Joohee Park, Christina Sahyoun, Jacinthe Frangieh, Léa Réthoré, Coralyne Proux, Linda Grimaud, Emilie Vessières, Jennifer Bourreau, César Mattei, Daniel Henrion, Céline Marionneau, Ziad Fajloun, Claire Legendre, Christian Legros
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This VTD-induced relaxation was insensitive to prazosin, an α1-adrenergic receptor antagonist, but abolished by atropine, a muscarinic receptor antagonist. Indeed, VTD-vasorelaxant effect was totally inhibited by the Na<sub>V</sub> channel blocker tetrodotoxin (0.3 µM), the NO synthase inhibitor L-NNA (20 µM), and low extracellular Na<sup>+</sup> concentration (14.9 mM) and was partially blocked by the NCX1 antagonist SEA0400 (45.4% at 1 µM). Thus, we assumed that the VTD-induced vasorelaxation in CAs was due to acetylcholine release by parasympathetic neurons, which induced NO synthase activation mediated by the NCX1-Ca<sup>2+</sup> entry mode in endothelial cells (ECs). We demonstrated NCX1 expression in ECs by RT-qPCR and immunohisto- and western immunolabelling. VTD did not induce an increase in intracellular Ca<sup>2+</sup> ([Ca<sup>2+</sup>]i), while SEA0400 partially blocked acetylcholine-triggered [Ca<sup>2+</sup>]i elevations in Mile Sven 1 ECs. 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引用次数: 0
摘要
植物生物碱毒素veratridine (VTD)是一种选择性电压门控Na+ (NaV)通道激活剂,被广泛用作血管生理学的药理工具。我们之前已经证明,在动脉中表达的NaV通道有助于小鼠肠系膜动脉(MAs)的血管张力。在这里,我们旨在通过小鼠结肠动脉(CAs)模型更好地表征VTD的作用机制。通过钢丝肌图,我们发现VTD诱导小鼠ca血管松弛。这种vtd诱导的松弛对α - 1肾上腺素受体拮抗剂吡唑嗪不敏感,但被毒蕈碱受体拮抗剂阿托品消除。事实上,vtd血管松弛作用被NaV通道阻滞剂河鲀毒素(0.3µM)、NO合酶抑制剂L-NNA(20µM)和低细胞外Na+浓度(14.9 mM)完全抑制,并被NCX1拮抗剂SEA0400部分阻断(1µM时45.4%)。因此,我们假设vtd诱导的CAs血管松弛是由于副交感神经细胞释放乙酰胆碱,诱导内皮细胞(ECs)中NCX1-Ca2+进入模式介导的NO合成酶激活。我们通过RT-qPCR和免疫组织和西方免疫标记证实了NCX1在ECs中的表达。VTD不诱导细胞内Ca2+ ([Ca2+]i)的增加,而SEA0400部分阻断了乙酰胆碱引发的Mile Sven 1 ec中[Ca2+]i的升高。综上所述,VTD激活了副交感神经元的NaV通道,然后激活了抵抗动脉的血管松弛,这可以解释VTD中毒后动脉低血压的原因。
Veratridine Induces Vasorelaxation in Mouse Cecocolic Mesenteric Arteries.
The vegetal alkaloid toxin veratridine (VTD) is a selective voltage-gated Na+ (NaV) channel activator, widely used as a pharmacological tool in vascular physiology. We have previously shown that NaV channels, expressed in arteries, contribute to vascular tone in mouse mesenteric arteries (MAs). Here, we aimed to better characterize the mechanisms of action of VTD using mouse cecocolic arteries (CAs), a model of resistance artery. Using wire myography, we found that VTD induced vasorelaxation in mouse CAs. This VTD-induced relaxation was insensitive to prazosin, an α1-adrenergic receptor antagonist, but abolished by atropine, a muscarinic receptor antagonist. Indeed, VTD-vasorelaxant effect was totally inhibited by the NaV channel blocker tetrodotoxin (0.3 µM), the NO synthase inhibitor L-NNA (20 µM), and low extracellular Na+ concentration (14.9 mM) and was partially blocked by the NCX1 antagonist SEA0400 (45.4% at 1 µM). Thus, we assumed that the VTD-induced vasorelaxation in CAs was due to acetylcholine release by parasympathetic neurons, which induced NO synthase activation mediated by the NCX1-Ca2+ entry mode in endothelial cells (ECs). We demonstrated NCX1 expression in ECs by RT-qPCR and immunohisto- and western immunolabelling. VTD did not induce an increase in intracellular Ca2+ ([Ca2+]i), while SEA0400 partially blocked acetylcholine-triggered [Ca2+]i elevations in Mile Sven 1 ECs. Altogether, these results illustrate that VTD activates NaV channels in parasympathetic neurons and then vasorelaxation in resistance arteries, which could explain arterial hypotension after VTD intoxication.
期刊介绍:
Toxins (ISSN 2072-6651) is an international, peer-reviewed open access journal which provides an advanced forum for studies related to toxins and toxinology. It publishes reviews, regular research papers and short communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.