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Biomedical subjects

L Edvinsson

Publications and source records attributed to L Edvinsson.

At least 181 records · Page 10Linked to original sources
PubMed1994

[Peptide modulation in vascular headache].

This article reviews recent developments in the field of vasoactive peptides in relation to certain types of headache. The equilibrium existing in the brain between contraction and dilatation of blood vessels is controlled by, among other factors, vasoactive peptides. Several of these have been discovered only recently and constitute a rapidly expanding field of research with exciting perspectives. Cranial blood vessels are innervated by sympathetic, parasympathetic and sensory nerve fibres, all of which contain certain vasoactive peptides as co-transmitters. Others, like endothelin, can be produced by the endothelium. There is evidence to suggest that vasoactive peptides of the trigeminovascular system are liberated in response to abnormal constriction of cranial blood vessels and contribute to headache. New drug therapies based on the activity of such substances are now being developed.

Cerebral Arteries↗
PubMed1994

Human endothelin ETA receptor antisense oligodeoxynucleotides inhibit endothelin-1 evoked vasoconstriction.

Antisense oligodeoxynucleotides to endothelin ETA receptor mRNA were used to characterize vascular smooth muscle receptors. The concentration-response curve showed a significant attenuation of endothelin-1-induced contraction in circular segments of the human superficial temporal artery. Endothelin ETB receptor antisense or mismatch oligodeoxynucleotides showed no alteration of the endothelin-1-induced contraction. Complementary experiments with the selective endothelin ETA receptor antagonist FR139317 demonstrated a shift of the concentration-response curve to the right in a competitive manner (pA2 = 6.93). The specific method of using the receptor antisense oligodeoxynucleotides approach revealed the presence of endothelin ETA receptors mediating contraction in the human superficial temporal artery.

Azepines↗
PubMed1994

Calcitonin gene-related peptide (human alpha-CGRP) counteracts vasoconstriction in human subarachnoid haemorrhage.

Calcitonin gene-related peptide (CGRP) is a neuropeptide co-stored with tachykinins (substance P, neurokinin A) in cerebrovascular sensory fibers in the trigeminal ganglion. Preceding studies on subarachnoid hemorrhage (SAH) revealed that an enhanced release of CGRP resulted in the selective loss of perivascular CGRP. Therefore, the present study was designed to evaluate the effects of intravenous administration of human alpha-CGRP on cerebral vasoconstriction in the postoperative course after SAH in 5 patients (8 infusions). Cerebral vasoconstriction was evaluated with transcranial Doppler sonography. The increase in the relationship between middle cerebral artery (MCA) velocity and internal carotid artery (ICA) velocity (the hemodynamic index) was used as an indicator of vasoconstriction and compared to the contralateral side. A significant reduction was found in the hemodynamic index during the CGRP infusion (4.3 +/- 0.5, P < 0.05) as to compared to before infusion (6.2 +/- 0.5). There was no measurable change in the hemodynamic index on the contralateral side. No significant change was observed in pulsatility index, blood pressure or consciousness during the peptide infusion. A significant increase in heart rate was observed during the infusion as compared to before and after infusion (90 +/- 4 vs. 76 +/- 5). Cardiac ultrasound data indicated a mean cardiac output increase of 1.9 liter/min, and a mean decrease in total peripheral resistance of 538 dynes s/cm5. The results obtained show that infusion of human alpha-CGRP may induce normalisation of cerebrovascular tone in SAH.

Adult↗
PubMed1994

Neuropeptide Y stimulates proliferation of human vascular smooth muscle cells: cooperation with noradrenaline and ATP.

