Mechanisms underlying potentiation of endothelin-1-induced myofilament Ca 2+ sensitization after subarachnoid hemorrhage

Yuichiro Kikkawa, Satoshi Matsuo, Katsuharu Kameda, Mayumi Hirano, Akira Nakamizo, Tomio Sasaki, Katsuya Hirano

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Increased vascular smooth muscle contractility has an important role in the development of cerebral vasospasm after subarachnoid hemorrhage (SAH). Myofilament Ca 2+ sensitivity is a major determinant of smooth muscle contractility. We investigated changes in the Ca 2+-sensitizing effect of endothelin-1 (ET-1) and the mechanisms underlying ET-1-induced Ca 2+ sensitization after SAH using a rabbit SAH model. After SAH, the contractile response to ET-1 was enhanced, and the ET A receptor expression was upregulated in the basilar artery. In α-toxin-permeabilized preparations, ET-1 induced enhanced and prolonged contraction after SAH, suggesting that ET-1-induced Ca 2+ sensitization is potentiated after SAH. Endothelin-1-induced Ca 2+ sensitization became less sensitive to inhibitors of Rho-associated coiled-coil protein kinase (ROCK) and protein kinase C (PKC) after SAH. The expression of PKCα, ROCK2, PKC-potentiated phosphatase inhibitor of 17 kDa (CPI-17) and myosin phosphatase target subunit 1 (MYPT1) was upregulated, and the level of phosphorylation of CPI-17 and MYPT1 was elevated after SAH. This study demonstrated for the first time that the Ca 2+-sensitizing effect of ET-1 on myofilaments is potentiated after SAH. The increased expression and activity of PKCα, ROCK2, CPI-17, and MYPT1, as well as the upregulation of ET A receptor expression are suggested to underlie the enhanced and prolonged Ca 2+ sensitization induced by ET-1.

Original languageEnglish
Pages (from-to)341-352
Number of pages12
JournalJournal of Cerebral Blood Flow and Metabolism
Volume32
Issue number2
DOIs
Publication statusPublished - Feb 2012

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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