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首页> 外文期刊>BMC Ear, Nose and Throat Disorders >Pharmacological reversal of endothelin-1 mediated constriction of the spiral modiolar artery: a potential new treatment for sudden sensorineural hearing loss
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Pharmacological reversal of endothelin-1 mediated constriction of the spiral modiolar artery: a potential new treatment for sudden sensorineural hearing loss

机译：内皮素-1介导的螺旋mod动脉收缩的药理学逆转：潜在的突然感觉神经性听力损失的新疗法

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Background Vasospasm of the spiral modiolar artery (SMA) may cause ischemic stroke of the inner ear. Endothelin-1 (ET-1) induces a strong, long-lasting constriction of the SMA by increasing contractile apparatus Ca2+ sensitivity via Rho-kinase. We therefore tested several Rho-kinase inhibitors and a cell-permeable analogue of cAMP (dbcAMP) for their ability to reverse ET-1-induced constriction and Ca2+-sensitization. Methods The present study employed SMA isolated from gerbil temporal bones. Ca2+sensitivity was evaluated by correlating vascular diameter and smooth muscle cell [Ca2+]i, measured by fluo-4-microfluorometry and videomicroscopy. Results The Rho-kinase inhibitors Y-27632, fasudil, and hydroxy-fasudil reversed ET-1-induced vasoconstriction with an IC50 of 3, 15, and 111 μmol/L, respectively. DbcAMP stimulated a dose-dependent vasodilation (Ec50 = 1 mmol/L) and a reduction of [Ca2+]i (EC50 = 0.3 μmol/L) of ET-1-preconstricted vessels (1 nmol/L). Fasudil and dbcAMP both reversed the ET-1-induced increase in Ca2+ sensitivity. Conclusion Rho-kinase inhibition and dbcAMP reversed ET-1-induced vasoconstriction and Ca2+-sensitization. Therefore, Rho-kinase inhibitors or cAMP modulators could possess promise as pharmacological tools for the treatment of ET-1-induced constriction, ischemic stroke and sudden hearing loss.
机译：背景螺旋mod动脉（SMA）的血管痉挛可能引起内耳缺血性中风。内皮素-1（ET-1）通过Rho激酶增加收缩装置Ca 2+ 的敏感性，从而诱导SMA强烈持久地收缩。因此，我们测试了几种Rho激酶抑制剂和cAMP的细胞渗透性类似物（dbcAMP）逆转ET-1诱导的收缩和Ca 2 + 致敏的能力。方法本研究采用从沙鼠颞骨中分离的SMA。 Ca 2 + 的敏感性通过将血管直径与平滑肌细胞[Ca 2 + ] i 相关联，通过fluo-4-microfluormetry和电子显微镜。结果Rho激酶抑制剂Y-27632，法舒地尔和羟基法舒地尔逆转了ET-1诱导的血管收缩，IC 50 分别为3、15和111μmol/ L。 DbcAMP刺激了剂量依赖性的血管舒张（Ec 50 = 1 mmol / L）和[Ca 2 + ] i （EC < sub> 50 = 0.3μmol/ L）的ET-1预缩血管（1 nmol / L）。 Fasudil和dbcAMP均逆转了ET-1诱导的Ca 2+ 敏感性的增加。结论Rho激酶抑制和dbcAMP逆转了ET-1引起的血管收缩和Ca 2 + 致敏。因此，Rho激酶抑制剂或cAMP调节剂有望作为治疗ET-1引起的收缩，缺血性中风和突然听力下降的药理学工具。

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