Since the sympathetic nervous system has been shown to exert a trophic influence on vascular smooth muscle cells (SMC), we studied the growth regulating effects of neuropeptide Y (NPY) in cooperation with the sympathetic co-transmitters noradrenaline and adenosine triphosphate (ATP) in human vascular SMC. NPY stimulated DNA synthesis in human SMC grown from subcutaneous arteries and veins (diameter: 0.4 mm) measured by [3H]thymidine incorporation. Also cell number and protein synthesis were stimulated. The effect was mediated through the Y1-receptor and not Y2 or Y3 since the Y1-selective NPY analogue Pro34-NPY and peptide YY stimulated mitogenesis in the same magnitude as NPY while the NPY-fragment NPY13-36 only had minor effects. The effect was blocked by pretreating the cells with pertussis toxin indicating a Gi/o-coupled effect. The other sympathetic co-transmitters, noradrenaline and ATP, also stimulated mitogenesis in the human SMC in a similar magnitude as NPY. When added together NPY and noradrenaline potentiated each other in the mitogenic response. ATP had mainly additive effects. This is the first demonstration that NPY, noradrenaline and ATP stimulates growth in human vascular SMC. This suggests a role of the sympathetic cotransmitters in modulating vascular tone, but also by inducing hypertrophy/hyperplasia with possible clinical consequences.

Adenosine Triphosphate↗
PubMed1994

Neuronal pathways to the rat conjunctiva revealed by retrograde tracing and immunocytochemistry.

The origin and neuropeptide content of nerve fibres in the rat conjunctiva were studied by retrograde tracing and denervations in combination with immunocytochemistry. Immunocytochemistry revealed nerve fibres containing neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), helospectin, substance P (SP), and calcitonin gene-related peptide (CGRP) around blood vessels, smooth muscle bundles and glands. Removal of the sphenopalatine ganglion eliminated the majority of the VIP-, PHI- and helospectin-containing fibres. Sympathectomy eliminated the majority of the NPY-containing fibres in the conjunctiva. Removal of both the sphenopalatine ganglion and the superior cervical ganglion led to further reduction of the NPY fibres. Injection of the retrograde tracer True Blue into the conjunctiva resulted in the appearance of labelled cell bodies in the trigeminal ganglion, the sphenopalatine ganglion, the superior cervical ganglion, and the ciliary ganglion. Judging from the number of labelled nerve cell bodies, the superior cervical ganglion contributes most to the innervation. These results indicate that the majority of NPY-containing nerve fibres in the conjunctiva derives from the superior cervical ganglion (sympathetic nerve supply). Most of the VIP- and a minor population of the NPY-containing fibres in the conjunctiva originate in the sphenopalatine ganglion (parasympathetic nerve supply). A sparse amount of VIP- and NPY-containing fibres derives from the ciliary ganglion. Nerve fibres containing SP and/or CGRP emanate from the trigeminal ganglia (sensory nerve supply). Together the findings indicate that several ganglia project to the conjunctiva and that many neuropeptides may be involved in the control of conjunctival activity.

Animals↗
PubMed1994

Plasma neuropeptide Y in the symptomatic limb of patients with causalgic pain.

The aim of this experiment was to measure the concentration of neuropeptide Y (NPY), a vasoactive transmitter which co-exists with noradrenaline in sympathetic nerve terminals, in venous blood taken from the painful and contralateral limbs of 16 patients with features of reflex sympathetic dystrophy (RSD) or causalgia. In nine patients tapping the skin of the affected limb provoked pain (allodynia). In seven of the nine patients with allodynia the concentration of NPY was lower on the painful side; similar results were obtained in only two of seven patients without widespread allodynia. In addition, the concentration of NPY was generally lower in the painful limb if it was warmer than the contralateral limb. These findings suggest that a reduction in sympathetic activity might accompany allodynia and influence vasomotor disturbances in patients with causalgic pain.

Adolescent↗
PubMed1994

Alpha-trinositol blocks the inhibitory effects of NPY on dilatation to forskolin but not the adenylyl cyclase activity induced by NPY or forskolin in guinea-pig cerebral vessels.

