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Biomedical subjects

L Edvinsson

Publications and source records attributed to L Edvinsson.

At least 271 records · Page 15Linked to original sources
PubMed1991

5-hydroxytryptamine antagonistic effects of ICI 169,369, ICI 170,809 and methysergide in human temporal and cerebral arteries.

ICI 169,369 and ICI 170,809 are two chemically novel 5-HT antagonists that have high affinity for the 5-HT2 binding site in rat cortex (Ki 1.79 x 10(-8)M and 6.6 x 10(-10)M, respectively). In human temporal artery preparations ICI 169,369 was shown to cause a progressive rightward shift of the 5-HT-response curve over the range 10(-7)-10(-5)M, while ICI 170,809 in these concentrations shifted the curve to the same degree (no dose dependency). In human cerebral vessels no effect was observed until a high concentration (10(-5)M) was used for either compounds. The mixed 5-HT1/5-HT2 antagonist, methysergide, induced a non parallel rightward shift of the 5-HT-induced concentration-effect curve with a depression of the maximum achievable response in both the temporal and cerebral artery. The mode of effect of ICI 169,369 and ICI 170,809 to block the 5-HT-induced contractions in human temporal vessels resembles that of the pure 5-HT2 antagonist ketanserin, thus suggesting that the two ICI compounds are mainly 5-HT2 antagonists. In high concentrations both ICI 169,369 and ICI 170,809 have vasorelaxant properties, explaining the reduction in maximum 5-HT-induced contraction seen at high antagonist concentrations.

Cerebral Arteries↗
PubMed1991

Innervation and effects of dilatory neuropeptides on cerebral vessels. New aspects.

The cerebral circulation is supplied with two vasodilator systems: the parasympathetic system storing vasoactive intestinal peptide, peptide histidine isoleucine, acetylcholine and in a subpopulation of nerves neuropeptide Y, and the sensory system, mainly originating in the trigeminal ganglion, storing substance P, neurokinin A and calcitonin gene-related peptide (CGRP). Recent knowledge of the innervation and effects of the dilator neuropeptides in the cerebral circulation is reviewed. Their role in the pathophysiology of subarachnoid hemorrhage and migraine has now received attention, with documentation of a clear linkage with the release of CGRP. In subarachnoid hemorrhage, other perivascular peptides are, to a lesser extent, involved.

Animals↗
PubMed1991

Endothelin: an endothelium-derived vasoactive peptide and its possible role in the pathogenesis of cerebral vasospasm.

The contractile response to endothelin has been examined in cerebral arteries from rats subjected to a prior subarachnoid haemorrhage (SAH) and compared with saline injected controls. Endothelin elicited strong concentration-dependent contraction of rat basilar artery segments. The response was slow in onset and long lasting. The endothelin-induced contraction was much stronger in the SAH compared to control animals. Our findings suggest a role of the peptide in the pathophysiology of cerebral vasospasm.

Animals↗
PubMed1990

Evidence that calcitonin gene-related peptide contributes to the capsaicin-induced relaxation of guinea pig cerebral arteries.

Pretreatment with capsaicin caused a depletion of substance P (SP)-, neurokinin A (NKA)- and calcitonin gene-related peptide (CGRP)-like immunoreactivity (-LI) from the trigeminal ganglion, dura mater and cerebral arteries. The effect of capsaicin on isolated basilar arteries of guinea pig resulted in a biphasic relaxant response of histamine precontracted vessels. The first phase of the capsaicin-induced relaxation was absent in capsaicin-treated guinea pigs. Furthermore, repeated administration of capsaicin decreased the first but not the second phase of relaxation, supporting the view that a stored agent was released, while the second phase probably was due to a direct effect of capsaicin per se. The biphasic effect was not modified by the SP antagonist Spantide in a concentration that blocks tachykinin response (3.10(-6) M), nor by removal of the endothelium. There was no significant difference in pD2 values (-log concentration eliciting half maximum relaxation) between relaxations induced by SP, NKA, neurokinin B, neuropeptide K or CGRP in capsaicin pretreated as compared to vehicle-treated animals. These results are in support of the assumption that CGRP is involved in the capsaicin-induced relaxation caused by release of vasoactive agents from sensory afferent nerves.

