Raf-1 kinase regulates smooth muscle contraction in the rat mesenteric arteries

Kunju Sathishkumar, Uma Yallampalli, Rebekah Elkins, Chandra Yallampalli

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

We investigated the potential role of Raf-1 kinase in mesenteric arterial contraction. Inhibitors of Raf-1 kinase, GW5074, L779450 and ZM 336372 reversed phenylephrine (PE)-induced mesenteric vascular contraction. Studies in vivo in rats showed that GW5074 inhibited PE-induced increase in mean arterial pressure in adult female Sprague-Dawley rats. Isometric tension studies in mesenteric arteries of rats showed that GW5074 did not change the KCl-evoked contraction but significantly inhibited the contractions to PE, 5-HT, U46619, endothelin 1, angiotensin II and phorbol 12, 13-dibutyrate (PDBu). In mesenteric vascular smooth muscle cells (VSMCs), PE stimulated increase in Raf-1 phosphorylation which was inhibited by GW5074. Measurement of [Ca2+]i with Fura-2 showed that GW5074-mediated inhibition of PE-induced contraction was not associated with decreases in [Ca2+]i. VSMCs treated with PE exhibited higher levels of the contractile proteins, p-MYPT1 and p-MLC 20, which was inhibited by GW5074. Similarly, PDBu induced increases in phosphorylation of Raf-1, MLC20 and MYPT1 and this was inhibited by GW5074. However, GW5074 did not have any significant effect on PE/PDBu-induced MEK/ERK activation. The results indicate that Raf-1 kinase plays an important role in the regulation of vascular contractility through regulation of calcium sensitization.

Original languageEnglish (US)
Pages (from-to)384-398
Number of pages15
JournalJournal of Vascular Research
Volume47
Issue number5
DOIs
StatePublished - Aug 1 2010

Keywords

  • Agonists
  • Blood pressure
  • Contraction
  • Extracellular signal-regulated kinase
  • Intracellular calcium
  • Mitogen-activated protein kinase
  • Protein kinase C
  • Raf-1
  • Vascular smooth muscle

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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