Biomedical subjects

J E Hardebo

Publications and source records attributed to J E Hardebo.

At least 37 records · Page 2Linked to original sources

PubMed1992

A cortical excitatory wave may cause both the aura and the headache of migraine.

Clinical and neurophysiological observations indicate that the symptoms of migraine aura result from the spread of an excitatory wave along the cortex from a primary focus. This excitation may start as a consequence of information overload on a low threshold cortical area. The transient neuronal excitatory wave is followed by a longer lasting "depressive" wave, which involves a substantial reduction in cortical blood flow (with an active constriction of resistance vessels) and ionic changes and transmitter release into the extracellular fluid compartment. As a consequence, trigeminal pain fibre endings in cortical venules may become activated and, via branches (axon reflexes) along the venous vascular tree, also multiple endings in dural venules. This will induce a neurogenic inflammation in the vessel walls, primarily in dural venules, experienced as headache by the sufferer when sufficiently many fibres have become activated. The pain fibre endings are equipped with serotonin1D-like receptors, which upon stimulation suppress the inflammatory process. This scenario offers a rational explanation for the beneficial effect of the acute, and some of the prophylactic, medications used in migraine.

Animals↗

PubMed1992

Vasoreactivity of the intracranial internal carotid artery.

The vasoreactivity of the intracranial segment of the internal carotid artery to transmitters, present in the perivascular sympathetic, parasympathetic and sensory nerves, as well as to other vasoactive agents of relevance for headache, was tested in man and monkey. The total arterial segment from both species is equipped with contractile receptors for noradrenaline, serotonin, prostaglandin F2 alpha, ergotamine and sumatriptan. Further, the total arterial segment dilated upon exposure to calcitonin gene-related peptide in both species. Other vascoactive transmitters, acetylcholine, substance P and neurokinin A, caused only weak dilatation, restricted to the proximal extracavernous segment in the monkey. The findings are discussed in relation to the pathogenesis and treatment of cluster headache.

Adult↗

PubMed1992

Influence of impulse pattern on noradrenaline release from sympathetic nerves in cerebral and some peripheral vessels.

Earlier findings suggested that the physiological firing rate in sympathetic nerves did not exceed 10 Hz. Later recordings have revealed that this is a net value: impulses are usually not continuous but occur in bursts of high frequencies separated by quiet periods. The effects of continuous and burst-like neurogenic activation in various isolated blood vessels were compared. In the first part of the study changes in vascular tone were registered. Electrical field stimulatory parameters were chosen to give tetrodotoxin-blockable, neurogenic responses. From dose-response experiments in rat caudal artery a net frequency of 6 Hz was chosen, for bursts usually designed as 30 Hz during 0.2 s followed by a quiet period of 0.8 s. In the rabbit ear artery the neurogenic contraction was enhanced by a mean of near 50% during stimulation with bursts. Now appeared a minor phentolamine-resistant portion, which was not due to release of NPY, 5-HT, histamine or ATP. Also in the rat caudal artery and monkey pial artery a significant enhancement of contraction was seen during burst simulation, whereas in the rabbit facial vein no significant difference in dilatation through beta-receptor activation was obtained. In vessels that do not normally respond with purely neurogenic contractions/dilatations during continuous stimulation, like pial arteries from the rat and rabbit, not even bursts revealed a neurogenic response. In a second series of experiments the influence of continuous and burst-like nerve activation on the release of [14C]noradrenaline was studied in monkey, rabbit and rat pial arteries, rat caudal artery and rabbit central ear artery and facial vein.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Vasomotion in the rat cerebral microcirculation recorded by laser-Doppler flowmetry.

In the present study, changes in frequency and amplitude of the rhythmic variations (vasomotion) in blood flow in the intact cerebral circulation of the rat were investigated using laser-Doppler flowmetry (LDF) during stepwise decrease in mean arterial blood pressure (MABP) and hyper- and hypocapnia. Experiments were performed on 12 adult Sprague-Dawley rats of either sex, anesthetized with alpha-chloralose. The rat's head was fixed on a stereotaxic frame and a small hole was made in the parietal bone but the dura and a thin inner bone layer were kept intact. The microvascular blood flow of the parietal cortex on the right or on both sides was continuously recorded by the laser-Doppler flowmeter (Periflux PF2B, Perimed, Stockholm, Sweden). The cerebral circulation of the rat exhibited vasomotion in control conditions with a frequency of 8-10 cycles per minute (cpm) and an amplitude of 5-10% of the cerebral blood flow (CBF). No significant changes in CBF could be detected when the MABP was above 60 mmHg, but it decreased significantly when MABP was reduced below 50 mmHg. However, during stepwise pressure reduction the vasomotion frequency decreased progressively while its amplitude showed a reversed U-shaped curve with a peak at 60-80 mmHg. During hypercapnia, the rhythmical oscillations showed a decrease in both frequency and amplitude, whereas during hypocapnia their frequency did not change but their amplitude increased. These results support the hypothesis that the vasomotion frequency might be dependent of the wall tension and cellular pH while its amplitude could be related to decreased tissue oxygenation.

