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Sökning: LAR1:lu > Refereegranskat > Edvinsson Lars

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21.
  • Ansar, Saema, et al. (författare)
  • MAPK signaling pathway regulates cerebrovascular receptor expression in human cerebral arteries
  • 2013
  • Ingår i: BMC Neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 14
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Cerebral ischemia results in enhanced expression of contractile cerebrovascular receptors, such as endothelin type B (ETB), 5-hydroxytryptamine type 1B (5-HT1B), angiotensin II type 1 (AT(1)) and thromboxane (TP) receptors in the cerebral arteries within the ischemic area. The receptor upregulation occurs via activation of the mitogen-activated protein kinases (MAPK) pathway. Previous studies have shown that inhibitors of the MAPK pathway diminished the ischemic area and contractile cerebrovascular receptors after experimental cerebral ischemia. The aim of this study was to examine if the upregulation of contractile cerebrovascular receptors after 48 h of organ culture of human cerebral arteries involves MAPK pathways and if it can be prevented by a MEK1/2 inhibitor. Human cerebral arteries were obtained from patients undergoing intracranial tumor surgery. The vessels were divided into ring segments and incubated for 48 h in the presence or absence of the specific MEK1/2 inhibitor U0126. The vessels were then examined by using in vitro pharmacological methods and protein immunohistochemistry. Results: After organ culture of the cerebral arteries the contractile responses to endothelin (ET)-1, angiotensin (Ang) II and thromboxane (TP) were enhanced in comparison with fresh human arteries. However, 5-carboxamidotryptamine (5-CT) induced decreased contractile responses after organ culture as compared to fresh arteries. Incubation with U0126 diminished the maximum contraction elicited by application of ET-1, Ang II and U46619 in human cerebral arteries. In addition, the MEK1/2 inhibitor decreased the contractile response to 5-CT. Immunohistochemistry revealed that organ culture resulted in increased expression of endothelin ETA, endothelin ETB angiotensin AT(2), 5-hydroxytryptamine 5-HT1B and thromboxane A2 receptors, and elevated levels of activated pERK1/2, all localized to the smooth muscle cells of the cerebral arteries. Co-incubation with U0126 normalized these proteins. Conclusion: The study demonstrated that there is a clear association between human cerebrovascular receptor upregulation via transcription involving activation of the MAPK pathway after organ culture. Inhibition of the MAPK pathways attenuated the vasoconstriction mediated by ET, AT and TP receptors in human cerebral arteries and the enhanced expression of their receptors. The results indicate that MAPK inhibition might be a novel target for treatment of cerebrovascular disorders.
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22.
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23.
  • Ansar, Saema, et al. (författare)
  • Neurokinin-1 receptor antagonism in a rat model of subarachnoid hemorrhage: prevention of upregulation of contractile ETB and 5-HT1B receptors and cerebral blood flow reduction
  • 2007
  • Ingår i: Journal of Neurosurgery. - 0022-3085. ; 106:5, s. 881-886
  • Tidskriftsartikel (refereegranskat)abstract
    • Object. Cerebral vasospasm following subarachnoid hemorrhage (SAH) leads to reduced cerebral blood flow (CBF) and to cerebral ischemia, in some cases even producing infarction and long-term disability. The goal of the present study was to investigate the hypothesis that inhibition of neurokinin-1 receptors (NK1Rs) by administration of L-822429 blunts the decrease in CBF as well as cerebrovascular receptor upregulation in an animal model of SAH. Methods. Subarachnoid hemorrhage was induced in rats by injection of 250 mu l of blood into the prechiasmatic cistern. The NK1R inhibitor L-822429 was injected intracisternally 30 minutes and 24 hours after the induction of SAH. Two days after SAH induction, the basilar arteries were harvested, and contractile responses to endothelin-1 (ET-1, an ETA- and ETB-receptor agonist) and 5-carboxamidotryptamine (a 5-hydroxytryptamine-1 [5-HT1]-receptor agonist) were investigated using sensitive myographs. To determine whether NK1R inhibition had an influence on local CBF after post-SAH, a quantitative autoradiographic technique was used. After SAH, the vascular receptor phenotype was changed in cerebral arteries through upregulation of contractile ET, and 5-HT1B receptors, while regional and total CBF were markedly reduced. Treatment with the selective NK1R inhibitor L-822429 prevented both the receptor upregulation and the reduction in regional and global CBF. Conclusions. The data reveal the coregulation of vascular receptor changes and blood flow effects, and also show that interaction with a small-molecule NK1R antagonist is a promising area Of focus for the development of specific treatments for SAH.
