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Research ArticleArticle

Antimitogenic Effects of Trapidil In Coronary Artery Smooth Muscle Cells by Direct Activation of Protein Kinase A

Detlef Bönisch, Artur-Aron Weber, Michael Wittpoth, Michael Osinski and Karsten Schrör
Molecular Pharmacology August 1998, 54 (2) 241-248; DOI: https://doi.org/10.1124/mol.54.2.241
Detlef Bönisch
Institut für Pharmakologie, Heinrich-Heine-Universität, Düsseldorf, Germany
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Artur-Aron Weber
Institut für Pharmakologie, Heinrich-Heine-Universität, Düsseldorf, Germany
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Michael Wittpoth
Institut für Pharmakologie, Heinrich-Heine-Universität, Düsseldorf, Germany
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Michael Osinski
Institut für Pharmakologie, Heinrich-Heine-Universität, Düsseldorf, Germany
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Karsten Schrör
Institut für Pharmakologie, Heinrich-Heine-Universität, Düsseldorf, Germany
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Abstract

The triazolopyrimidine trapidil has been found in controlled clinical trials to prevent restenosis after vascular injury. Although trapidil is widely regarded as a platelet-derived growth factor receptor (PDGF) antagonist, its precise mode of action is still unknown. This study was designed to investigate the inhibition of mitogenesis by trapidil in cultured bovine coronary artery smooth muscle cells (SMC) and to identify major signal transduction pathways involved. Trapidil inhibited PDGF-BB-induced mitogenesis in SMC in a concentration-dependent manner. Comparable inhibitory effects were obtained after stimulation of smooth muscle cells by phorbol ester, which suggests that the action of trapidil was not restricted to PDGF receptor-mediated mechanisms. Trapidil also inhibited PDGF- and phorbol ester-induced mitogen-activated protein kinase as well as Raf-1 kinase activity. As a possible target of trapidil, stimulation of cellular protein kinase A (PKA) activity was detected. Trapidil also induced the phosphorylation of vasodilator-stimulated phosphoprotein in SMC. Antimitogenic effects of trapidil were completely abolished by PKA inhibitors. Neither a direct stimulation of cAMP formation nor a phosphodiesterase inhibition was observed at antimitogenic concentrations of trapidil. However, trapidil directly activated purified PKA holoenzyme in a cAMP-independent manner. In conclusion, trapidil exerts its antimitogenic effects on SMC by direct activation of PKA. Thus, PKA-mediated inhibition of the Raf-1/MAP kinase pathway may be involved in the antimitogenic actions of the compound.

Footnotes

    • Received December 12, 1997.
    • Accepted April 14, 1998.
  • Send reprint requests to: Karsten Schrör, M.D., Institut für Pharmakologie, Heinrich-Heine-Universität Düsseldorf, Moorenstraße 5, D-40225 Düsseldorf, Germany. E-mail: schroer{at}pharma.uni-duesseldorf.de

  • This study was supported in part by the Deutsche Forschungsgemeinschaft (SFB 351, D7) and the Forschungsgruppe Herz-Kreislauf e.V., Düsseldorf, Germany.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 54 (2)
Molecular Pharmacology
Vol. 54, Issue 2
1 Aug 1998
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Research ArticleArticle

Antimitogenic Effects of Trapidil In Coronary Artery Smooth Muscle Cells by Direct Activation of Protein Kinase A

Detlef Bönisch, Artur-Aron Weber, Michael Wittpoth, Michael Osinski and Karsten Schrör
Molecular Pharmacology August 1, 1998, 54 (2) 241-248; DOI: https://doi.org/10.1124/mol.54.2.241

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Research ArticleArticle

Antimitogenic Effects of Trapidil In Coronary Artery Smooth Muscle Cells by Direct Activation of Protein Kinase A

Detlef Bönisch, Artur-Aron Weber, Michael Wittpoth, Michael Osinski and Karsten Schrör
Molecular Pharmacology August 1, 1998, 54 (2) 241-248; DOI: https://doi.org/10.1124/mol.54.2.241
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