Animals↗

PubMed1992

Role of endothelium in the responses of human intracranial arteries to a slight reduction of extracellular magnesium.

The effect of a slight reduction of extracellular magnesium on the tone of precontracted small human pial arteries and the dependence of the response on the functional integrity of the vascular endothelium was investigated in vitro. A decrease in extracellular magnesium from 1.2 to 0.8 mM resulted in sustained relaxation when the endothelium was intact. When the endothelium was disrupted, the same reduction resulted in an elevation of tone. These results suggest that small changes in extracellular magnesium modulate human cerebro-arterial tone through an endothelium-derived relaxing factor rather than by altering smooth muscle tone directly.

Acetylcholine↗

PubMed1992

Uptake and release of serotonin in rat cerebrovascular nerves after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Serotonin released from platelets has been suggested as one substance causing the vasospasm following subarachnoid hemorrhage. We studied whether such serotonin is able to constrict pial vessels. METHODS: We studied the uptake of serotonin in pial perivascular nerves by immunohistochemistry. We measured the contractile response in rat basilar artery after in vitro incubation with serotonin and during electrical field stimulation of perivascular nerves following experimental subarachnoid hemorrhage. RESULTS: After incubation with serotonin, electrical field stimulation caused a tetrodotoxin- and ketanserin-blockable contractile response. We observed no such response in vessels from rats treated with 6-hydroxydopamine or after blockade of serotonin uptake. After subarachnoid hemorrhage, a pronounced network of serotonin-immunoreactive nerve fibers was demonstrated in the vessel wall. In vessels from control rats, no serotonin fibers were seen, and in vessels from 6-hydroxydopamine-treated animals with subarachnoid hemorrhage only a few such fibers were seen. Electrical field stimulation of the basilar artery from rats tested 2 or 16 hours (but not 10 minutes or 24 hours) after subarachnoid hemorrhage showed contractile responses that were prevented by tetrodotoxin, ketanserin, and prior 6-hydroxydopamine treatment. CONCLUSIONS: Our study demonstrates a capacity of the perivascular sympathetic nerves to take up serotonin both in vitro and during the early phase of subarachnoid hemorrhage. Such uptake may help to remove excess serotonin from the subarachnoid space. Only if serotonin is subsequently released upon nerve activation may minor smooth muscle contraction develop.

Animals↗

PubMed1992

Regional differences in the contractile activity of neuropeptide Y, endothelin, oxytocin and vasopressin: comparison with non-peptidergic constrictors. An in vitro study in the basilar and mesenteric arteries of the rat.

The vasoconstrictor effect of the peptides neuropeptide Y (NPY), endothelin (ENDO), vasopressin (VPR) and oxytocin (OXY) (10(-11)-10(-7) M) was compared in the isolated basilar (BAS) and mesenteric (MES) arteries of rat. The contractile activity of these peptides was compared to that of three nonpeptidergic constrictors: noradrenaline (NA), serotonin (5-hydroxytryptamine, 5-HT) and prostaglandin F2 alpha (PGF2 alpha) (10(-8)-10(-4) M). As regards EC50 values, PGF2 alpha was equally potent in both vessels studied, 5-HT was more potent in BAS and NA was without contractile effect in BAS. Pronounced regional differences were found for the peptides studied. BAS was more sensitive in EC50 values to the peptides in the order ENDO > or = VRP > OXY > NPY. In MES, OXY and NPY caused no and VPR caused weak contraction, whereas the effect of ENDO was pronounced, with a similar EC50 value as in BAS. In conclusion, marked regional differences were found in response to contractile agents in the vascular beds studied. Peptidergic constrictor mechanisms might be of large importance in the regulation of cerebral blood flow during physiological or pathophysiological conditions.

Animals↗

PubMed1991

Anatomical basis for a parasympathetic and sensory innervation of the intracranial segment of the internal carotid artery in man. Possible implication for vascular headache.

