| 51. |
- Cao, YX, et al.
(author)
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Induces vasodilatation of rat mesenteric artery in vitro mainly by inhibiting receptor-mediated Ca2+-influx and Ca2+-release
- 2005
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In: Archives of Pharmacal Research. - 1976-3786. ; 28:6, s. 709-715
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Journal article (peer-reviewed)abstract
- The purpose of this study was to investigate the effect of atropine on peripheral vasodilation and the mechanisms involved. The isometric tension of rat mesenteric artery rings was recorded in vitro on a myograph. The results showed that atropine, at concentrations greater than 1 mu M, relaxed the noradrenalin (NA)-precontracted rat mesenteric artery in a concentration-dependent manner. Atropine-induced vasodilatation was mediated, in part, by an endothelium-dependent mechanism, to which endothelium-derived hyperpolarizing factor may contribute. Atropine was able to shift the NA-induced concentration-response curve to the right, in a non-parallel manner, suggesting the mechanism of atropine was not mediated via the alpha(1)-adrenoreceptor. The beta-adrenoreceptor and ATIP sensitive potassium channel, a voltage dependent calcium channel, were not involved in the vasodilatation. However, atropine inhibited the contraction derived from NA and CaCl2 in Ca2+-free medium, in a concentration dependent manner, indicating the vasodilatation was related to the inhibition of extracellular Ca2+ influx through the receptor-operated calcium channels and intracellular Ca2+ release from the Ca (2+) store. Atropine had no effect on the caffeine-induced contraction in the artery segments, indicating the inhibition of intracellular Ca2+ release as a result of atropine most likely occurs via the IP3 pathway rather than the ryanodine receptors. Our results suggest that atropine-induced vasodilatation is mainly from artery smooth muscle cells due to inhibition of the receptor-mediated Ca2+-influx and Ca2+-release, and partly from the endothelium mediated by EDHF.
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| 52. |
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| 53. |
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| 54. |
- Cervin, Anders, et al.
(author)
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Functional effects of neuropeptide Y receptors on blood flow and nitric oxide levels in the human nose
- 1999
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In: American Journal of Respiratory and Critical Care Medicine. - : American Thoracic Society. - 1535-4970 .- 1073-449X. ; 160:5, s. 1724-1728
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Journal article (peer-reviewed)abstract
- The aim of this study was to examine dose-dependent effects of intranasal application of neuropeptide Y (NPY) on nasal mucosal blood flow, blood content, and intranasal nitric oxide (NO) concentration. Blood flow was measured by laser Doppler flowmetry (LDF) and blood content by rhinomanometry. Mucosal biopsies were taken for investigation of Y1 and Y2 receptor mRNA expression, using the reverse transcriptase-polymerase chain reaction (RT-PCR). Intranasal application of NPY evoked a dose-dependent reduction of nasal mucosal blood flow. Maximal vasoconstriction, seen at 12 nmol, was -37.5 +/- 6.2%, p < 0.05 (n = 9). The vasoconstrictive effect developed within 2 to 4 min and lasted > 17 min. NPY evoked a dose-dependent reduction of nasal airway resistance (NAR) on the ipsilateral side. Maximal decrease was -24.0 +/- 10.0% at 12 nmol, p < 0.05 (n = 9). There was a decrease in nasal NO production on the ipsilateral side after application of NPY 12 nmol (-7.4 +/- 1.2%, p < 0.05, n = 8). RT-PCR products corresponding to Y1 receptor but not Y2 receptor mRNA were obtained from biopsies of the nasal mucosa. In conclusion, NPY is a potent vasoconstrictor in the human nose reducing mucosal blood flow, as well as the blood content. The effect is probably mediated via Y1 receptors. NPY receptor agonists may prove beneficial in the treatment of the congested nose in allergic or vasomotor rhinitis.
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| 55. |
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| 56. |
- Chan, K. Y., et al.