Animals↗
PubMed1990

Second messenger systems: functional role in cerebrovascular smooth muscle regulation.

The role of two second messenger systems in alterations of cerebrovascular smooth muscle tone was examined in feline cerebral arteries using an in vitro preparation of vessel segments and cortical pial vessels in situ. Forskolin, which is known to activate adenylate cyclase, elicited a concentration-dependent relaxation of arteries preconstricted with prostaglandin F2 alpha (PGF2 alpha) (EC50 was approximately 300 nM). Microapplication of forskolin around individual cortical arteries and arterioles in situ elicited a dose-dependent dilatation. The maximum increase in arteriolar calibre was 54 +/- 4% from pre-injection calibre and EC50 was approximately 100 nM. Phorbol 12,13 dibutyrate (PDBu), which activates protein kinase C, elicited strong contractions of cerebral vessels. In vitro, PDBu contracted vessel segments in a concentration-dependent manner (EC50 was approximately 100 nM). Similarly, PDBu elicited potent dose-dependent constriction of pial arterioles in situ. The maximum response to PDBu was a 37 +/- 5% reduction in arteriolar calibre and the concentration eliciting EC50 was approximately 100 nM. These data provide an assessment to capacity of feline cerebral arteries to dilate and contract in response to adenylate cyclase and protein kinase C activation respectively.

Animals↗
PubMed1990

Neuropeptide Y in cerebrovascular function: comparison of membrane potential changes and vasomotor responses evoked by NPY and other vasoconstrictors in the guinea pig basilar artery.

The membrane depolarization and vasomotor response evoked by NPY and other vasoconstrictors were compared in guinea pig basilar artery. Concentrations below the pD2 value of amines and PGF2 alpha induced contractions without significant membrane depolarization, while higher agonist concentrations depolarized the membrane slightly. Potassium-induced contractions were paralleled by strong depolarization. NPY evoked a slow depolarization which correlated to vasoconstriction over a wide concentration range. The mechanism of activation did not appear to involve the endothelium. The results suggest that NPY induces prolonged cerebrovascular smooth muscle tone by evoking longlasting depolarization, at least partly in conjunction with activation of voltage-operated calcium channels.

Animals↗
PubMed1990

Small pial vessels, but not choroid plexus, exhibit specific biochemical correlates of functional cholinergic innervation.

In an attempt to provide the biochemical foundations for a putative cholinergic innervation of small pial vessels and choroid plexus, we have assessed their ability to specifically accumulate choline, synthesize and release acetylcholine (ACh) in response to depolarization. Our results show that both small pial vessels and choroid plexus avidly accumulate choline via a sodium-dependent mechanism which could be inhibited by hemicholinium-3 (IC50 in pial vessels = 47.8 microM). Light microscopic examination of radioautographs from vessels incubated with [3H]choline revealed two distinct sites of accumulation in the vessel wall. One site probably corresponded to nerve terminals and the other was closely associated with the endothelial cells. In small pial vessels, a major proportion (60%-70%) of the choline acetyltransferase (ChAT) activity could be inhibited by 4-naphthylvinylpyridine (4-NVP), a potent inhibitor of neuronal ChAT; and, following either K+ or veratridine depolarization, a Ca2(+)-dependent release of authentic [3H]ACh could be measured. In contrast, the choroid plexus exhibited a rather low ChAT activity which was not inhibited by 4-NVP and no release of ACh could be detected in this tissue following depolarization. Altogether, the results of the present study show that (1) small pial vessels exhibit all the most selective biochemical markers that are characteristic of cholinergic nerves; (2) [3H]choline in pial vessels can be accumulated in non-neuronal elements which probably correspond to the endothelial cells; and (3) the choroid plexus failed to exhibit convincing biochemical markers that would attest in favor of a functional cholinergic innervation.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1990

Local cerebral blood flow following the intrastriatal administration of vasoactive intestinal peptide or peptide histidine isoleucine in the rat.