There is much data showing correlation between forskolin-induced relaxation and production of cyclic AMP. But are these processes coupled or two phenomena occurring in parallel? This question was studied in guinea-pig cerebral vessels by using NPY as a strong inhibitor and alpha-trinositol as its antagonist. The basal cyclic AMP content of cerebral vessel segments in the control group was 670 +/- 53 fmol/mg wet weight (w.w.). Forskolin (10(-7), 3 x 10(-7) and 10(-6) M) increased the formation of cyclic AMP to 738 +/- 86 (ns), 699 +/- 81 (ns) and 1158 +/- 132 fmol/mg w.w. (p < 0.05), respectively. alpha-trinositol (10(-8)-10(-6) M) neither reduced the formation of cyclic AMP compared to basal cyclic AMP levels nor affected the forskolin-stimulated increase of cyclic AMP (p > 0.05). On the other hand, NPY (10(-7) M) not only decreased basal formation of cyclic AMP (p < 0.05) but also attenuated the forskolin-stimulated increase of cyclic AMP (p < 0.005). The inhibitory effects of NPY on both basal levels of cyclic AMP and forskolin-induced increase of cyclic AMP were not reversed by the application of alpha-trinositol (10(-8)-10(-6) M). In studies on vasomotor responses, forskolin (10(-9)-10(-5) M) induced a concentration-dependent relaxation of precontracted guinea-pig basilar arteries. NPY (10(-7) M) shifted the forskolin-induced relaxation of the basilar arteries towards higher forskolin concentrations. This inhibitory effect of NPY was reversed by alpha-trinositol (10(-6) M). We conclude that 1) NPY decreases basal and forskolin-stimulated cyclic AMP levels; 2) alpha-trinositol neither reverses the inhibitory effect of NPY on nor modulates basal or forskolin-stimulated cyclic AMP levels; 3) However, the antagonistic effect of NPY on forskolin-induced relaxation is significantly reversed by administration of alpha-trinositol. This demonstrates a dissociation of the dilator effects of forskolin and its generation of cyclic AMP.

Adenylyl Cyclases↗
PubMed1994

alpha-Trinositol blocks neuropeptide Y-induced inositolphosphate formation in cerebral vessels.

Neuropeptide Y (NPY) induces contraction of guinea-pig basilar arteries via activation of Y1 receptors. This contraction is blocked by D-myo-inositol-1,2,6-triphosphate (alpha-trinositol). Previous binding studies have shown that alpha-trinositol has no effect at Y1 or Y2 binding sites thus the antagonistic effect should occur at the level of a second messenger. We have examined the effects of NPY on the formation of inositol phosphates (IP) and have looked for an antagonistic effect of alpha-trinositol. NPY (10(-9)-3 x 10-(-7) M) induced strong concentration-dependent contraction of basilar arteries from young guinea-pigs (weight 200-250 g) (Emax: 76.4 +/- 11.1%) but not of arteries from old guinea-pigs (weight > 500 g) (Emax: 2.8 +/- 1.5%). [Pro34]NPY and PYY induced contraction of similar magnitude and potency, whereas NPY13-36 had only a weak effect. This demonstrates an effect via the Y1 type of NPY receptor. The contraction induced by NPY was blocked by alpha-trinositol (p < 0.05). LiCI (2 x 10-4) M), used to inhibit IP breakdown, had no effect on the contraction induced by NPY. NPY (10(-10)-10(-8) M) increased the formation of IP in cerebral vessels from young guinea-pigs from 357 +/- 48 cpm/mg w.w. to 900 +/- 233 cpm/mg w.w. However, there was no alteration in IP formation in cerebral vessels from old guinea-pigs (NPY 10(-9)-10(-7) M). In the presence of alpha-trinositol (10(-8)-10(-6) M) the NPY induced stimulation of IP formation was totally abolished.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1994

Vasoactive intestinal peptide (VIP) like peptides in the cerebral circulation of the cat.