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24.
  • Ansar, Saema, et al. (författare)
  • Protein kinase C inhibition prevents upregulation of vascular ET(B) and 5-HT(1B) receptors and reverses cerebral blood flow reduction after subarachnoid haemorrhage in rats.
  • 2007
  • Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 27:1, s. 21-32
  • Tidskriftsartikel (refereegranskat)abstract
    • The pathogenesis of cerebral ischaemia after subarachnoid haemorrhage (SAH) still remains elusive. The purpose of the present study was to examine whether specific protein kinas C (PKC) inhibition in rats could alter the transcriptional SAH induced Endothelin (ET) type B and 5-hydroxytryptamine type 1B (5-HT1B) receptor upregulation and prevent the associated cerebral blood flow (CBF) reduction. The PKC inhibitor RO-31-7549 or vehicle was injected intracisternally after the induced SAH in rats (n = 3 to 10 in each groups for each method). The involvement of the PKC isoforms was investigated with Western blot; only PKC delta and PKC alpha subtypes were increased after SAH RO-31-7549 treatment abolished this. At 2 days after the SAH basilar and middle cerebral arteries were harvested and the contractile response to endothelin-1 (ET-1; ETA and ETB receptor agonist) and 5-carboxamidotryptamine (5-CT; 5-HT1B receptor agonist) were investigated with a myograph. The contractile responses to ET-1 and 5-CT were increased (P < 0.05) after SAH compared with sham operated rats. In parallel, the ETB and 5-HT1B receptor mRNA and protein expression were significantly elevated after SAH, as analysed by quantitative real-time polymerase chain reaction and immunohistochemistry, respectively. Administration of RO-31-7549 prevented the upregulated contraction elicited by application of ET-1 and 5-CT in cerebral arteries and kept the ETB and 5-HT1B receptor mRNA and protein levels at pre-SAH levels. Regional and global CBF evaluated by an autoradiographic technique were reduced by 60% 64% after SAH (P < 0.05) and prevented by treatment with RO-31-7549. Our study suggests that PKC plays an important role in the pathogenesis of cerebral ischaemia after SAH.
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25.
  • Ansar, Saema, et al. (författare)
  • Subarachnoid Hemorrhage Induces Enhanced Expression of Thromboxane A(2) Receptors in Rat Cerebral Arteries.
  • 2010
  • Ingår i: Brain Research. - : Elsevier BV. - 1872-6240 .- 0006-8993. ; 1316, s. 163-172
  • Tidskriftsartikel (refereegranskat)abstract
    • Cerebral ischemia remains the key cause of morbidity and mortality after subarachnoid hemorrhage (SAH) with a pathogenesis that is still poorly understood. The aim of the present study was to examine the involvement of thromboxane A(2) receptors (TP) in the patophysiology of cerebral ischemia after SAH in cerebral arteries. SAH was induced in rats by injecting 250 microl blood into the prechiasmatic cistern. Two days after the SAH, cerebral arteries were harvested and contractile responses to the TP receptor agonist U46619 were investigated with myographs. In addition, the contractile responses were examined after pretreatment with selective TP receptor antagonist GR3219b. The TP receptor RNA and protein levels were analyzed by quantitative real-time PCR and immunohistochemistry, respectively. The global and regional cerebral blood flows (CBF) were quantified with an autoradiographic technique. SAH resulted in enhanced contractile responses to U46619 as compared to sham. The TP receptor antagonist GR3219b abolished the enhanced contractile responses to U46619 observed after SAH. The TP receptor mRNA level was elevated after SAH as compared to sham. The level of TP receptor protein on the smooth muscle cells (SMC) was increased in SAH compared to sham, Global and regional CBF was reduced in SAH as compared to sham. The results demonstrate that SAH results in CBF reduction and this is associated with enhanced expression of TP receptors in the SMC of cerebral arteries and microvessels.
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26.