The effect of the intrastriatal microinjection of either vasoactive intestinal peptide (VIP) or a related peptide-peptide histidine isoleucine (PHI)-on local cerebral blood flow in the striatum was examined using iodo[14C]antipyrine quantitative autoradiography. In 37 rats, an injection needle was inserted into a chronically implanted guide cannula and 1 microliter of vehicle, VIP or PHI was injected into the striatum. Blood flow in sham controls was reduced by 15% in proximity to the injection site, when compared with blood flow in the contralateral uninjected control side (P less than 0.01). Similarly, following PHI administration (20 pmol), blood flow in the striatum was reduced by 14% when compared to that contralaterally (P less than 0.02). In contrast, following VIP administration (20 pmol), blood flow in proximity to the injection site was increased compared to flow in the contralateral striatum in 4/8 animals with the mean flow being elevated by 10% (n.s.) compared to blood flow contralaterally. VIP and PHI had similar effects on local cerebral glucose utilization in the caudate nucleus, their response being equivalent to that of sham animals. These experiments suggest that VIP and PHI have a differential influence on the microvasculature of the caudate nucleus, with VIP but not PHI mediating cerebrovascular dilation.

Animals↗
PubMed1990

Vasoactive peptide release in the extracerebral circulation of humans during migraine headache.

The innervation of the cranial vessels by the trigeminal nerve, the trigeminovascular system, has recently been the subject of study in view of its possible role in the mediation of some aspects of migraine. Since stimulation of the trigeminal ganglion in humans leads to facial pain and flushing and associated release of powerful neuropeptide vasodilator substances, their local release into the extracerebral circulation of humans was determined in patients who had either common or classic migraine. Venous blood was sampled from both the external jugular and cubital fossa ipsilateral to the side of headache. Plasma levels of neuropeptide Y, vasoactive intestinal polypeptide, substance P, and calcitonin gene-related peptide were determined using sensitive radioimmunoassays for each peptide, and values for the cubital fossa and external jugular and a control population were compared. A substantial elevation of the calcitonin gene-related peptide level in the external jugular but not the cubital fossa blood was seen in both classic and common migraine. The increase seen in classic migraine was greater than that seen with common migraine. The other peptides measured were unaltered. This finding may have importance in the pathophysiology of migraine.

Adult↗
PubMed1990

Neuropeptide levels in Alzheimer's disease and dementia with frontotemporal degeneration.

The CSF levels of somatostatin-LI (SLI), neuropeptide Y (NPY-LI) and Delta Sleep Inducing Peptide (DSIP-LI) have been measured in patients with dementia of Alzheimer type (DAT) and dementia with frontotemporal degeneration of non-Alzheimer type (FTD). The distribution pattern of cortical degeneration differs between these two types of dementia. DAT shows degeneration of mainly temporo-parietal and temporo-limbic structures, whereas FTD discloses its main degeneration in the frontotemporal regions (Brun, 1987). The somatostatin-LI was significantly reduced both in DAT and FTD. NPY-LI showed a significant reduction in DAT but not in FTD. A tendency to a reduction with duration of the disease was observed in DAT whereas the contrary was noted in FTD. The DSIP-LI levels were reduced in DAT and slightly increased in FTD. The study provides an evidence of neurochemical differences between the two primary degenerative dementias.

Adult↗
PubMed1990

Peptidergic innervation of the cerebral circulation. Role in subarachnoid hemorrhage in man.

The present paper reviews recent studies in monkey and man adding further to understanding of the role of perivascular peptides in the pathophysiology of subarachnoid haemorrhage. 1. The perivascular fibers, sympathetic fibers (storing noradrenaline, neuropeptide Y), parasympathetic fibers (storing acetylcholine, vasoactive intestinal peptide, peptide histidine methionine and neuropeptide Y) and sensory fibers (storing tachykinins, calcitonin gene-related peptide) were traced using True Blue in monkey. 2. Tracing studies of the monkey middle-cerebral artery (MCA) innervation confirmed earlier studies in rats and cats, with superior cervical and trigeminal ganglia as main immunostaining areas, and contralateral involvement in the superior cervical and trigeminal ganglia. Sphenopalatine immunostaining was scarce. 3. The release of neuropeptides in the external jugular vein in humans in the postoperative course after subarachnoid hemorrhage, using radioimmunoassay, was correlated to hemodynamical changes (vasoconstriction) monitored with Doppler ultrasound on middle cerebral (MCA) and internal carotid arteries (ICA)). 4. Neuropeptide Y-like immunoreactivity (NPY-LI) levels were increased compared to controls in patients with hemodynamic changes, and in some patients a relationship was found between velocities and NPY-LI. 5. Calcitonin gene-related peptide-LI levels were also increased in connection with vasospasm. In patients with MCA lesions a correlation of 0.61, p = 0.0002 was found between hemodynamic index (V MCA/V ICA) and CGRP-LI. The possible sympathetic and trigemino-cerebrovascular activation are discussed.

Animals↗
PubMed1990

Changes in the levels of neuropeptide Y-LI in the external jugular vein in connection with vasoconstriction following subarachnoid haemorrhage in man. Involvement of sympathetic neuropeptide Y in cerebral vasospasm.

NPY is a putative neurotransmitter mainly co-localized with noradrenaline in sympathetic fibers which innervate the cerebral vasculature. The origin of most of the perivascular NPY fibers seems to be in the superior cervical ganglion. To investigate involvement of Neuropeptide Y (NPY) mechanisms in subarachnoid haemorrhage (SAH), twenty patients with SAH were investigated. NPY-LI (-like immunoreactivity) levels in the external jugular vein were assessed using radioimmunoassay in blood samples collected post-operatively (or after SAH in non-surgical patients) on days 1,2,3, 5,7 and 9. These levels were compared with the clinical course and blood flow velocity changes monitored with ultrasonic Doppler equipment from both middle cerebral arteries (MCA) and both internal carotid arteries (ICA). Compared to NPY-LI levels in 14 controls (mean 116 +/- 3 pmol/1), increased levels (up to 253 pmol/l) and a close relationship between velocities and NPY-LI levels were found in a subpopulation of the SAH patients. When comparing the mean haemodynamic index (V MCA/ipsilateral V ICA) and mean NPY-LI levels in each of the 20 patients, a correlation of r = 0.75, p = 0.0001 was found. Increased NPY-LI were found (131 +/- 8 pmol/l) when simultaneous Doppler velocity recordings showed vasoconstriction (Haemodynamic index greater than 5) compared with samples taken when the haemodynamic index was less than 5, p less than 0.05. When MCA velocity exceeded 120 cm/sec. increased levels were found (129 +/- 9 pmol/l) compared with the conditions when MCA velocity was less than 120 cm/sec (113 +/- 5 pmol/l), p = 0.06. The results indicate a possible NPY involvement in cerebral vasoconstriction after SAH.

Adult↗
PubMed1990

Atrial natriuretic peptide-LI following subarachnoid haemorrhage in man.

Atrial natriuretic peptide-like immunoreactivity (ANP-LI) was measured in plasma from the external jugular vein (EJV) in the postoperative course of 11 patients with aneurysmal subarachnoid haemorrhage. Samples were taken on day, 1, 2, 3, 5, 7 and 9 after operation and ANP-LI levels were determined using radioimmunoassay. Ten healthy volunteers were investigated with one EJV plasma sample. Comparing the whole group of SAH patients with the control group, no significant differences in ANP-LI levels were found. In one patient very high ANP-LI levels were found together with high mean plasma sodium levels and high urine sodium excretion. This suggests that there is no general correlation between plasma ANP-LI and SAH; in occasional patients such a correlation may be secondary to changes in plasma sodium levels.

Adult↗
PubMed1990

Neuropeptide Y antagonistic properties of D-myo-inositol-1.2.6-trisphosphate in guinea pig basilar arteries.