Two ganglionic cell groups, located close together and called the internal carotid ganglion, not described before in man, were demonstrated extradurally on the ventrolateral surface of the human internal carotid artery (ICA), where the greater superficial petrosal nerve is joined by the (greater) deep petrosal nerve to form the vidian nerve. The two ganglionic cell groups have fiber connections to the ICA, and consist of 50-70 cells each. By immunohistochemistry the majority of cells in one of the groups were shown to contain vasoactive intestinal polypeptide (VIP) and choline acetyltransferase (ChAT) indicating a parasympathetic function, whereas most cells in the other group contained substance P (SP) and possibly calcitonin gene-related peptide (CGRP), transmitters in pain fibers. Lateral to the intracavernous segment of ICA 10-150 scattered or aggregated VIP- and ChAT-positive cells were found, with fiber connections to the ophthalmic nerve, the ICA, the abducent nerve and the sphenopalatine ganglion. These cells may represent aberrant parasympathetic (sphenopalatine) ganglia, here referred to as cavernous ganglion. By radioimmunoassay substantial amounts of VIP, SP and CGRP were measured in both the extradural and the intracavernous segment of the ICA. Thus, the intracranial segment of the ICA is most likely innervated by parasympathetic and pain fibers from the internal carotid ganglion, sensory fibers from the ophthalmic division of the trigeminal ganglion, and parasympathetic fibers from the sphenopalatine and/or cavernous ganglion. Clinical implications for the activation of these nerves to cause pain, dilatation and edema in this segment of the ICA during attacks of cluster headache and painful ophthalmoplegic syndromes are discussed.

Adult↗

PubMed1991

The pathway of parasympathetic nerve fibers to cerebral vessels from the otic ganglion in the rat.

It has previously been shown that the otic ganglion contributes to the innervation of pial arteries in the rat with parasympathetic fibers, but the exact pathway from the ganglion to the vessels has been unknown. Further, the precise course of the lesser superficial petrosal nerve in the rat has not been described. In this research we show, by combining retrograde neuronal tracer technique and immunohistochemical demonstration of transmitters, that the fibers leave the ganglion in the lesser superficial petrosal nerve, running on the anterior and medial inner surface of the tympanic bulla to reach the greater superficial petrosal nerve, and deviate via the deep petrosal nerve to the wall of the internal carotid artery. Various other nerves were excluded as possible pathways.

Animals↗

PubMed1991

An amplifying effect of exogenous and neurally stored 5-hydroxytryptamine on the neurogenic contraction in rat tail artery.

1. The interactions between sympathetic neuroeffector transmission and 5-hydroxytryptamine (5-HT) were investigated in segments of rat isolated tail artery. 2. Contractile responses to field stimulation of the artery segments were abolished by tetrodotoxin (3 x 10(-7) M). A subthreshold concentration of acutely applied exogenous 5-HT (10(-8) M) markedly enhanced the contractions induced by sympathetic nerve stimulation, through an action on postjunctional 5-HT2-receptors. 3. The amplifying effect of 5-HT involved an enhanced influx of extracellular calcium into the smooth muscle cells. In contrast, the neurogenic contractions in vessels not exposed to 5-HT were not dependent on extracellular calcium. 4. The adrenergic component of the amplified response involved postjunctional alpha 1- but not alpha 2- adrenoceptor activation. 5. Exposure of the vessels to 5-HT (5 x 10(-7) M) for 30 min resulted in uptake of the amine into the perivascular sympathetic nerves, as demonstrated by immunohistochemistry. After chemical sympathectomy with 6-hydroxydopamine in vitro or in vivo, or surgical sympathectomy, there was little or no uptake. 6. Exposure to 5-HT followed by repeated washing resulted in an enhancement of the neurogenic contraction, which was still fully tetrodotoxin-sensitive. The enhanced response was blocked by ketanserin (10(-8) M) and prevented by the presence of the 5-HT uptake blocker, paroxetine (3 x 10(-8) M), during the period of exposure to 5-HT.

Animals↗

PubMed1991

On pain mechanisms in cluster headache.

Various possible pathophysiological mechanisms to explain the pain in cluster headache are reviewed. Several locations for the initiation of pain along the primary afferent pathways in cranial nerves are discussed, together with the local mechanisms that might be responsible. These include neurogenic inflammation of large cranial vessels, irritation of vascular pain fibres by compression of dilated vessels in bony canals, and irritative foci in or around cranial sensory ganglia. In particular, recent neuroanatomical and pharmacological findings on nociceptive innervation of the intracranial segment of the internal carotid artery are commented upon. The possibilities for referred pain to explain the location of pain is illustrated. Evidence for involvement of central pain modulatory systems in the pain production is discussed. Finally a synthesis is made of the probable peripheral and central pain mechanisms in the disease.