  • Ansar, Saema, et al. (författare)
  • Subarachnoid hemorrhage induces upregulation of vascular receptors and reduction in rCBF via an ERKI/2 mechanism
  • 2008
  • Ingår i: Cerebral Vasospasm: New Strategies in Research and Treatment. - Vienna : Springer Vienna. - 0065-1419. - 9783211757178 ; 104, s. 65-67
  • Konferensbidrag (refereegranskat)abstract
    • Previous studies have shown that endothelin type B (ETB) and 5-hydroxytryptamine type IB (5-HTIB) receptors are upregulated following subarachnoid hemorrhage (SAH). The purpose of the present study was to test whether extracellular signal-regulated kinase (ERKI/2) inhibition could alter the degree of SAH induced receptor upregulation in addition to prevent the cerebral blood flow (CBF) reduction. The ERKI/2 inhibitor SB386023-b was injected intra cisternally in conjunction with and after the induced SAH in rats. Two days after SAH cerebral arteries were harvested and the contractile response to endothelin-1 (ET-I) and 5-carboxamidotryptamine (5-CT) were investigated with a myograph. The contractile responses to ET-I and 5-CT were increased after SAH compared to sham. Administration of SB-386023-b prevented the upregulated contraction elicited by application of ET-I and 5-CT in cerebral arteries. Regional CBF evaluated by an autoradiographic technique, revealed a reduced CBF by 50% after SAH this was prevented by treatment with SB-386023-b. The results indicate that an ERKI/2 mechanism is involved in cerebral vasospasm and ischemia associated with SAH.
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27.
  • Ansar, Saema, et al. (författare)
  • Subtype activation and interaction of protein kinase C and mitogen-activated protein kinase controlling receptor expression in cerebral arteries and microvessels after subarachnoid hemorrhage
  • 2008
  • Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 39:1, s. 185-190
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and Purpose-The pathogenesis of cerebral ischemia associated with subarachnoid hemorrhage (SAH) still remains elusive. The aim of this study was to examine the involvement of mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) subtypes in the pathophysiology of cerebral ischemia after SAH in cerebral arteries and microvessels and to examine temporal activation of the kinases. We hypothesize that treatment with a MAPK or PKC inhibitor will prevent the SAH-induced kinase activation in brain vessels. Methods-SAH was induced by injecting 250 mu L blood into the prechiasmatic cistern in the rat. The activation of different MAPK and PKC isotypes in large circle of Willis cerebral arteries and intracerebral microvessels was examined at 0, 1, 3, 6, 12, 24, and 48 hours after SAH and after intrathecal treatment with PKC or MAPK inhibitor by use of Western blot. Results-Among the 8 investigated PKC isoforms, only PKC delta was activated at 1 hour and at 48 hours, whereas PKC alpha was activated at 48 hours after SAH. For the MAPKs, there was early phosphorylation at 1 hour of extracellular signal-regulated kinase 1/2, whereas c-jun N-terminal kinase and p38 showed enhanced phosphorylation only at 48 hours after SAH. The pattern was identical in large cerebral arteries and in intracerebral microvessels. Treatment with either the PKC (RO-31-7549) or the raf (SB386023-b) inhibitor prevented the kinase activation. Conclusions-The results show that specific subtypes of the MAPK and PKC pathways are activated in cerebral arteries after SAH and the PKC and raf inhibitors are able to prevent this activation.
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28.
  • Baun, Michael, et al. (författare)
  • Pharmacological characterization and expression of VIP and PACAP receptors in isolated cranial arteries of the rat
  • 2011
  • Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 670:1, s. 186-194
  • Tidskriftsartikel (refereegranskat)abstract
    • Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating peptide (PACAP) are potent vasodilators in animals and humans. PACAP infusion but not VIP infusion precipitates migraine attacks in migraine patients. The vascular effects of VIP and the two varieties of PACAP (PACAP-27 and PACAP-38) were investigated versus selective antagonists in segments of rat middle cerebral arteries (MCA), basilar arteries (BA) and middle meningeal arteries (MMA) using myographs. The luminal and abluminal effects of VIP were studied using perfusion myograph. mRNA expression of the relevant receptors (VPAC(1), VPAC(2) and PAC(1)) was examined by in situ hybridization. There was no significant difference in relaxant potency of the peptides in the MCA. In BA the relaxant potency was VIP>PACAP-27 = PACAP-38. Relaxant responses were either absent or very weak in MMA. VIP was found to be somewhat more potent in BA than in the MCA. Maxadilan, a selective PAC(1)-receptor agonist, showed no relaxant effect in either vessel. The VPAC(2)-antagonist PG 99-465 alone proved ineffective in the MCA, while it had a weak effect on BA. The VPAC(1)-antagonist PG 97269 inhibited relaxation induced by both VIP and the PACAPs in cerebral vessels. In combination, the two antagonists demonstrated better effect than either alone. VIP applied luminally via perfusion myograph caused no dilatation, indicating lack of endothelial involvement. In situ hybridization demonstrated the presence of mRNA for all three receptors in the smooth muscle cells of the vessels. In conclusion, migraine-like headache induced by PACAP-38 infusion is unlikely to be caused by direct vasodilator action on intracranial vessels. (C) 2011 Elsevier B.V. All rights reserved.
