Biomedical subjects

J E Hardebo

Publications and source records attributed to J E Hardebo.

At least 55 records · Page 3Linked to original sources

PubMed1990

Kinetic studies on uptake of serotonin and noradrenaline into pial arteries of rats.

A population of cerebrovascular nerve fibers have recently been found to store serotonin (5-hydroxytryptamine; 5-HT). There is reason to assume that these 5-HT-containing fibers have a sympathetic rather than an intracerebral origin. This was further elucidated in the present study in which the uptake mechanisms of 5-HT and noradrenaline (NA) were characterized and compared in rat pial arteries by measuring the accumulation of [3H]5-HT and [14C]NA under various experimental conditions in vitro. Sympathectomized vessels served as blanks. The uptake into the perivascular sympathetic nerves was dependent on time as well as concentration and was saturable. The Km values were similar, 0.17 microM for 5-HT and 0.15 microM for NA, but the Vmax value was 10 times higher for NA (2.38 and 25 pmol/mg/15 min, respectively). The two amines competed with each other in the sympathetic uptake, as studied by inhibition of the accumulation of one labeled amine by the other nonlabeled amine. Corticosterone, acting on the extraneuronal process, significantly inhibited the 5-HT uptake but had no substantial effect on NA. Reserpine, blocking the intraaxonal vesicular stores, markedly attenuated the accumulation of NA, but not of 5-HT. The selective uptake blocker paroxetine reduced the 5-HT uptake with much higher potency than the NA uptake, whereas desipramine predominantly inhibited NA uptake. The pial 5-HT uptake was not significantly affected by lesion of the raphe complex, whereas it was reduced to half following superior cervical ganglionectomy. The results suggest that the 5-HT present in nerves associated with pial vessels at the base of the brain is taken up through an efficient axonal mechanism, functionally related but not identical to the uptake process for NA.

Animals↗

PubMed1990

Selective electrical stimulation of postganglionic cerebrovascular parasympathetic nerve fibers originating from the sphenopalatine ganglion enhances cortical blood flow in the rat.

Recently, the origins and pathways of cerebrovascular acetylcholine- and vasoactive intestinal polypeptide-containing nerves have been elucidated in detail in the rat: The sphenopalatine ganglion is the major source for postganglionic parasympathetic fibers to the vascular beds of the cerebral hemispheres. To clarify the functional role of the nerves on cerebral blood vessels in vivo, brain cortical microvascular blood flow was measured in rats during electrical stimulation of these particular postganglionic fibers. Animals were subjected to transection of the right nasociliary nerve 2 weeks before the flow measurements to eliminate activation of peptidergic sensory fibers. Relative change in microvascular blood flow was continuously recorded by a laser-Doppler flowmeter system under alpha-chloralose anesthesia. The postganglionic fibers were electrically stimulated just proximal to the ethmoidal foramen by a bipolar platinum electrode (5 V; 0.5 ms; 3, 10, 30, 60 Hz; as a continuous stimulation for 90 s). Stimulation at 10 Hz induced a marked increase of the cortical blood flow (CoBF) on the ipsilateral side, whereas no change was observed on the contralateral side. It reached a maximum mean value of 42.5% at 46 s, and then slightly declined during the remaining stimulation period. No significant changes were observed in the mean arterial blood pressure or blood gases during or after stimulation. Both atropine and scopolamine failed to alter this flow increase. Electrical stimulation of the postganglionic fibers at different frequencies revealed a maximal increase in the CoBF at 30 Hz in the control situation (47.2%), but at 10 Hz after scopolamine administration (51.6%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Origins and pathways of choline acetyltransferase-positive parasympathetic nerve fibers to cerebral vessels in rat.

