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

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.