Cluster Headache↗

PubMed1991

Migraine--why and how a cortical excitatory wave may initiate the aura and headache.

A large number of clinical and neurophysiological observations are reviewed that clearly indicate that the symptoms of migraine aura result from a spread of an excitatory wave along the cortex from a primary focus. This excitation may start as a consequence of information overload to a low threshold cortical area. The transient neuronal excitation is followed by a long-lasting period of reduced cortical flow, which involves a substantial component of active constriction of resistance vessels, even persisting for several hours during the headache phase. When the excitatory wave has reached and activated free pain fiber endings in sufficiently many cortical vessels, off-branching peripheral motor endings of these fibers may become activated via axon reflexes. These motor endings may be located in cortical microvessels or in small vessels around large dural vessels. This leads to a neurogenic inflammation in the vessel walls, experienced as headache by the sufferer. The wall of dural sinuses offers a rational explanation for the beneficial effect of most medications used in migraine.

Cerebral Arteries↗

PubMed1991

Activation of pain fibers to the internal carotid artery intracranially may cause the pain and local signs of reduced sympathetic and enhanced parasympathetic activity in cluster headache.

Several clinical and circulatory physiological observations indicate that the internal carotid artery (ICA) with proximal pial and orbital-periorbital branches, as well as external carotid vessels adjacent to the orbital region, are involved in the autonomic symptoms of an attack of cluster headache. Evidence is presented here that an activation of pain fibers innervating the intracranial segment of ICA may cause not only the retroorbital pain of an attack but also, via the mechanical effect of a neurogenic inflammation in the vessel wall, the local symptoms of a sympathetic defect and, via a reflex are to the parasympathetic pathway along the greater superficial petrosal nerve, the local symptoms from glands and vessels of parasympathetic discharge. Dilation of the intracranial ICA due to activation of this parasympathetic pathway may aggravate pain. Possible mechanisms behind such a local pain fiber activation are discussed.

Carotid Artery, Internal↗

PubMed1991

Pathways of parasympathetic and sensory cerebrovascular nerves in monkeys.

Using immunohistochemistry, we studied the origins and pathways of parasympathetic and sensory nerve fibers to the pial arteries in four squirrel monkeys. Following its application to the surface of the middle cerebral artery, the retrograde axonal tracer True Blue accumulated in parasympathetic neurons of the sphenopalatine ganglion and the internal carotid ganglion. The latter is strategically located where the internal carotid artery enters the cranium. Fibers from the sphenopalatine ganglion reach the internal carotid artery in the cavernous sinus region after running as rami orbitales. Before reaching the internal carotid artery, the fibers bypass aberrant sphenopalatine ganglia, with the most distant, the cavernous ganglion, being located in the cavernous sinus region. True Blue also accumulated in sensory neurons of the ophthalmic and maxillary divisions of the trigeminal ganglion and in sensory neurons of the internal carotid ganglion. Fibers from the ophthalmic division of the trigeminal ganglion reach the internal carotid artery as a branch through the cavernous sinus, bypassing the cavernous ganglion. Fibers from the maxillary division also bypass the cavernous ganglion after reaching it via a recurrent branch of the orbitociliary nerve. Thus, the cavernous ganglion forms a confluence zone for parasympathetic and sensory fibers in the region. In addition, parasympathetic and sensory fibers leave the confluence zone to follow the abducent and trochlear nerves backward to the basilar artery and tentorium cerebelli, respectively. Clinical implications are discussed.

Animals↗

PubMed1991

Lack of neural control and reactivity to vasoactive agents in malignant glioma arteries.

Vessels in malignant brain tumors have a defective blood-brain barrier. It is important to know if tumor vessels respond to vasoactive agents, since systemic administration of vasodilatory agents together with chemotherapy could increase the access of these drugs to the tumor. It was found that arteries in human malignant gliomas have no neural control and are totally nonreactive to various vasoactive agents. The vessels lose their reactivity within 1 to 2 mm outside the visible tumor front.

Brain Neoplasms↗

PubMed1990

Central origins of preganglionic fibers to the sphenopalatine ganglion in the rat. A fluorescent retrograde tracer study with special reference to its relation to central catecholaminergic systems.

