Park Joohee, Sahyoun Christina, Frangieh Jacinthe, Réthoré Léa, Proux Coralyne, Grimaud Linda, Vessières Emilie, Bourreau Jennifer, Mattei César, Henrion Daniel, Marionneau Céline, Fajloun Ziad, Legendre Claire, Legros Christian
Univ. Angers, INSERM, CNRS, MITOVASC, Equipe CarME, SFR ICAT, 49000 Angers, France.
Laboratory of Applied Biotechnology (LBA3B), Department of Cell Culture, Azm Center for Research in Biotechnology and Its Applications, EDST, Lebanese University, Tripoli 1300, Lebanon.
Toxins (Basel). 2024 Dec 10;16(12):533. doi: 10.3390/toxins16120533.
The vegetal alkaloid toxin veratridine (VTD) is a selective voltage-gated Na (Na) channel activator, widely used as a pharmacological tool in vascular physiology. We have previously shown that Na 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 Na 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-Ca 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 ([Ca]i), while SEA0400 partially blocked acetylcholine-triggered [Ca]i elevations in Mile Sven 1 ECs. Altogether, these results illustrate that VTD activates Na channels in parasympathetic neurons and then vasorelaxation in resistance arteries, which could explain arterial hypotension after VTD intoxication.
植物生物碱毒素藜芦定（VTD）是一种选择性电压门控钠（Na）通道激活剂，在血管生理学中广泛用作药理学工具。我们之前已经表明，动脉中表达的钠通道有助于小鼠肠系膜动脉（MA）的血管张力。在此，我们旨在使用小鼠盲结肠动脉（CA）（一种阻力动脉模型）更好地表征VTD的作用机制。使用线肌动描记法，我们发现VTD在小鼠CA中诱导血管舒张。这种VTD诱导的舒张对α1肾上腺素能受体拮抗剂哌唑嗪不敏感，但被毒蕈碱受体拮抗剂阿托品消除。实际上，VTD的血管舒张作用完全被钠通道阻滞剂河豚毒素（0.3 μM）、一氧化氮合酶抑制剂L-NNA（20 μM）和低细胞外钠浓度（14.9 mM）抑制，并且被NCX1拮抗剂SEA0400（1 μM时为45.4%）部分阻断。因此，我们推测VTD在CA中诱导的血管舒张是由于副交感神经元释放乙酰胆碱，其在内皮细胞（EC）中通过NCX1-Ca内流模式诱导一氧化氮合酶激活。我们通过RT-qPCR以及免疫组织化学和western免疫标记证明了EC中NCX1的表达。VTD未诱导细胞内钙（[Ca]i）增加，而SEA0400部分阻断了乙酰胆碱触发的Mile Sven 1 EC中[Ca]i升高。总之，这些结果表明VTD激活副交感神经元中的钠通道，进而导致阻力动脉血管舒张，这可以解释VTD中毒后的动脉低血压。
