Possible Role of Protein Kinase C-Dependent Smooth Muscle Contraction in the Pathogenesis of Chronic Cerebral Vasospasm

Abstract

Summary:In the present study, we investigate the pos sible role of protein kinase C (PKC)-dependent smooth muscle contraction in cerebral vasospasm following sub arachnoid hemorrhage (SAH), employing the beagle "two-hemorrhage" model. The occurrence of chronic va sospasm was angiographically confirmed on day 7 in the basilar artery, which was exposed via the transclival ap proach. The artery was superfused with aerated Krebs Henseleit solution containing various agents, and the sub sequent changes in the basilar artery diameter were re corded by successive angiography. The preexisting spasm was not ameliorated by local application of neuro transmitter antagonists (atropine, methysergide, phentol amine, 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 ar tery. In another experiment, an intrinsic PKC activator,The refractoriness of chronic vasospasm to va sodilator therapy has been well documented (Bevan and Bevan, 1988). Particularly, the Ca2+ -antagonist nimodipine, administered via various routes, has in variably failed to reverse chronic vasospasm (Espi nosa et aI. , 1984; Grotenhuis et aI., 1984; Nosko et aI., 1985; Lewis et aI., 1988). Since agonist-induced smooth muscle contraction has been thought to be dependent on intracellular influx of external Ca2+, Received December 28, 1989; revised July 23, 1990; accepted July 24, 1990. 1431,2-diacylglycerol (DAG), in the basilar artery, the CSF, and the cisternal clot of beagles exposed to two hemor rhages was measured on days 1, 2,4,7, and 14 using the DAG kinase method. On days 2, 4, and 7, the DAG con tent of the basilar artery showed a significant and pro longed increase (150-190% of control), whereas it was unchanged on days I and 14. Throughout the experimen tal period, there was a significant linear correlation be tween 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 vaso spasm. Key Words: Cerebral vasospasm-l,2-Diac ylglycerol-H-7-Protein kinase C-Vascular smooth muscle.it has been conjectured that the primary cause of chronic vasospasm might be the changes in the physical properties in the arterial wall rather than active smooth muscle contraction (Bevan and Be van, 1988; Findlay et aI., 1989; Kim et aI., 1989).However, it has recently been shown that during the sustained phase of agonist-induced smooth mus cle contraction, neither the intracellular concentra tion of Ca2+ nor the phosphorylation of myosin light chain is increased (DeFeo and Morgan, 1985;Kamm and Stull, 1985). To explain the force main tenance during the sustained phase of smooth mus cle contraction, the occurrence of a "latch mechanism" in the myosin-actin i...

Mechanism of Endothelin-1–Induced Contraction in Rabbit Basilar Artery

“…16 ET-1 induced a transient translocation of PKC activity from the cytosol to the membrane, and staurosporine reduced ET-1-induced contraction in bovine cerebral arteries. 17 The failure of calphostin C in reducing ET-1-induced contraction in this study is actually consistent with some previous reports that staurosporine and H-7 18 but not calphostin C 19 attenuated cerebral vasospasm in animal models. However, because of the discrepancy between the effects of staurosporine and calphostin C in this study, the role of PKC in ET-1-induced contraction in rabbit basilar artery remains unconfirmed and requires further investigation.…”

Functional Roles of the Rho/Rho Kinase Pathway and Protein Kinase C in the Regulation of Cerebrovascular Constriction Mediated by Hemoglobin

“…9,11 One of the hypotheses proposed for Ca 2ϩ sensitization in vascular smooth muscle involves PKC, a group of enzymes that are broadly engaged in vital cellular functions, including smooth muscle contraction. 12 The concept of a role for PKC in cerebral vasospasm is supported by the observations that phorbol esters, potent activators of PKC, induce angiographic vasospasm, 13 and that the PKC inhibitors improve the outcome in experimental models of vasospasm. 14 Whether PKC activation may initiate vasospasm is unclear, but an important step may be the phosphorylation of CPI-17 (PKC-potentiated phosphatase inhibitory protein of 17 kDa), an inhibitor protein involved in the regulation of MLCP.…”

Protein kinase C regulates vascular myogenic tone through activation of TRPM4

“…It was recently reported that TRPM4 is present in the pulmonary artery smooth muscle (50), consistent with the possibility that PKC-dependent activation of TRPM4 could contribute to HPV. A number of studies report that PKC inhibitors block or attenuate cerebral vaso-spasm in models of subarachnoid hemorrhage (30,31), suggesting that PKC activity has a prominent role in the development of this pathology (21). Our findings that PKC activates TRPM4 in cerebral artery vascular smooth muscle, which serves to depolarize these cells and induce vasoconstriction, are consistent with a potential role for the channel in PKCrelated vascular pathologies and suggest that TRPM4 might be a novel, putative pharmacological target for the treatment of such conditions.…”