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 language | English (US) |
---|---|
Pages (from-to) | 414-418 |
Number of pages | 5 |
Journal | Hypertension |
Volume | 33 |
Issue number | 1 II |
DOIs | |
State | Published - Jan 1999 |
Keywords
- Arachidonic acid
- Cytochrome P450
- Kinase
- Muscle, smooth, vascular
- Potassium channels
- Renal circulation
ASJC Scopus subject areas
- Internal Medicine