by itself. Following opening of the structural blood-brain barrier, the circulating amines also passed through into the neuropil where they were concentrated within neurons, as demonstrated by prior depletion of endogenous monoamine transmitters by reserpine. Thus, both enzymatic and morphologic mechanisms in the blood-brain barrier ar involved in impeding the passage of monoamines into the cerebral parenchyma.

Animals↗
PubMed1979

5-HT antagonism on cerebral and common carotid arteries by the 5-HT uptake inhibitors femoxetine and paroxetine.

The 5-hydroxytryptamine (5-HT) antagonism of methysergide was compared with that of the phenylpiperidine 5-HT uptake inhibitors, paroxetine and femoxetine, using two different models; the isolated cat middle cerebral artery and the common carotid artery of pithed rat perfused with the rat's own blood (autoperfusion). The extracorporeal circulation consisted of about 1.5 ml blood, which was temperature regulated to 36-38 degrees at the inlet to the carotid vessel by an automatic thermistor coupled heating system. In these experiments systemic blood pressure responses and perfusion pressure responses to 5-HT were recorded simultaneously. The 5-HT induced contractile response of the middle cerebral artery was reduced in a noncompetitive way by both uptake inhibitors at concentrations above 0.3 microM which is about 100 times the concentration needed for methysergide. In autoperfusion experiments inhibition was observed only at 5 mg/kg of both drugs. However, methysergide 0.001 mg/kg totally abolished all 5-HT responses. The uptake inhibitors can therefore be described as weak 5-HT antagonists.

Animals↗
PubMed1979

Studies on the enzymatic blood-brain barrier: quantitative measurements of DOPA decarboxylase in the wall of microvessels as related to the parenchyma in various CNS regions.

The presence of DOPA decarboxylase in cerebral microvessels (capillaries and venules) impedes the passage of circulating amine precursors into the brain. The relative amount of DOPA decarboxylase in this trapping mechanism as compared to the parenchyma per se was estimated in various CNS regions, measuring the formation of dopamine from L-DOPA in vitro or in vivo in two experimental models on rats and rabbits: (1) On the basis of the treatment with a peripheral decarboxylase inhibitor (carbidopa, which inhibits also microvascular DOPA decarboxylase in the CNS) it could be calculated that the enzyme in the microvessels of the caudate nucleus (rich in catecholamine nerve terminals), cerebellum (poor in catecholamine nerves), and spinal cord comprised 25, 91 and 79 per cent, respectively, of the total enzyme activity. (2) Measurement of dopamine formation in the spinal cord following transection at the midthoracic level (which causes degeneration of the catecholamine neurons caudal to the lesion since they are all descending) indicated that a similar fraction as found in the carbidopa model, 71%, of the total tissue decarboxylase activity resided in the microvessel walls. The results show that a considerable portion of tissue decarboxylase in the CNS is present in the microvessel walls, where it represents part of an enzymatic blood-brain barrier mechanism.

Animals↗
PubMed1979

Estimation of cerebral extraction of circulating compounds by the brain uptake index method: influence of circulation time, volume injection, and cerebral blood flow.

The Oldendorf "brain uptake index" method for estimating and characterizing the transport of circulating substances across the blood-brain barrier in the rat has been widely applied. The present study illustrates that minimizing the volume injected into the circulation to 10 microliters or less is necessary. Otherwise the flow artefacts, induced by the injected volume and the rate of injection, will influence the index. This principle is also relevant to techniques using intracarotid injections for the direct study of cerebral blood flow. The study also elucidates the need for reducing the circulation time after injection to about 5 sec, to avoid artefacts due to metabolism and back diffusion to the circulation of the substances studied.

Animals↗
PubMed1979

A comparative study on the uptake and subsequent decarboxylation of monoamine precursors in cerebral microvessels.

The endothelial cells and pericytes of brain microvessels (capillaries and small veins) are equipped with an enzymatic barrier, impeding the passage of circulating amino acids, such as amine precursors, into the brain. The properties of this mechanism was studied in brain slices and isolated microvessels from various species including man and also fetal material, following incubation in dihydroxyphenylalanine (DOPA), 5-hydroxytryptophan (5-HTP) and dihydroxyphenylserine (DOPS). A stereospecific, energy-dependent uptake leading to accumulation in the brain microvessel walls was found in all species studied; this process was found to exist already prenatally. The capacity of decarboxylation, the second step in the trapping mechanism at the blood-brain interphase, showed considerable species variation. The enzyme was present also in fetal brain microvessels. Inhibition experiments provided support for the presence of monoamine oxidase, but absence of catechol-O-methyl transferase, in the microvessel walls.

5-Hydroxytryptophan↗
PubMed1978

Influence of the cerebrovascular sympathetic innervation on regional flow, autoregulation, and blood-brain barrier function.

Experiments have been done on rats, rabbits and baboons to elucidate the role of the cranial sympathetic nerves originating in the superior cervical ganglia in the regulation of local cerebral blood flow, including its autoregulation, and in blood-brain barrier functions. Flow was measured by the [14C] ethanol technique, thermoclearance, and xenon-133 clearance. Blood-brain barrier functions were studied by the extravasation of an Evan's blue-albumin complex and by calculation of brain uptake index for two compounds (noradrenaline and inulin). Electrical stimulation of the sympathetic nerves reduces regional flow to a degree that is related to the amount of local perivascular innervation. The breakthrough of autoregulation during induced systemic hypertension is prevented by bilateral stimulation of the superior cervical ganglia. Acute sympathectomy markedly enhances the vascular penetration both at normotension (tested by brain uptake index for noradrenaline and inulin) and rapidly induced hypertension (evidenced by extravasation of Evans' blue). This extravasation of Evans' blud during acute hypertension can be counteracted by sympathetic nerve stimulation. The results give further support for the view that the cranial sympathetic nerves afford an efficient control of the cerebrovascular bed.

