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Regulation of Cardiovascular Functions by Eicosanoids and Other Lipid Mediators

Mechanism of rat mesenteric arterial K_ATP channel activation by 14,15-epoxyeicosatrienoic acid

¹Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota; and ²Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas

Submitted 31 March 2005 ; accepted in final form 5 December 2005

Recently, we reported that 11,12-epoxyeicosatrienoic acid (11,12-EET) potently activates rat mesenteric arterial ATP-sensitive K⁺ (K_ATP) channels and produces significant vasodilation through protein kinase A-dependent mechanisms. In this study, we tried to further delineate the signaling steps involved in the activation of vascular K_ATP channels by EETs. Whole cell patch-clamp recordings [0.1 mM ATP in the pipette, holding potential (HP) = 0 mV and testing potential (TP) = –100 mV] in freshly isolated rat mesenteric smooth muscle cells showed small glibenclamide-sensitive K_ATP currents (19.0 ± 7.9 pA, n = 5) that increased 6.9-fold on exposure to 5 µM 14,15-EET (132.0 ± 29.0 pA, n = 7, P < 0.05 vs. control). With 1 mM ATP in the pipette solution, K_ATP currents (HP = 0 mV and TP = –100 mV) were increased 3.5-fold on exposure to 1 µM 14,15-EET (57.5 ± 14.3 pA, n = 9, P < 0.05 vs. baseline). In the presence of 100 nM iberiotoxin, 1 µM 14,15-EET hyperpolarized the membrane potential from –20.5 ± 0.9 mV at baseline to –27.1 ± 3.0 mV (n = 6 for both, P < 0.05 vs. baseline), and the EET effects were significantly reversed by 10 µM glibenclamide (–21.8 ± 1.4 mV, n = 6, P < 0.05 vs. EET). Incubation with 5 µM 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE), a 14,15-EET antagonist, abolished the 14,15-EET effects (31.0 ± 11.8 pA, n = 5, P < 0.05 vs. 14,15-EET, P = not significant vs. control). The 14,15-EET effects were inhibited by inclusion of anti-G_s antibody (1:500 dilution) but not by control IgG in the pipette solution. The effects of 14,15-EET were mimicked by cholera toxin (100 ng/ml), an exogenous ADP-ribosyltransferase. Treatment with the ADP-ribosyltransferase inhibitors 3-aminobenzamide (1 mM) or m-iodobenzylguanidine (100 µM) abrogated the effects of 14,15-EET on K_ATP currents. These results were corroborated by vasodilation studies. 14,15-EET dose-dependently dilated isolated small mesenteric arteries, and this was significantly attenuated by treatment with 14,15-EEZE or 3-aminobenzamide. These results suggest that 14,15-EET activates vascular K_ATP channels through ADP-ribosylation of G_s.

ATP-sensitive potassium channel; mesenteric artery; G_s; ADP-ribosylation

This article has been cited by other articles:

				T. Lu, D. Ye, X. Wang, J. M. Seubert, J. P. Graves, J. A. Bradbury, D. C. Zeldin, and H.-C. Lee Cardiac and vascular KATP channels in rats are activated by endogenous epoxyeicosatrienoic acids through different mechanisms J. Physiol., September 1, 2006; 575(2): 627 - 644. [Abstract] [Full Text] [PDF]