Abstract
Epoxyeicosatrienoic acids (EETs) are considered to be endothelium-derived hyperpolarizing factors, and are potent activators of the large-conductance, Ca2+-activated K+ (BKCa) channel in vascular smooth muscle. Here, we investigate the signal transduction pathway involved in the activation of BKCa channels by 11,12-EET and 11,12-EET stable analogs in rat mesenteric vascular smooth muscle cells. 11,12-EET and the 11,12-EET analogs, 11-nonyloxy-undec-8(Z)-enoic acid (11,12-ether-EET-8-ZE), 11-(9-hydroxy-nonyloxy)-undec-8(Z)-enoic acid (11,12-ether-EET-8-ZE-OH) and 11,12-trans-oxidoeicosa-8(Z)-enoic acid (11,12-tetra-EET-8-ZE), caused vasorelaxation of mesenteric resistance arteries. Mesenteric myocyte whole-cell (perforated-patch) currents were substantially (∼150%) increased by 11,12-EET and 11,12-EET analogs. Single-channel recordings were conducted to identify the target for 11,12-EET. 11,12-EET and 11,12-EET analogs also increased mesenteric myocyte BKCa channel activity in cell-attached patches. Similar results were obtained in cell-free patches. Baseline mesenteric myocyte BKCa channel activity (NPo) in cell-free patches averaged less than 0.001 at +50 mV and 11,12-EET (1 µmol/L) increased NPo to 0.03 ± 0.02 and 11,12-EET analogs (1 µmol/L) increased NPo to 0.09 ± 0.006. Inhibition of protein phosphatase 2A (PP2A) activity with okadaic acid (10 nmol/L) completely reversed 11,12-EET stimulated BKCa channel activity and greatly attenuated 11,12-ether-EET-8-ZE mesenteric resistance artery vasorelaxation. 11,12-EET and 11,12-EET analogs increased mesenteric myocyte PP2A activity by 3.5-fold. Okadaic acid and the EET inhibitor, 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) inhibited the 11,12-EET mediated increase in PP2A activity. These findings provide initial evidence that PP2A activity contributes to 11,12-EET and 11,12-EET analog activation of mesenteric resistant artery BKCa channels and vasorelaxation.
Original language | American English |
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Journal | Prostaglandins and Other Lipid Mediators |
Volume | 83 |
State | Published - Jan 1 2007 |
Keywords
- 11
- 11 (9 hydroxynonyloxy)undec 8 enoic acid
- 11 nonyloxyundec 8 enoic acid
- 12 epoxyeicosatrienoic acid analog
- 12 oxidoeicosa 8 enoic acid
- 14
- 14-Eicosatrienoic Acid
- 15 epoxyeicosa 5 enoic acid
- 8
- Animals
- Calcium-Activated
- Calcium-dependent K+ channels
- Cells
- Charybdotoxin
- Cultured
- Eicosanoids
- Endothelium-derived hyperpolarizing factor
- Ion Channel Gating
- Mesenteric
- Mesenteric Arteries
- Muscle
- Muscle Cells
- Phosphoprotein Phosphatase
- Potassium Channels
- Rats
- Smooth
- Sprague-Dawley
- Vascular
- Vascular Resistance
- Vascular smooth muscle
- Vasodilation
- animal cell
- artery resistance
- article
- calcium activated potassium channel
- calcium conductance
- cell free system
- controlled study
- endothelium derived hyperpolarizing factor
- enzyme activity
- enzyme inhibition
- epoxyicosatrienoic acid
- male
- mesenteric artery
- muscle cell
- nonhuman
- okadaic acid
- patch clamp
- phosphoprotein phosphatase 2A
- rat
- signal transduction
- smooth muscle fiber
- unclassified drug
- vasodilatation
Disciplines
- Circulatory and Respiratory Physiology