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      Interactive Role of Protein Kinase C-δ with Rho-Kinase in the Development of Cerebral Vasospasm in a Canine Two-Hemorrhage Model

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          Abstract

          Background: We previously reported that protein kinase C (PKC)-δ was initially translocated from the cytosol to the membrane fraction (on day 4), followed by PKC-α, with the progression of cerebral vasospasm after subarachnoid hemorrhage (SAH) on day 7. Rho/Rho-kinase pathways have also been proposed to be involved in the vasospasm. Thus we investigated the interactive role of Rho-kinase and PKC in the development of cerebral vasospasm after SAH. Methods: The cerebral vasospasm was produced using a ‘two-hemorrhage’ canine model. The animals were treated with Y-27632, a Rho-kinase inhibitor, and rottlerin, a PKC-δ inhibitor, both injected into the cisterna magna. Results: Y-27632 inhibited the vasospasm, 20-kDa myosin light chain (MLC<sub>20</sub>) phosphorylation, and PKC-δ translocation after the second injection of autologous blood on day 4. In contrast, Y-27632 did not affect the vasospasm on day 7. Rottlerin also inhibited the vasospasm on day 4, but had no effect on MLC<sub>20</sub> phosphorylation and RhoA translocation. The vasospasm was accompanied with the phosphorylation of caldesmon (CaD), an actin-linked regulatory protein, which was strongly attenuated by Y-27632 and rottlerin. The application of PKC-δ to skinned strips of isolated canine basilar arteries caused a contraction and an increase in CaD phosphorylation. Conclusion: The development of cerebral vasospasm after SAH (on day 4) is caused by at least two mechanisms: one involves MLC<sub>20</sub> phosphorylation mediated by the inhibition of MLC<sub>20</sub> phosphatase by Rho-kinase, and the other CaD phosphorylation mediated by the activation of PKC-δ by Rho-kinase, which results in the alleviation of the inhibition by CaD of myosin Mg<sup>2+</sup>-ATPase activity.

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          Most cited references 14

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          Specificity and mechanism of action of some commonly used protein kinase inhibitors.

          The specificities of 28 commercially available compounds reported to be relatively selective inhibitors of particular serine/threonine-specific protein kinases have been examined against a large panel of protein kinases. The compounds KT 5720, Rottlerin and quercetin were found to inhibit many protein kinases, sometimes much more potently than their presumed targets, and conclusions drawn from their use in cell-based experiments are likely to be erroneous. Ro 318220 and related bisindoylmaleimides, as well as H89, HA1077 and Y 27632, were more selective inhibitors, but still inhibited two or more protein kinases with similar potency. LY 294002 was found to inhibit casein kinase-2 with similar potency to phosphoinositide (phosphatidylinositol) 3-kinase. The compounds with the most impressive selectivity profiles were KN62, PD 98059, U0126, PD 184352, rapamycin, wortmannin, SB 203580 and SB 202190. U0126 and PD 184352, like PD 98059, were found to block the mitogen-activated protein kinase (MAPK) cascade in cell-based assays by preventing the activation of MAPK kinase (MKK1), and not by inhibiting MKK1 activity directly. Apart from rapamycin and PD 184352, even the most selective inhibitors affected at least one additional protein kinase. Our results demonstrate that the specificities of protein kinase inhibitors cannot be assessed simply by studying their effect on kinases that are closely related in primary structure. We propose guidelines for the use of protein kinase inhibitors in cell-based assays.
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            Regulation of Myosin Phosphatase by Rho and Rho-Associated Kinase (Rho-Kinase)

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              Delayed cerebral vasospasm is not reversible by aminophylline, nifedipine, or papaverine in a "two-hemorrhage" canine model.

              Angiographic spasm of cerebral arteries was produced in dogs by successive injections of cisternal blood 48 hours apart. Angiograms were taken before and after each cisternal injection. There was progressively greater angiographic vasospasm of the basilar artery. Intravenous aminophylline, 10 mg/kg/hr, reversed vessel constriction on the 1st and 3rd day after one injection of cisternal blood. On the 5th day after two blood injections (on Day 1 and Day 3), intravenous aminophylline, nifedipine (1 mg/kg), and intra-arterial bolus injection of 2 mg/kg papaverine failed to reverse the constriction. The intractable constriction produced in this model resembles that found in patients. The calcium antagonist, nifedipine, is as ineffective as the more traditional vasodilators in reversing vasospasm in this model.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2005
                February 2005
                28 January 2005
                : 42
                : 1
                : 67-76
                Affiliations
                aDepartment of Cellular and Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka, and bDepartment of Neurosurgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, Japan
                Article
                83093 J Vasc Res 2005;42:67–76
                10.1159/000083093
                15637442
                © 2005 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 7, References: 23, Pages: 10
                Categories
                Research Paper

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