Animals↗
PubMed1978

Demonstration of 5-hydroxytryptamine receptors through inhibition by methergoline in cat pial arteries in vitro.

1 In an attempt to characterize further the nature of the 5-hydroxytryptamine (5-HT)-induced contraction of intracranial vessels, cat's middle cerebral artery was exposed to this amine and the specific 5-HT receptor antagonist, methergoline, under standardized conditions in vitro. Methergoline, in increasing concentrations, produced a parallel shift of the log dose-response curve for 5-HT. 2 The Arunlakshana-Schild plot gave a straight line with a slope of -0.85. The figure corresponding to the pA2 value was 8.80. 3 The findings offer further support for the assumption that the 5-HT-induced intracranial vasoconstriction is mediated by specific 5-HT receptors.

Animals↗
PubMed1978

Effects of dopaminergic agonists and antagonists on isolated cerebral blood vessels.

The vasomotor response of dopamine and dopaminergic agonists was studied in vitro on middle cerebral arteries from cat and pial arteries from humans. The action of various inhibitors was tested in order to define the receptors involved. A contractile response could be obtained by epinine, apomorphine and dopamine in the mentioned order of potency. The effect was 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 dilatation could be evoked by the dopaminergic agonists on actively contracted pial arteries. The relative potency was epinine greater than dopamine greater than apomorphine. The order of potency for the agonists, together with blocking experiments (including a parallel shift in the log dose-response curve induced by bulbocapnine), indicated that the vasodilatation is mediated by specific dopamine receptors.

Animals↗
PubMed1978

Effect of exogenous noradrenaline on local cerebral blood flow after osmotic opening of the blood-brain barrier in the rat.

1. The regional penetration into the brain of exogenous labelled noradrenaline (following unilateral injection into the internal carotid artery) was correlated with the effect of this amine on regional cerebral blood flow as measured by the [14C]ethanol technique in anaesthetized rats. 2. A hyperosmolar solution of urea was injected into the ipsilateral internal carotid artery to induce osmotic opening of the blood-brain barrier. 3. The extent of the blood-brain barrier damage was followed by macroscopic and fluorescence microscopic visualization of systemically injected Evans blue, and by the determination of the brain uptake index for noradrenaline. 4. The extravasation of Evans blue was restricted to the brain areas nourished by the internal carotid artery on the same side as the injection. 5. The normally low penetration of noradrenaline into the brain was enhanced fourfold in those brain regions that showed Evans blue extravasation following the administration of hypertonic urea. 6. In the same regions, the systemic administration of noradrenaline markedly increased local cerebral blood flow, compared to the contralateral hemisphere that was unaffected by the injection of urea. This effect on regional cerebral blood flow was blocked by the beta-receptor antagonist, propranolol.

Animals↗
PubMed1978

Pharmacological in vitro analysis of amine-mediated vasomotor functions in the intracranial and extracranial vascular beds.

The cerebrovascular system (the extra- as well as intracerebral vessels) receives a well-developed innervation by the adrenergic (originating in the superior cervical sympathetic ganglia) and cholinergic nerves. In addition, recent immunohistochemical studies have shown the presence of vasodilatory peptidergic nerve fibres. There may be an association of cerebral blood vessels also with various aminergic nerve systems of intracerebral origin. Besides the nerves, amine-containing mast cells are often located in close relation to the brain vessels. The specific receptors mediating the contractile and dilatory response of the various vasoactive amines--noradrenaline, dopamine, 5-hydroxytryptamine, histamine, acetylcholine--have been characterized in detail in pharmacological experiments. There is a number of major differences in the reactivity of cerebral vessels as compared to vasomotor functions in the peripheral circulation. The observations and results provide a basis for a better understanding of physiological neurogenic control mechanisms in the cerebral circulation, and they may also have implications for the interpretation of pathophysiological phenomena related to, for example, migraine and the vasospasm following subarachnoid hemorrhage.

Cerebral Arteries↗
PubMed1978

Potentiation and antagonism of serotonin effects on intracranial and extracranial vessels. Possible implications in migraine.

The vasoconstrictor action of serotonin and its interaction with drugs (methysergide, pizotifen, cyproheptadine, ergotamine, dihydroergotamine) that have serotonin-antagonistic properties and that are used in the treatment of migraine were studied on isolated feline and human intracranial and extracranial arteries in vitro. The intracranial vessels were more sensitive to serotonin than the extracranial ones. The serotonin antagonists caused the expected impairment of the serotonin-induced contraction. In minute doses, the various compounds potentiated the contraction produced by serotonin. There is reason to believe that the mechanism responsible for this interaction is selective for tryptaminergic agents. This dual action of the serotonin antagonists may contribute to a beneficial effect in migraine by an interference during both the vasoconstrictory and vasodilatory phase.

Animals↗
PubMed1978

Vasomotor response of cerebral blood vessels to dopamine and dopaminergic agonists.

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.

Animals↗
PubMed1977

Effects of intraventricular 6-hydroxydopamine on cerebrovascular CO2 reactivity in anesthetized rats.

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.

Animals↗