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Activation of rat mesenteric arterial K_ATP channels by 11,12-epoxyeicosatrienoic acid

Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota

Submitted 10 May 2004 ; accepted in final form 20 August 2004

Epoxyeicosatrienoic acids (EETs), the cytochrome P-450 epoxygenase metabolites of arachidonic acid, are candidates of endothelium-derived hyperpolarizing factors. We have previously reported that EETs are potent activators of cardiac ATP-sensitive K⁺ (K_ATP) channels, but their effects on the vascular K_ATP channels are unknown. With the use of whole cell patch-clamp techniques with 0.1 mM ATP in the pipette and holding at –60 mV, freshly isolated smooth muscle cells from rat mesenteric arteries had small glibenclamide-sensitive currents at baseline (13.1 ± 3.9 pA, n = 5) that showed a 7.2-fold activation by 10 µM pinacidil (94.1 ± 21.9 pA, n = 7, P < 0.05). 11,12-EET dose dependently activated the K_ATP current with an apparent EC₅₀ of 87 nM. Activation of the K_ATP channels by 500 nM 11,12-EET was inhibited by inclusion of the PKA inhibitor peptide (5 µM) but not by the inclusion of the PKC inhibitor peptide (100 µM) in the pipette solution. These results were corroborated by vasoreactivity studies. 11,12-EET produced dose-dependent vasorelaxation in isolated small mesenteric arteries, and this effect was reduced by 50% with glibenclamide (1 µM) preincubation. The 11,12-EET effects on vasorelaxation were also significantly attenuated by preincubation with cell-permeant PKA inhibitor myristoylated PKI(14–22), and, in the presence of PKA inhibitor, glibenclamide had no additional effects. These results suggest that 11,12-EET is a potent activator of the vascular K_ATP channels, and its effects are dependent on PKA activities.

ATP-sensitive K⁺ channel; mesenteric artery; protein kinase A

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