Attenuation of canine cerebral vasospasm after subarachnoid hemorrhage by protein kinase C inhibitors despite augmented phosphorylation of myosin light chain.
The purpose of the present study is to assess the roles of protein kinase C (PKC) isoforms, especially PKC delta and alpha, and 20-kD myosin light chain (MLC(20)) phosphorylation in the mechanism of cerebral vasospasm following subarachnoid hemorrhage (SAH). We had shown that those PKC isoforms are involved in the development of cerebral vasospasm. Using PKC isoform-specific inhibitors in a 'two- hemorrhage' canine model, we examined changes in the development of cerebral vasospasm, translocation of PKC isoforms and MLC(20) phosphorylation level in canine basilar arteries. A PKC inhibitor (5 microM rottlerin for PKC delta or chelerythrine for PKC alpha) was injected into the cisterna magna on day 4 before the second hemorrhage. The treatment was continued daily until day 7. Rottlerin inhibited the initial phase of vasospasm and PKC delta translocation, but did not significantly inhibit PKC alpha translocation. Chelerythrine inhibited cerebral vasospasm, and the translocation of both PKC delta and alpha throughout the entire course of the study. Although cerebral vasospasm after SAH was inhibited by each PKC inhibitor, the MLC(20) phosphorylation level remained elevated as in the untreated hemorrhage-control study. We conclude that cerebral vasospasm following SAH depends on PKC delta and alpha, while the enhancement of MLC(20) phosphorylation contributes little to this form of vasospasm.
Nishizawa
Shigeru
S
Department of Neurosurgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan. nisizawa@hama-med.ac.jp
Obara
Kazuo
K
Koide
Masayo
M
Nakayama
Koichi
K
Ohta
Seiji
S
Yokoyama
Tetsuo
T
D000098:Acetophenones / Q000494:pharmacology; D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D001578:Benzopyrans / Q000494:pharmacology; D002533:Cerebral Angiography; D002536:Cerebral Arteries / Q000000981:diagnostic imaging / Q000201:enzymology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008297:Male; D018994:Myosin Light Chains / Q000378:metabolism*; D010617:Phenanthridines / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy*; D020301:Vasospasm, Intracranial / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology
D000098:Acetophenones; D000470:Alkaloids; D053119:Benzophenanthridines; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D018994:Myosin Light Chains; D010617:Phenanthridines; C085746:rottlerin; C016299:chelerythrine; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta