Endothelin-1–Induced Vasospasms of Spiral Modiolar Artery Are Mediated by Rho-Kinase–Induced Ca 2+ Sensitization of Contractile Apparatus and Reversed by Calcitonin Gene–Related Peptide

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Abstract
Background and Purpose— 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). Methods— 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. Results— 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. Conclusions— 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.