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29.
  • Belin, Andrea Carmine, et al. (författare)
  • Calcitonin gene-related peptide (CGRP) and cluster headache
  • 2020
  • Ingår i: Brain Sciences. - : MDPI AG. - 2076-3425. ; 10:1
  • Forskningsöversikt (refereegranskat)abstract
    • Cluster headache (CH) is a severe primary headache with a prevalence of 1/1000 individuals, and a predominance in men. Calcitonin gene-related peptide (CGRP) is a potent vasodilator, originating in trigeminal neurons and has a central role in CH pathophysiology. CGRP and the CGRP receptor complex have recently taken center stage as therapeutic targets for primary headaches, such as migraine. Multiple CGRP and CGRP receptor monoclonal antibodies, as well as small molecule antagonists (gepants) are on their way constituting a new frontier of migraine and possibly CH medication. During a CH attack, there is an activation of the trigeminal-autonomic reflex with the release of CGRP, and inversely if CGRP is administered to a CH patient in an active disease phase, it triggers an attack. Increased levels of CGRP have been found in ipsilateral jugular vein blood during the active phase of CH. This process is hypothesized to have a key role in the intense pain perception and in the associated distinctive vasodilation. So far, clinical tests of CGRP antibodies have been inconclusive in CH patients. This review summarizes the current state of knowledge on the role of CGRP in CH pathology, and as a target for future treatments.
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30.
  • Bengtsson, Christine, et al. (författare)
  • Effect of Medication on Microvascular Vasodilatation in Patients with Systemic Lupus Erythematosus
  • 2010
  • Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7843 .- 1742-7835. ; 107:6, s. 919-924
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to investigate the microvascular responses in the skin, to local heat, iontophoretically administered acetylcholine and to sodium nitroprusside in relation to cardiovascular damage in patients with systemic lupus erythematosus (SLE) and matched controls. We also wanted to examine if the ongoing medication in SLE patients influenced this vascular response. We investigated 30 women with SLE and compared them with 20 age and sex-matched controls. The cutaneous blood flow response to local heat (+44 degrees C), iontophoretically administered endothelium-dependent (acetylcholine), as well as independent (sodium nitroprusside) vasodilatation, was measured by laser Doppler flowmetry. Clinical data and medication were retrieved from the clinical database and patient records. The cutaneous microvascular reactivity did not differ between SLE patients and a group of matched controls nor did it correlate with cardiovascular damage [assessed by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR-DI)]. However, patients on antimalarial drugs (hydroxychloroquine n = 8 and chloroquine diphosphate n = 3) responded more strongly to sodium nitroprusside (endothelium-independent vasodilatation) compared with those without antimalarial drugs (p < 0.01). The response to acetylcholine was higher among patients on warfarin compared with those without (p < 0.05), whereas glucocorticoid use (>= 5 mg daily) was associated with reduced response to acetylcholine (p < 0.05). Smokers in general tended to have a lower response to acetylcholine (p = 0.064). Smoking SLE patients versus non-smoking SLE patients had a significantly lower response to acetylcholine (p = 0.01). Medication with antimalarial drugs-enhanced endothelium-independent vasodilatation, while glucocorticoid use was associated with reduction and warfarin-treatment with enhancement of endothelium-dependent vasodilatation. Therefore, despite there is no difference in microvascular endothelium-dependent vasodilatation, other factors such as medication and smoking may affect vasodilatation in SLE patients.
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