The present study was designed to study the localization and effects of some VIP-related peptides on the cerebral circulation in cats. A rich supply of nerve fibres containing vasoactive intestinal peptide- (VIP) was seen. Nerve fibres containing pituitary adenylate cyclase activating peptide and helospectin-like immunoreactivity (-IR) were moderate in numbers whereas only a sparse supply of fibres containing helodermin-IR was seen. Double immunostaining revealed that the majority of PACAP- and helospectin-IR nerve fibres contained VIP. Using a sensitive in vitro system prostaglandin F2 alpha-precontracted circular segments of the cat middle cerebral artery relaxed upon administration of VIP, PACAP, helospectin I, helospectin II and helodermin. These effects were non-endothelium dependent with pD2-values varying between 7.6 and 8.1. The maximum relaxation varied between 47% and 79% of precontraction. Local cerebral blood flow was studied in anaesthetised cats. Cortical injection of PACAP-38, helospectin or helodermin, 5 micrograms in a volume of 1 microliter, revealed moderate and consistent increases in flow. The increase in cerebral blood flow was rapid and concentration-dependent with maximum increases of 18 +/- 6% for PACAP, 21 +/- 5% for helodermin, 16 +/- 7% for helospectin I and 19 +/- 5% for helospectin II. The vehicle caused no significant response (2 +/- 4%).

Animals↗
PubMed1994

Endothelin-A receptors mediate contraction in human cerebral, meningeal and temporal arteries.

Endothelin-1 (ET-1), an endothelium-derived vasoconstrictor peptide, produced strong contractions in human cerebral, meningeal and temporal arteries. The isopeptides ET-2 and ET-3 also showed potent constrictor activity; however, ET-3 was less potent. The selective ETA receptor antagonist FR 139317 mediated a shift to the right of the concentration-response curve of ET-1. These results suggest that the powerful constriction elicited by the endothelin-isopeptides in cerebral, meningeal and temporal arteries is mediated through ETA receptors.

Azepines↗
PubMed1994

The innervation of guinea pig epicardial coronary veins: immunohistochemistry, ultrastructure and vasomotility.

The innervation and vasomotor responses to several vasoactive agents of guinea pig epicardial coronary veins were investigated by means of immunohistochemical, histochemical, ultrastructural and in vitro pharmacological techniques. The use of an antiserum to the general neuronal marker protein gene product 9.5 revealed that coronary veins are supplied by a network of fine varicose nerve fibres in the adventitia. The majority of the nerve fibres possessed neuropeptide Y (NPY) and tyrosine hydroxylase immunoreactivity. Only a few nerve fibres displayed substance P, neuropeptide K (NK) and calcitonin gene-related peptide (CGRP) immunoreactivity. In double stained preparations substance P immunoreactivity was co-localized with NK and CGRP in the same nerve fibres. Nerve fibres containing vasoactive intestinal peptide (VIP) immunoreactivity or acetylcholinesterase activity were not detected. Endothelin immunoreactivity was also found in the vein endothelial cells. Ultrastructural studies revealed the presence of axon varicosities at the adventitial-medial border. In vitro pharmacological studies showed that endothelin-1 and -2 elicited a significant contractile response of epicardial vein segments. Noradrenaline, NPY, serotonin and uridine 5'-triphosphate induced only a relatively weak contractile response in the vein segments. Although vasodilatory responses were difficult to examine in these preparations, it was found that substance P, CGRP and VIP elicited a relaxation of the vein segments. These results indicate that guinea pig epicardial coronary veins are innervated by several nerve populations, however, the control of vasomotor tone of coronary veins appears to be predominantly regulated by 'non-neuronal' vasoactive agents such as endothelin and 5-HT.

Acetylcholinesterase↗
PubMed1994

FR139317, a specific ETA-receptor antagonist, inhibits cerebral activation by intraventricular endothelin-1 in conscious rats.

