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This Article Full Text Full Text (PDF) All Versions of this Article: 575/2/627    most recent jphysiol.2006.113985v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lu, T. Articles by Lee, H.-C. Search for Related Content PubMed PubMed Citation Articles by Lu, T. Articles by Lee, H.-C. Related Collections Cardiovascular

¹ Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
² Division of Intramural Research, National Institute of Environmental Health Science, Research Triangle Park, NC 27709, USA

We have reported that epoxyeicosatrienoic acids (EETs), the cytochrome P450 (CYP) epoxygenase metabolites of arachidonic acid (AA), are potent sarcolemmal ATP-sensitive K⁺ (K_ATP) channel activators. However, activation of cardiac and vascular K_ATP channels by endogenously produced EETs under physiological intracellular conditions has not been demonstrated and direct comparison of the mechanisms whereby EETs activate the K_ATP channels in cardiac myocytes versus vascular smooth muscle cells has not been made. In this study, we examined the effects of AA on K_ATP channels in freshly isolated cardiac myocytes from rats, wild-type (WT) and transgenic mice overexpressing CYP2J2 cDNA, and mesenteric arterial smooth muscle cells from rats. We also compared the activation of cardiac and vascular K_ATP channels by extracellularly and intracellularly applied 11,12-EET. We found that 1 µM AA enhanced K_ATP channel activities in both cardiac and vascular smooth muscle cells, and the AA effects were inhibited by preincubation with CYP epoxygenase inhibitors. Baseline cardiac K_ATP current densities in CYP2J2 transgenic mice were 190% higher than those of WT mice, and both were reduced to similar levels by CYP epoxygenase inhibition. Western blot analysis showed that expression of Kir6.2 and SUR2A was similar between WT and CYP2J2 transgenic hearts. 11,12-EET (5 µM) applied intracellularly enhanced the K_ATP currents by 850% in cardiac myocytes, but had no effect in vascular smooth muscle cells. In contrast, 11,12-EET (5 µM) applied extracellularly increased K_ATP currents by 520% in mesenteric arterial smooth muscle cells, but by only 209% in cardiac myocytes. Preincubation with 100 µM m-iodobenzylguanidine or 5 µM myristoylated PKI amide did not alter the activation of cardiac K_ATP channels by 5 µM 11,12-EET, but significantly inhibited activation of vascular K_ATP channels. Moreover, EET only enhanced the inward component of cardiac K_ATP currents, but activated both the inward and outward components of vascular K_ATP currents. Our results indicate that endogenously derived CYP metabolites of AA potently activate cardiac and vascular K_ATP channels. EETs regulate cardiac electrophysiology and vascular tone by K_ATP channel activation, albeit through different mechanisms: the cardiac K_ATP channels are directly activated by EETs, whereas activation of the vascular K_ATP channels by EETs is protein kinase A dependent.

(Received 22 May 2006; accepted after revision 15 June 2006; first published online 22 June 2006)
Corresponding author H.-C. Lee: Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Email: lee.honchi{at}mayo.edu

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