The presence of cholinergic nerve fibers in the brain vasculature has been a matter of controversy, partly due to the lack of a reliable histochemical marker. Accordingly, no distinct information about the origin and pathways for such fibers has been available. In the present study on the rat pial vasculature, utilizing a choline acetyltransferase (ChAT) antibody, which is able to demonstrate this enzyme in peripheral nervous tissue, evidence was obtained for an innervation by cholinergic fibers of large pial arteries. Vasoactive intestinal polypeptide (VIP) was present in or in close association with these fibers. By the aid of the retrograde axonal tracer True Blue (TB) applied to the middle cerebral arterial wall, such fibers were shown to originate in a subgroup of ChAT-positive cells in the sphenopalatine, otic, and internal carotid ganglia, which, in addition, contained VIP. The ChAT-positive pial nerve fibers were few in relation to the VIP-immunoreactive fibers, as was also illustrated by the few TB-positive cells in the ganglia that were ChAT positive as compared with the number of cells that were VIP positive. Only a small population of ChAT-containing neurons in these ganglia appeared to project to the pial vessels. The pathway from the sphenopalatine ganglion is via a membranous structure on the medial orbital wall, through the ethmoidal foramen, and along the internal ethmoidal artery to reach the circle of Willis. The fibers from the internal carotid and otic ganglia probably bridge to the internal carotid artery in the carotid canal, those from the otic ganglion after an initial course in the lesser superficial petrosal nerve.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Characterization of a neurogenic and a direct smooth muscle component in the contractile response to electrical field stimulation in rat tail artery.

1. The extent to which neuronal transmitter release contributes to the contractions induced by transmural nerve stimulation of the rat tail artery at various stimulus intensities was characterized. 2. Using tetrodotoxin, which blocks conduction of the action potential along the nerves, and omega-conotoxin GVIA, a blocker of transmitter release from the nerve terminals, as well as chemical and surgical denervations of the perivascular sympathetic nerves, a neurogenic and a direct smooth muscle component could be clearly separated. 3. The neurogenic component was fast in onset, rise and decline (after the end of stimulus), and showed a voltage dependency only at lower stimulus intensities. The non-neurogenic component was slower in onset, rise and decline, and showed a strict voltage dependency throughout the whole stimulus range. This implies that the non-neurogenic component becomes increasingly prominent at high, non-physiological voltages. Mechanisms underlying the declining neurogenic contractile response at the stronger stimulus intensities are discussed. 4. We found no evidence supporting the existence of a possible tetrodotoxin- or omega-conotoxin GVIA-resistant contractile component originating from the perivascular nerves (sympathetic or non-sympathetic). Thus, in order to get a purely neurogenic response stimulus intensities should be minimized to give a contraction that is fully sensitive to these two agents. 5. Transmitter release from the perivascular sympathetic nerves was fully responsible for the purely neurogenic contractions. Activation of postjunctional alpha 1-adrenergic receptors was mainly involved, with a substantial contribution from alpha 2-receptors, and a minor contribution from neuropeptide Y receptors. There was no evidence for a contractile component linked to activation of so-called gamma-adrenergic receptors. 6. Beta-adrenergic receptors, serotonergic, cholinergic, prostanoic or purinergic mechanisms do not appear to contribute to the neurogenic (or the non-neurogenic) response. The neurogenic contraction does not utilize potential-sensitive calcium channels.

Acetylcholine↗

PubMed1990

Effect on cortical blood flow of electrical stimulation of trigeminal cerebrovascular nerve fibres in the rat.

It has recently been demonstrated in the rat that the majority of cerebrovascular pain fibres containing immunoreactive substance P and calcitonin gene-related peptide reach the vessels via the nasociliary nerve, a branch of the ophthalmic trigeminal division. In order to elucidate the effect of these nerves on blood flow in vivo, the relative changes in cortical microvascular flow were continuously monitored by a laser-Doppler flowmeter system during electrical nerve stimulation, with the central nerve connection cut and after removal of neighbouring dilatory parasympathetic nerves. The nasociliary nerve on one side was stimulated proximal to the ethmoidal foramen by a bipolar platinum electrode. Activation at different frequencies, continuously or as bursts with a constant voltage, impulse duration and total stimulus length, revealed that a maximum increase in blood flow amounting to 16.7% after 36 s was obtained with continuous stimulation at 10 Hz. Flow markedly declined during the following 1-min stimulation period. No changes in contralateral cortical blood flow, mean arterial blood pressure or blood gases were observed during or after stimulation. The present study demonstrates for the first time that direct and selective electrical activation of trigeminal cerebrovascular nerves induces an increase, albeit small and transient, in blood flow within the brain.

