title: Mechanisms underlying potentiation of endothelin-1-induced myofilament Ca(2+) sensitization after subarachnoid hemorrhage.
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.
authors.affiliation: Division of Molecular Cardiology, Research Institute of Angiocardiology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Kikkawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsuo
authors.forename: Katsuharu
authors.initials: K
authors.lastname: Kameda
authors.forename: Mayumi
authors.initials: M
authors.lastname: Hirano
authors.forename: Akira
authors.initials: A
authors.lastname: Nakamizo
authors.forename: Tomio
authors.initials: T
authors.lastname: Sasaki
authors.forename: Katsuya
authors.initials: K
authors.lastname: Hirano
mesh_terms: D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism*; D005786:Gene Expression Regulation; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009210:Myofibrils / Q000378:metabolism*; D043263:Myosin-Light-Chain Phosphatase / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011817:Rabbits; D044022:Receptor, Endothelin A / Q000235:genetics; D013345:Subarachnoid Hemorrhage / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D014661:Vasoconstriction / Q000187:drug effects; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: C491521:CPI-17 protein, Oryctolagus cuniculus; D019332:Endothelin-1; D009124:Muscle Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D044022:Receptor, Endothelin A; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D043263:Myosin-Light-Chain Phosphatase; D002118:Calcium