Role of tyrosine kinase and PKC in the vasoconstrictor response to 20- HETE in renal arterioles

Cheng Wen Sun, J R Falck, David R. Harder, Richard J. Roman

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

The present study examined the hypothesis that activation of protein kinase C (PKC), components of the mitogen-activated protein (MAP) kinase pathway, or both contributes to the inhibitory effects of 20- hydroxyeicosatetraenoic acid (20-HETE) on K+-channel activity and its vasoconstrictor response in renal arterioles. 20-HETE (0.1 to 50 μmol/L) dose-dependently produced a 30% increase in PKC activity and a fivefold rise in the expression of active extracellular signal-regulated kinase 1 (ERK1) and ERK2 proteins in renal microvessels. 20-HETE (0.01 to 1 μmol/L) reduced the diameter of isolated perfused renal interlobular arterioles by 33±2%. Blockade of PKC activity with an N-myristoylated PKC pseudosubstrate inhibitor (Myr-PKCi, 100 μmol/L) or calphostin C (0.5 μmol/L) had no significant effect on the vasoconstrictor response to 20-HETE. In contrast, the tyrosine kinase inhibitors genistein (30 μmol/L) and tyrphostin 25 (10 μmol/L) reduced the response to 20-HETE by 76.5±2.1% and 67.5±1.8%, respectively. A specific inhibitor of mitogen-activated extracellular signal- regulated kinase (MEK), PD98059, had no effect on the vasoconstrictor response to 20-HETE. In cell-attached patches on renal vascular smooth muscle cells, 20-HETE reduced the open state probability of a large-conductance K+ channel (from 0.0026±0.0004 to 0.0006±0.0001). The Myr-PKCi (100 μmol/L) did not alter the inhibitory effects of 20-HETE on this channel. In contrast, the tyrosine kinase inhibitor genistein (30 μmol/L) blocked the inhibitory effects of 20-HETE on the large-conductance K+ channel. These data suggest that 20-HETE activates the MAP kinase system in renal arterioles and that the activation of a tyrosine kinase, which is proximal to MEK in this cascade, contributes to the inhibitory effects of 20-HETE on K+-channel activity and its vasoconstrictor effects in the renal arterioles.

Original languageEnglish (US)
Pages (from-to)414-418
Number of pages5
JournalHypertension
Volume33
Issue number1 II
DOIs
StatePublished - Jan 1999

Keywords

  • Arachidonic acid
  • Cytochrome P450
  • Kinase
  • Muscle, smooth, vascular
  • Potassium channels
  • Renal circulation

ASJC Scopus subject areas

  • Internal Medicine

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