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Biomedical subjects

J E Hardebo

Publications and source records attributed to J E Hardebo.

At least 91 records · Page 5Linked to original sources

Species variation in the cerebrovascular response to neurotransmitters and related vasoactive agents.

Constrictory and dilatory responses of pial arteries to various receptor stimulants and modulators were evaluated in vitro and compared in rat, rabbit, cat and man. For the constrictory response, differences were noted especially in the rabbit, which responded strongly to histamine but poorly to noradrenaline and prostaglandin F2 alpha. Histamine was a prominent dilator, but only in rat and man. Isoprenaline induced effective vasodilation only in rat, and dopamine was efficient only in human pial arteries.

Animals↗

Cerebrovascular permeability and cerebral blood flow in hypertension induced by gammahydroxybutyric acid. An experimental study in the rat.

A sustained increase in blood pressure was obtained by intraperitoneal (i.p.) or intravenous (i.v.) administration of gammahydroxybutyric acid (GHBA, 1 g/kg) in rats under nitrous oxide anesthesia and in conscious rats with indwelling catheters in the aorta and a jugular vein. Evans blue-albumin and 125I-labeled serum albumin, given i.v. before GHBA, were used to study the function of the blood-barrier in rats killed 60 min after the injection of the drug. Brains from rats subjected to acute hypertension while awake showed less extravasation of albumin than did brains from anesthetized rats. Sectioning of the cervical symphatetic nerves did not increase extravasation in conscious rats. The cerebral blood flow, determined with the 14C-ethanol technique, did not significantly differ in GHBA-treated rats and controls. Because of the sustained increase in blood pressure, GHBA-induced hypertension might be a useful model for the study of long-term effects on the brain of hypertensive opening of the blood-brain barrier.

Anesthesia, General↗

Action of 4-aminopyridine on the cerebral circulation.

4-Aminopyridine (4-AP) facilitates both inhibitory and excitatory synaptic activity in the central nervous system, and may, therefore, be a drug of potential therapeutic use in brain diseases with a disturbed synaptic transmission. In the present study the vasomotor effects upon isolated feline brain vessels, and regional cerebral blood flow and brain cortical metabolism in rats were examined. At high concentrations (above 10-6 M) a minor vasoconstriction was obtained of isolated pial vessels. Measurements of regional cerebral blood flow using the 14C-ethanol technique resulted in a significant increase in blood flow of caudate nucleus (93%), thalamus (74%) and cerebellum (82%). The arteriovenous oxygen difference of cortical tissue was reduced from 3.20 mmol O2/ml to 1.69 mmol O2/ml by 4-AP. This was not associated with an increase in cortical blood flow. Calculation of the cortical metabolic rate of oxygen, however, failed to demonstrate any significant change.

Aminopyridines↗

Cerebral microembolization in the rat: changes in blood-brain barrier permeability and cerebral blood flow as related to the degree of ischemia.

Unilateral cerebral microembolism was performed in the rat by injecting calibrated, 50 micrometers in diameter, carbonized microspheres into the internal carotid artery. The events that follow brain ischemia due to cerebral embolization were studied by the analysis of the blood-brain barrier (BBB) function, the degree of regional cerebral blood flow (CBF) and the development of brain edema. Two hours after embolization there was no change in the brain water content. The local CBF (14C-ethanol technique) was only reduced in the ipsilateral hemisphere. Twenty-four hours after embolization the brain water content was increased significantly in the ipsilateral, but not in the contralateral hemisphere. Local CBF further decreased in the ipsilateral hemisphere and a reduction in flow was also observed in the contralateral hemisphere. Embolization led to an increase in the BBB permeability, analysed as regional penetrability of 3H-dextran and of Evans blue-albumin complexes, which was restricted to the side of the injection of the microspheres.

Animals↗

Opening of the blood-brain barrier by acute elevation of intracarotid pressure.