Animals↗

PubMed1989

Origins of substance P- and calcitonin gene-related peptide-containing nerves in the internal carotid artery of rat.

An aggregation of substance P (SP)- and calcitonin gene-related peptide (CGRP)-containing nerve cells (internal carotid mini-ganglion) is described at the junction between the greater superficial petrosal nerve and the internal carotid nerve close to the internal carotid artery. A retrograde tracer dye technique demonstrates that this ganglion and the trigeminal and superior vagal ganglia supply the internal carotid artery with SP/CGRP fibers at, above and below this level, respectively. Implications of this finding for cranial painful syndromes in man are discussed.

Animals↗

PubMed1989

Galanin-positive nerves of trigeminal origin innervate rat cerebral vessels.

(GAL)-positive nerve fibers in rat cerebral vessels were demonstrated by immunohistochemistry, and their origin in the trigeminal ganglia and pathway in the nasociliary nerve to the vessels was shown by retrograde tracer technique and nerve transection. Some fibres in the vertebrobasilar system appear to originate in extracranial sources. With the antiserum used only few GAL fibers could be seen in the vessels, mostly in the vertebrobasilar system. In neonatally sympathectomized animals a rich network could be visualized in most pial arteries - still particularly in the vertebrobasilar system - probably as a result of a diminished competition for nerve growth factor. No vasomotor effect of GAL could be detected in isolated segments of pial arteries, neither in normal nor in sympathectomized animals, which rules out a direct postsynaptic effect on vascular tone. GAL did not display prejunctional modulatory action on the adrenergic nerves present in the vascular preparations. A sensory function of GAL is discussed.

Adrenergic Fibers↗

PubMed1989

Trigeminal fibre collaterals storing substance P and calcitonin gene-related peptide associate with ganglion cells containing choline acetyltransferase and vasoactive intestinal polypeptide in the sphenopalatine ganglion of the rat. An axon reflex modulating parasympathetic ganglionic activity?

In immunohistochemical studies on rat two types of nerve fibres, both showing substance P and calcitonin gene-related peptide-like immunoreactivity, have been localized in the sphenopalatine ganglion, the principal cells of which contain both vasoactive intestinal polypeptide and choline acetyltransferase. One fine-calibre fibre type forms basket-like arrangements around approximately 3-5% of the principal neurons, whereas another, more coarse type traverses the ganglion without making contacts with the ganglion cells. By transection of nerves connecting with the ganglion, in combination with retrograde tracing experiments, it was concluded that the fine-calibre fibres exclusively come from the trigeminal ganglion, whereas the second type in addition, and mainly, originate in the internal carotid ganglion which is situated along the greater superficial petrosal nerve and the pterygoid nerve at their junction with the internal carotid nerve. The brain vasculature was shown to be one target structure for the innervated principal cells in the sphenopalatine ganglion. The arrangement provides the functional possibility for a modulatory interaction between the autonomic and sensory systems, thus resembling an axon reflex mechanism in the peripheral nervous system.

Animals↗

PubMed1989

Origins and pathways of cerebrovascular nerves storing substance P and calcitonin gene-related peptide in rat.

Origins and pathways of cerebrovascular substance P- and calcitonin gene-related peptide-positive nerves in rat were studied by immunohistochemistry combined with denervation experiments and retrograde axonal tracer technique. The two peptides have been found to coexist in one and the same neuron. After sectioning of the nasociliary nerve bilaterally the substance P/calcitonin gene-related peptide fibers in the rostral half of the circle of Willis and its branches were eliminated, whereas the number decreased in the caudal half of the circle of Willis and rostral two thirds of the basilar artery. Substance P/calcitonin gene-related peptide fibers in the internal carotid arteries, the caudal third of the basilar artery and the vertebral arteries were not affected by the nerve section. After application of the retrograde axonal tracer True Blue onto the proximal segment of the middle cerebral artery the dye accumulated in several Substance P/calcitonin gene-related peptide-containing cells in the ophthalmic division of the ipsilateral trigeminal ganglion and in a few cells in the maxillary trigeminal division and in the internal carotid miniganglion. No other cranial ganglia accumulating the dye contained any substance P/calcitonin gene-related peptide-positive cells. It is concluded that the rostral portion and part of the caudal portion of the cerebral vessels are innervated by substance P/calcitonin gene-related peptide-containing fibers from the trigeminal ganglion and the internal carotid miniganglion. The great majority of trigeminal fibers reach the vessels via the nasociliary nerve of the ophthalmic division, which enters the cranial cavity through the ethmoidal foramen, whereas fibers from the miniganglion project directly to the bypassing internal carotid artery. A probable pathway for the fibers from the maxillary division is suggested. The caudal portion receives, in addition, a supply from other sensory ganglia (lower cranial and/or upper cervical dorsal root ganglia).

