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Vol. 59, Issue 5, 1044-1050, May 2001
Institut für Pharmakologie und Klinische Pharmakologie,
Heinrich-Heine-Universität Düsseldorf, Germany
Migration and proliferation of vascular smooth muscle cells (SMC) in
response to platelet-derived growth factor (PDGF) and other mitogens
play an important role in restenosis after coronary angioplasty.
Elevation of both cAMP and cGMP has been shown to inhibit SMC
mitogenesis. The aim of this study was to examine the antimitogenic
actions of organic nitrates and sildenafil and to clarify the role of
cyclic nucleotide-dependent protein kinases (PKA, PKG) in this action.
Organic nitrates [glycerol trinitrate (GTN), isosorbide 5'-mononitrate
(ISMN), pentaerythrityl-tetranitrate (PETN)] and the PDE5 inhibitor
sildenafil reduced PDGF-induced DNA synthesis, measured by
(3H]thymidine incorporation. GTN, ISMN, and PETN acted
synergistically with sildenafil (1 µM) on inhibition of PDGF-induced
DNA synthesis, increase of intracellular cyclic nucleotides, and
vasodilator-stimulated phosphoprotein phosphorylation. The highly
selective PKA inhibitor PKI abolished these actions of sildenafil and
organic nitrates, whereas the PKG inhibitors KT5823 and
(Rp)-8-pCPT-cGMPS had no effect. In addition, selective
activation of PKG without inhibition of PDE3 by the cGMP analog
8-pCPT-cGMP (100 µM) had no antimitogenic effect. The data suggest
that 1) organic nitrates and sildenafil exert antimitogenic actions by
activation of PKA via inhibition of PDE3, but not by activation of PKG
and 2) that antimitogenic effects of organic nitrates are potentiated
by sildenafil at therapeutic plasma levels.
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