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.

• Authors: Elias Q Scherer, Michael Herzog, Philine Wangemann
• Journal: Stroke (Stroke) Vol. 33 Issue 12 Pg. 2965-71 (Dec 2002) ISSN: 1524-4628 [Electronic] United States
• PMID: 12468798 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Amides
• Antihypertensive Agents
• Dansyl Compounds
• Endothelin Receptor Antagonists
• Endothelin-1
• Enzyme Inhibitors
• Intracellular Signaling Peptides and Proteins
• Peptides, Cyclic
• Pyridines
• Receptor, Endothelin A
• Y 27632
• 5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide
• Protein Serine-Threonine Kinases
• rho-Associated Kinases
• Phosphoprotein Phosphatases
• Myosin-Light-Chain Phosphatase
• Calcitonin Gene-Related Peptide
• cyclo(Trp-Asp-Pro-Val-Leu)
• Calcium

Topics

• Amides (pharmacology)
• Animals
• Antihypertensive Agents (pharmacology)
• Arteries (drug effects, physiology, physiopathology)
• Calcitonin Gene-Related Peptide (pharmacology)
• Calcium (metabolism)
• Dansyl Compounds (pharmacology)
• Ear, Inner (blood supply)
• Endothelin Receptor Antagonists
• Endothelin-1 (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Gerbillinae
• Intracellular Signaling Peptides and Proteins
• Myosin-Light-Chain Phosphatase
• Peptides, Cyclic (pharmacology)
• Phosphoprotein Phosphatases (antagonists & inhibitors, metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Pyridines (pharmacology)
• Receptor, Endothelin A
• Regional Blood Flow (drug effects)
• Signal Transduction (drug effects)
• Vascular Patency (drug effects)
• Vasoconstriction (drug effects)
• Vasospasm, Intracranial (chemically induced, physiopathology)
• rho-Associated Kinases