Animals↗

PubMed1989

Low CSF met-enkephalin levels in cluster headache are elevated by acupuncture.

Significantly lower met-enkephalin levels were found in CSF from cluster headache sufferers as compared to age-matched healthy volunteers, whereas it was not possible to demonstrate any clear-cut difference for beta-endorphin. CSF opioid levels may rise following manual or electroacupuncture. It was studied whether traditional Chinese (manual) acupuncture affected CSF levels of met-enkephalin or beta-endorphin in these patients, and to what extent this treatment would be beneficial for the headache. A significant rise in lumbar CSF met-enkephalin levels was found, whereas no clear change in beta-endorphin levels was obtained. The treatment was, however, of little value in preventing the headache.

Acupuncture Therapy↗

PubMed1989

Excitatory amino acids and cerebrovascular tone.

Levels of excitatory amino acids in the brain extracellular fluid compartment rise during pathological conditions in the brain such as ischaemia, anoxia and epilepsy. One such amino acid, glutamate, is present in sensory nerve fibres innervating, for example, cerebral vessels. Enhanced levels of circulating glutamate and aspartate are found in migraine sufferers. The present study examined whether excitatory amino acids, in concentrations found in the brain extracellular fluid compartment during pathological conditions, exert a direct effect on cerebrovascular tone. As tested in flow-regulating pial arteries from rat, cat and man, no such constrictive or dilatory effect was obtained.

Adult↗

PubMed1989

Characterization of dilatation induced by electrical field stimulation in mammalian cerebral and peripheral vessels.

The ability of electrical field stimulation in releasing transmitter from isolated blood vessels in vitro, during recordings of constrictor or dilator responses, is dependent upon an appropriate choice of stimulation parameters which avoid concomitant change in tone due to a direct effect on the vascular smooth muscle membrane. In many species, including man, small arteries such as pial arteries frequently respond to electrical field stimulation with a dilatation which is TTX-resistant. Such dilatations occur even with stimulus parameters of 7.5 V/60 mA at 0.1 ms, 6 Hz. The stimulation parameters required to induce the TTX-resistant response are just above those needed to obtain a purely neurogenic contractile or dilatory response in vessels equipped with a dense net of adrenergic nerves, such as rabbit central ear artery, and, in addition, highly sensitive postsynaptic alpha- or beta-adrenergic receptors, such as the buccal segment of the facial vein. This prompted us to characterize further the nature of the response. It was tested whether the relaxation, despite being TTX-resistant, might be neurogenic in origin. 4-Aminopyridine, in doses that usually enhance the transmitter release from nerves, did not affect the response. Blockade by a variety of dilator antagonists, the presence of excess amounts of known dilators or removal or emptying of known vasodilator nerves did not inhibit the response. Removal of extracellular calcium did not abolish the response. Therefore, it is highly unlikely that neuronal release is involved to any measurable extent in this response. The relaxation was not significantly affected by removal of endothelium, blockade of endothelium-derived relaxing factor, or interference with mast cells. At modest stimulatory parameters (12-13 V/96-104 mA at 0.1 ms, 7-8 V/56-64 mA at 0.3 ms, at 6 Hz) chlorine gas bubbles could be seen forming at the electrode or mounting hook; this gas is toxic to the musculature and relaxes a pre-contracted vessel. At stronger stimulation (greater than 12 V/96 mA, greater than 0.3 ms at 6 Hz) a relaxation supervened that was almost prevented by scavengers of oxygen free-radical metabolites. This relaxation was partly irreversible, indicating damage to the contractile elements. We conclude that when studying electrically induced release of vasodilator transmitters in vessels not equipped with an highly effective transmitter/receptor function, even a small rise in stimulatory parameters--in order to enhance transmitter release--causes relaxations that are non-neurogenic.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1989

Endothelin is a potent constrictor of human intracranial arteries and veins.