A method for local opening of the blood-brain barrier in the territory of one internal carotid artery in the rat is described. A local hypertensive insult is induced by rapid infusion of blood into the internal carotid via the external carotid. The hemodynamic changes caused by the infusion, in particular relation to the threshold and extent of barrier opening, are analyzed. This mode of hypertensive barrier opening may be advantageous to those in which the insult is induced systematically, especially when studying the cerebrovascular effects of neurotransmitter catecholamines, since all the latter methods interfere with adrenergic mechanisms. Further, unilateral intracarotid infusion may allow the territory of the contralateral middle cerebral artery to be used as internal control.

Animals↗

The effect of temperature elevation on the cerebrovascular response to noradrenaline and 5-hydroxytryptamine.

Fever frequently complicates stroke and subarachnoid haemorrhage. A transient rise in transmitter monoamine levels of plasma and cerebrospinal fluid occurs in these diseases. The present study demonstrates an enhanced vasoconstrictor response of cerebral vessels to noradrenaline-but not 5-hydroxytryptamine-following a rise in temperature. The augmented response is more likely due to an impaired inactivation (re-uptake) of the amine than to an altered sensitivity of the post-synaptic alpha-adrenergic receptor, since it could be reproduced by pretreatment with cocaine. The finding indicates that it may be important to combat fever in these patients.

Animals↗

Vasodilatation augments the blood-brain barrier lesions induced by an acute rise in intracarotid pressure.

The vessel wall tension is the product of pressure and internal radius divided by the vessel wall thickness. Hence, dilated vessels will be exposed to higher tension at a given intraluminal pressure. Provided the rise in cerebrovascular intraluminal pressure is sufficiently prominent, transient opening of the morphologic blood-brain barrier will occur. In the present study pressure increase, not sufficient in itself to cause barrier opening, was induced. However, at concomitant dilatation of the vessels--as induced by CO2 or papaverine--under otherwise identical pressure conditions a barrier opening was obtained. Hence, vasodilatation of cerebral vessels will increase their vulnerability to hypertension.

Animals↗

Hemodynamic changes in brain caused by local infusion of hyperosomolar solutions, in particular relation to blood-brain barrier opening.

The intracarotid infusion of hyperosmolar aqueous solutions such as urea is widely used to transiently open the blood-brain barrier in various animal species. In the present study in the rat an attempt was made to analyze the hemodynamic changes caused by the intracarotid infusions with special reference to possible mechanisms underlying the barrier opening. The cerebral blood flow (as reflected by the cerebral venous outflow rate) intracranial pressure, intracarotid pressure and systemic blood pressure were continuously measured during and following the infusions. It was found that intracarotid infusions of hyperosomolar solutions induce cerebral vasodilation and flow increase. Autoregulation is impaired. Probably, a direct vasodilator mechanism is involved but, depending on volume and osmolarity of the solution used, the changes may be heavily influenced by vascular distention due to intracarotid pressure effect, and by systemic pressure changes. These mechanisms are in common with other methods for barrier opening. The local vasomotor and systemic effects of a hyperosmolar solution of urea, capable of opening the barrier, are not normalized until about 6 min after the administration.

Animals↗

Barrier mechanisms for neurotransmitter monoamines and their precursors at the blood-brain interface.

