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

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.