Possible role of protein kinase C-dependent smooth muscle contraction in the pathogenesis of chronic cerebral vasospasm.
In the present study, we investigate the possible role of protein kinase C (PKC)-dependent smooth muscle contraction in cerebral vasospasm following subarachnoid hemorrhage (SAH), employing the beagle "two-hemorrhage" model. The occurrence of chronic vasospasm was angiographically confirmed on day 7 in the basilar artery, which was exposed via the transclival approach. The artery was superfused with aerated Krebs-Henseleit solution containing various agents, and the subsequent changes in the basilar artery diameter were recorded by successive angiography. The preexisting spasm was not ameliorated by local application of neurotransmitter antagonists (atropine, methysergide, phentolamine, and diphenhydramine), calmodulin inhibitors (R24571 and W-7), or a calcium antagonist, nicardipine. However, the application of PKC inhibitors such as H-7 and staurosporine induced significant dilation of the artery. In another experiment, an intrinsic PKC activator, 1,2-diacylglycerol (DAG), in the basilar artery, the CSF, and the cisternal clot of beagles exposed to two hemorrhages was measured on days 1, 2, 4, 7, and 14 using the DAG kinase method. On days 2, 4, and 7, the DAG content of the basilar artery showed a significant and prolonged increase (150-190% of control), whereas it was unchanged on days 1 and 14. Throughout the experimental period, there was a significant linear correlation between the DAG content and the angiographical diameter of the basilar artery. The above results indicate that SAH leads to an increase in the DAG level within the cerebral artery through an as yet unknown mechanism and that subsequent activation of the PKC-dependent contractile system participates in the occurrence of chronic vasospasm.
Matsui
T
T
Department of Neurosurgery, Saitama Medical Center/School, Japan.
Takuwa
Y
Y
Johshita
H
H
Yamashita
K
K
Asano
T
T
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D004075:Diglycerides / Q000378:metabolism; D004285:Dogs; D002546:Ischemic Attack, Transient / Q000503:physiopathology*; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology*; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019311:Staurosporine; D014664:Vasodilation / Q000187:drug effects
C011439:1,2-diacylglycerol; D000470:Alkaloids; D004075:Diglycerides; D007546:Isoquinolines; D010879:Piperazines; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D019311:Staurosporine