A comprehensive series of time-related behavioral, physiological and cerebral metabolic studies was conducted using conscious Sprague-Dawley rats to discern the anti-endothelin (ET) properties of the specific ETA receptor antagonist, FR139317. Endothelin-1 (9 pmol given by injection into one lateral ventricle, i.c.v.) produced convulsions, acute arterial hypertension, arterial hyperglycemia, and hyperventilation. Brain structures close to the i.c.v. site of injection, such as the caudate nucleus, lateral septal nucleus, corpus callosum and hippocampal CA3 medial lamellae, as well as 14 other individual structures, displayed moderate-to-intense levels of metabolic activation after endothelin. Data were assessed quantitatively by means of the autoradiographic [14C]deoxyglucose technique combined with image analysis. Neural circuits in the efferent projection paths of the stimulated forebrain structures, such as the midbrain oculomotor complex, amygdaloid nuclei, substantia nigra pars reticulata and caudal subicular subregions of the hippocampal formation, were stimulated focally by endothelin. Specific medullary nuclei and cerebellar cortical subregions displayed high rates of glucose metabolism following endothelin injection at the time of maximum behavioral and physiological stimulation. I.c.v. treatment with > or = 14 nmol FR139317 before endothelin significantly inhibited the effects produced by the peptide. At the highest dose of FR139317 (28 nmol), there was only mild behavioral stimulation following endothelin injection, and hypermetabolic responses in the brain were abolished except in two specific areas of the cerebellar cortex (approx 40% increases in metabolic activity in the copula pyramis and paramedian lobule). The results indicate that the cerebral stimulatory effects of i.c.v. endothelin are mediated by the A type of endothelin receptor. By itself, i.c.v. FR139317 had no effects on the parameters assessed. Further evaluation of FR139317 is warranted as a possible therapeutic agent for neuropathologies suspected of deriving from central neural or vascular stimulation by endothelin, such as aneurysmal vasospasm, ischemia, excitotoxicity, and peptide-mediated epilepsies.

Animals↗
PubMed1994

Demonstration of neuropeptide containing nerves and vasomotor responses to perivascular peptides in human cerebral arteries.

A rich supply of nerve fibers containing neuropeptide Y-like (NPY-LI) and tyrosine hydroxylase-like immunoreactivity was seen in human cerebral arteries, arterioles and veins. Only a sparse supply of vasoactive intestinal polypeptide (VIP-LI), substance P (SP-LI), and calcitonin gene-related peptide (CGRP-LI) was demonstrated in the walls of human cerebral vessels. In isolated ring segments of human cerebral arteries, NPY and noradrenaline caused vasoconstriction but did not potentiate each other. VIP, peptide histidine methionine, SP, neurokinin A, and CGRP relaxed arteries precontracted by prostaglandin F2 alpha. The degree of innervation and the vasomotor responses are discussed in relation to migraine pathophysiology.

Calcitonin Gene-Related Peptide↗
PubMed1994

Endothelins: a role in cerebrovascular disease?

Vasoactive factors produced and released by the endothelium exert a powerful influence on vascular tone in the cerebral circulation. Impaired endothelium-dependent responses, such as decreased production of endothelium-derived relaxing factors, and/or release of endothelium-derived contractile factors may give rise to different pathophysiological conditions. Among the endothelium-derived contractile factors the endothelins have recently received particular attention. Endothelin-1 is the major isoform in the endothelin family, which also includes endothelin-2 and endothelin-3. Endothelin-1 is synthesized within the endothelium of cerebral vessels, whereas both endothelin-1 and endothelin-3 in addition have been identified in neurons and glia. Recent electrophysiological work has suggested a neuromodulatory role for these peptides, but at present the general interest is mainly focused on their vasoactive role. Physiological stimuli such as hypoxia, anoxia, and hemodynamic shear stress will stimulate the endothelial endothelin production. In the brain, at least two types of specific subreceptors have been cloned; ETA receptors, exclusively associated with blood vessels and ETB receptors also found on glial, epithelial, and ependymal cells. The endothelins seem so far to be the most potent vasoconstrictors yet identified. The circulating plasma levels of immunoreactive endothelin are low. Since more than 80% of the total amount released from endothelial cells seems to be secreted towards the underlying smooth muscle, endothelins have been ascribed a local vasoregulatory role. Endothelins are believed to be involved in several of our most common cerebrovascular diseases and the present review comments on their possible pathophysiological role in subarachnoid haemorrhage, cerebral ischemia, and migraine.

