Scherer Elias Q, Herzog Michael, Wangemann Philine
Anatomy and Physiology Department, Kansas State University, Manhattan, KS 66506, USA.
Stroke. 2002 Dec;33(12):2965-71. doi: 10.1161/01.str.0000043673.22993.fd.
Vasospasms of the spiral modiolar artery may cause an ischemic stroke of the inner ear that manifests itself by a sudden hearing loss. Previously we have shown that endothelin-1 (ET-1) induces vasospasms of the spiral modiolar artery. Here we tested the hypotheses that ET-1-induced vasospasms are (1) reversible by ET(A) receptor antagonists; (2) mediated by a Ca(2+) sensitization of the contractile apparatus via a Rho-kinase-induced inhibition of myosin light chain phosphatase; and (3) reversible by the vasodilator calcitonin gene-related peptide (CGRP).
The Ca(2+) sensitivity of the contractile apparatus was evaluated by correlation between the smooth muscle cell Ca(2+) concentration and the vascular diameter, which were measured by microfluorometry with the fluorescent dye fluo-4 and videomicroscopy, respectively.
ET-1-induced vasospasms were prevented but not reversed by the ET(A) receptor antagonists BQ-123 and BMS-182874. The Ca(2+) sensitivity of the contractile apparatus was increased by ET-1 and by inhibition of myosin light chain phosphatase with calyculin A and was decreased by CGRP. ET-1-induced vasospasms and Ca(2+) sensitization were prevented and reversed by the Rho-kinase antagonist Y-27632 and by CGRP.
ET-1 induces vasospasms of the spiral modiolar artery via ET(A) receptor-mediated activation of Rho-kinase, inhibition of myosin light chain phosphatase, and an increase in Ca(2+) sensitivity, which is reversed by CGRP. The observation that vasospasms were reversed by Y-27632 but not by BQ-123 or BMS-182874 suggests that Rho-kinase, rather than the ET(A) receptor, is the most promising pharmacological target for the treatment of ET-1-induced vasospasms, ischemic strokes, and sudden hearing loss.
蜗轴螺旋动脉痉挛可能导致内耳缺血性卒中，表现为突发听力丧失。此前我们已表明内皮素 -1（ET -1）可诱导蜗轴螺旋动脉痉挛。在此，我们检验了以下假设：（1）ET -1诱导的痉挛可被ET(A)受体拮抗剂逆转；（2）通过Rho激酶诱导的肌球蛋白轻链磷酸酶抑制作用，由收缩装置的Ca(2+)敏化介导；（3）可被血管舒张剂降钙素基因相关肽（CGRP）逆转。
通过平滑肌细胞Ca(2+)浓度与血管直径之间的相关性评估收缩装置的Ca(2+)敏感性，分别用荧光染料fluo -4通过显微荧光测定法和视频显微镜测量二者。
ET(A)受体拮抗剂BQ -123和BMS -182874可预防但不能逆转ET -1诱导的痉挛。ET -1以及用花萼海绵诱癌素A抑制肌球蛋白轻链磷酸酶可增加收缩装置的Ca(2+)敏感性，而CGRP可降低该敏感性。Rho激酶拮抗剂Y -27632和CGRP可预防并逆转ET -1诱导的痉挛和Ca(2+)敏化。
ET -1通过ET(A)受体介导的Rho激酶激活、肌球蛋白轻链磷酸酶抑制以及Ca(2+)敏感性增加来诱导蜗轴螺旋动脉痉挛，而CGRP可逆转这一过程。Y -27632可逆转痉挛，而BQ -123或BMS -182874则不能，这一观察结果表明，对于治疗ET -1诱导的痉挛、缺血性卒中和突发听力丧失，Rho激酶而非ET(A)受体是最有前景的药理学靶点。