The antagonistic properties on neuropeptide Y (NPY)-induced contraction of the guinea pig basilar artery of D-myo-inositol-1.2.6-triphosphate (PP56) has been examined using a sensitive in vitro system. It was observed that PP56 did not per se cause contraction or relaxation of precontracted vessel segments. However, it was found to be a non-competitive antagonist of NPY-induced contraction. This effect was observed in the concentration range 10(-8)-10(-6) M PP56. A slight potentiation of endothelin I-induced contraction was seen at high concentrations (10(-3) M). In contrast there was no modulation of the contractile effects elicited by bradykinin, noradrenaline, 5-hydroxytryptamine (5-HT) or prostaglandin F2 alpha (PGF2 alpha) apart from a slight reduction in maximum effect at 10(-4) M and 10(-3) M PP56. PP56 was observed to possess antihistaminic and anticholinergic properties in the concentration range 10(-5) M-10(-3) M. The relaxant effects of vasoactive intestinal peptide, calcitonin gene-related peptide, neurokinin A and substance P were only modified to a minor extent by PP56 in concentrations of 10(-4) M and 10(-3) M. In conclusion, PP56 appears to be the first non-peptide which potently and rather selectively antagonizes NPY-induced contractions of the guinea pig basilar artery. In high concentrations, PP56 may modify the responses of other agents tested, including histamine and acetylcholine.

Acetylcholine↗
PubMed1990

Stimulation of the superior sagittal sinus in the cat causes release of vasoactive peptides.

External jugular vein blood was sampled in the anesthetized cat during electrical stimulation of the superior sagittal sinus (SSS), and the levels of calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), substance P (SP) and neuropeptide Y (NPY) were measured with sensitive radioimmunoassays. CGRP levels rose by 85% and VIP levels by 300% while there was no change in SP or NPY levels in the same samples. These data provide the first evidence that activation of the trigeminovascular system, by selective stimulation of nociceptive craniovascular afferents, causes releases of vasodilator peptides and further implicates this system in the pathophysiology of migraine.

Animals↗
PubMed1990

Peptide-containing nerve fibres in guinea-pig coronary arteries: immunohistochemistry, ultrastructure and vasomotility.

The peptidergic innervation of guinea-pig coronary arteries was investigated by means of immunohistochemical, ultrastructural and in vitro pharmacological techniques. A network of nerves was demonstrated in all major epicardial arteries by means of an antiserum to the neuronal marker protein gene product 9.5. The majority of nerve fibres possessed neuropeptide Y (NPY) and tyrosine hydroxylase (TH) immunoreactivity, the number and distribution of nerves immunoreactive for NPY being similar to that of nerves containing TH immunoreactivity. Numerous nerve fibres displaying immunoreactivity for substance P, neuropeptide K and calcitonin gene-related peptide (CGRP) were also found. In double-stained preparations substance P immunoreactivity was co-localized with CGRP and with neuropeptide K immunoreactivities in the same varicose nerve fibres. Ultrastructural studies revealed the presence of numerous axon varicosities at the adventitial-medial border. NPY immunoreactivity was localized in large granular vesicles in nerve varicosities which also contained numerous small granular vesicles. Large granular vesicle-containing nerves also displayed immunoreactivity for dopamine-beta-hydroxylase. With an in vitro method, the vasomotor responses to perivascular peptides were characterized in epicardial and intramyocardial arteries. In epicardial arteries neither noradrenaline nor NPY elicited a contractile response. Only in some intramyocardial arteries was an NPY-mediated contraction demonstrated. No potentiating effect of noradrenaline and NPY was observed in either epicardial or intramyocardial arterial segments. In contrast, CGRP, substance P and vasoactive intestinal peptide (VIP) all produced a concentration-dependent relaxation of both epicardial and intramyocardial arteries. These results suggest that peptide-containing nerves associated with guinea-pig coronary arteries may predominantly be involved in mediating vasodilation.

Animals↗