(author)
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Characterization of the Calcitonin Gene-Related Peptide Receptor Antagonist Telcagepant (MK-0974) in Human Isolated Coronary Arteries
- 2010
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In: Journal of Pharmacology and Experimental Therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 1521-0103 .- 0022-3565. ; 334:3, s. 746-752
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Journal article (peer-reviewed)abstract
- The sensory neuropeptide calcitonin gene-related peptide (CGRP) plays a role in primary headaches, and CGRP receptor antagonists are effective in migraine treatment. CGRP is a potent vasodilator, raising the possibility that antagonism of its receptor could have cardiovascular effects. We therefore investigated the effects of the antimigraine CGRP receptor antagonist telcagepant (MK-0974) [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan- 3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-c arboxamide] on human isolated coronary arteries. Arteries with different internal diameters were studied to assess the potential for differential effects across the coronary vascular bed. The concentration-dependent relaxation responses to human alpha CGRP were greater in distal coronary arteries (i.d. 600-1000 mu m; E-max = 83 +/- 7%) than proximal coronary arteries (i.d. 2-3 mm; E-max = 23 +/- 9%), coronary arteries from explanted hearts (i.d. 3-5 mm; E-max = 11 +/- 3%), and coronary arterioles (i.d. 200-300 mu m; E-max = 15 +/- 7%). Telcagepant alone did not induce contraction or relaxation of these coronary blood vessels. Pretreatment with telcagepant (10 nM to 1 mu M) antagonized alpha CGRP-induced relaxation competitively in distal coronary arteries (pA(2) = 8.43 +/- 0.24) and proximal coronary arteries and coronary arterioles (1 mu M telcagepant, giving pK(B) = 7.89 +/- 0.13 and 7.78 +/- 0.16, respectively). alpha CGRP significantly increased cAMP levels in distal, but not proximal, coronary arteries, and this was abolished by pretreatment with telcagepant. Immunohistochemistry revealed the expression and colocalization of the CGRP receptor elements calcitonin-like receptor and receptor activity-modifying protein 1 in the smooth muscle cells in the media layer of human coronary arteries. These findings in vitro support the cardiovascular safety of CGRP receptor antagonists and suggest that telcagepant is unlikely to induce coronary side effects under normal cardiovascular conditions.
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| 57. |
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| 58. |
- Chen, Qingwen, et al.
(author)
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Cigarette smoke extract promotes human vascular smooth muscle cell proliferation and survival through ERK1/2- and NF-κB-dependent pathways.
- 2010
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In: The Scientific World Journal. - : Hindawi Limited. - 2356-6140 .- 1537-744X. ; 10, s. 2139-2156
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Journal article (peer-reviewed)abstract
- Tobacco use is one of the major risk factors of cardiovascular disease. The underlying molecular mechanisms that link cigarette smoke to cardiovascular disease remain unclear. The present study was designed to examine the effects of dimethyl sulfoxide (DMSO)-soluble smoke particles (DSPs) on human aortic smooth muscle cell (HASMC) cultures, and to explore the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) and nuclear factor-kappaB (NF-κB) signal mechanisms involved. Serum-starved HASMCs were treated with DSPs for up to 48 h. DSPs promoted cell proliferation in a concentration-dependent manner from 0.05 to 0.2 μl/ml. Activation of ERK1/2 and NF-κB was seen after exposure to DSPs. This occurred in parallel with the increase in cell population, bromodeoxyuridine incorporation, and cyclinD1/cyclin-dependent kinase 4 expression. Blocking phosphorylation of ERK1/2 by MAPK inhibitors U0126 and PD98059, and inhibiting activation of NF-κB by IkappaB (IκB) kinase inhibitors wedelolactone or IMD-0354, abolished the DSP effects. However, either a p38 inhibitor (SB203580) or an inhibitor of lipopolysaccharide (polymyxin B), or nicotinic receptor blockers (mecamylamine and alpha-bungarotoxin), did not inhibit a DSP-induced increase in the cell population. DSPs increased the expression of intercellular adhesion molecule 1 and the release of interleukin-6 in HASMCs, both of which were inhibited by ERK1/2 or NF-κB pathway inhibitors. Furthermore, cell apoptosis and necrosis were found in serum-starved HASMCs. DSPs decreased cell death and increased B-cell leukemia/lymphoma 2 expression. Blocking phosphorylation of ERK1/2 or NF-κB attenuated DSP-induced cell death inhibition. Cigarette smoke particles stimulate HASMC proliferation and inhibit cell death. The intracellular signal mechanisms behind this involve activation of ERK1/2 and NF-κB pathways.
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| 59. |
- Chen, Qing-wen, et al.
(author)
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Role of ERK/MAPK in endothelin receptor signaling in human aortic smooth muscle cells.