Endothelin, a peptide produced in endothelial cells, was found to be a potent constrictor of human pial arteries through a direct, slow action on the smooth muscle cell, with a pD2 value of 8.54. It was less potent as a constrictor in pial veins (pD2 7.80) and in branches of the middle meningeal artery and superficial temporal artery (pD2 7.61 and 7.77). The major component of the contractile response in the arteries comprises an effect on potential-operated calcium channels, as evidenced by tests with nimodipine. Endothelin may regulate intracranial vessels tonically during physiological as well as pathophysiological conditions.

Adult↗

PubMed1988

Origins and pathways of cerebrovascular vasoactive intestinal polypeptide-positive nerves in rat.

In order to clarify the origins and pathways of vasoactive intestinal polypeptide (VIP)-containing nerve fibers in cerebral blood vessels of rat, denervation experiments and retrograde axonal tracing methods (true blue) were used. Numerous VIP-positive nerve cells were recognized in the sphenopalatine ganglion and in a mini-ganglion (internal carotid mini-ganglion) located on the internal carotid artery in the carotid canal, where the parasympathetic greater superficial petrosal nerve is joined by the sympathetic fibers from the internal carotid nerve, to form the Vidian nerve. VIP fiber bridges in the greater deep petrosal nerve and the internal carotid nerve reached the wall of the internal carotid artery. Two weeks after bilateral removal of the sphenopalatine ganglion or sectioning of the structures in the ethmoidal foramen, VIP fibers in the anterior part of the circle of Willis completely disappeared. Very few remained in the middle cerebral artery, the posterior cerebral artery, and rostral two-thirds of the basilar artery, whereas they remained in the caudal one-third of the basilar artery, the vertebral artery, and intracranial and carotid canal segments of the internal carotid artery. One week after application of true blue to the middle cerebral artery, dye accumulated in the ganglion cells in the sphenopalatine, otic and internal carotid mini-ganglion; some of the cells were positive for VIP. The results show that the VIP nerves in rat cerebral blood vessels originate: (a) in the sphenopalatine, and otic ganglion to innervate the circle of Willis and its branches from anterior and caudally and (b) from the internal carotid mini-ganglion to innervate the internal carotid artery at the level of the carotid canal and to some extent its intracranial extensions.

Animals↗

PubMed1988

Differential vasomotor action of noradrenaline, serotonin, and histamine in isolated basilar artery from rat and guinea-pig.

Vasomotor effects of the amines, serotonin (5-hydroxytryptamine; 5-HT), noradrenaline (NA) and histamine, were studied in isolated basilar arteries (BA) of the rat and guinea-pig in vitro. 5-HT produced marked contraction in rat BA, about 70% of that induced by high (124 mM) K+ solution. This response was inhibited by the specific 5-HT2 receptor antagonist, ketanserin, with a pA2 value of 9.35. In the guinea-pig, 5-HT caused only moderate contraction amounting to 30% of that produced by K+. Ketanserin at concentrations up to 10(-6) M showed a comparatively small, non-surmountable inhibition of the contraction. EC50 values for 5-HT in the guinea-pig and rat were 5.65 x 10(-8) M and 3.70 x 10(-7) M, respectively. NA had no effect on rat BA, but moderately contracted guinea-pig BA. The contraction was not altered by yohimbine but was inhibited by prazosin. Histamine contracted guinea-pig BA with a maximum that was 110% of the K+-induced contraction. It was not changed by the H2 antagonist, cimetidine. The H1 antagonist, pyrilamine, caused competitive inhibition with a pA2 of 9.20 at a slope of 0.94. In preconstricted rat BA, histamine induced vasodilatation in a concentration-dependent manner. The H1 agonist, pyridylethylamine (PEA), and the H2 agonist, impromidine, dilated less effectively than histamine. The vasodilatation induced by histamine was inhibited by the H2 antagonist, cimetidine, and to a smaller extent by the H1-receptor antagonist, pyrilamine. Removal of the endothelium abolished the vasodilator effect of PEA but not that of impromidine. In vessels with intact endothelium, the vasodilatation caused by histamine was slightly reversed by pyrilamine, which did not affect the dilatation in endothelium denuded vessels. Cimetidine markedly reversed this vasodilator effect in both intact and endothelium denuded preparations; in the latter the counteraction was almost complete. In precontracted guinea-pig vessels, histamine failed to induce dilatation even in the presence of the H1 antagonist, pyrilamine. Thus, 5-HT-induced contraction is mediated by 5-HT2 receptors in the rat and probably by 5-HT1 receptors in the guinea pig. NA failed to contract rat BA but contracted guinea-pig BA through alpha 1 receptors. Histamine was a potent dilator agent in rat BA through a combination of both H1 and H2 receptors. The dilatation mediated by the H1 receptors, but not that mediated by H2 receptors, was endothelium-dependent. Histamine caused strong vasoconstriction in the guinea-pig BA through H1 receptors.

