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Calcium antagonists ameliorate ischemia-induced endothelial cell permeability by inhibiting protein kinase C

Item Type:Article
Title:Calcium antagonists ameliorate ischemia-induced endothelial cell permeability by inhibiting protein kinase C
Creators Name:Hempel, A. and Lindschau, C. and Maasch, C. and Mahn, M. and Bychkov, R. and Noll, T. and Luft, F.C. and Haller, H.
Abstract:BACKGROUND: Dihydropyridines block calcium channels; however, they also influence endothelial cells, which do not express calcium channels. We tested the hypothesis that nifedipine can prevent ischemia-induced endothelial permeability increases by inhibiting protein kinase C (PKC) in cultured porcine endothelial cells. METHODS AND RESULTS: Ischemia was induced by potassium cyanide/deoxyglucose, and permeability was measured by albumin flux. Ion channels were characterized by patch clamp. [Ca2+]i was measured by fura 2. PKC activity was measured by substrate phosphorylation after cell fractionation. PKC isoforms were assessed by Western blot and confocal microscopy. Nifedipine prevented the ischemia-induced increase in permeability in a dose-dependent manner. Ischemia increased [Ca2+]i, which was not affected by nifedipine. Instead, ischemia-induced PKC translocation was prevented by nifedipine. Phorbol ester also increased endothelial cell permeability, which was dose dependently inhibited by nifedipine. The effects of non-calcium-channel-binding dihydropyridine derivatives were similar. Analysis of the PKC isoforms showed that nifedipine prevented ischemia-induced translocation of PKC-alpha and PKC-zeta. Specific inhibition of PKC isoforms with antisense oligodeoxynucleotides demonstrated a major role for PKC-alpha. CONCLUSIONS: Nifedipine exerts a direct effect on endothelial cell permeability that is independent of calcium channels. The inhibition of ischemia-induced permeability by nifedipine seems to be mediated primarily by PKC-alpha inhibition. Anti-ischemic effects of dihydropyridine calcium antagonists could be due in part to their effects on endothelial cell permeability.
Keywords:Cells, Ischemia, Proteins, Calcium, Animals, Swine
Publisher:American Heart Association
Page Range:2523-2529
Date:18 May 1999
Official Publication:http://circ.ahajournals.org/cgi/content/abstract/99/19/2523
PubMed:View item in PubMed

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