- 2009
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In: BMC Cell Biology. - : Springer Science and Business Media LLC. - 1471-2121. ; 10:Jul 3
-
Journal article (peer-reviewed)abstract
- ABSTRACT: muscle cells (VSMCs) through activation of endothelin type A (ETA) and type B (ETB) receptors. The extracellular signal-regulated kinase 1 and 2 (ERK1/2) mitogen-activated protein kinases (MAPK) are involved in ET-1-induced VSMC contraction and proliferation. This study was designed to investigate the ETA and ETB receptor intracellular signaling in human VSMCs and used phosphorylation (activation) of ERK1/2 as a functional signal molecule for endothelin receptor activity. RESULTS: Subconfluent human VSMCs were stimulated by ET-1 at different concentrations (1 nM-1 microM). The activation of ERK1/2 was examined by immunofluorescence, Western blot and phosphoELISA using specific antibody against phosphorylated ERK1/2 protein. ET-1 induced a concentration- and time- dependent activation of ERK1/2 with a maximal effect at 10 min. It declined to baseline level at 30 min. The ET-1-induced activation of ERK1/2 was completely abolished by MEK1/2 inhibitors U0126 and SL327, and partially inhibited by the MEK1 inhibitor PD98059. A dual endothelin receptor antagonist bosentan or the ETA antagonist BQ123 blocked the ET-1 effect, while the ETB antagonist BQ788 had no significant effect. However, a selective ETB receptor agonist, Sarafotoxin 6c (S6c) caused a time-dependent ERK1/2 activation with a maximal effect by less than 20% of the ET-1-induced activation of ERK1/2. Increase in bosentan concentration up to 10 microM further inhibited ET-1-induced activation of ERK1/2 and had a stronger inhibitory effect than BQ123 or the combined use of BQ123 and BQ788. To further explore ET-1 intracellular signaling, PKC inhibitors (staurosporin and GF109203X), PKC-delta inhibitor (rottlerin), PKA inhibitor (H-89), and phosphatidylinositol 3-kinase (PI3K) inhibitor (wortmannin) were applied. The inhibitors showed significant inhibitory effects on ET-1-induced activation of ERK1/2. However, blockage of L-type Ca2+ channels or calcium/calmodulin-dependent protein kinase II, chelating extracellular Ca2+ or emptying internal Ca2+ stores, did not affect ET-1-induced activation of ERK1/2. CONCLUSION: The ETA receptors predominate in the ET-1-induced activation of ERK1/2 in human VSMCs, which associates with increments in intracellular PKC, PKA and PI3K activities, but not Ca2+ signalling.
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| 60. |
- Christensen, Simon Topp, et al.
(author)
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Exploration of Physiological and Pathophysiological Implications of miRNA-143 and miRNA-145 in Cerebral Arteries
- 2019
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In: Journal of Cardiovascular Pharmacology. - 1533-4023. ; 74:5, s. 409-419
-
Journal article (peer-reviewed)abstract
- Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke with a high short-term mortality rate which leads to cognitive impairments that reduce the quality of life of the majority of patients. The miRNA-143/145 cluster is highly expressed in vascular smooth muscle cells (VSMC) and has been shown to be necessary for differentiation and function, as well as an important determinant for phenotypic modulation/switching of VSMCs in response to vascular injury. We aimed to determine whether miRNA-143 and miRNA-145 are important regulators of phenotypical changes of VSMCs in relation to SAH, as well as establishing their physiological role in the cerebral vasculature. We applied quantitative PCR to study ischemia-induced alterations in the expression of miRNA-143 and miRNA-145, for rat cerebral vasculature, in an ex vivo organ culture model and an in vivo SAH model. To determine the physiological importance, we did myograph studies on basilar and femoral arteries from miRNA-143/145 knockout mice. miRNA-143 and miRNA-145 are not upregulated in the vasculature following our SAH model, despite the upregulation of miR-145 in the organ culture model. Regarding physiological function, miRNA-143 and miRNA-145 are very important for general contractility in cerebral vessels in response to depolarization, angiotensin II, and endothelin-1. Applying an anti-miRNA targeting approach in SAH does not seem to be a feasible approach because miRNA-143 and miRNA-145 are not upregulated following SAH. The knockout mouse data suggest that targeting miRNA-143 and miRNA-145 would lead to a general reduced contractility of the cerebral vasculature and unwanted dedifferentiation of VSMCs.
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