Published online before print March 13, 2003, doi: 10.1161/01.RES.0000066663.12256.B2
© 2003 American Heart Association, Inc.
Integrative Physiology |
Functional Roles of the Rho/Rho Kinase Pathway and Protein Kinase C in the Regulation of Cerebrovascular Constriction Mediated by Hemoglobin
Relevance to Subarachnoid Hemorrhage and Vasospasm
From the Department of Pharmacology, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada. Present address of Grant Wickman is Pfizer Global Research and Development, La Jolla, San Diego, Calif.
Correspondence to Bozena Vollrath, PhD, Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7. E-mail bozena.vollrath{at}ualberta.ca
Although there is evidence that the Rho/Rho kinase pathway and protein kinase C (PKC) are involved in the development of cerebral vasospasm, the mechanism by which subarachnoid hemorrhage (SAH) activates these pathways is unclear. A large body of evidence points to oxyhemoglobin (OxyHb) as a major causative component of blood clot responsible for vasospasm. Therefore, the present studies were conducted to explore whether the Rho/Rho kinase and PKC may be involved in a sustained vasoconstriction induced by OxyHb in cerebral arteries. OxyHb evoked sustained vasoconstriction in the endothelium-denuded rabbit basilar arteries, which was reversed by the selective inhibitors of Rho kinase, Y-27632, and HA-1077, with the IC50 values of 0.26±0.02 and 0.74±0.1 µmol/L, respectively. In quiescent cerebrovascular smooth muscle (CVSM) cells, OxyHb induced Rho translocation, as assessed by immunoblotting, with a time course, which paralleled the contractile action of OxyHb. Rho translocation was also observed in intact arteries stimulated with OxyHb for 24 hours (219%) and 48 hours (160%). The increase in Rho translocation was fully inhibited by GGTI-297, an inhibitor of Rho prenylation. OxyHb also caused significant translocation of both PKC
and PKC
(P<0.01), which was maximal at the time corresponding to maximal tension developed in response to OxyHb. Ro-32-0432, an inhibitor of PKC, attenuated vasoconstriction mediated by OxyHb in basilar artery. These results show, for the first time, that OxyHb-mediated signaling in CVSM utilizes the Rho/Rho kinase and PKC-based mechanisms.
Key Words: hemoglobin • vasospasm • smooth muscle • Rho kinase • protein kinase C
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