The integrity of the endothelial cell lining of the cerebrovascular bed constitutes a morphological blood-brain barrier mechanism to neurotransmitter monoamines. Circulating monoamines are prevented from entering the brain primarily at the luminal membrane of the endothelial ling. The small percentage of amines that may pass this membrane is deaminated within the endothelial cells and pericytes of brain microvessels (capillaries, venules, and small veins) and, in the case of large parenchymal and pial vessels, in the smooth muscle layers, where O-methylation also takes place. In the choroid plexus a corresponding deamination and O-methylation takes place in the epithelial cells. The presence of these enzymes constitutes a further, enzymatic, blood-brain barrier in the brain vessels for these monoamines. The monoamine precursors L-3,4-dihydroxyphenylalanine (L-dopa) and L-5-hydroxytryptophan readily pass from the luminal endothelial cell membrane but are trapped by another enzymatic barrier mechanism. Within the endothelial cells and pericytes of the microvasculature, these compounds are decarboxylated to their corresponding amines and then immediately deaminated. One clinical implication of these enzymatic barrier mechanisms is the use of decarboxylase and monoamine oxidase inhibitors as adjuncts to L-dopa treatment of Parkinson disease; these substances facilitate the entry of L-dopa into brain and thus increase the amount of dopamine available at receptor sites. A brief hypertensive or hypertonic stimulus can transiently open the blood-brain barrier through an effect on endothelial cell linings. High circulating concentrations of monoamines can also open the morphological barrier, but probably only indirectly by inducing an acute rise in systemic blood pressure. Once the barrier is open, systemically administered monoamines enter the brain parenchyma, where they can induce pronounced changes in cerebral blood flow and metabolism.

5-Hydroxytryptophan↗

Effect of an anion transport inhibitor on blood-brain barrier lesions during acute hypertension. Possible prevention of transendothelial vesicular transport.

Opening of the blood-brain barrier (BBB) by a hypertensive insult comprises the formation of endothelial micropinocytosis. Constricted vessels are less vulnerable to the insult. In the present study SITS (4-acetamido-4'-isothiocyano-stilbene-2,2'-disulfonic acid disodium) was shown to prevent leakage across the BBB into the brain parenchyma following a hypertensive insult induced by a local increase of the intraluminal pressure in anesthetized rats and by i.v. administration of adrenaline or bicuculline in conscious unrestrained animals. Since SITS induced an increase in cerebral blood flow the protection cannot be explained by a constrictory action on the cerebral vessels. SITS is a drug with complex action on the cell membrane including an inhibitory effect on anion transport mechanisms and on some c-AMP mediated processes. It is possible that the protection of BBB observed in the present study is connected to a reduction of c-AMP but membrane stabilizing effect can at present not be excluded.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗

Vincristine reduces damage of the blood-brain barrier induced by high intravascular pressure.

A reversible opening of the structural blood-brain barrier (BBB) was accomplished in rats by rapidly increasing the hydrostatic pressure either through forced intracarotid infusion of autologous blood or i.v. administration of angiotensin, whose effect was exaggerated by previous injection of the vasodilator, papaverine. The extent of barrier damage was evaluated in terms of the extravasation of Evans blue-albumin complex or the brain uptake of circulating [14C]inulin. Pretreatment of the animals with the antimitotic agent, vincristine, significantly reduced the barrier damage. This is interpreted as an effect of vincristine on intracellular microtubule systems, which may be involved in the vesicular transport across the endothelial cells of brain microvessels.

Angiotensin II↗

Enzymes related to monoamine transmitter metabolism in brain microvessels.

The activities of tyrosine hydroxylase, aromatic L-aminoacid decarboxylase, monoamine oxidase, and catechol-O-methyltransferase were measured in microvessel (capillaries and venules), parenchymal arterioles, and pial vessels from rat brains, and the decarboxylase activity was compared in brain microvessels from rabbit, cat, dog, pig, cow, baboon, and man. Cranial sympathectomy was performed to estimate the neuronal contribution to the enzyme activities. All vascular regions had substantial activities of the various enzymes studied. The activity of aromatic L-aminoacid decarboxylase in cerebral microvessels was high in rat, dog, pig, cow, and man; intermediate in rabbit and cat; and low in baboon. In addition to this enzyme, cerebral microvessels also contained tyrosine hydroxylase and monoamine oxidase. Aromatic aminoacid decarboxylase and monoamine oxidase serve an enzymatic barrier function at the microvascular level, whereas the main function of tyrosine hydroxylase is probably to synthesize monoamines within nerve terminals that remain in close association with microvessels under the conditions used for preparation of the microvascular fraction. In larger intracerebral and pial vessels monoamine oxidase was present both in the wall itself and in perivascular sympathetic nerves; the remaining two enzymes had a primarily neuronal localization. The latter types of vessels also contained catechol-O-methyltransferase in their walls.

