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.
OBJECTIVE
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.
Scherer
Elias Q
EQ
Anatomy and Physiology Department, Kansas State University, Manhattan, KS 66506, USA.
Herzog
Michael
M
Wangemann
Philine
P
D000577:Amides / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001158:Arteries / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D003619:Dansyl Compounds / Q000494:pharmacology; D007758:Ear, Inner / Q000098:blood supply; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005849:Gerbillinae; D047908:Intracellular Signaling Peptides and Proteins; D043263:Myosin-Light-Chain Phosphatase; D010456:Peptides, Cyclic / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D044022:Receptor, Endothelin A; D012039:Regional Blood Flow / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014654:Vascular Patency / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D020301:Vasospasm, Intracranial / Q000139:chemically induced* / Q000503:physiopathology; D054460:rho-Associated Kinases
D000577:Amides; D000959:Antihypertensive Agents; D003619:Dansyl Compounds; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D010456:Peptides, Cyclic; D011725:Pyridines; D044022:Receptor, Endothelin A; C108830:Y 27632; C085754:5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D010749:Phosphoprotein Phosphatases; D043263:Myosin-Light-Chain Phosphatase; D015740:Calcitonin Gene-Related Peptide; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium