Published Online
on November 14, 2002

A more recent version of this article appeared on December 1, 2002

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Submitted on July 23, 2002
Accepted on July 24, 2002

Endothelin-1-Induced Vasospasms of Spiral Modiolar Artery Are Mediated by Rho-Kinase-Induced Ca²⁺ Sensitization of Contractile Apparatus and Reversed by Calcitonin Gene-Related Peptide

Elias Q. Scherer MD; Michael Herzog MD; and Philine Wangemann PhD^*

From the Anatomy and Physiology Department, Kansas State University, Manhattan.

^* To whom correspondence should be addressed. E-mail: Wange{at}vet.ksu.edu.

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 Ca²⁺ 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 Ca²⁺ sensitivity of the contractile apparatus was evaluated by correlation between the smooth muscle cell Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ 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.

Key words: calcium signaling • cell communication • cochlea • regional blood flow • signal transduction • vasospasm

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