Animals↗

Barrier mechanisms for neutrotransmitter monoamines in the choroid plexus.

Studies were performed on choroid plexuses from mouse and rat. The plexus tissue, sympathectomized to avoid interference from adrenergic nerves, is able to accumulate L-DOPA as well as NA and 5-HT against a concentration gradient. Within the plexus tissue these compounds are metabolized by aromatic L-amino acid decarboxylase, MAO and COMT, whose activities were determined radiometrically. On the basis of this and the fate of systemically administered L-DOPA and DA studied by fluorescence histochemistry it is suggested that the epithelium of the choroid plexus provides not only a structural but also an enzymatic barrier for transmitter amines. The enzymatic barrier for amine precursors is considerably less sufficient at this blood-CSF interphase. The trapping of monoamines resembles the enzymatic barrier present in the endothelial cells and pericytes at the microvascular level of the blood-brain interphase.

Animals↗

Characterization of the in vitro uptake of monoamines into brain microvessels.

The ability of brain microvessels to take up and metabolize transmitter monoamines (DA, NA, A and 5-HT) was studied in tissues from several species (rat, guinea-pig, cat, dog, baboon, man) in vitro. Following incubation, slices were analyzed by fluorescence histochemistry and isolated microvessels by measurement of radioactivity from tritiated amine. Provided the MAO activity was inhibited a strong accumulation, similar for all animals tested, occurred in the wall (endothelial cells and pericytes) of capillaries and venules--but not in larger vessels--of all species. The degree of amine uptake and accumulation and the conditions under which it was inhibited suggested that it reflected a saturable, energy-dependent process, with characteristics of both the extraneuronal and neuronal type of uptake processes. The mechanism may serve as an inactivation of transmitter monoamines at the blood-brain interphase, thereby assisting in the control of transmitter levels in the cerebral extracellular compartment.

Animals↗

Cerebrovascular sympathetic denervation and blood-brain barrier function in conscious rats.

Electrical stimulation of the sympathetic nerves to the cerebrovascular bed enables the resistance vessels to better withstand a high blood pressure in terms of blood-brain barrier integrity. Sympathetic denervation could hence be expected to lead to a decrease in cerebrovascular tone and increased vulnerability of the blood-brain barrier. In the present study acute hypertension was induced in conscious unrestrained rats by administration of angiotensin or bicuculline. The albumin leakage into the brain, as studied by Evans blue-albumin and 125I labelled human serum albumin, was not enhanced in acutely or chronically sympathectomized rats compared to controls.

Angiotensin II↗

Interaction of a potential antimigraine drug (Org GC 94) with the vasomotor action of serotonin.

The interaction of a potential anti-migraine drug (Org GC 94) with the vasomotor action of 5-HT in vitro in feline, canine and human intra- and extracranial arteries, as well as in vivo in the canine nasal vascular bed as been investigated. In the two in vitro preparations, i.e. using superfusion or bath techniques, the intracranial vessels were more sensitive to 5-HT vasoconstriction than the extracranial ones. As both the maximum contraction and the slope of the dose-response curves were reduced by increasing concentrations of Org GC 94, the antagonism of 5-HT did not involve competitive blockade of 5-HT receptors. The dilator response was tested in arteries brought to a higher tone with prostaglandin F2 alpha. 5-HT produced a dose-dependent dilatation which, like the vasoconstriction, was antagonized in a non-competitive manner by Org GC 94. Intra-arterial injections of 5-HT provoked nasal vasoconstriction and this response was clearly potentiated by Org GC 94 in low doses while higher doses inhibited the vascular response to 5-HT. The specific effect of Org GC 94 in vivo may be the potentiation of 5-HT-induced vasoconstriction. The hypothesis is discussed that the so-called anti-5-HT agents act in migraine patients as partial agonists of 5-HT, mimicking rather than antagonizing 5-HT.

Animals↗