The brainstem origin of preganglionic fibers to the sphenopalatine ganglion in rat was revealed by the aid of the retrograde axonal tracer True Blue (which does not traverse to a second order neuron) applied deep in the sphenopalatine ganglion or the Vidian nerve on one side. The majority of fibers originate in the ipsilateral lacrimo-muconasal nucleus in the ventrolateral rostral medulla oblongata and caudal pons. A smaller number of fibers originate more dorsomedially and caudally in the medullary reticular formation. After application to the ganglion a third small group of labelled neurons was found more rostrally in the brainstem, in the reticular formation ventrolateral to the caudal part of the dorsal raphe nucleus. Simultaneous visualization of catecholaminergic nerves revealed that the labelled neurons in the lacrimo-muconasal nucleus were heavily innervated by catecholaminergic fibers. It appears from previous studies that the preganglionic neurons may not be cholinergic. None of the labelled neurons in the brainstem stained positively for catecholamines. Thus, further studies are required to elucidate the transmitter(s) used in these neurons.

Animals↗

PubMed1990

Neuropeptide Y co-exists with vasoactive intestinal polypeptide and acetylcholine in parasympathetic cerebrovascular nerves originating in the sphenopalatine, otic, and internal carotid ganglia of the rat.

Neuropeptide Y co-exists with noradrenaline in the majority of the sympathetic nerves supplying cerebral blood vessels. However, after sympathectomy in the rat the number of cerebrovascular neuropeptide Y nerve fibers are only reduced in number despite a complete disappearance of the adrenergic markers. The origin of these non-sympathetic neuropeptide Y fibers was studied by nerve transections and retrograde axonal tracing utilizing True Blue. Three days after bilateral superior cervical sympathectomy, the number of neuropeptide Y-containing nerve fibers decreased to about 40% of that in non-treated animals. One week after True Blue application on the proximal portion of the middle cerebral artery, the tracer accumulated in neurons of the sphenopalatine, otic, and internal carotid ganglia. Of these cells 80%, 95% and 5%, respectively, were neuropeptide Y-positive. Some of the True Blue/neuropeptide Y-positive cells displayed immunoreactivity for vasoactive intestinal polypeptide and some were positive for choline acetyltransferase. Two weeks after bilateral removal of the sphenopalatine ganglion or transection of postganglionic fibers from the ganglion reaching the pial vessels through the ethmoidal foramen, together with subsequent sympathectomy, no neuropeptide Y-containing nerve fibers could be observed on the anterior cerebral and internal ethmoidal artery or the distal portion of the middle cerebral artery, whereas a few nerve fibers remained on the proximal portion of the middle cerebral artery, internal carotid artery, and the rostral portion of the basilar artery. In conclusion, neuropeptide Y in cerebrovascular nerves is co-stored not only with noradrenaline in sympathetic nerves from the superior cervical ganglion, but also with acetylcholine (reflected in the presence of choline acetyltransferase) and vasoactive intestinal polypeptide in parasympathetic nerves originating in the sphenopalatine, otic, and internal carotid ganglia.

Acetylcholine↗

PubMed1990

Amine-induced responses of pial and penetrating cerebral arteries: evidence for heterogeneous responses.

Middle cerebral arteries (MCAs) of rabbits were compared with two types of small branches (less than 100-microns outer diameter), penetrating arteries (PAs) and surface arteries (SAs), by determining their mechanical reactivity to several amines and standard contractile agents. Two techniques were employed: (a) measurement of isometric tension of 1-mm rings (MCA, PA, or SA); (b) measurement of perfusion pressure of segments consisting of essentially MCA or essentially PA. Both techniques revealed similar reactivity of the different types of vessel to acetylcholine, i.e., relaxations to a maximum of 52-78%, and similar strong contractile responses to histamine, although the MCA was more sensitive. Under H1 blockade, histamine dilated the PA (both techniques) and the MCA (perfusion technique), but not the SA. Relatively weak contractile responses to serotonin were observed in the MCA (both techniques) and the PA (perfusion technique), but not the SA (isometric tension only); no dilative responses could be elicited. Responses to noradrenaline varied with the vessel considered: The MCA contracted only, whereas the PA weakly contracted or relaxed at basal tone, and many preparations relaxed after precontraction with uridine triphosphate; the SA did not react. Relaxation of precontracted PA by noradrenaline occurred at relatively low concentrations and was antagonized by propranolol at 3 x 10(-7) or 3 x 10(-6) M. These results reveal very significant differences in the segmental reactivity to amines and suggest that noradrenaline released from sympathetic fibers might have opposing actions in the major pial arteries and the smaller penetrating branches.

Acetylcholine↗