Amino Acid Sequence↗
PubMed1994

Neuropeptides in migraine and cluster headache.

The cerebral circulation is invested by a rich network of neuropeptide Y (NPY) and noradrenaline containing sympathetic nerve fibers in arteries, arterioles and veins. However, the nerve supply of vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP) containing fibers is sparse. While noradrenaline and NPY cause vasoconstriction, VIP, SP and CGRP are potent vasodilators. Stimulation of the trigeminal ganglion in cat and man elicits release of SP and CGRP. Subjects with spontaneous attacks of migraine show release of CGRP in parallel with headache. Cluster headache patients have release of CGRP and VIP during bouts. Treatment with sumatriptan aborts headache in migraine and cluster headache as well as the concomitant peptide release.

Animals↗
PubMed1994

Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies.

Cluster headache is a rare very severe disorder that is clinically well characterized with a relatively poorly understood pathophysiology. In this study patients with episodic cluster headache fulfilling the criteria of the International Headache Society were examined during an acute spontaneous attack of headache to determine the local cranial release of neuropeptides. Blood was sampled from the external jugular vein ipsilateral to the pain before and after treatment of the attack. Samples were assayed for calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), substance P and neuropeptide Y. Attacks were treated with either oxygen inhalation, sumatriptan or an opiate. Thirteen patients were studied of whom 10 were male and three female. All had well-established typical attacks of cluster headache when blood was sampled. During the attacks external jugular vein blood levels of CGRP and VIP were raised while there was no change in neuropeptide Y or substance P. Calcitonin gene-related peptide levels rose to 110 +/- 7 pmol/l (normal: < 40) while VIP levels rose to 20 +/- 3 pmol/l (normal: < 7). Treatment with both oxygen and subcutaneous sumatriptan reduced the CGRP level to normal, while opiate administration did not alter the peptide levels. These data demonstrate for the first time in vivo human evidence for activation of the trigeminovascular system and the cranial parasympathetic nervous system in an acute attack of cluster headache. Furthermore, it is shown that both oxygen and sumatriptan abort the attacks and terminate activity in the trigeminovascular system.

Adult↗
PubMed1994

Effects of vasoconstrictors on rabbit coronary arteries exposed to iohexol with addition of electrolytes (sodium and calcium).

RATIONAL AND OBJECTIVES: A well-known side effect of contrast media (CM) is vasodilation. Different types of CM in vitro inhibit the action of vasoconstrictors to various degrees. The nonionic CM iohexol inhibits the action less than ionic CM. In this study, the authors investigate whether the addition of electrolytes to iohexol causes less inhibition of the vasoconstrictors. Vasoconstriction dependent on potential-operated calcium channels (POCs) (potassium chloride), or receptor-operated calcium channels (ROCs) (histamine, endothelin-1, and prostaglandin F2 [PGF2 alpha]) was specifically studied. METHODS: Segments of rabbit coronary arteries were mounted between two L-shaped prongs in tissue baths with buffer solution or solutions of iohexol (140 mg I/mL) with addition of different concentrations of NaCl and CaCl2. The responses of the vessels to increasing concentrations of a vasoconstrictor were examined. Concentration of vasoconstrictor versus contractile response curves were plotted, and the maximal contraction of the vasoconstrictor (Emax) and half maximal constriction were calculated. RESULTS: Addition of 30 mM NaCl and 1.5 mM CaCl2 caused a vasoconstriction to KCl in iohexol almost identical to its vasoconstriction in buffer. Higher concentrations of NaCl caused decreasing Emax of all vasoconstrictors. The inhibition of the ROC-dependent vasoconstrictors could not be normalized by the addition of electrolytes. CONCLUSIONS: The inhibition of the POC-dependent vasoconstrictor was caused by "ion toxicity" of iohexol. The inhibition of the ROC-dependent vasoconstrictors was caused by other mechanisms, in a manner compatible with a blocking effect on ROCs.

Animals↗