Adrenergic alpha-Antagonists↗

PubMed1988

Functional heterogeneity of the cerebrovascular endothelium.

We have investigated the heterogeneity of endothelial cells from especially two aspects. One is the biochemical and functional differences in their cerebral and peripheral vascular beds, focusing on the capillaries, in regard to the blood-brain barrier properties of the endothelium in the brain. The other aspect concerns the various functional roles that the endothelial cells may play in the regulation of cerebral blood flow by vasoactive neurotransmitters, in terms of the enzymatic and morphological blood-brain barriers, the contractile properties of the capillary endothelium and the endothelium-mediated vasodilatation in the brain.

Animals↗

PubMed1987

P1- and P2-purine receptors in brain circulation.

As there is increasing evidence that purines are involved in cerebral vasodilatation, purine receptors were characterized pharmacologically in pial arteries from rabbit, cat and man, and compared with purine receptors in various non-cerebral vascular beds. Use of agonists and antagonists allows purine receptors to be divided into P1 and P2 receptors. The location of these receptors on the surface of the various cells in the cerebrovascular wall was determined. P1 receptors, stimulated primarily by adenosine, are located on the smooth muscle cells, causing relaxation. P2 receptors, stimulated primarily by ADP and ATP, are located on endothelial cells and cause relaxation, and are also found on smooth muscle cells where they cause contraction. Slowly degradable ATP analogues were considerably more potent constrictors than ATP but not equally potent as dilators, which might indicate minor differences between the P2 receptors on smooth muscle and on endothelium. The P1 receptor was further subclassified into the A2 type. Adenosine may also reach an intracellular purine receptor, via an uptake process, to cause additional relaxation, as was shown with an intracellular purine receptor agonist in cat pial arteries. Brain vessels were found to be considerably more sensitive to purines than most non-cerebral vessels studied.

2-Chloroadenosine↗

PubMed1987

Vasomotor effects of neurotransmitters and modulators on isolated human pial veins.

Vasomotor reactivity of human pial veins, obtained in conjunction with neurosurgical operations, was studied in vitro. The effect of transmitters in nerves previously recognized in these vessels, as well as that of neuromodulators, was characterized. A comparison of these effects with their effects in the nearby pial arteries of the same patients was made. It was found that the veins were equipped with more sensitive alpha-adrenergic receptors (lower EC50 values) than the arteries. The reverse was found for 5-hydroxytryptamine. Acetylcholine, which causes an endothelium-dependent dilation of pial arteries, contracted the veins despite an apparently intact endothelium. Considering the lower maximum values in veins, responses to histamine, the neuropeptides calcitonin gene-related peptide, bradykinin, and neuropeptide Y; and prostaglandins (PGE1 and PGF2 alpha) were principally the same in the arteries and veins. The dilatory responses to vasoactive intestinal polypeptide and substance P were less pronounced in veins than in arteries. The veins only transiently contracted to a depolarizing potassium solution; calcium influx promotors and inhibitors, as well as calcium-free solution, did not affect the contractile ability of the vein, contrasting to the reactivity of the artery. This clearly indicates that the veins are not substantially dependent upon calcium influx for their acute contractile ability.

Cerebral Veins↗